OBSTETRIC
ANESTHESIA
CHESTNUT’S
OBSTETRIC
ANESTHESIA:
PRINCIPLES AND
PRACTICE FIFTH EDITION
David H. Chestnut, MD Warwick D. Ngan Kee, BHB,
Professor of Anesthesiology MBChB, MD, FANZCA, FHKCA,
Chief, Division of Obstetric Anesthesiology
Vanderbilt University School of Medicine FHKAM
Nashville, Tennessee Professor
Department of Anaesthesia and Intensive Care
Formerly, Director of Medical Education The Chinese University of Hong Kong
Gundersen Health System Shatin, Hong Kong, China
Professor of Anesthesiology
Associate Dean for the Western Academic
Campus
Yaakov Beilin, MD
University of Wisconsin School of Medicine Professor of Anesthesiology and Obstetrics
and Public Health Gynecology and Reproductive Sciences
La Crosse, Wisconsin Director of Obstetric Anesthesiology
Vice Chair for Quality
Cynthia A. Wong, MD Department of Anesthesiology
Professor and Vice Chair of Anesthesiology Icahn School of Medicine at Mount Sinai
Northwestern University Feinberg School of New York, New York
Medicine
Section Chief for Obstetric Anesthesiology Jill M. Mhyre, MD
Northwestern Memorial Hospital Associate Professor of Anesthesiology
Chicago, Illinois The University of Arkansas for Medical Sciences
Little Rock, Arkansas
Lawrence C. Tsen, MD
Associate Professor of Anaesthesia Naveen Nathan, MD*
Harvard Medical School Assistant Professor of Anesthesiology
Vice Chair, Faculty Development and Education Northwestern University Feinberg School of
Director of Anesthesia, Center for Reproductive Medicine
Medicine Northwestern Memorial Hospital
Department of Anesthesiology, Perioperative Chicago, Illinois
and Pain Medicine
Associate Director, Center for Professionalism *Graphics Editor
and Peer Support
Brigham and Women’s Hospital
Boston, Massachusetts
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
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Printed in China
To my husband, Lawrence, and our children, Anna, Molly, Leah, and Sofie
CAW
To my wife, Rosemary, and our children, Sam, Nick, Ellie, and Katie
WDNK
To my wife, Karen; our children, Shani, Shua, and Yehuda and Aliza; my parents,
Adelle and Isaiah; and my parents-in-law, Susan and Maurice
YB
The editors gratefully acknowledge the work of the fol- Chapter 16: Problems of Early Pregnancy
lowing authors who contributed to chapters of previous Robert C. Chantigian, MD
editions of this book. Their expertise, wisdom, and schol- Paula D. M. Chantigian, MD
arship have provided the foundation for the fifth edition.
Chapter 17: Nonobstetric Surgery during Pregnancy
Chapter 2: Physiologic Changes of Pregnancy Sheila E. Cohen, MB, ChB, FRCA
Kenneth A. Conklin, MD, PhD Norah N. Naughton, MD
Anita Backus Chang, MD
Chapter 18: Obstetric Management of Labor and
Chapter 3: Uteroplacental Blood Flow Vaginal Delivery
James C. Eisenach, MD Frank J. Zlatnik, MD
Carl P. Weiner, MD
Chapter 20: The Pain of Childbirth and Its Effect on
Chapter 4: The Placenta: Anatomy, Physiology, and the Mother and the Fetus
Transfer of Drugs Theodore G. Cheek, MD
Norman L. Herman, MD, PhD Brett B. Gutsche, MD
Robert R. Gaiser, MD
Chapter 5: Fetal Physiology
Andrew P. Harris, MD, MHS Chapter 22: Systemic Analgesia: Parenteral and
Kenneth E. Nelson, MD Inhalational Agents
Marsha L. Wakefield, MD
Chapter 6: Antepartum Fetal Assessment and Tanya Jones, MB, ChB, MRCP, FRCA
Therapy
Katharine D. Wenstrom, MD Chapter 23: Epidural and Spinal Analgesia/
Katherine Campbell, MD Anesthesia for Labor and Vaginal Delivery
Beth Glosten, MD
Chapter 9: Neonatal Assessment and Resuscitation Brian K. Ross, MD, PhD
Rhonda L. Zuckerman, MD David H. Chestnut, MD
Marvin Cornblath, MD Edward T. Riley, MD
Linda S. Polley, MD
Chapter 10: Fetal and Neonatal Neurologic Injury
Donald H. Penning, MD Chapter 26: Anesthesia for Cesarean Delivery
Laurence S. Reisner, MD
Chapter 12: Spinal, Epidural, and Caudal Anesthesia: Dennis Lin, MD
Anatomy, Physiology, and Technique Krzysztof M. Kuczkowski, MD
David L. Brown, MD
Vijaya Gottumkkala, MBBS, MD, FRCA Chapter 27: Postoperative and Chronic Pain:
Systemic and Regional Analgesic Techniques
Chapter 13: Local Anesthetics and Opioids Robert K. Parker, DO
Hilda Pedersen, MD David Hepner, MD
Mieczyslaw Finster, MD Sunil Eappen, MD
Chapter 14: Pharmacology and Nonanesthetic Drugs Chapter 28: Postoperative Analgesia: Epidural and
during Pregnancy and Lactation Spinal Techniques
Jennifer R. Niebyl, MD Raymond S. Sinatra, MD, PhD
Chakib M. Ayoub, MD
Chapter 15: In Vitro Fertilization and Other Assisted
Reproductive Technology
Robert D. Vincent, Jr., MD
vii
viii Acknowledgment of Contributors to Previous Editions
Chapter 29: Aspiration: Risk, Prophylaxis, and Chapter 38: Antepartum and Postpartum Hemorrhage
Treatment David C. Mayer, MD
Thomas S. Guyton, MD Fred J. Spielman, MD
Charles P. Gibbs, MD Elizabeth A. Bell, MD, MPH
Kathleen A. Smith, MD
Chapter 30: The Difficult Airway: Risk, Assessment,
Prophylaxis, and Management Chapter 39: Embolic Disorders
Sheila D. Cooper, MD Kathleen M. Davis, MD
Jonathan L. Benumof, MD
Laurence S. Reisner, MD Chapter 41: Autoimmune Disorders
Krzysztof M. Kuczkowski, MD David H. Chestnut, MD
John A. Thomas, MD
Carin A. Hagberg, MD Chapter 42: Cardiovascular Disease
Marsha L. Thornhill, MD
Chapter 31: Postpartum Headache William R. Camann, MD
Sally K. Weeks, MBBS Miriam Harnett, MB, FFARCSI
Philip S. Mushlin, MD
Chapter 32: Neurologic Complications of Pregnancy Lawrence C. Tsen, MD
and Neuraxial Anesthesia
Philip R. Bromage, MBBS, FRCA, FRCPC† Chapter 44: Hematologic and Coagulation Disorders
Robert B. Lechner, MD, PhD
Chapter 33: Medicolegal Issues in Obstetric
Anesthesia Chapter 46: Liver Disease
William Gild, MB, ChB, JD Robert W. Reid, MD
H. S. Chadwick, MD David H. Chestnut, MD
Lisa Vincler Brock, JD
Brian K. Ross, MD, PhD Chapter 48: Musculoskeletal Disorders
Edward T. Crosby, MD, FRCPC
Chapter 34: Preterm Labor and Delivery
Joan M. McGrath, MD Chapter 50: Obesity
David H. Chestnut, MD David Dewan, MD
Holly A. Muir, MD, FRCPC
Cynthia A. Wong, MD Chapter 52: Renal Disease
Robert W. Reid, MD
Chapter 36: Hypertensive Disorders David H. Chestnut, MD
Desmond Writer, MB, ChB, FRCA, FRCPC
David R. Gambling, MB, BS, FRCPC Chapter 54: Substance Abuse
David J. Birnbach, MD
Chapter 37: Fever and Infection
Harvey Carp, PhD, MD Chapter 55: Trauma and Critical Care
David H. Chestnut, MD B. Wycke Baker, MD
†
Deceased
Contributors
ix
x Contributors
M. Shankar Hari, Dip. Epi., MD, FRCA, FFICM Marie E. Minnich, MD, MMM, MBA, CPE
Intensive Care Medicine, Guys and St Thomas’ NHS Associate, Division of Anesthesiology, Geisinger Health
Foundation Trust, London, United Kingdom System, Danville, Pennsylvania
Contributors xi
Errol R. Norwitz, MD, PhD Felicity Reynolds, MD, MBBS, FRCA, FRCOG
Chair and Louis E. Phaneuf Professor of Obstetrics ad eundem
and Gynecology, Department of Obstetrics and Emeritus Professor of Obstetric Anaesthesia, St.
Gynecology, Tufts University School of Medicine, Thomas’ Hospital, London, United Kingdom
Boston, Massachusetts
Mark D. Rollins, MD, PhD
Geraldine O’Sullivan, MD, FRCA† Associate Professor, Director of Fetal Anesthesia,
Consultant Anaesthetist, Obstetric Anaesthesia, Guys Departments of Anesthesia and Perioperative Care
and St Thomas’ NHS Foundation Trust, London, and Surgery, University of California, San Francisco,
United Kingdom San Francisco, California
Janelle R. Walton, MD
Assistant Professor of Obstetrics and Gynecology,
Division of Maternal-Fetal Medicine, Feinberg
School of Medicine, Northwestern University,
Chicago, Illinois
Preface
The first edition of this text was published exactly 20 prominent anesthesiologists and obstetricians from 20
years ago. In the preface to the first edition, I identified states and 7 countries.
two goals: (1) to collate the most important information The fifth edition cover again features a striking
that anesthesia providers should know about obstetrics, maternal-fetal image, which draws attention to the fact
and (2) to prepare a thorough and user-friendly review of that the anesthesia provider and the obstetrician provide
anesthesia care for obstetric patients. I asked each con- simultaneous care for two (or more) patients—both the
tributor to write a thorough, scholarly discussion of the mother and her unborn child(ren). The new cover image
subject and also to provide clear, practical recommenda- was created by an extraordinarily talented anesthesiolo-
tions for clinical practice. Those goals remain intact in gist and artist, Naveen Nathan, MD, who prepared
the fifth edition, and the result is a comprehensive abundant new illustrations (and revised existing illustra-
resource for all anesthesia providers (and obstetricians) tions) throughout the text. We are indebted to Dr. Nathan
who provide care for pregnant women. for his invaluable contributions as graphics editor for the
The fifth edition is an extensive revision with much fifth edition.
new content. A new chapter discusses psychiatric disor- It remains gratifying to receive positive feedback on
ders, 14 chapters have been rewritten from start to finish, this text. At the risk of sounding self-congratulatory, I
and most other chapters have undergone substantial revi- should like to summarize the three most common com-
sion. The trauma chapter now includes a focused review ments about the first four editions: The content is com-
of critical care medicine, and other chapters have been prehensive, the material is both current and relevant,
expanded to include discussions of obstetric pharmacol- and the writing is clear. Indeed, the other editors and I
ogy and chronic pain. The chapters on fetal physiology place high value on clarity. I trust that you will conclude
and fetal and neurologic injury have undergone extensive that the fifth edition meets and perhaps exceeds the stan-
revision, as have the chapters on problems of early preg- dards set by the previous four editions.
nancy, preterm labor, hemorrhage, embolic disorders, The other editors and I would like to acknowledge the
obesity, and airway management. The chapter on cardio- important roles of four groups of special people. First,
vascular disease was rewritten by a cardiologist who is we express our heartfelt thanks to the 79 distinguished
also an anesthesiologist. The chapter on hypertensive and talented contributors to the fifth edition (including
disorders not only underwent comprehensive revision, Linda S. Polley, MD, who helped edit the fourth
but also was moved so that it is now grouped with other edition), as well as the contributors to previous editions
obstetric complications. And the keystone chapters on of this text. Second, we gratefully acknowledge the
neuraxial labor analgesia and cesarean delivery under- invaluable help provided by our competent and loyal
went extensive revision to include abundant new infor- assistants, including Jennifer Lee and Jodi Vogel. Third,
mation that is highly relevant for clinical practice. we acknowledge the encouragement, expertise, and atten-
The fifth edition includes 26 new contributors. I am tion to detail provided by the professional production
also happy to welcome three outstanding new editors: team at Elsevier. And finally, we should like to thank you,
Warwick D. Ngan Kee, BHB, MBChB, MD, the readers, not only for your continued confidence in
FANZCA, FHKCA, FHKAM (our first international this text, but especially for your ongoing commitment to
editor), Yaakov (Jake) Beilin, MD, and Jill M. Mhyre, the provision of safe and compassionate care for pregnant
MD. Both Cynthia A. Wong, MD, and Lawrence C. women and their unborn children.
Tsen, MD, have continued their work as editors, and Dr.
Wong has assumed editorial responsibility equal to my David H. Chestnut, MD
own. Each chapter has been carefully reviewed by at least
Micah 6:8
two editors, and we sought the input of all six editors for
resolution of difficult issues. Altogether, the fifth edition
reflects the collective wisdom of a diverse group of
xiii
C H A P T E R 1
CHAPTER OUTLINE
For I heard a cry as of a woman in travail, anguish as of contributions. He also designed obstetric forceps (which
one bringing forth her first child, the cry of the daughter still bear his name), discovered the anesthetic properties
of Zion gasping for breath, stretching out her hands, of chloroform, made important innovations in hospital
“Woe is me!” architecture, and wrote a textbook on the practice of
—JEREMIAH 4:31 witchcraft in Scotland that was used by several genera-
tions of anthropologists.3
“The position of woman in any civilization is an index of An imposing man, Simpson had a large head, a massive
the advancement of that civilization; the position of mane of hair, and the pudgy body of an adolescent. Con-
woman is gauged best by the care given her at the birth temporaries described his voice as “commanding,” with
of her child.” So wrote Haggard1 in 1929. If his thesis is a wide range of volume and intonation. Clearly Simpson
true, Western civilization made a giant leap on January had “presence” and “charisma.” These attributes were
19, 1847, when James Young Simpson used diethyl ether indispensable to someone in his profession, because in
to anesthetize a woman with a deformed pelvis for deliv- the mid-nineteenth century, the role of science in the
ery. This first use of a modern anesthetic for childbirth development of medical theory and practice was minimal;
occurred a scant 3 months after Morton’s historic dem- rhetoric resolved more issues than facts. The medical
onstration of the anesthetic properties of ether at the climate in Edinburgh was particularly contentious and
Massachusetts General Hospital in Boston. Strangely vituperative. In this milieu, Simpson had trained, com-
enough, Simpson’s innovation evoked strong criticism peted for advancement and recognition, and succeeded.
from contemporary obstetricians, who questioned its The rigor of this preparation served him well. Initially,
safety, and from many segments of the lay public, who virtually every prominent obstetrician, including Mont-
questioned its wisdom. The debate over these issues gomery of Dublin, Ramsbotham of London, Dubois of
lasted more than 5 years and influenced the future of Paris, and Meigs of Philadelphia, opposed etherization
obstetric anesthesia.2 for childbirth. Simpson called on all of his professional
and personal finesse to sway opinion in the ensuing
controversy.
JAMES YOUNG SIMPSON
Few people were better equipped than Simpson to deal
with controversy. Just 36 years old, Simpson already had MEDICAL OBJECTIONS TO THE USE
7 years’ tenure as Professor of Midwifery at the Univer- OF ETHER FOR CHILDBIRTH
sity of Edinburgh, one of the most prestigious medical
schools of its day (Figure 1-1). By that time, he had Shortly after Simpson administered the first obstetric
established a reputation as one of the foremost obstetri- anesthetic, he wrote, “It will be necessary to ascertain
cians in Great Britain, if not the world. On the day he anesthesia’s precise effect, both upon the action of the
first used ether for childbirth, he also received a letter of uterus and on the assistant abdominal muscles; its influ-
appointment as Queen’s Physician in Scotland. Etheriza- ence, if any, upon the child; whether it has a tendency
tion for childbirth was only one of Simpson’s to hemorrhage or other complications.”4 With this
3
4 PART I Introduction
OPIOIDS AND OBSTETRICS of the century may have been important more for popu-
larizing morphine than for suggesting that scopolamine
The next major innovation in obstetric anesthesia came be given with morphine.
approximately 50 years later. Dämmerschlaff, which means Physicians reacted to twilight sleep as they had reacted
“twilight sleep,” was a technique developed by von Stein- to diethyl ether several years earlier. They resisted it,
büchel14 of Graz and popularized by Gauss15 of Freiberg. questioning whether the benefits justified the risks.
It combined opioids with scopolamine to make women Patients also reacted as they had before. Not aware of, or
amnestic and somewhat comfortable during labor (Figure perhaps not concerned with, the technical considerations
1-4). Until that time, opioids had been used sparingly for that confronted physicians, patients harbored few doubts
obstetrics. Although opium had been part of the medical and persuaded physicians to use it, sometimes against the
armamentarium since the Roman Empire, it was not used physicians’ better judgment. The confrontation between
extensively, in part because of the difficulty of obtaining physicians and patients was particularly strident in the
consistent results with the crude extracts available at that United States. Champions of twilight sleep lectured
time. Therapeutics made a substantial advance in 1809 throughout the country and published articles in popular
when Sertürner, a German pharmacologist, isolated magazines. Public enthusiasm for the therapy subsided
codeine and morphine from a crude extract of the poppy slightly after 1920, when a prominent advocate of the
seed. Methods for administering the drugs remained method died during childbirth. She was given twilight
unsophisticated. Physicians gave morphine orally or by a sleep, but her physicians said that her death was unrelated
method resembling vaccination, in which they placed a to any complication from its use. Whatever anxiety this
drop of solution on the skin and then made multiple small incident may have created in the minds of patients, it did
puncture holes with a sharp instrument to facilitate not seriously diminish their resolve. Confronted by such
absorption. In 1853, the year Queen Victoria delivered firm insistence, physicians acquiesced and used twilight
her eighth child, the syringe and hollow metal needle sleep with increasing frequency.19,20
were developed. This technical advance simplified the Although the reaction of physicians to twilight sleep
administration of opioids and facilitated the development resembled their reaction to etherization, the medical
of twilight sleep approximately 50 years later.16 milieu in which the debate over twilight sleep developed
Although reports of labor pain relief with hypodermic was quite different from that in which etherization was
morphine appeared as early as 1868, few physicians deliberated. Between 1850 and 1900, medicine had
favored its use. For example, in an article published in changed, particularly in Europe. Physiology, chemistry,
Transactions of the Obstetrical Society of London, Sansom17 anatomy, and bacteriology became part of medical theory
listed the following four agents for relief of labor pain: and practice. Bright students from America traveled to
(1) carbon tetrachloride, the use of which he favored; leading clinics in Germany, England, and France. They
(2) bichloride of methylene, which was under evaluation; returned with new facts and methods that they used to
(3) nitrous oxide, which had been introduced recently by examine problems and critique ideas. These develop-
Klikgowich of Russia; and (4) chloroform. He did not ments became the basis for the revolution in American
mention opioids, but neither did he mention diethyl medical education and practice launched by the Flexner
ether, which many physicians still favored. Similarly, report published in 1914.21
Gusserow,18 a prominent German obstetrician, described Obstetrics also changed. During the years preceding
using salicylic acid but not morphine for labor pain. (Von World War I, it had earned a reputation as one of the
Baeyer did not introduce acetylsalicylic acid to medical most exciting and scientifically advanced specialties.
practice until 1899.) In retrospect, von Steinbüchel’s and Obstetricians experimented with new drugs and tech-
Gauss’s descriptions of twilight sleep in the first decade niques. They recognized that change entails risk, and
they examined each innovation more critically. In addi-
tion, they turned to science for information and methods
to help them solve problems of medical management.
Developments in obstetric anesthesia reflected this
change in strategy. New methods introduced during this
time stimulated physicians to reexamine two important
but unresolved issues, the effects of drugs on the child,
and the relationship between pain and labor.
Carl Koller40 introduced regional anesthesia when he never explained why uterine ischemia that results from
used cocaine for eye surgery in 1884. Recognizing the fear causes pain, whereas ischemia that results from a
potential of Koller’s innovation, surgeons developed normal contraction does not. In other words, Dick-Read,
techniques for other procedures. Obstetricians quickly like Simpson a century earlier, claimed no necessary or
adopted many of these techniques for their own use. The physiologic relationship between labor pain and contrac-
first papers describing obstetric applications of spinal, tions. Dick-Read’s book, written more for the public than
lumbar epidural, caudal, paravertebral, parasacral, and for the medical profession, represented a regression of
pudendal nerve blocks appeared between 1900 and 1930 almost a century in medical thought and practice. It is
(see Figure 1-4).41-43 Recognition of the potential effects important to note that contemporary methods of child-
of regional anesthesia on labor developed more slowly, birth preparation do not maintain that fear alone causes
primarily because obstetricians seldom used it. They con- labor pain. However, they do attempt to reduce fear by
tinued to rely on inhalation agents and opioids, partly education and to help patients manage pain by teaching
because few drugs and materials were available for techniques of self-control. This represents a significant
regional anesthesia at that time, but also because obstetri- difference from and an important advance over Dick-
cians did not appreciate the chief advantage of regional Read’s original theory.
over general anesthesia—the relative absence of drug
effects on the infant. Moreover, they rarely used regional
anesthesia except for delivery, and then they often used SOME LESSONS
elective forceps anyway. This set of circumstances limited
their opportunity and motivation to study the effects of History is important in proportion to the lessons it
regional anesthesia on labor. teaches. With respect to obstetric anesthesia, four lessons
Among early papers dealing with regional anesthesia, stand out. First, every new drug and method entails risks.
one written by Cleland44 stands out. He described his Physicians who first used obstetric anesthesia seemed
experience with paravertebral anesthesia, but he also reluctant to accept this fact, perhaps because of their
wrote a thoughtful analysis of the nerve pathways mediat- inexperience with potent drugs (pharmacology was in its
ing labor pain, an analysis he based on information he infancy) or because they acceded too quickly to patients,
had gleaned from clinical and laboratory studies. Few who wanted relief from pain and had little understanding
investigators were as meticulous or insightful as Cleland. of the technical issues confronting physicians. Whatever
Most of those who studied the effects of anesthesia simply the reason, this period of denial lasted almost half a
timed the length of the first and second stages of labor. century, until 1900. Almost another half-century passed
Some timed the duration of individual contractions or before obstetricians learned to modify their practice to
estimated changes in the strength of contractions by pal- limit the effects of anesthetics on the child and the labor
pation. None of the investigators measured the intrauter- process.
ine pressures, even though a German physician had Second, new drugs or therapies often cause problems
described such a method in 1898 and had used it to evalu- in completely unexpected ways. For example, in 1900,
ate the effects of morphine and ether on the contractions physicians noted a rising rate of puerperal fever.48
of laboring women.45 The timing was odd. Several decades had passed since
More detailed and accurate studies of the effects of Robert Koch had suggested the germ theory of disease
anesthesia started to appear after 1944. Part of the stimu- and since Semmelweis had recognized that physicians
lus was a method for continuous caudal anesthesia intro- often transmit infection from one woman to the next
duced by Hingson and Edwards,46 in which a malleable with their unclean hands. With the adoption of
needle remained in the sacral canal throughout labor. aseptic methods, deaths from puerperal fever had dimin-
Small, flexible plastic catheters eventually replaced mal- ished dramatically. During the waning years of the nine-
leable needles and made continuous epidural anesthesia teenth century, however, they increased again. Some
even more popular. With the help of these innovations, physicians attributed this resurgence of puerperal fever
obstetricians began using anesthesia earlier in labor. to anesthesia. In a presidential address to the Obstetrical
Ensuing problems, real and imagined, stimulated more Society of Edinburgh in 1900, Murray49 stated the
studies. Although good studies were scarce, the strong following:
interest in the problem represented a marked change
from the early days of obstetric anesthesia. I feel sure that an explanation of much of the increase of
Ironically, “natural childbirth” appeared just as maternal mortality from 1847 onwards will be found in,
regional anesthesia started to become popular and as cli- first the misuse of anaesthesia and second in the ridiculous
nicians began to understand how to use it without dis- parody which, in many hands, stands for the use of
rupting labor. Dick-Read,47 the originator of the natural antiseptics. … Before the days of anaesthesia, interference
method, recognized “no physiological function in the was limited and obstetric operations were at a minimum
body which gives rise to pain in the normal course of because interference of all kinds increased the conscious
health.” He attributed pain in an otherwise uncompli- suffering of the patient. … When anaesthesia became
cated labor to an “activation of the sympathetic nervous possible, and interference became more frequent because it
system by the emotion of fear.” He argued that fear made involved no additional suffering, operations were
the uterus contract and become ischemic and therefore undertaken when really unnecessary … and so
painful. He said that women could avoid the pain if they complications arose and the dangers of the labor
simply learned to abolish their fear of labor. Dick-Read increased.
1 The History of Obstetric Anesthesia 11
Although it was not a direct complication of the use the protective mechanisms that it may invoke in times of
of anesthesia in obstetric practice, puerperal fever stress; and the normal mechanisms that regulate the
appeared to be an indirect consequence of it. amount and distribution of blood flow to the uterus and
Changes in obstetric practice also had unexpected placenta. At this point, we have only the most rudimen-
effects on anesthetic complications. During the first tary understanding of the interaction of anesthesia with
decades of the twentieth century, when cesarean deliver- any of these processes. Only a fraction of the information
ies were rare and obstetricians used only inhalation anal- available from basic science has been used to improve
gesia for delivery, few women were exposed to the risk of obstetric anesthesia care. Realizing the rewards from the
aspiration during deep anesthesia. As obstetric practice clinical use of such information may be the most impor-
changed and cesarean deliveries became more common, tant lesson from the past and the greatest challenge for
this risk rose. The syndrome of aspiration was not identi- the future of obstetric anesthesia.
fied and labeled until 1946, when obstetrician Curtis
Mendelson50 described and named it. The pathophysiol-
ogy of the syndrome had already been described by Win- KEY POINTS
ternitz et al.,51 who instilled hydrochloric acid into the
lungs of dogs to simulate the lesions found in veterans • Physicians have debated the safety of obstetric
poisoned by gas during the trench warfare of World War anesthesia since 1847, when James Young
I. Unfortunately, the reports of these studies, although Simpson first administered anesthesia for
excellent, did not initiate any change in practice. Change delivery. Two issues have dominated the debate:
occurred only after several deaths of obstetric patients the effects of anesthesia on labor and the effects
were highly publicized in lay, legal, and medical publica- of anesthesia on the newborn.
tions. Of course, rapid-sequence induction, currently • Despite controversy, physicians quickly
recommended to reduce the risk of aspiration, creates incorporated anesthesia into clinical practice,
another set of risks—those associated with a failed largely because of their patients’ desire to avoid
intubation. childbirth pain.
The third lesson offered by the history of obstetric • Only after obstetric anesthesia was in use for
anesthesia concerns the role of basic science. Modern many years did problems become apparent.
medicine developed during the nineteenth century after
physicians learned to apply principles of anatomy, physi- • Important milestones in obstetric anesthesia are
ology, and chemistry to the study and treatment of the introduction of inhalation agents in 1847, the
disease. Obstetric anesthesia underwent a similar pattern expanded use of opioids in the early decades of
of development. Studies of placental structure and func- the twentieth century, and the refinement of
tion called physicians’ attention to the transmission of regional anesthesia starting in the mid-twentieth
drugs and the potential effects of drugs on the infant. century.
Similarly, studies of the physiology and anatomy of the • Outstanding conceptual developments are (1)
uterus helped elucidate potential effects of anesthesia on Zweifel’s idea that drugs given to the mother
labor. In each instance, lessons from basic science helped cross the placenta and affect the fetus and (2)
improve patient care. Apgar’s idea that the condition of the newborn is
The fourth and perhaps the most important lesson is the most sensitive assay of the quality of
the role that patients have played in the use of anesthesia anesthetic care of the mother.
for obstetrics. During the nineteenth century it was • The history of obstetric anesthesia suggests that
women who pressured cautious physicians to incorporate the major improvements in patient care have
routine use of anesthesia into their obstetric practice. A followed the application of principles of basic
century later, it was women again who altered patterns of science.
practice, this time questioning the overuse of anesthesia
for routine deliveries. In both instances the pressure on
physicians emanated from prevailing social values regard- References
ing pain. In 1900 the public believed that pain, and in 1. Haggard HW. Devils, Drugs, and Doctors: The Story of the Science
particular obstetric pain, was destructive and something of Healing from Medicine-Man to Doctor. New York, Harper &
that should be avoided. Half a century later, with the Brothers, 1929.
advent of the natural childbirth movement, many people 2. Caton D. What a Blessing. She Had Chloroform: The Medical and
Social Response to the Pain of Childbirth from 1800 to the Present.
began to suggest that the experience of pain during child- New Haven, Yale University Press, 1999.
birth, perhaps even in other situations, might have some 3. Shepherd JA. Simpson and Syme of Edinburgh. Edinburgh, E & S
physiologic if not social value. Physicians must recognize Livingstone, 1969.
and acknowledge the extent to which social values may 4. Simpson WG, editor. The Works of Sir JY Simpson, Vol II: Anaes-
shape medical “science” and practice.52,53 thesia. Edinburgh, Adam and Charles Black, 1871:199-200.
5. Levinson A. The three Meigs and their contribution to pediatrics.
During the past 60 years, scientists have accumulated Ann Med Hist 1928; 10:138-148.
a wealth of information about many processes integral to 6. Dubois P. On the inhalation of ether applied to cases of midwifery.
normal labor: the processes that initiate and control lac- Lancet 1847; 49:246-249.
tation; neuroendocrine events that initiate and maintain 7. Ramsbotham FH. The Principles and Practice of Obstetric Medi-
cine and Surgery in Reference to the Process of Parturition with
labor; the biochemical maturation of the fetal lung and Sixty-four Plates and Numerous Wood-cuts. Philadelphia, Blanchard
liver; the metabolic requirements of the normal fetus and and Lea, 1855.
12 PART I Introduction
8. Report of the Committee Appointed by the Royal Medical and 31. Knipe WHW. The Freiburg method of däammerschlaf or twilight
Chirurgical Society to Inquire into the Uses and the Physiological, sleep. Am J Obstet Gynecol 1914; 70:884.
Therapeutical, and Toxical Effects of Chloroform, as Well as into 32. Calmes SH. Virginia Apgar: a woman physician’s career in a devel-
the Best Mode of Administering it, and of Obviating Any Ill Con- oping specialty. J Am Med Wom Assoc 1984; 39:184-8.
sequences Resulting from its Administration. Med Chir Trans 1864; 33. Apgar V. A proposal for a new method of evaluation of the newborn
47:323-442. infant. Curr Res Anesth Analg 1953; 32:260-7.
9. Sykes WS. Essays on the First Hundred Years of Anaesthesia, Vol I. 34. Thoms H. Anesthesia á la Reine—a chapter in the history of anes-
Park Ridge, IL, Wood Library Museum of Anesthesiology, 1982. thesia. Am J Obstet Gynecol 1940; 40:340-6.
10. Caton D. The secularization of pain. Anesthesiology. 1985; 35. Meigs CD. Obstetrics, the Science and the Art. Philadelphia,
62:493-501. Blanchard and Lea, 1865:364-76.
11. Wagenknecht E, editor. Mrs. Longfellow: Selected Letters and 36. Channing W. A Treatise on Etherization in Childbirth. Boston,
Journals of Fanny Appleton Longfellow (1817-1861). New York, William D. Ticknor and Company, 1848.
Longmans, Green, 1956. 37. Montgomery WFH. Objections to the Indiscriminate Administra-
12. Cohen M, editor. Nature: The Philosophy of John Stuart Mill. tion of Anaesthetic Agents in Midwifery. Dublin, Hodges and
New York, Modern Library, 1961:463-7. Smith, 1849.
13. Simpson WG, editor. The Works of Sir JY Simpson, Vol II: Anaes- 38. Head H. On disturbances of sensation with especial reference to
thesia. Edinburgh, Adam and Charles Black, 1871:177. the pain of visceral disease. Brain 1893; 16:1-1132.
14. von Steinbüchel R. Vorläufige mittheilung über die anwendung von 39. Gertsman NM. Über uterusinnervation an hand des falles einer
skopolamin-morphium-injektionen in der geburtshilfe. Centralb- geburt bei quersnittslähmung. Monatsschrift Gebürtshüfle Gyn
latt Gyn 1902; 30:1304-6. 1926; 73:253-7.
15. Gauss CJ. Die anwendung des skopolamin-morphium-dämmer- 40. Koller C. On the use of cocaine for producing anaesthesia on the
schlafes in der geburtshilfe. Medizinische Klinik 1906; 2:136-8. eye. Lancet 1884; 124:990-2.
16. Macht DI. The history of opium and some of its preparations and 41. Kreis O. Über medullarnarkose bei gebärenden. Centralblatt
alkaloids. JAMA 1915; 64:477-81. Gynäkologie 1900; 28:724-7.
17. Sansom AE. On the pain of parturition, and anaesthetics in obstet- 42. Bonar BE, Meeker WR. The value of sacral nerve block anesthesia
ric practice. Trans Obstet Soc Lond 1868; 10:121-40. in obstetrics. JAMA 1923; 89:1079-83.
18. Gusserow A. Zur lehre vom stoffwechsel des foetus. Arch Gyn 43. Schlimpert H. Concerning sacral anaesthesia. Surg Gynecol Obstet
1871; 3:241. 1913; 16:488-92.
19. Wertz RW, Wertz DC. Lying-In: A History of Childbirth in 44. Cleland JGP. Paravertebral anaesthesia in obstetrics. Surg Gynecol
America. New York, Schocken Books, 1979. Obstet 1933; 57:51-62.
20. Leavitt JW. Brought to Bed: Childbearing in America, 1750-1950. 45. Hensen H. Ueber den einfluss des morphiums und des aethers auf
New York, Oxford University Press, 1986. die wehenthätigkeit des uterus. Archiv für Gynakologie 1898;
21. Kaufman M. American Medical Education: The Formative Years, 55:129-77.
1765-1910. Westport, CT, Greenwood Press, 1976. 46. Hingson RA, Edwards WB. Continuous caudal analgesia: an analy-
22. Mayow J. Tractatus quinque medico-physici. Quoted in: sis of the first ten thousand confinements thus managed with the
Needham J. Chemical Embryology. New York: Hafner Publishing, report of the authors’ first thousand cases. JAMA 1943;
1963. 123:538-46.
23. Snow J. On the administration of chloroform during parturition. 47. Dick-Read G. Childbirth Without Fear: The Principles and Prac-
Assoc Med J 1853; 1:500-2. tice of Natural Childbirth. New York, Harper & Row, 1970.
24. Caton D. Obstetric anesthesia and concepts of placental transport: 48. Lea AWW. Puerperal Infection. London, Oxford University Press,
a historical review of the nineteenth century. Anesthesiology 1977; 1910.
46:132-7. 49. Murray M. Presidential address to the Obstetrical Society of Edin-
25. Zweifel P. Einfluss der chloroformnarcose kreissender auf den burgh, 1900. Quoted in: Cullingworth CJ. Oliver Wendell Holmes
fötus. Klinische Wochenschrift 1874; 21:1-2. and the contagiousness of puerperal fever. J Obstet Gynaecol Br
26. Zweifel P. Die respiration des fötus. Arch Gyn 1876; 9:291-305. Emp 1905; 8:387-8.
27. Spiegelberg O. A Textbook of Midwifery. Translated by JB Hurry. 50. Mendelson CL. The aspiration of stomach contents into the lungs
London, The New Sydenham Society, 1887. during obstetric anesthesia. Am J Obstet Gynecol 1946;
28. Gwathmey JT. A further study, based on more than twenty thou- 52:191-205.
sand cases. Surg Gynecol Obstet 1930; 51:190-5. 51. Winternitz MC, Smith GH, McNamara FP. Effect of intrabron-
29. Terry CE, Pellens M. The Opium Problem. Camden, NJ, Bureau chial insufflation of acid. J Exp Med 1920; 32:199-204.
of Social Hygiene, 1928. 52. Caton D. “The poem in the pain”: the social significance of pain
30. Gillette WR. The narcotic effect of morphia on the new-born in Western civilization. Anesthesiology 1994; 81:1044-52.
child, when administered to the mother in labor. Am J Obstet, Dis 53. Caton D. Medical science and social values. Int J Obstet Anesth
Women Child 1877; 10:612-23. 2004; 13:167-73.
PA RT I I
Metabolism was among the first areas of physiology uterus.1-4 Subsequent studies established that the highest
to influence clinical practice. By the beginning of the rates of fetal metabolism occurred during the periods of
twentieth century, physiologists had established many of most rapid growth, thereby reaffirming another physio-
the principles that we recognize today, including normal logic principle—the high metabolic cost of synthesizing
rates of oxygen consumption and carbon dioxide produc- new tissue.5
tion, the relationship between oxygen consumption and The aforementioned studies gave clinicians estimates
heat production, and the relationship between metabolic of the stress imposed by pregnancy. To maintain homeo-
rate, body weight, and surface area among individuals and stasis during pregnancy, a pregnant woman had to make
species. Almost simultaneously, clinicians began to apply an appropriate adjustment in each of the physiologic
these principles to their studies of patients in different mechanisms involved in the delivery of substrates to the
states of health and disease. fetal placental unit and in the excretion of metabolic
In one early study, physiologist Magnus-Levy1 found wastes. Thus, for every increment in fetal weight, clini-
an exception to the rule that basal metabolic rate varied cians could expect to find a proportional change in all the
in proportion to body surface area. As he measured a mechanisms involved in the delivery of substrate to the
woman’s oxygen consumption during pregnancy, he fetus and in the excretion of all byproducts. In fact, sub-
observed that her metabolic rate increased out of propor- sequent clinical studies established predictable changes in
tion to increments in her body weight and surface area. uterine blood flow, cardiac output, blood volume, minute
Subsequent studies by other investigators established ventilation, the dissipation of body heat, and the renal
the basis of this phenomenon. Per unit of weight, the excretion of nitrogenous waste and other materials.
fetus, placenta, and uterus together consumed oxygen
(and released carbon dioxide and heat) at a higher REFERENCES
rate than the mother. In effect, the metabolism of a preg- 1. Magnus-Levy A. Stoffwechsel und Nahrungsbedarf in der
nant woman represented the sum of two independent Schwangerschaft. A. Geburtsh. u. Gynaek lii:116-84
2. Carpenter TM, Murlin JR. The energy metabolism of mother and
organisms, each metabolizing at its own rate in propor- child just before and just after birth. AMA Arch Intern Med 1911;
tion to its own surface area. Thus, each kilogram of 7:184-222.
maternal tissue consumed oxygen at a rate of approxi- 3. Root H, Root HK. The basal metabolism during pregnancy and the
mately 4 mL/min, whereas the average rate for the fetus, puerperium. Arch Intern Med 1923; 32:411-24.
placenta, and uterus was approximately 12 mL/min, 4. Sandiford I, Wheeler T. The basal metabolism before, during, and
after pregnancy. J Biol Chem 1924; 62:329-52.
although it could rise as high as 20 mL/min. Therefore, 5. Caton D, Henderson DJ, Wilcox CJ, Barron DH. Oxygen consump-
during pregnancy, the mother’s metabolism was the sum tion of the uterus and its contents and weight at birth of lambs. New
of her metabolic rate plus that of the fetus, placenta, and York: Garland STPM Press, 1978:123-34.
C H A P T E R 2
Physiologic Changes of
Pregnancy
Robert Gaiser, MD
CHAPTER OUTLINE
Marked anatomic and physiologic changes occur during BODY WEIGHT AND COMPOSITION
pregnancy that allow the woman to adapt to the develop-
ing fetus and its metabolic demands. The enlarging The mean maternal weight increase during pregnancy is
uterus places mechanical strain on the woman’s body. 17% of the prepregnancy weight or approximately 12 kg.1
Greater hormonal production by the ovaries and the pla- It results from an increase in the size of the uterus and
centa further alters maternal physiology. The hallmark of its contents (uterus, 1 kg; amniotic fluid, 1 kg; fetus and
successful anesthetic management of the pregnant woman placenta, 4 kg), increases in blood volume and interstitial
is recognition of these anatomic and physiologic changes fluid (approximately 1 kg each), and deposition of new fat
and appropriate adaptation of anesthetic techniques to and protein (approximately 4 kg). The weight gain during
account for them. The physiologic alterations of normal pregnancy recommended by the Institute of Medicine
pregnancy and their anesthetic implications are reviewed reflects the increased incidence of obesity2 and depends
in this chapter. on the prepregnancy body mass index (BMI; Table 2-1).
15
16 PART II Maternal and Fetal Physiology
Central Hemodynamics
The expected weight increase during the first trimester For accurate determination of central hemodynamic
in a nonobese individual is 1 to 2 kg, and there is a 5- to changes during pregnancy, measurements should be
6-kg increase in each of the last two trimesters. The made with the patient in a resting position, tilted to the
recommended gain is less in obese individuals. Obesity is left, to minimize aortic and vena caval compression.
a major problem in the United States and has many Comparisons must be made with an appropriate control,
implications for obstetric anesthesia (see Chapter 50). such as prepregnancy values or a matched group of non-
Excessive weight gain during pregnancy is a risk factor pregnant women. If control measurements are made
for a long-term increase in BMI.3 during the postpartum period, a sufficient interval must
have elapsed for hemodynamic parameters to have
returned to prepregnancy values; this may take 24 weeks
CARDIOVASCULAR CHANGES or more.11
Cardiac output begins to increase by 5 weeks’ gesta-
Physical Examination and tion and is 35% to 40% above baseline by the end of the
Cardiac Studies first trimester.9,12 It continues to increase throughout the
second trimester until it is approximately 50% greater
Pregnancy causes the heart to increase in size, a result of than nonpregnant values (Figures 2-1 and 2-2).9,11,13-15
both greater blood volume and increased stretch and Cardiac output does not change from this level during
force of contraction.4 These changes, coupled with the the third trimester. Some studies have reported a decrease
elevation of the diaphragm from the expanding uterus, in cardiac output during the third trimester; typically this
cause several changes in the physical examination and in is when measurements are made in the supine position
cardiac studies. and thus reflects aortocaval compression rather than a
Changes in heart sounds include accentuation of the true gestational decline.
first heart sound with exaggerated splitting of the mitral The initial increase in cardiac output results from an
and tricuspid components (Box 2-1).5 The second heart increase in heart rate, which occurs by the fourth to fifth
sound changes little, although the aortic-pulmonic inter- week of pregnancy.9 The heart rate increases 15% to 25%
val tends to vary less with respiration during the third above baseline by the end of the first trimester and
trimester, a finding without clinical significance. A fourth remains relatively unchanged from that level for the
heart sound may be heard in 16% of pregnant women, remainder of the pregnancy.9,11-16 Cardiac output contin-
although typically it disappears at term. A grade II sys- ues to increase during the second trimester because of an
tolic ejection murmur is commonly heard at the left increase in stroke volume. Stroke volume increases by
sternal border6; the murmur is considered a benign flow approximately 20% during the first trimester and by 25%
2 Physiologic Changes of Pregnancy 17
HR Hyperdynamic
150
SV
100
(% change from prepregnant)
125
80 Normal
Cardiac output
LVSWI (g • m • M–2)
100
75 60
Depressed
50 40
25
20
0
1s
Ac
1
3r
2
2n
2n
2
La
Im
hr
da
d
w
t
tiv
d
d
te
5 10 15 20 25
k
ys
nt
ed
to 30% above baseline during the second trimester.9,11,12,16 ventricle accommodating a greater volume without an
The increase in stroke volume correlates with increasing increase in pressure.
estrogen levels.1 Left ventricular mass increases by 23% Myocardial contractility increases, as demonstrated
from the first to the third trimester.17 Cardiac output by higher velocity of left ventricular circumferential
increases to meet the demands of the developing fetus, fiber shortening (Figure 2-3).9,13,16 Tissue Doppler
and the distribution of cardiac output to the uterine cir- imaging, which is relatively independent of preload, has
culation increases from 5% to 12% during the second been used to assess diastolic function.19 Left ventricular
half of pregnancy.18 diastolic function is not impaired during pregnancy,
Left ventricular end-diastolic volume increases during whereas systolic function is increased during the second
pregnancy, whereas end-systolic volume remains trimester.
unchanged, resulting in a larger ejection fraction.9,11-14,16 The increase in cardiac output during pregnancy
Central venous, pulmonary artery diastolic, and pulmo- results in increased perfusion to the uterus, kidneys, and
nary capillary wedge pressures are within the normal extremities. Uterine blood flow increases from a baseline
nonpregnant range.15 The apparent discrepancy between value of approximately 50 mL/min to a level at term of
left ventricular filling pressure and end-diastolic volume 700 to 900 mL/min.20-24 Approximately 90% of this flow
is explained by hypertrophy and dilation, with the dilated perfuses the intervillous space, with the balance perfusing
18 PART II Maternal and Fetal Physiology
the myometrium.22 At term, skin blood flow is approxi- occurs when the woman is in the lateral position, as
mately three to four times the nonpregnant level, result- documented by angiography.38 This finding is consistent
ing in higher skin temperature.25 Renal plasma flow is with the 75% elevation above baseline of femoral venous
increased by 80% at 16 to 26 weeks’ gestation but declines and lower inferior vena cava pressures.39 Despite caval
to 50% above the nonpregnant baseline at term.26 compression, collateral circulation maintains venous
The U.S. Department of Health and Human Services return, as reflected by the right ventricular filling pres-
recommends that pregnant women have at least 150 sure, which is unaltered in the lateral position.15
minutes of moderate-intensity aerobic activity every In the supine position, nearly complete obstruction of
week27; however, most women do not achieve this goal. the inferior vena cava is evident at term.40 Blood returns
Pregnant women are less active, with only half as many from the lower extremities through the intraosseous,
meeting guidelines for vigorous activity compared with vertebral, paravertebral, and epidural veins.41 However,
nonpregnant women.28 For every two women who exer- this collateral venous return is less than would occur
cise before pregnancy, one will not do so during preg- through the inferior vena cava, resulting in a decrease in
nancy. Failure to exercise results in greater gestational right atrial pressure.42 Compression of the inferior vena
weight gain.29 Exercise is safe for the fetus29,30; in a study cava occurs as early as 13 to 16 weeks’ gestation and is
of 45 women, exercise on a treadmill of moderate inten- evident from the 50% increase in femoral venous pres-
sity (40% to 59% of heart rate reserve) did not affect fetal sure observed when these women assume the supine
heart or umbilical artery Doppler indices.30 position (Figure 2-4).43 By term, femoral venous and
During exercise, maximal oxygen consumption is lower inferior vena caval pressures are approximately 2.5
greater in pregnancy,31 especially during cardiovascular times the nonpregnant measurements in the supine
exercise. The rate of increase in minute ventilation is position.39,43
greater with exercise during pregnancy.32 Cardiac output In the supine position, the aorta may be compressed
is also greater, primarily from increased stroke volume33 by the term gravid uterus. This compression accounts for
and increased oxygen delivery to the fetus. lower pressure in the femoral versus the brachial artery
in the supine position.44,45 These findings are consistent
with angiographic studies in supine pregnant women,
Blood Pressure which show partial obstruction of the aorta at the level
Positioning, gestational age, and parity affect blood pres- of the lumbar lordosis and enhanced compression during
sure measurements. Brachial sphygmomanometry yields periods of maternal hypotension.46
the highest measurements in the supine position and the At term, the left lateral decubitus position results in
lowest measurements in the lateral position.14,34 Blood less enhancement of cardiac sympathetic nervous system
pressure increases with maternal age, and for a given age, activity and less suppression of cardiac vagal activity than
nulliparous women have a higher mean pressure than the supine or right lateral decubitus position.47 Women
parous women.35 Systolic, diastolic, and mean blood pres- who assume the supine position at term gestation experi-
sure decrease during midpregnancy and return toward ence a 10% to 20% decline in stroke volume and cardiac
baseline as the pregnancy approaches term.36 Diastolic output,48,49 consistent with the fall in right atrial filling
blood pressure decreases more than systolic blood pressure. Blood flow in the upper extremities is normal,
pressure, with early to mid-gestational decreases of whereas uterine blood flow decreases by 20% and lower
approximately 20%.37 The changes in blood pressure are extremity blood flow decreases by 50%.50 Perfusion of
consistent with changes in systemic vascular resistance, the uterus is less affected than that of the lower extremi-
which decreases during early gestation, reaches its nadir ties because compression of the vena cava does not
(35% decline) at 20 weeks’ gestation, and increases during obstruct venous outflow via the ovarian veins.51 The
late gestation. Unlike blood pressure, systemic vascular adverse hemodynamic effects of aortocaval compression
resistance remains approximately 20% below the non- are reduced once the fetal head is engaged.44,45 The sitting
pregnant level at term.11,15 A postulated explanation for position has also been shown to result in aortocaval com-
the decreased systemic vascular resistance is the develop- pression, with a decrease in cardiac output of 10%.52
ment of a low-resistance vascular bed (the intervillous Flexing the legs rotates the uterus to compress against
space) as well as vasodilation caused by prostacyclin, the vena cava. Short intervals in the sitting position, such
estrogen, and progesterone. The lower blood pressure as occurs during epidural catheter placement, have no
persists beyond the pregnancy. A longitudinal study of impact on uteroplacental blood flow.
2304 initially normotensive women over 20 years showed Some term pregnant women exhibit an increase in
that nulliparous women at baseline who subsequently brachial artery blood pressure when they assume the
delivered one or more infants had a blood pressure that supine position, which is caused by higher systemic vas-
was 1 to 2 mm Hg lower than corresponding women cular resistance from compression of the aorta. Up to
who did not have children. This finding demonstrates 15% of women at term experience bradycardia and a
that pregnancy may create long-lasting vascular changes.37 substantial drop in blood pressure when supine, the
so-called supine hypotension syndrome.53 It may take several
minutes for the bradycardia and hypotension to develop,
Aortocaval Compression and the bradycardia is usually preceded by a period of
The extent of compression of the aorta and inferior vena tachycardia. The syndrome results from a profound drop
cava by the gravid uterus depends on positioning and in venous return for which the cardiovascular system is
gestational age. At term, partial vena caval compression not able to compensate.
2 Physiologic Changes of Pregnancy 19
32
30 Femoral
Antecubital
28
26
24
large- and small-airway function are minimally altered *Relative to nonpregnant state.
during pregnancy. The shape of flow-volume loops, the From Conklin KA. Maternal physiological adaptations during
absolute flow rates at normal lung volumes,69 forced expi- gestation, labor and the puerperium. Semin Anesth 1991;
10:221-34.
ratory volume in one second (FEV1), the ratio of FEV1
to forced vital capacity (FVC), and closing capacity are
unchanged during pregnancy.70 There is no significant
change in respiratory muscle strength during pregnancy Percentage of predicted
despite the cephalad displacement of the diaphragm. Fur-
110%
thermore, despite the upward displacement of the dia- FEV1
+5% +15%
+
No
Change
+45%
-5%
-25%
-20%
-2
-15%
FIGURE 2-6 ■ Lung volumes and capacities
during pregnancy. ERV, expiratory reserve
volume; FRC, functional residual capacity;
IC, inspiratory capacity; IRV, inspiratory
reserve volume; RV, residual volume; TLC,
total lung capacity; TV, tidal volume; VC,
vital capacity.
be increased by 10% (approximately 188 mL) by placing closely during pregnancy and postpartum, dyspnea was
the patient in a 30-degree head-up position.78 not due to alterations in central ventilatory control or
respiratory mechanical factors but rather to the aware-
Ventilation and Blood Gases ness of the increased ventilation.82 Exercise has no effect
on pregnancy-induced changes in ventilation or alveolar
During pregnancy, respiratory rate and pattern remain gas exchange.83 The hypoxic ventilatory response is
relatively unchanged. Minute ventilation increases via an increased during pregnancy to twice the normal level,
increase in tidal volume from 450 to 600 mL and a small secondary to elevations in estrogen and progesterone
increase in respiratory rate of 1 to 2 breaths/min.79 This levels.84 This increase occurs despite blood and cerebro-
occurs primarily during the first 12 weeks of gestation spinal fluid (CSF) alkalosis.
with a minimal increase thereafter. The ratio of total dead During pregnancy, Pao2 increases to 100 to 105 mm Hg
space to tidal volume remains constant during pregnancy, (13.3 to 14.0 kPa) as a result of greater alveolar ventila-
resulting in an increase in alveolar ventilation of 30% to tion (Table 2-4).85 The higher Pao2 results from the
50% above baseline. The increase in minute ventilation decline in Paco2 and a lower arteriovenous oxygen differ-
results from hormonal changes and from an increase ence, which reduces the impact of venous admixture on
in CO2 production at rest by approximately 30% to Pao2.86,87 As pregnancy progresses, oxygen consumption
300 mL/min. The latter is closely related to the blood continues to increase, and cardiac output increases to a
level of progesterone,80 which acts as a direct respiratory lesser extent, resulting in a reduced mixed venous oxygen
stimulant. The progesterone-induced increase in chemo- content and increased arteriovenous oxygen difference.
sensitivity results in a steeper slope and a leftward shift of After mid gestation, pregnant women in the supine posi-
the CO2-ventilatory response curve. This change occurs tion frequently have a Pao2 less than 100 mm Hg
early in pregnancy and remains constant until delivery.69 (13.3 kPa). This occurs because the FRC may be less than
Dyspnea is a common complaint during pregnancy, closing capacity, resulting in closure of small airways
affecting up to 75% of women.81 Contributing factors during normal tidal volume ventilation.85 Moving a preg-
include increased respiratory drive, decreased Paco2, the nant woman from the supine to the erect or lateral decu-
enlarging uterus, larger pulmonary blood volume, anemia, bitus position improves arterial oxygenation and reduces
and nasal congestion. Dyspnea typically begins in the first the alveolar-to-arterial oxygen gradient. The increased
or second trimester but improves as the pregnancy pro- oxygen tension facilitates the transfer of oxygen across
gresses. In a study in which 35 women were observed the placenta to the fetus.
22 PART II Maternal and Fetal Physiology
Paco2 declines to approximately 30 mm Hg (4.0 kPa) TABLE 2-5 Hematologic Parameters at Term
by 12 weeks’ gestation but does not change further during Gestation
the remainder of pregnancy. Although a gradient exists
between the end-tidal CO2 tension and Paco2 in non- Change* or Actual
pregnant women, the two measurements are equivalent Parameter Measurement
during early pregnancy,88 at term gestation,89 and in the Blood volume +45%*
postpartum period.90 This is attributable to a reduction Plasma volume +55%*
in alveolar dead space, which results from an increase in Red blood cell volume +30%*
cardiac output during pregnancy. The mixed venous Pco2 Hemoglobin concentration (g/dL) 11.6
is 6 to 8 mm Hg (0.8 to 1.1 kPa) below the nonpregnant Hematocrit 35.5%
level from the later first trimester until term.1
Metabolic compensation for the respiratory alkalosis *Relative to nonpregnant state.
of pregnancy reduces serum bicarbonate concentration Adapted from Conklin KA. Maternal physiological adaptations
during gestation, labor, and puerperium. Semin Anesth 1991;
to approximately 20 mEq/L, the base excess by 2 to 10:221-34.
3 mEq/L, and the total buffer base by approximately
5 mEq/L.91 This compensation is incomplete, as demon-
strated by the elevation of venous,92 capillary,93 and arte-
rial85 blood pH by 0.02 to 0.06 units. 50
RBC
Metabolism and Respiration during Plasma
Labor and the Puerperium
physiologic hypervolemia facilitates delivery of nutrients increases during pregnancy and correlates significantly
to the fetus, protects the mother from hypotension, and with blood volume.106
reduces the risks associated with hemorrhage at delivery. Red blood cell volume increases in response to
The decrease in blood viscosity from the lower hemato- elevated erythropoietin concentration107 and the erythro-
crit creates lower resistance to blood flow, which may be poietic effects of progesterone, prolactin, and placental
an essential component of maintaining the patency of the lactogen. Both hemoglobin concentration and hematocrit
uteroplacental vascular bed. decrease after conception to approximately 11.2 g/dL
The increase in plasma volume results from fetal and and 34%, respectively, by mid gestation,102,103 which is
maternal hormone production, and several systems may a 15% decrease from prepregnancy levels. During the
play a role. Additionally, the expansion of plasma volume late third trimester, the hemoglobin concentration and
may help to maintain blood pressure in the presence of hematocrit increase to approximately 11.6 g/dL and
decreased vascular tone.103,105 The maternal concentra- 35.5%, respectively, because red blood cell volume
tions of estrogen and progesterone increase nearly 100- increases more than plasma volume. Women who do
fold during pregnancy. Estrogens increase plasma renin not receive iron supplements during pregnancy have
activity, enhancing renal sodium absorption and water greater decreases in hemoglobin concentration and
retention via the renin-angiotensin-aldosterone system. hematocrit.102
Fetal adrenal production of the estrogen precursor dehy-
droepiandrosterone may be the underlying control
mechanism. Progesterone also enhances aldosterone pro-
Plasma Proteins
duction. These changes result in marked increases in Plasma albumin concentration decreases from a nonpreg-
plasma renin activity and aldosterone level as well as in nant range of 4.1-5.3 g/dL to 3.1-5.1 g/dL in the first
retention of approximately 900 mEq of sodium and trimester, 2.6-4.5 g/dL in the second trimester, and
7000 mL of total body water. The concentration of 2.3-4.2 g/dL in the third trimester (Table 2-6).104,108,109
plasma adrenomedullin, a potent vasodilating peptide, The globulin level decreases by 10% in the first trimester
and then increases throughout the remainder of preg-
nancy to 10% above the prepregnancy value at term.108
The albumin-globulin ratio decreases during pregnancy
from 1.4 to 0.9, and the total plasma protein concentra-
Percentage decrease from nonpregnant values
tion decreases from 7.8 to 7.0 g/dL.109 Maternal colloid
0% osmotic pressure decreases by approximately 5 mm Hg
5% Hemoglobin
during pregnancy.15,110,111 The plasma cholinesterase con-
centration falls by approximately 25% during the first
10% Hematocrit trimester and remains at that level until the end of
15% pregnancy.112,113
20%
Coagulation
25%
Pregnancy is associated with enhanced platelet turnover,
30% clotting, and fibrinolysis (Box 2-2). Thus, pregnancy rep-
35% resents a state of accelerated but compensated intravas-
First Second Third
trimester trimester trimester
cular coagulation.
Increases in platelet factor 4 and beta-thromboglobulin
FIGURE 2-8 ■ The decrease in both hemoglobin concentration signal elevated platelet activation, and the progressive
and hematocrit during pregnancy underlies the physiologic increase in platelet distribution width and platelet volume
anemia of pregnancy. The decrease is greater for hematocrit are consistent with greater platelet consumption during
and the greatest decreases occur during the third trimester.
(Based on data from Abbassi-Ghanavati M, Greer LG, Cunningham
pregnancy.114-116 Platelet aggregation in response to col-
FG. Pregnancy and laboratory studies: a reference table for clini- lagen, epinephrine, adenosine diphosphate, and arachi-
cians. Obstet Gynecol 2009; 114:1326-31.) donic acid is increased.117 Despite changes in platelet
at 6 to 9 weeks postpartum. The hemoglobin concentra- During pregnancy, the uterine mucosa is characterized
tion and hematocrit decrease during the first 3 postpar- by a large number of maternal immune cells found in
tum days, increase gradually during the next 3 days close contact with the trophoblast. The fetal expression
(because of a reduction in plasma volume), and continue of paternal antigens requires adaptations in the maternal
to increase to prepregnancy measurements by 3 weeks immune system so that the fetus is not perceived by the
postpartum.135 mother as “foreign.”140,141 This “immune tolerance”
Cesarean delivery results in a blood loss of approxi- occurs because of a lack of fetal antigen expression,
mately 1000 mL within the first few hours of delivery.133 because of separation of the mother from the fetus, or
The hematocrit in the immediate postpartum period is from a functional suppression of the maternal lympho-
lower after cesarean delivery than after vaginal delivery cytes.142 During the first trimester of pregnancy, T lym-
because of the greater blood loss during cesarean phocytes express granulysin, a novel cytolytic protein,
delivery.133 which provides a protective role at the maternal-fetal
Albumin and total protein concentrations and colloid interface.143 Human T cells may be classified into T-helper
osmotic pressure decline after delivery and gradually cells types 1 and 2 (Th1 and Th2) on the basis of their
return to prepregnancy levels by 6 weeks postpartum.110 cytokine production. Successful pregnancy is associated
The plasma cholinesterase value decreases below the pre- with a predominant Th2 cytokine profile. Th1 cytokines
delivery level by the first postpartum day and remains at are detrimental to pregnancy. These cells also produce
that decreased level during the next week.112,113 Globulin natural antimicrobial agents within the uterus, which are
concentrations are elevated throughout the first postpar- important for prevention of uterine infection during
tum week.108 pregnancy.144
Beginning with delivery and during the first postpar-
tum day, there is a rapid decrease in the platelet count and
in the concentrations of fibrinogen, factor VIII, and plas- THE GASTROINTESTINAL SYSTEM
minogen and an increase in antifibrinolytic activity.136
Clotting times remain shortened during the first postpar- Anatomy, Barrier Pressure, and
tum day,137 and thromboelastography remains consistent Gastroesophageal Reflux
with a hypercoagulable state.131 During the first 3 to 5 days
postpartum, increases are noted in the fibrinogen concen- The stomach is displaced upward toward the left side of
tration and platelet count, changes that may account for the diaphragm during pregnancy, and its axis is rotated
the greater incidence of thrombotic complications during approximately 45 degrees to the right from its normal
the puerperium.137 The coagulation profile returns to the vertical position. This altered position displaces the
nonpregnant state by 2 weeks postpartum.136 intra-abdominal segment of the esophagus into the thorax
in most women, causing a reduction in tone of the lower
esophageal high-pressure zone (LEHPZ), which nor-
THE IMMUNE SYSTEM mally prevents the reflux of gastric contents. Progestins
also may contribute to a relaxation of the LEHPZ.145
The blood leukocyte count increases progressively during Approximately 30% to 50% of women experience
pregnancy from the prepregnancy level of approximately gastroesophageal reflux disease (GERD) during preg-
6,000/mm3 to between 9,000 and 11,000/mm3.119 This nancy,146 with the majority (80%) experiencing regurgita-
change reflects an increase in the number of polymor- tion not heartburn (pyrosis) (20%).147 The prevalence of
phonuclear cells, with the appearance of immature gran- GERD is approximately 10% in the first trimester, 40%
ulocytic forms (myelocytes and metamyelocytes) in most in the second trimester, and 55% in the third trimester.
pregnant women. The proportion of immature forms In the first trimester of pregnancy, basal LEHPZ pres-
decreases during the last 2 months of pregnancy. The sure may not change, but the sphincter is less responsive
lymphocyte, eosinophil, and basophil counts decrease, to physiologic stimuli that usually increase pressure.148 In
whereas the monocyte count does not change. The leu- the second and third trimesters, LEHPZ pressure gradu-
kocyte count increases to approximately 13,000/mm3 ally decreases to approximately 50% of basal values,
during labor and increases further to an average of reaching a nadir at 36 weeks’ gestation and returning to
15,000/mm3 on the first postpartum day.135 By the sixth prepregnancy values at 1 to 4 weeks postpartum (Table
postpartum day, the leukocyte count decreases to an 2-7). Risk factors for GERD in pregnancy include gesta-
average of 9,250/mm3, although the count is still above tional age, heartburn antecedent to pregnancy, and
normal at 6 weeks postpartum. multiparity. Gravidity, prepregnancy BMI, and weight
Polymorphonuclear leukocyte function is impaired gain during pregnancy do not correlate with the occur-
during pregnancy, as evidenced by depressed neutrophil rence of reflux, whereas maternal age has an inverse
chemotaxis and adherence.138 This impairment may correlation.147,149
account for the greater incidence of infection during
pregnancy and improved symptoms in some pregnant
women with autoimmune diseases (e.g., rheumatoid
Gastrointestinal Motility
arthritis). Levels of immunoglobulins A, G, and M are Gastric emptying is not altered during pregnancy. This
unchanged during gestation, but humoral antibody titers has been demonstrated by studies that measured the
to certain viruses (e.g., herpes simplex, measles, influenza absorption of orally administered acetaminophen150-152
type A) are decreased.139 and by studies that assessed the emptying of a test meal
26 PART II Maternal and Fetal Physiology
by radiographic,153 ultrasonographic,152,154 dye dilution,155 last until 12 to 16 weeks’ gestation.167 Of these women,
epigastric impedance,156 and applied potential tomo- 1% to 5% will develop symptoms that persist throughout
graphic157 techniques. In a study of morbidly obese the pregnancy, known as hyperemesis gravidarum (see
women at term, no difference was noted between gastric Chapter 16).
emptying of 300 mL and 50 mL of water, suggesting that
fasting guidelines should not differ for obese versus lean Gastric Function during Labor
parturients.158
Esophageal peristalsis and intestinal transit are slowed
and the Puerperium
during pregnancy,154,159 which has been attributed to the Gastric emptying is slowed during labor, as shown by
inhibition of gastrointestinal contractile activity by pro- ultrasonographic imaging, emptying of a test meal,
gesterone. However, this inhibition may be an indirect and the rate of absorption of oral acetaminophen.168,169
action that results from a negative effect of progesterone Direct measurements show that the mean gastric volume
on the plasma concentration of motilin, which declines increases.170 However, in one study, postpartum gastric
during pregnancy.154 Up to 40% of women suffer from volume was found to be no different in parturients who
constipation at some time during their pregnancy.160 The consumed water in labor compared with those who con-
prevalence of constipation is greatest in the first two tri- sumed an isotonic sports drink composed of mixed car-
mesters of gestation and declines in the third trimester. bohydrates and electrolytes.171 Gastric acid secretion may
decrease during labor because only 25% of parturients
who are in labor have gastric pH of 2.5 or less.172 Gastric
Gastric Acid Secretion emptying is delayed during the early postpartum period
Early work suggested that both basal and maximal gastric but returns to prepregnancy levels by 18 hours postpar-
acid secretion decline in mid gestation, reaching a nadir tum.173 Gastric volume and pH values are similar in
at 20 to 30 weeks’ gestation.161 Van Thiel et al.162 demon- fasting women more than 18 hours after delivery and in
strated no difference in basal or peak gastric acid secretion nonpregnant individuals who have fasted before elective
in four pregnant women studied in each trimester and at surgery.174-176 The effects of opioids and neuraxial anal-
1 to 4 weeks postpartum, although a plasma gastrin level gesia on gastric emptying are discussed in Chapters 23
significantly lower than postpartum levels was observed and 29.
during the first trimester. Levels of gastric pH and serum
gastrin concentration were compared in 100 women who
were not in labor but were scheduled for elective cesarean THE LIVER AND GALLBLADDER
delivery and in 100 nonpregnant women undergoing
gynecologic surgery.163 The pH was lower in the pregnant Liver size, morphology, and blood flow do not change
group (2.4 versus 3.0), but serum gastrin levels were not during pregnancy, although the liver is displaced upward,
different despite the fact that gastrin is secreted by the posterior, and to the right during late pregnancy.
placenta from 15 weeks’ gestation onward.164 Other Serum levels of bilirubin, alanine aminotransferase,
studies that have examined stomach contents have shown aspartate aminotransferase, and lactate dehydrogenase
that approximately 80% of both pregnant and nonpreg- increase to the upper limits of the normal range during
nant women have a gastric pH of 2.5 or less, approxi- pregnancy.177 The total alkaline phosphatase activity
mately 50% have gastric volumes of 25 mL or greater, and increases twofold to fourfold, mostly from production by
40% to 50% exhibit both low pH and gastric volume the placenta. Excretion of sulfobromophthalein into bile
greater than 25 mL. These results are similar to those decreases, whereas the hepatic extraction and retention
obtained from studies of women at a mean gestation of of this compound increases.178
15 weeks.165 Biliary stasis and greater secretion of bile with choles-
terol increase the risk of gallbladder disease during preg-
nancy.179 The incidence of gallstones is 5% to 12% in
Nausea and Vomiting pregnant women.180 One in 1,600 to 1 in 10,000 women
Approximately 80% of pregnant women will experience undergo cholecystectomy during pregnancy. Progester-
nausea and vomiting during pregnancy.166 The symptoms one inhibits the contractility of gastrointestinal smooth
typically start between 4 to 9 weeks’ gestation and may muscle, leading to gallbladder hypomotility.181 The size
2 Physiologic Changes of Pregnancy 27
of the total bile acid pool increases by about 50% during respectively).189,190 Proteinuria (> 300 mg/24 h) has been
pregnancy, and the relative proportions of the various described without the diagnosis of preeclampsia.191
bile acids change.182 The changes in the composition of However, women with isolated proteinuria are more
bile revert rapidly after delivery, even in patients with likely to progress to preeclampsia than women with iso-
gallstones. lated hypertension. The protein-to-creatinine ratio in a
random urine sample correlates well with a 24-hour
urine protein measurement, and a value of greater than
THE KIDNEYS 0.18 has been estimated as indicating significant protein-
uria192; this test may be an alternative method if time is
Owing to an increase in total intravascular volume, both lacking for a 24-hour urine collection. The degree of
renal vascular and interstitial volume increase during proteinuria in normal pregnancy also correlates with ges-
pregnancy. These increases are reflected in enlarged tation. Women with twin pregnancies have greater
kidneys, with renal volume increased by as much as protein excretion compared with those with singleton
30%.183 Vasodilation of the kidneys contributes to the pregnancies.193
overall decline in systemic vascular resistance during the Glucose is filtered and almost completely absorbed in
first trimester. The collecting system, including the renal the proximal tubule. In the nonpregnant state, a small
calyces, pelvis, and ureters, dilates. Hydronephrosis may amount of glucose is excreted. Pregnancy imposes a
occur in 80% of women by mid pregnancy.184 change in the glucose resorptive capacity of the proximal
Both the glomerular filtration rate (GFR) and the tubules, so all pregnant women exhibit an elevation of
renal plasma flow increase markedly during pregnancy glucose excretion. Of pregnant women who have normal
secondary to reduced renal vascular resistance.26 The glucose tolerance to an oral load and normal glucose
renal plasma flow is 75% greater than nonpregnant excretion when not pregnant, approximately half will
values by 16 weeks’ gestation and is maintained until 34 exhibit a doubling of glucose excretion. Most of the
weeks, when a slight decline occurs. By the end of the remainder have increases of 3 to 10 times the nonpreg-
first trimester, the GFR is 50% greater than baseline, nant amount, and a small proportion (< 10%) excrete as
and this rate is maintained until the end of pregnancy. much as 20 times the nonpregnant amount.194 Overall,
The GFR does not return to prepregnancy levels until the amount of glucose excreted in the third trimester is
3 months postpartum. Because the GFR does not several times greater than that in the nonpregnant state.
increase as rapidly or as much as the renal plasma flow, The normal nonpregnant pattern of glucose excretion is
the filtration fraction decreases from nonpregnant levels reestablished within a week after delivery.
until the third trimester.185 The potential role of nitric The kidney is also involved in maintenance of acid-
oxide in the renal vasodilation was tested and confirmed base status during pregnancy. An increase in alveolar ven-
in a rat model.186 tilation results in respiratory alkalosis. A compensatory
Creatinine clearance is increased to 150 to 200 mL/min response occurs in the kidney, with greater bicarbonate
from the normal baseline values of 120 mL/min.187 The excretion and a decline in serum bicarbonate levels. The
increase occurs early in pregnancy, reaches a maximum decrease in serum bicarbonate affects the pregnant
by the end of the first trimester, decreases slightly near woman’s ability to buffer an acid load.
term, and returns to the prepregnancy level by 8 to 12
weeks postpartum.185 These renal hemodynamic altera-
tions are among the earliest and most dramatic maternal
adaptations to pregnancy. The increased GFR results
NONPLACENTAL ENDOCRINOLOGY
in reduced blood concentrations of nitrogenous metabo- Thyroid Function
lites. The blood urea nitrogen concentration decreases
to 8 to 9 mg/dL by the end of the first trimester and The thyroid gland enlarges by 50% to 70% during preg-
remains at that level until term.187 Serum creatinine nancy because of follicular hyperplasia and greater
concentration is a reflection of skeletal muscle production vascularity. The estrogen-induced increase in thyroid-
and urinary excretion. In pregnancy, skeletal muscle pro- binding globulin results in a 50% increase in total triio-
duction of creatinine remains relatively constant but dothyronine (T3) and thyroxine (T4) concentrations
the GFR is increased, resulting in a reduced serum creati- during the first trimester, which are maintained until
nine concentration. The serum creatinine concentration term.195 The concentrations of free T3 and T4 do not
decreases progressively to 0.5 to 0.6 mg/dL by the end change. The concentration of thyroid-stimulating
of pregnancy. The serum uric acid level declines in hormone (TSH) decreases during the first trimester but
early pregnancy because of the rise in GFR, to 2.0 to returns to the nonpregnant level shortly thereafter and
3.0 mg/dL by 24 weeks’ gestation.188 Subsequently, the undergoes no further change during the remainder of
uric acid level begins to increase, reaching the prepreg- pregnancy. The fetal thyroid gland cannot produce
nancy level by the end of pregnancy. Tubular reabsorption thyroid hormone until the end of the first trimester and
of urate accounts for this elevated uric acid level during relies solely on maternal T4 production during this criti-
the third trimester. cal time of development and organogenesis.
Total protein excretion and urinary albumin excretion Approximately 4% to 7% of women of childbearing
are higher than nonpregnant levels. Average 24-hour age are either hypothyroid or at risk of hypothyroidism
total protein and albumin excretion are 200 mg and during pregnancy.196 Only 20% to 30% of affected women
12 mg, respectively (upper limits are 300 mg and 20 mg, demonstrate symptoms of hypothyroidism, likely because
28 PART II Maternal and Fetal Physiology
symptoms of hypothyroidism mimic features of preg- lumbar lordosis, placing mechanical strain on the lower
nancy.197 In a large study of 502,036 pregnant women, back. The hormonal changes of pregnancy may also play
15% of tested women had gestational hypothyroidism, a role. Relaxin, a polypeptide hormone of the insulin-like
with 33% of these women demonstrating symptoms.198 growth factor family, is associated with remodeling of
Based on these results, many physicians advocate univer- collagen fibers and pelvic connective tissue. The primary
sal screening, which appears to be cost effective, given source of circulating relaxin is the corpus luteum; the
the risk of decreased intelligence in the offspring, miscar- placenta is a secondary source. Serum relaxin levels in
riage, and postpartum bleeding if hypothyroidism is left early pregnancy are positively correlated with the pres-
untreated.199 ence of back pain.206
Women who develop low back pain during pregnancy
may avoid subsequent pregnancy to prevent recurrence.
Glucose Metabolism These women have a very high risk of a new episode
Mean blood glucose concentration remains within the during a subsequent pregnancy.207 In the majority of
normal range during pregnancy, although the concentra- patients, low back pain during pregnancy responds to
tion may be lower in some women during the third tri- activity and postural modification. Exercises to increase
mester compared with nonpregnant individuals.200 This the strength of the abdominal and back muscles are
finding is explained by the greater glucose demand of the helpful. Scheduled rest periods with elevation of the feet
fetus and the placenta. The relative hypoglycemic state to flex the hips and decrease the lumbar lordosis help
results in fasting hypoinsulinemia. Pregnant women also relieve muscle spasm and pain.208
exhibit exaggerated starvation ketosis. The enhancement of the lumbar lordosis during preg-
Pregnant women are insulin resistant because of hor- nancy alters the center of gravity over the lower extremi-
mones such as placental lactogen secreted by the pla- ties (Figure 2-10) and may lead to other mechanical
centa.201 The blood glucose levels after a carbohydrate problems. Exaggerated lumbar lordosis tends to stretch
load are greater in pregnant women than in nonpregnant the lateral femoral cutaneous nerve, possibly resulting in
women, despite a hyperinsulinemic response. These meralgia paresthetica, with paresthesia or sensory loss
changes resolve within 24 hours of delivery. over the anterolateral thigh. Anterior flexion of the neck
and slumping of the shoulders usually accompany the
enhanced lordosis, sometimes leading to a brachial plexus
Adrenal Cortical Function neuropathy.
The concentration of corticosteroid-binding globulin
(CBG) doubles during gestation as a result of an estrogen-
induced enhancement of hepatic synthesis.202 The ele-
vated CBG value results in a 100% increase in the plasma
cortisol concentration at the end of the first trimester and
a 200% increase at term. The concentration of unbound,
metabolically active cortisol at the end of the third tri-
mester is two and one-half times the nonpregnant level.
The increase in free cortisol results from greater produc-
tion and reduced clearance. Protein binding of cortico-
steroids is affected by an increase in the CBG concentration
and a decrease in the serum albumin level. CBG binding
capacity usually saturates at low concentrations of gluco-
corticoids. Clearance of betamethasone is greater during
pregnancy, possibly because the drug is metabolized by
placental enzymes.203
(mL/min/100g of brain)
50
Despite compression of the dural sac by the epidural should receive crystalloid, colloid, or blood for volume
veins, the CSF pressure in pregnant women is the same replacement.100
as in nonpregnant women.226 Uterine contractions and
pushing result in an increase in CSF pressure that is
secondary to acute increases in epidural vein distention. General Anesthesia
Airway Management, Oxygenation,
Sympathetic Nervous System and Ventilation
Dependence on the sympathetic nervous system for Changes in the maternal airway and respiratory physiol-
maintenance of hemodynamic stability increases progres- ogy mandate modification of airway management during
sively throughout pregnancy and reaches a peak at pregnancy (Box 2-3) (see Chapter 30). The proportion of
term.227-229 The dependence on the sympathetic nervous pregnant women with a Mallampati IV classification
system returns to that of the nonpregnant state by 36 to increases by 34% between 12 and 38 weeks’ gestation.235
48 hours postpartum. Vascular engorgement of the airway results in edema of
the oral and nasal pharynx, larynx, and trachea,236 which
may lead to difficult tracheal intubation and difficult
ANESTHETIC IMPLICATIONS mask ventilation. Airway edema may be exacerbated in
patients with upper respiratory tract infection or pre-
Positioning eclampsia and in those who have been pushing for a long
time during the second stage of labor. Management of
Aortocaval compression, decreased blood pressure and the difficult obstetric airway is discussed in Chapter 30.
cardiac output, and impairment of uteroplacental blood Because FRC is reduced, oxygen consumption is
flow occur when a pregnant woman is placed in the increased, and FRC is less than closing capacity in
supine position. This may compromise fetal well- up to 50% of supine individuals.70 Pregnant women
being and neonatal outcome during labor or cesarean become hypoxemic more rapidly than nonpregnant
delivery.230-232 Therefore, after 20 weeks’ gestation, the women during episodes of apnea. During apnea
supine position should be avoided and the uterus should accompanying rapid-sequence induction of general
be displaced to the left by placement of a wedge under- anesthesia, Pao2 decreases twice as rapidly (139 versus
neath the right hip or by tilting the operating table to the 58 mm Hg/min) in pregnant versus nonpregnant
left (Figure 2-12). Anesthetic drugs or techniques that women.237 Denitrogenation is achieved faster in preg-
cause venodilation further reduce venous return with nant versus nonpregnant women because of elevated
caval obstruction. Studies performed with pregnant minute ventilation and decreased FRC. However, after
women placed in the lateral position have not shown
major decreases in cardiac output.233,234
complete denitrogenation via inhalation of 100% oxygen, of succinylcholine is similar between pregnant and non-
parturients tolerate only 2 to 3 minutes of apnea, versus pregnant women, and recovery may even be faster because
9 minutes in nonpregnant patients, before oxygen satura- the larger volume of distribution results in a lower initial
tion decreases to less than 90%. drug concentration and a shorter time before the thresh-
Ventilation should be adjusted to maintain Paco2 at old for recovery is attained. Pregnant women may be less
approximately 30 mm (4 kPa). This can be achieved with sensitive than nonpregnant women to comparable plasma
minute ventilation of 121 mL/kg/min; in comparison, concentrations of succinylcholine, a feature that also may
77 mL/kg/min is required to maintain a comparable contribute to more rapid recovery during pregnancy.
Paco2 in nonpregnant women.238 Decreased plasma bicar- Pregnant and postpartum women exhibit enhanced
bonate concentration reduces buffering capacity in preg- sensitivity to the aminosteroid muscle relaxants
nancy. Allowing the Paco2 to increase to the normal level vecuronium and rocuronium.250,251 The greater sensi-
for nonpregnant women results in respiratory acidosis. tivity to vecuronium is not explained by altered pharma-
cokinetics because the drug exhibits increased clearance
and a shortened elimination half-life in pregnant
Intravenous and Inhalation Anesthetics
women.252 The mean onset time and clinical duration of
Propofol requirement decreases 10% during the first cisatracurium are significantly shorter in women imme-
trimester239; this decrease is not accounted for by proges- diately after delivery than in nonpregnant women.253
terone because the dose reduction does not correlate with
progesterone levels. The elimination half-life of propofol Chronotropic Agents and Vasopressors
is unaffected by pregnancy, although clearance may be
higher.240 The average induction dose of thiopental in Pregnancy reduces the chronotropic response to isopro-
pregnant women is 18% lower in the first trimester and terenol and epinephrine because of down-regulation of
35% lower at term compared with that in nonpregnant beta-adrenergic receptors.254 These agents are less-
women.241,242 The elimination half-life of thiopental in sensitive markers of intravascular injection during admin-
pregnant women is 26.1 hours, compared with 11.5 hours istration of an epidural test dose in pregnant patients than
in nonpregnant women243; this is explained by a marked in nonpregnant patients. Because of down-regulation of
increase in volume of distribution despite increased clear- adrenergic receptors, treatment of hypotension requires
ance. Plasma protein binding of thiopental is similar in higher doses of vasopressors such as phenylephrine in
term pregnant and nonpregnant women.243 pregnant women than in nonpregnant women.
The rate of rise of alveolar versus inspired anesthetic
concentration (FA/FI) of volatile anesthetics, and thus
the speed of induction, is increased during pregnancy Neuraxial Analgesia and Anesthesia
because of greater minute ventilation and reduced FRC, Technical Considerations and Positioning
despite higher cardiac output.
The minimum alveolar concentration (MAC) for vola- Increased lumbar lordosis during pregnancy may reduce
tile anesthetics is up to 40% lower in pregnancy.244-246 the vertebral interspinous gap, thus creating technical
Although MAC is a spinal nociceptive reflex that involves difficulty in administering neuraxial anesthesia (Box 2-4
both sensory and motor components,247 practitioners and Figure 2-13) (see Chapter 12). Widening of the
have interpreted this decrease in MAC as indicating that
pregnant patients have a decreased requirement for
inhaled anesthetics. However, this interpretation has
been questioned. Ueyama et al.248 compared bispectral
index values in 15 patients undergoing cesarean delivery BOX 2-4 Neuraxial Anesthesia:
with sevoflurane general anesthesia versus 15 patients
undergoing elective gynecologic surgery and found no ANESTHETIC IMPLICATIONS OF MATERNAL
difference between groups. This finding suggests that the PHYSIOLOGIC CHANGES
hypnotic effect of sevoflurane was not enhanced by preg-
nancy. The investigators concluded that although preg- TECHNICAL CONSIDERATIONS
nancy may decrease MAC, it does not decrease volatile • Lumbar lordosis increased
anesthetic requirements, and suggested that parturients • Apex of thoracic kyphosis at higher level
should be given the same dose of volatile anesthetics as • Head-down tilt when in lateral position
nonpregnant patients. Further work is required to TREATMENT OF HYPOTENSION
confirm these findings. • Decreased sensitivity to vasopressors*
LOCAL ANESTHETIC DOSE REQUIREMENTS†
Muscle Relaxants
• Subarachnoid dose reduced 25%
Pseudocholinesterase activity is decreased by 24% • Epidural dose unaltered or slightly reduced
before delivery and by 33% on the third postpartum
day.249 It returns to normal 2 to 6 weeks postpartum. The *Compared with nonpregnant women.
†Change in the segmental dose requirement compared with
reduced activity does not usually result in clinically rel- nonpregnant women.
evant prolongation of paralysis after a single dose of suc- Modified from Conklin KA. Maternal physiologic adaptations during
cinylcholine. Twitch height recovery after administration gestation, labor, and the puerperium. Semin Anesth 1991; 10:221-34.
32 PART II Maternal and Fetal Physiology
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217. Santiago JR, Nolledo MS, Kinzler W, Santiago TV. Sleep and requirement for inhaled anesthetic agents. Anesthesiology 1974;
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38 PART II Maternal and Fetal Physiology
246. Preckel B, Bolten J. Pharmacology of modern volatile anaesthet- 259. Hirabayashi Y, Shimizu R, Saitoh K, et al. Acid-base state of
ics. Best Pract Res Clin Anaesthesiol 2005; 19:331-48. cerebrospinal fluid during pregnancy and its effect on spread of
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nociceptive withdrawal reflex is accompanied by reduced dorsal 260. Barclay DL, Renegar OJ, Nelson EW Jr. The influence of inferior
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248. Ueyama H, Hagihira S, Takashina M, et al. Pregnancy does not 261. Hirabayashi Y, Shimizu R, Saitoh K, Fukuda H. Spread of sub-
enhance volatile anesthetic sensitivity on the brain: an electroen- arachnoid hyperbaric amethocaine in pregnant women. Br J
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249. Shnider SM. Serum cholinesterase activity during pregnancy, 262. Hogan QH, Prost R, Kulier A, et al. Magnetic resonance
labor and the puerperium. Anesthesiology 1965; 26:335-9. imaging of cerebrospinal fluid volume and the influence of body
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252. Dailey PA, Fisher DM, Shnider SM, et al. Pharmacokinetics, 264. Abouleish EI. Postpartum tubal ligation requires more bupiva-
placental transfer, and neonatal effects of vecuronium and pan- caine for spinal anesthesia than does cesarean section. Anesth
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1984; 60:569-74. 265. Grundy EM, Zamora AM, Winnie AP. Comparison of spread of
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thesiology 1988; 69:626-8. Analg 1966; 45:848-51.
255. Fagraeus L, Urban BJ, Bromage PR. Spread of epidural analgesia 267. Santos AC, DeArmas PI. Systemic toxicity of levobupivacaine,
in early pregnancy. Anesthesiology 1983; 58:184-7. bupivacaine, and ropivacaine during continuous intravenous infu-
256. Datta S, Lambert DH, Gregus J, et al. Differential sensitivities of sion to nonpregnant and pregnant ewes. Anesthesiology 2001;
mammalian nerve fibers during pregnancy. Anesth Analg 1983; 95:1256-64.
62:1070-2. 268. Moir DD. Ventilatory function during epidural analgesia. Br J
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Intraneural lidocaine uptake compared with analgesic differences 269. Egbert LD, Tamersoy K, Deas TC. Pulmonary function during
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rabbit vagus nerve. Anesth Analg 1987; 66:123-6. Anaesthesia 2004; 59:350-3.
C H A P T E R 3
CHAPTER OUTLINE
Uteroplacental blood flow is responsible for the delivery ANATOMY AND STRUCTURE
of oxygen and nutrients to the fetus. A normal uteropla-
cental circulation is essential for healthy fetal growth and The blood supply to the uterus is derived mainly from
development. Acute reduction in uteroplacental blood the uterine arteries (Figure 3-1) with a smaller, variable
flow may rapidly threaten fetal viability. Chronic reduc- contribution from the ovarian arteries. Although the
tion in uteroplacental blood flow, as may occur from pelvic vasculature shows anatomic variation,3 the uterine
abnormal development of the placental vasculature, leads artery arises bilaterally from the anterior division of the
to gestational pathologic processes such as preeclampsia internal iliac (hypogastric) artery, whereas the ovarian
and fetal growth restriction (also known as intrauterine artery arises from the anterolateral abdominal aorta
growth restriction) and may even predispose the fetus to below the renal arteries. The uterine artery passes medi-
developing cardiovascular disease during subsequent ally to the side of the uterus, where it supplies branches
adulthood.1 The uteroplacental circulation undergoes to the cervix and vagina and ascends between the two
circadian changes2 and may be affected by parturition, layers of the broad ligament, yielding arcuate arteries
disease, and anesthetic techniques and drugs. An under- that supply the body of the uterus to the junction with
standing of the regulation of uteroplacental circulation is the fallopian tubes. During pregnancy, flow may differ
an important foundation for the safe provision of obstet- between the right and left uterine arteries; Konje et al.4
ric anesthesia and assists in the management of many estimated that vessel diameter was approximately 11%
pregnancy-related diseases. Research in this area is active greater and blood flow was approximately 18% greater
but complicated by ethical considerations. Much of the in the uterine artery on the same side as the placenta
available knowledge comes from studies in animals, par- compared with the contralateral artery. Anastomoses are
ticularly sheep but also nonhuman primates and other formed with the contralateral uterine artery, the vaginal
species. It is important to consider possible interspecies arteries, and the ovarian arteries. The arcuate arteries
differences and to critically examine the methodology give rise to small branches that supply the myometrium
and context of animal research when extrapolating find- and large radial arteries that branch deeply and enter the
ings into recommendations for clinical care. endometrium to form the convoluted spiral arteries.
39
40 PART II Maternal and Fetal Physiology
Ovarian artery
Internal iliac (hypogastric) artery
Uterine artery
Branch to fallopian tube
Branch to round
ligament Vaginal artery
Ovary
Uterus
Bladder
Ureter
of the possibility of intrinsic flow matching, it is believed higher fetoplacental weight ratio in rodents (20 : 1) than
that these circulations are independently regulated.11 in humans (6 : 1).15
Margin of Safety
400 Common iliac
Studies in animals have demonstrated that, in normal
Blood flow (mL/ min)
delivery, fetal oxygen uptake was not significantly affected Causes of Decreased Uterine
by variations in uterine blood flow; moreover, fetal BOX 3-1
Blood Flow
oxygen uptake became flow dependent only when uterine
oxygen delivery was reduced to less than half the baseline DECREASED PERFUSION PRESSURE
value. Boyle et al.,28 investigating the effects of acute Decreased uterine arterial pressure:
uterine arterial embolization with microspheres in sheep, • Supine position (aortocaval compression)
found a linear decrease in fetal aortic oxygen tension as • Hemorrhage/hypovolemia
uterine blood flow decreased. However, uterine oxygen • Drug-induced hypotension
consumption did not decrease and fetal hydrogen ion • Hypotension during sympathetic blockade
concentration did not increase until uterine blood flow Increased uterine venous pressure:
had decreased to approximately 50% of the baseline • Vena caval compression
value. As uterine blood flow diminished, a reduction in • Uterine contractions
uterine venous oxygen content and a greater arteriove- • Drug-induced uterine tachysystole
(oxytocin, local anesthetics)
nous oxygen content difference were observed, indicating • Skeletal muscle hypertonus
an increase in oxygen extraction. Gu et al.29 reported (seizures, Valsalva maneuver)
comparable findings with the compression of the common
uterine artery by an inflatable occluder in sheep. INCREASED UTERINE VASCULAR RESISTANCE
Although the preceding experiments were conducted Endogenous vasoconstrictors:
in sheep, the same principles may apply to humans. The • Catecholamines (stress)
human placenta, like the sheep placenta, is a relatively • Vasopressin (in response to hypovolemia)
inefficient oxygen exchanger. Thus, in humans and sheep, Exogenous vasoconstrictors:
the transfer rate of oxygen is affected less by decreases in • Epinephrine
placental perfusion than the transfer rate in animals with • Vasopressors (phenylephrine > ephedrine)
• Local anesthetics (in high concentrations)
more efficient placentas, such as the rabbit and guinea
pig. Of interest, this difference may afford some protec-
tion in humans, because alterations in placental perfusion
in animals with more efficient placentas frequently result
in spontaneous abortion.30 Animal data would also suggest pressure and uterine venous pressure) and vascular resis-
the presence of a significant physiologic buffer that tance, as represented in the following equation:
protects the fetus during transient fluctuations in utero-
placental perfusion (e.g., changes in endogenous vaso-
Uterine perfusion pressure (1)
constrictor levels, uterine contractions, and parturition).31 Uterine blood flow =
This may partially explain why clinical studies have failed Uterine vascular resistance
to demonstrate fetal acidosis when alpha-adrenergic ago-
nists are used to maintain maternal blood pressure during Thus, there are several ways that uterine blood flow can
neuraxial anesthesia,32 despite experimental data showing decrease (Box 3-1). First, uterine blood flow may decline
that these agents reduce uteroplacental perfusion in labo- with reductions in perfusion pressure because of decreased
ratory animals.33 These observations are based on an uterine arterial pressure—for example, during systemic
assumption of normal physiology; the presence of pathol- hypotension from hemorrhage, aortocaval compression,
ogy likely diminishes any margin of safety. or sympathetic blockade during neuraxial anesthesia.
Second, uterine blood flow may decline with reductions
in perfusion pressure caused by increased uterine venous
Changes during Parturition pressure—for example, with vena caval compression,
With the onset of the uterine contractions of labor, utero- increased intrauterine pressure during uterine contrac-
placental perfusion undergoes cyclical changes. During tions, drug effects (e.g., oxytocin, cocaine), and Valsalva
uterine contractions, a decrease in perfusion occurs that is maneuvers that accompany maternal expulsive efforts
inversely related to the strength of the contraction and the during the second stage of labor. Third, uterine blood
increase in intrauterine pressure.31 Conversely, during flow may decline because of increased uterine vascular
uterine relaxation, there is a period of hyperemia when resistance, which may be caused by a number of factors,
perfusion is increased. Placental perfusion is believed to including endogenous vasoconstrictors that are released
be more sensitive to these contraction-induced changes in response to stress, exogenous vasoconstrictors, and
than myometrial or endometrial blood flow.34 Within the compression of endometrial spiral arterioles with uterine
first few hours of parturition, uterine blood flow in sheep contractions.34
decreases on average by 50% or more, although there is
notable inter-individual variation.35
MECHANISMS OF VASCULAR CHANGES
AND REGULATION
Clinical Determinants of Uterine
Blood Flow Vascular Changes during Pregnancy
In the acute setting, uterine blood flow is related to perfu- Because mean arterial pressure decreases slightly during
sion pressure (the difference between uterine arterial pregnancy, the increase in uteroplacental blood flow is
3 Uteroplacental Blood Flow 43
6 Steroid Hormones
Uterine vascular resistance 5
(mm Hg•min/mL) Steroids play an integral role in the development and
4 regulation of the uteroplacental circulation. Estrogen and
progesterone are especially important, and there is evi-
3
dence that cortisol may also contribute.
2 Estrogen has a fundamental role in the short- and
long-term uterine vascular changes during pregnancy.
1
Plasma concentrations of estrogen, initially derived from
0 the ovaries and later predominantly from the placenta,
Nonpregnant 60–100 130–140
Days′ gestation Days′ gestation
rise concomitantly with the increase in uterine blood flow
during pregnancy. Exogenously administered estrogen
FIGURE 3-4 ■ Changes in uterine vascular resistance with gesta- causes uterine vasodilation and a marked rise in uterine
tion. Data are mean ± SE. (Adapted from Rosenfeld CR. Distribu- blood flow, independent of systemic effects.40 Angiogenic
tion of cardiac output in ovine pregnancy. Am J Physiol 1977; and vasodilatory effects of estrogen are meditated via
232:H231-5.) estrogen receptors ER-α and ER-β, which are structur-
ally and functionally distinct. The majority of these
receptors are located in the nucleus and mediate genomic
effects by regulating transcription of genes that are par-
dependent on a substantial decrease in uterine vascular ticularly responsible for the longer-term uterine angio-
resistance (Figure 3-4), together with increased cardiac genic responses. There are also membrane receptors that
output and intravascular volume. The main factors con- mediate nongenomic effects by up-regulating endothelial
tributing to the decrease in vascular resistance include production of nitric oxide through the activation of endo-
vascular remodeling, changes in vascular reactivity, and thelial nitric oxide synthase (eNOS) and the augmenta-
the development of the widely dilated placental tion of eNOS protein expression.41
circulation. Progesterone modulates the effect of estrogen on
Vascular remodeling of arteries in the uterus during uterine blood flow. In a nonpregnant sheep model, exog-
pregnancy is believed to include increases in both vessel enous progesterone administered alone had no uterine
diameter and vessel length. In humans, both vessel vasodilatory effect but had an inhibitory effect when
lengthening and straightening of coiled vessels may combined with estrogen.38 Progesterone down-regulates
occur.12 According to Poiseuille’s law, vascular resistance expression of estrogen receptors.42 An increase in the
is decreased in proportion to the fourth power of the estrogen-progesterone ratio parallels the increase in
radius, whereas resistance is increased in proportion to uterine blood flow in late pregnancy in many species.43
the first power of vessel length; as such, the effects of Plasma cortisol levels approximately double during
changes in vessel diameter dominate, resulting in an pregnancy. Cortisol has both systemic and local effects
overall decrease in resistance. Palmer et al.,13 using serial on uterine blood flow. Systemically, cortisol contributes
Doppler studies during pregnancy, observed that uterine to regulation of uterine blood flow by increasing plasma
artery diameter is doubled by 21 weeks’ gestation, volume. Although cortisol is believed to decrease eNOS
whereas there is no change in the diameter of the protein expression and decrease nitric oxide release, it
common iliac or external iliac arteries. These investiga- potentiates the response to vasoconstrictor agents includ-
tors also showed that uterine artery mean flow velocity ing angiotensin II, vasopressin, and norepinephrine.
increased progressively during pregnancy to values eight Attenuation of these effects occurs during pregnancy.38
times greater than those of nonpregnancy. In parallel
with arterial changes, there is also structural remodeling
of uterine veins in pregnancy. This includes increases in Decreased Response to
diameter and distensibility and decreases in elastin
content.36 Although blood viscosity decreases during
Vasoconstrictors
pregnancy and also contributes to reduced uterine vas- In pregnancy, there is a generalized reduction in response
cular resistance, this is considered a relatively minor to endogenous and exogenous vasoconstrictors, including
effect compared with vascular changes.37 angiotensin II, endothelin, thromboxane, epinephrine,
Changes in vascular reactivity during pregnancy norepinephrine, phenylephrine, serotonin, thromboxane,
include a vasodilatory response that is meditated at endo- and arginine vasopressin.44-46 The relative refractoriness
thelial and vascular smooth muscle levels.38 The growth of the systemic and uterine circulations varies for differ-
of the placenta creates a low-resistance vascular pathway ent agents, which has important implications for the
by eliminating the intramyometrial microcirculation and regulation and maintenance of uteroplacental blood flow.
creating an intervillous space.39 This has functional char- During pregnancy, concentrations of angiotensin II
acteristics of an arteriovenous shunt.15 in maternal blood are increased twofold to threefold47;
The mechanisms underlying the vascular changes however, the vasopressor response to angiotensin II is
during pregnancy are incompletely understood. Contrib- attenuated.48 This refractoriness is diminished in patients
uting factors include steroid hormones, decreased in whom preeclampsia develops.48 The uterine circula-
response to vasoconstrictors, endothelium-derived vaso- tion is less responsive to angiotensin II than the systemic
dilators, increased shear stress, and venoarterial exchange. circulation. Thus, infusion of physiologic doses of
44 PART II Maternal and Fetal Physiology
angiotensin II has been shown to have minimal effect on methyl ester (L-NAME) decreases uterine blood flow
uteroplacental blood flow while increasing systemic and also reverses refractoriness to vasoconstrictors.61
blood pressure.49 The difference in sensitivity of the Long-term inhibition of nitric oxide synthase causes
uterine and systemic circulations to angiotensin II is con- hypertension and fetal growth restriction in rats.62
sidered an important physiologic adaptation during preg-
nancy that contributes to the redistribution of cardiac
output, the increase in uterine blood flow, and possibly
Other Vasoactive Substances
the maintenance of uterine blood flow during normal Atrial and brain natriuretic peptides attenuate the
fluctuations in blood pressure.50 response to angiotensin II, and intravenous infusion of
Sensitivity to vasoconstrictors such as epinephrine, atrial natriuretic peptide reduces blood pressure while
norepinephrine, and phenylephrine is attenuated increasing uterine blood flow in preeclamptic women.63
during pregnancy.51 However, in contrast to the responses Protein kinase C activity is decreased in uterine, but not
to angiotensin II, the uterine circulation is more respon- systemic, arteries of pregnant sheep and may cause vaso-
sive to these agents than the systemic circulation.51 Thus, dilation and an increase in uterine blood flow; this may
during hemorrhage or other major stresses that result in have a regulatory effect on local ovarian and placental
large catecholamine release, it is unlikely that uteropla- estrogen production.43 Studies in rats have shown a
cental perfusion will be preferentially preserved above decrease in endogenous endothelin-dependent vasocon-
essential maternal perfusion.52 strictor tone in uteroplacental vessels, which may con-
The mechanism underlying the difference in vascular tribute to the increase in placental blood flow in late
sensitivity between the uterine and systemic circulations gestation.64 Uterine vascular resistance in early preg-
is unclear, but distribution of receptor subtypes is believed nancy may be increased by relaxin, which may have
to be important.53 There are two distinct subtypes of a role in modulating the effects of estrogen and
angiotensin II receptors: AT1R and AT2R. In most tissues, progesterone.65
including systemic vascular smooth muscle, AT1R recep-
tors are predominant and mediate vasoconstriction.
However, AT2R receptors, which do not mediate smooth
Shear Stress
muscle contraction, account for 75% to 90% of angio- Shear stress, the frictional forces on the vessel wall from
tensin II binding in uterine artery and myometrium.54,55 blood flow, is believed to be an important stimulus for
uteroplacental vasodilation and remodeling.66 The reduc-
tion in downstream resistance resulting from the forma-
Vasodilators tion of the placenta would be expected to increase the
The greater synthesis and higher circulating concentra- upstream flow velocity and thus shear stress.39 Nitric
tions of endothelial-derived vasodilators during preg- oxide is considered an important mediator of this effect
nancy are believed to modulate systemic and uterine because increases in eNOS expression and nitric oxide
vascular responses to angiotensin II and other vasocon- production are witnessed with shear stress and because
strictors.56 Uterine vascular production of prostacyclin stripping the endothelium or pretreatment with L-NAME
is greater than systemic vascular production, which prob- reduces or abolishes flow-induced vasodilation.66 Studies
ably contributes to maintaining uteroplacental blood flow in vitro have shown that shear stress also increases endo-
in opposition to the effects of circulating vasoconstric- thelial production of prostacyclin.
tors.57 An enhanced response to angiotensin II during
pregnancy has been demonstrated with the systemic and
local infusion of indomethacin (which blocks prostacyclin
Venoarterial Signaling
production).58 However, inhibition of prostaglandin syn- It has been postulated that growth factors or signal sub-
thesis by an infusion of indomethacin induces only a stances secreted by the placenta and/or myometrium
transient decrease in uteroplacental blood flow, indicat- could pass from uterine veins to adjacent uterine arteries;
ing that uteroplacental blood flow is not solely dependent this may provide a system whereby the uterus and pla-
on the continued production of prostacyclin.56 centa regulate their own perfusion.39 Possible candidates
Nitric oxide is synthesized from arginine in vascular for signal substances include vascular endothelial growth
endothelial cells and stimulates soluble guanylate cyclase factor and placental growth factor. Confirmation of
in vascular smooth muscle, resulting in vascular relax- whether this mechanism is important in humans is
ation through increases in cyclic guanosine monophos- awaited.
phate. Synthesis of nitric oxide is an important mechanism
underlying changes in systemic and uterine vascular resis-
tance, attenuated responses to vasoconstrictors, and METHODS OF MEASUREMENT OF
vascular effects of estrogen during pregnancy.59 During UTEROPLACENTAL BLOOD FLOW
pregnancy, uterine arteries have increased eNOS activity,
higher levels of eNOS messenger ribonucleic acid and Many techniques have been used to measure uteropla-
eNOS protein, and increased biosynthesis of nitric oxide cental blood flow in animals and humans. The approaches
and cyclic guanosine monophosphate.59,60 Removal of the used in different studies have varied according to the
vascular endothelium diminishes or eliminates the refrac- nature of the experimental question, the existing state of
toriness of the uterine artery to vasoconstrictors45 and technology, and ethical considerations and limitations.
inhibition of nitric oxide synthesis by N-nitro-L-arginine All methods have an inherent potential for error.
3 Uteroplacental Blood Flow 45
MMFS
A
D
Time
Overall effect
variable, partly because of differences in study design, –0.10 –0.05 0.00 0.05 0.10
techniques used, and clinical circumstances. However, Weighted mean difference
most studies have shown no change or an increase in (umbilical cord arterial blood pH)
uteroplacental blood flow after administration of epidural
analgesia.77-80 Some studies have shown an increase in FIGURE 3-8 ■ Results from a meta-analysis of trials comparing
phenylephrine and ephedrine for the management of hypoten-
uterine vascular resistance indices,81,82 but with no effect sion during spinal anesthesia for cesarean delivery. The chart
on neonatal outcomes. There is evidence that in women shows the effect of choice of vasopressor on umbilical cord
with preeclampsia, epidural analgesia using a plain local arterial pH. Data are mean difference with 95% confidence inter-
anesthetic may reduce uterine artery resistance78 and vals. (Modified from Lee A, Ngan Kee WD, Gin T. A quantitative
increase intervillous blood flow.83 Ginosar et al.84 reported systematic review of randomized controlled trials of ephedrine
versus phenylephrine for the management of hypotension during
that antenatal continuous epidural infusion of ropiva- spinal anesthesia for cesarean delivery. Anesth Analg 2002;
caine in preterm patients with preeclampsia reduced 94:920-6.)
uterine artery resistance. Further work is required to
determine whether this might have therapeutic potential
for short-term prolongation of pregnancy. circulation have had mixed results. Most Doppler studies
Fetal bradycardia is sometimes observed after com- have shown that fluid preload before the initiation of
bined spinal-epidural techniques and has been attributed neuraxial analgesia does not change vascular resistance
to decreases in uteroplacental blood flow; the mechanism indices,89 although a decrease has been reported.90
for this association is unclear. Although alterations in
uteroplacental blood flow have been primarily attributed
to maternal hypotension and respiratory depression,85
Vasopressors
another postulated mechanism is uterine tachysystole The effects of vasopressors on uteroplacental blood flow
(hypertonus) caused by a rapid decrease in circulating and the resulting implications for clinical drug selection
catecholamine concentrations (see Chapter 23).86 Addi- are controversial. Animal and in vitro studies have
tional studies are needed to evaluate the relationship observed that uteroplacental blood flow was better main-
between neuraxial anesthetic techniques, uteroplacental tained using ephedrine versus alpha-adrenergic agonists
blood flow, and fetal bradycardia. such as phenylephrine, metaraminol, and methoxamine,33
which likely reflects the predominant beta-adrenergic
effects of ephedrine. In addition, in vitro studies in preg-
Hypotension nant sheep evaluating the effects of ephedrine on blood
Hypotension occurring during neuraxial blockade, vessels have demonstrated enhanced vasoconstrictor
depending on its magnitude and duration, may decrease activity on the femoral versus uterine vessels and
uteroplacental blood flow for several reasons—reduction decreased uterine vasoconstriction as a result of nitric
in perfusion pressure,17 reflex release of endogenous vaso- oxide release.91 In contrast, an increase in the uterine
constrictors, diversion (steal) of blood to the lower arteriolar vasoconstrictor response to phenylephrine has
limbs,87 and response to administered vasopressors.33 been observed during pregnancy.92 However, in clinical
The rapid and extensive sympathetic blockade during studies, umbilical arterial blood pH and base excess have
spinal anesthesia, and some of the methods used to treat been observed to be greater with the use of alpha-
hypotension, may account for the observation that umbil- adrenergic agonists in comparison to ephedrine to main-
ical arterial blood pH is lower with spinal anesthesia tain maternal blood pressure during spinal anesthesia for
than with epidural or general anesthesia for cesarean cesarean delivery (Figure 3-8).93-100 A comparison of dif-
delivery.88 ferent infusion regimens of phenylephrine, titrated to
keep maternal systolic blood pressure near baseline,
observed no depression of fetal pH and base excess
Intravenous Fluid Loading despite very large total doses (up to 2500 µg) before
Studies of the effect of intravenous fluid boluses used delivery.32 In contrast, large doses of ephedrine admin-
in conjunction with assessment of the uteroplacental istered to maintain blood pressure during spinal
48 PART II Maternal and Fetal Physiology
anesthesia for cesarean delivery depressed umbilical arte- phenylephrine and ephedrine had similar effects on
rial blood pH and base excess in a dose-dependent uterine blood flow, fetal pH, and base excess as found in
manner.101 the initial study, with the exception that fetal lactate con-
The explanation for the discrepancy between experi- centration was greater in the phenylephrine group.106
mental and clinical data is complex and incompletely Although the investigators speculated that this exception
determined. Animal studies are not always appropriate might reflect impaired fetal clearance of lactate, the pla-
models for clinical situations. Under clinical conditions, cental embolization may have narrowed the margin
Doppler studies have shown some evidence that uterine of safety for uteroplacental blood flow and increased
vascular resistance is increased by alpha-adrenergic fetal lactate production in the phenylephrine group.
agonists,94 but this finding has not been consistent.100 Ngan Kee et al.107 compared phenylephrine and ephed-
Although data suggest that alpha-adrenergic agonists rine for maintaining blood pressure in patients receiving
increase uterine vascular resistance more than systemic spinal anesthesia for nonelective cesarean delivery,
vascular resistance, the difference may be primarily due 24% of whom had evidence of fetal compromise.
to an effect in the myometrium, with relative sparing of The results showed that although umbilical arterial and
the vessels that perfuse the placenta.102 In addition, utero- venous blood lactate concentrations were lower in the
placental blood flow in humans has a margin of safety phenylephrine group, umbilical arterial blood pH and
that appears to allow modest decreases in uterine blood base excess values were similar in the two groups.
flow (caused by clinically appropriate doses of alpha- However, umbilical arterial and venous blood Po2 mea-
adrenergic agonists) to occur without compromising surements were lower in the phenylephrine group, sug-
oxygen transfer. Finally, the propensity of ephedrine to gesting that although phenylephrine may have caused
worsen fetal acid-base status may be related less to its some reduction in uteroplacental perfusion, adequate
effects on uteroplacental blood flow and more to direct oxygen supply was likely maintained by increased oxygen
beta-adrenergic receptor–mediated fetal metabolic extraction.
effects. When compared with phenylephrine, ephedrine In summary, ephedrine and phenylephrine both con-
has been observed to cross the placenta to a greater extent tinue to be used clinically for maintaining maternal blood
and be associated with higher fetal levels of lactate, pressure during the administration of neuraxial anesthe-
glucose, epinephrine, and norepinephrine.103 sia. Although most experimental data suggest that utero-
Thus, when considering the choice of vasopressor for placental perfusion is likely to be better maintained
clinical use, the anesthesiologist should take into account with ephedrine than with alpha-adrenergic agonists, this
the sum effect on fetal oxygen supply and demand balance advantage may be outweighed by other considerations,
rather than the isolated effects on uteroplacental blood such as differences in efficacy for maintaining blood pres-
flow. In this respect, clinical studies do not favor the use sure and direct fetal effects that occur from the placental
of ephedrine. In addition, the slow onset and long dura- transfer of the drug.
tion of action of ephedrine make it more difficult to
titrate than phenylephrine. Conversely, the use of phen-
ylephrine is commonly associated with a reflex slowing
Local Anesthetics
of heart rate and a corresponding decrease in cardiac Studies in vitro have shown that local anesthetics constrict
output. At modest doses, this decrease reflects a normal- arteries directly and inhibit endothelium-mediated vaso-
ization of the cardiac output that is elevated secondary to dilation.108 High concentrations of local anesthetic can
decreased afterload after the initiation of spinal anesthe- decrease uteroplacental blood flow by stimulating vaso-
sia; at larger doses, alpha-adrenergic agents can cause constriction and myometrial contractility.109,110 A com-
cardiac output to decrease below baseline.104 The impli- parative study in pregnant sheep showed that bupivacaine
cations of these findings on uteroplacental blood flow are was more potent than either lidocaine or 2-chloroprocaine
controversial because the relative importance of main- in decreasing uterine blood flow.110 However, the adverse
taining cardiac output versus maintaining uterine perfu- effects of local anesthetics were seen only at concentra-
sion pressure is unknown. Overall, to date, studies tions in excess of those observed clinically, with two
comparing ephedrine and other vasopressors in humans possible exceptions: (1) the unintentional intravenous
have not demonstrated differences in clinical neonatal injection of local anesthetic and (2) the use of local anes-
outcome. thetics for a paracervical block. At clinically relevant
Limited data are available for the comparison of vaso- doses, no adverse effect on uteroplacental blood flow was
pressors in the presence of fetal compromise or placental reported.111 Although initially the inherent vasoconstric-
insufficiency. Erkinaro et al.105,106 developed a sheep tor properties of ropivacaine were a matter of concern,
model to compare the effects of phenylephrine and studies in animals111 and humans112 have not shown that
ephedrine after a period of experimental fetal hypoxia. administration of ropivacaine results in a reduction in
Hypotension was induced by epidural anesthesia and uterine blood flow.
then corrected with either phenylephrine or ephedrine.
In an initial study, ephedrine was associated with better
restoration of uterine artery blood flow, but no differ-
Epinephrine and α2-Adrenergic Agonists
ences in fetal acid-base measurements or lactate concen- Epinephrine is often combined with local anesthetic
tration were observed.105 However, in a second study, agents in obstetric anesthesia. Wallis et al.76 found that
these investigators embolized the placenta with micro- the epidural injection of 1.5% 2-chloroprocaine with epi-
spheres to model placental insufficiency and found that nephrine (10 µg/mL) produced a small, brief reduction
3 Uteroplacental Blood Flow 49
in uterine blood flow in pregnant sheep. In contrast, an intravenous bolus of ketamine in pregnant sheep.
Alahuhta et al.113 reported that epidural bupivacaine with Similarly, Strümper et al.128 reported that neither racemic
epinephrine (5 µg/mL) had no effect on intervillous nor S+-ketamine affected uterine perfusion in pregnant
blood flow in women undergoing cesarean delivery. sheep. Few data are available on the direct effects of
Studies have not shown a reduction in uteroplacental etomidate on uteroplacental blood flow.
blood flow as a result of the absorption of epinephrine During the intravenous induction of general anesthe-
from local anesthetic solutions given epidurally to healthy sia, uteroplacental perfusion may be affected by indirect
women during labor.114 However, one study observed mechanisms such as blood pressure changes and the sym-
that the addition of epinephrine (85 to 100 µg) to epidu- pathetic response to laryngoscopy and endotracheal intu-
ral bupivacaine increased Doppler indices of uteropla- bation. Jouppila et al.129 reported that intervillous blood
cental vascular resistance in hypertensive parturients with flow decreased by 22% to 50% during induction of
chronic fetal asphyxia.115 Therefore, some anesthesia general anesthesia for cesarean delivery with thiopental
providers avoid epidural administration of epinephrine- 4 mg/kg, succinylcholine 1 mg/kg, and endotracheal
containing local anesthetic solutions to women with pre- intubation. Gin et al.130 compared thiopental 4 mg/kg
eclampsia. Commonly, epinephrine (10 to 15 µg) is and propofol 2 mg/kg in patients undergoing elective
included in the epidural test dose. Marcus et al.116 cesarean delivery. These investigators found that venous
reported that repeated epidural injections of epinephrine plasma concentrations of epinephrine and norepineph-
(10 to 15 µg) did not decrease uterine blood flow in rine increased after endotracheal intubation in both
pregnant sheep; however, the same dose injected intrave- groups, but maximum norepinephrine concentrations
nously reduced uterine blood flow, with a maximum were lower in the propofol group. No differences in
decrease of 43% observed at 1 minute. neonatal outcomes were observed. Levinson et al.131
The epidural and intrathecal administration of α2- found that intravenous ketamine increased blood pres-
adrenergic agonists (e.g., clonidine, dexmedetomidine) sure with a concomitant rise in uterine blood flow in
has been a subject of clinical investigations. Intravenous, pregnant sheep. Addition of a rapid-acting opioid (e.g.,
but not epidural, administration of clonidine decreased alfentanil, remifentanil) during induction of general
uterine blood flow in gravid ewes.117,118 anesthesia may minimize the increase in circulating cat-
echolamines that occurs after laryngoscopy and endotra-
cheal intubation.132,133 Although the use of such opioids
Opioids might attenuate any decrease in uterine blood flow, the
Opioids are often combined with local anesthetic agents potential for neonatal respiratory depression should be
for epidural and intrathecal analgesia during labor and considered.
the peripartum period. Intrathecal opioids have been
implicated as contributing to a greater risk for fetal bra-
dycardia when used for labor analgesia compared with
Inhalational Agents
non-intrathecal opioid neuraxial analgesic techniques.119 Studies in pregnant sheep have shown that usual clinical
The mechanism for this effect has been postulated as an doses (i.e., 0.5 to 1.5 minimum alveolar concentration) of
increase in uterine tone and a resulting decrease in utero- the volatile anesthetic agents, including isoflurane, des-
placental blood flow, although further research is needed. flurane, and sevoflurane, have little or no effect on uterine
Craft et al.120,121 observed that neither epidural fentanyl blood flow, although deeper planes of anesthesia are asso-
nor morphine had a significant effect on uterine blood ciated with reductions in cardiac output, maternal blood
flow in gravid ewes. Alahuhta et al.122 reported that epi- pressure, and uterine blood flow.134,135 Nonetheless, high
dural sufentanil 50 µg did not alter uterine artery blood concentrations of inhalational agents (approximately 2
flow velocity waveform indices in laboring women. Intra- minimum alveolar concentration) have been used during
thecal meperidine and sufentanil, however, may be asso- ex utero intrapartum treatment procedures without evi-
ciated with hypotension that may potentially decrease dence of impaired fetal gas exchange.136 A dose-dependent
uterine blood flow.123,124 reduction in uterine tone caused by inhalational agents
would be expected to increase uterine blood flow in clini-
cal circumstances in which tone is increased (e.g., hyper-
GENERAL ANESTHESIA stimulation with oxytocin, cocaine overdose, placental
abruption). Overall, there is little reason to choose one
Induction Agents inhalational agent over another on the basis of an agent’s
effects on uterine blood flow.
Available data suggest that the commonly used induction
agents have minimal or no direct adverse effect on utero-
placental blood flow. Allen et al.125 found that thiopental
Ventilation
inhibited the response of human myometrial arteries to Although moderate levels of hypoxemia and hypercapnia
contractile agents in vitro but had no effect on relaxation do not affect uteroplacental blood flow,137 marked altera-
induced by prostacyclin. Alon et al.126 reported that tions may reduce blood flow indirectly by mechanisms
uterine blood flow did not change significantly during most likely involving sympathetic activation and cate-
induction and maintenance of propofol anesthesia in cholamine release. The effect of hypocapnia on uteropla-
pregnant sheep. Craft et al.127 reported that uterine tone cental blood flow is controversial. Some investigators
increased but uterine blood flow remained constant after have noted that hyperventilation with hypocapnia caused
50 PART II Maternal and Fetal Physiology
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54 PART II Maternal and Fetal Physiology
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CHAPTER 4
CHAPTER OUTLINE
ANATOMY Dexmedetomidine
Embryology Benzodiazepines
Comparative Anatomy Opioids
Vascular Architecture Local Anesthetics
PHYSIOLOGY Muscle Relaxants
Barrier Function Anticholinergic Agents
Hormonal Function Anticholinesterase Agents
Regulation of Placental Blood Flow Antihypertensive Agents
Transport Mechanisms Vasopressor Agents
Transfer of Respiratory Gases and Nutrients Anticoagulants
Drug Delivery Systems
DRUG TRANSFER Disease States
Pharmacokinetic Principles
Inhalation Anesthetic Agents PLACENTAL PATHOLOGY
Induction Agents
Perimetrium
expanding amnion surrounds and applies itself over the
Myometrium connecting stalk and yolk sac, the cylindrical umbilical
Chorionic laeve cord takes on its mature form.4
Amnion Placental development is a dynamic process influenced
by many factors. Nitric oxide plays an important role in
Marginal embryo development, implantation, and trophoblast
Umbilical
zone invasion in diverse species.6 Human endothelial nitric
artery oxide synthase (eNOS) expression in the syncytiotropho-
Intervillous
space
blast and early endothelium occurs in the first trimester.
Later in pregnancy, eNOS increases and becomes more
Chorionic
Umbilical plate prominent in the syncytiotrophoblast and endothelial
vein cells. Vasculogenesis and angiogenesis depend on vascu-
lar endothelial growth factor (VEGF) and its receptors
Umbilical VEGFR-1 (Flt-1) and VEGFR-2 (Flk-2), transforming
cord growth factor-β1 (TGF-β1), and angiopoietin 1 and 2,
Septum
which exert their effects in part through nitric oxide.
Junctional zone Hypoxia also plays an important role in placental devel-
Basal plate opment and angiogenesis by stimulating trophoblast
invasion and differentiation via hypoxia-inducible factor-
alpha, which activates VEGF and eNOS. Relative hypoxia
must be maintained in early placental development
because the placental-fetal unit cannot tolerate the oxida-
FIGURE 4-1 ■ The placenta is a complex structure that brings the tive stress of reactive oxygen species during organogen-
maternal and fetal circulations into close apposition for esis.7 Oxygen levels influence the placental vascular
exchange of substances. (Redrawn from Kaufmann P, Hans-Georg
F. Placental development. In Polin RA, Fox WW, Abman SH, editors.
sensitivity to vasodilators and constrictors. In vitro studies
Fetal and Neonatal Physiology. 3rd edition. Philadelphia, Saunders, have shown that NOS inhibition and hypoxia indepen-
2004:85-96.) dently increase placental perfusion pressure. Both of
these effects are prevented by nitric oxide donors, sug-
gesting a common pathway with the effect of hypoxia
proliferate as cellular columns into the syncytiotropho- mediated partly by low NOS activity.6
blast. These columns with their syncytiotrophoblast The development of preeclampsia is related, at least
covering extend into the maternal blood lacunae and rep- in part, to abnormal placental growth and implantation
resent primary villi. Further mesodermal invasion into at this early stage of development (see Chapter 36). In
the core of these primary villi marks the metamorphosis patients with preeclampsia, the villous tree has longer
into secondary villi. Cellular differentiation of the villi capillaries with fewer branches.6 Vascular dysfunction
mesoderm results in the formation of a network of blood occurs mainly from changes in vascular structure and
cells and vessels; this transition allows their classification activation of nitric oxide synthesis rather than from
as tertiary villi. The vascular components of each villus altered responses to nitric oxide and vasoconstrictors.
develop connections within the chorionic plate and into DNA, gene expression, and manipulation of gene
the stalk that connects the developing embryo and primi- expression control placental development, fetal develop-
tive placenta. Penetration of the cytotrophoblast contin- ment, adult phenotype expression, and clinical diseases,
ues through the syncytiotrophoblastic layer until many even into subsequent generations.2,8 The evolving field of
of the villi reach the decidua and form anchoring villi epigenetics explores the prolonged effect of maternal
(Figure 4-1).4,5 and paternal environmental influences; gene expression
Villi continue to develop and undergo extensive becomes altered by DNA methylation, histone modifica-
branching into treelike structures; the branches, which tion, and noncoding RNA. At fertilization, global DNA
extend into the lacunar (or intervillous) spaces, enlarge methylation is erased so at the blastocyst stage (implanta-
the surface area available for exchange. Further villous tion) the genome is hypomethylated.8 DNA methylation
maturation results in a marked reduction in the cytotro- occurs in a specific manner so the trophectoderm
phoblastic component and a shortening of the distance (which becomes the placenta) remains relatively hypo-
between the fetal villi and maternal intervillous blood.4 methylated (50% to 70%) compared with the inner cell
The growing embryo within the blastocyst attaches to mass tissue (which becomes somatic human tissue).
the chorion through a connecting or body stalk. Meso- Genomic imprinting causes the silencing of one allele-
dermal components of this stalk coalesce to form the specific copy of a gene. DNA methylation of imprinted
allantoic (or rudimentary umbilical) vessels. As the genes occurs at the germ cell stage but is not involved
embryo continues its exponential growth phase, the con- in the methylation remodeling. Indeed, the human pla-
necting stalk shifts ventrally from its initial posterior centa exhibits extensive intraplacental mosaicism in an
attachment. The expansive open region at the ventral X-chromosome inactivation pattern. Individual placental
surface of the embryo constricts as the body wall grows cotyledons are derived from only a few cells, leading to
and closes. By so doing, the body wall surrounds the yolk cotyledon mosaicism. Even the process of in vitro fertil-
stalk, allantois, and developing vessels within the con- ization produces an altered imprinted gene methylation
necting stalk to form the primitive umbilicus. As the pattern in the placenta.
4 The Placenta: Anatomy, Physiology, and Transfer of Drugs 57
Altered gene methylation has been linked to clinical the expense of the mother. The growth of the placenta
disease states.8 Increased long interspersed nuclear and fetus is influenced by maternal anabolic status, pla-
element-1 (LINE1) gene methylation is associated with cental growth hormone, insulin-like growth factor-1,
early-onset preeclampsia. Compared with disease-free leptin, and glucocorticoids.11 Whether maternal or fetal
matched tissue, early-onset preeclampsia is associated in origin, increased glucocorticoids signal adverse envi-
with hypomethylation of 34 specific genes, whereas only ronmental conditions and result in reduced glucose and
4 hypomethylated genes were associated with late-onset amino acid transfer to the fetus. Indeed, competition
preeclampsia.9 Thus, DNA and DNA regulatory changes between mother and fetus for resource allocation has
influence not only early placental development but also been termed the kinship theory, in which imprinted genes
the occurrence of pregnancy-associated disease. influence the balance of nutrient allocation in a context-
Human studies have demonstrated fetal programming specific manner.11
of childhood and adult disease. For example, a study
showed that adults who were exposed in utero to episodes
of malnutrition developed reduced glucose tolerance,
Comparative Anatomy
atherogenic lipid profiles, and a doubled rate of cardio- The placentas of different species differ greatly, begin-
vascular diseases; these disease states were associated with ning with their method of uterine attachment, which can
hypomethylation of regulatory areas for insulin-like include adhesion, interdigitation, and fusion. In addition,
growth factor-2 and other genes.2 In utero exposure to a the number of tissue layers between the maternal and
high-fat diet can lead to an increased incidence of diabe- fetal circulations differ. The most commonly used pla-
tes in offspring. Maternal stress during pregnancy can cental categorization system, the Grossner classification,
lead to infant neurodevelopmental disorders.2 uses the number of tissue layers in the placental barrier
The placenta grows dramatically from the third month to help differentiate species (Figure 4-2).12
of gestation until term, with a direct correlation between The ability of the placenta to transfer various sub-
placental growth and fetal growth. By term, the mature stances differs among species. The markedly thicker
placenta is oval and flat, with an average diameter of epitheliochorial placenta found in sheep, a species com-
18.5 cm, weight of 500 g, and thickness of 23 mm. At monly used for placental transfer studies, has three
term, the human fetal-placental weight constitutes 6% of maternal layers (epithelium, connective tissue, and endo-
maternal weight. Placental weight increases 0.7% per thelium) that separate maternal from fetal blood. By
day, with active fetal growth contributing up to 1.5% of contrast, the human hemochorial placenta lacks these
fetal body mass per day.10 The allocation of nutrient and maternal layers, which allows maternal blood to bathe
metabolic resources for fetal growth potentially come at fetal tissues directly (see Figure 4-2). As a result, species
1 2 3
Endothelium
FETAL Mesoderm
Trophoblast
Epithelium
MATERNAL Connective
tissue
Endothelium
Epitheliochorial Syndesmochorial Endotheliochorial
4 5 6
FIGURE 4-2 ■ Modification of Grossner’s original classification scheme, showing the number and types of tissue layers between the
fetal and maternal circulations. Examples of each are as follows: (1) epitheliochorial, sheep; (2) syndesmochorial, no known exam-
ples; (3) endotheliochorial, dogs and cats; (4) hemochorial, human and hamster; (5) endothelioendothelial, bandicoot (Australian
opossum); and (6) hemoendothelial, Rocky Mountain pika. (Modified from Ramsey EM. The Placenta: Human and Animal. New York,
Praeger Publishers, 1982.)
58 PART II Maternal and Fetal Physiology
differ in the transfer of substances through the placenta; the intervillous space.14 The increased diameter of the
for example, fatty acids cannot cross through the pla- vessels decreases blood velocity and reduces blood
centa in sheep as they do in humans.13 This wide diver- pressure.
sity in placental structure and function among species The intervillous space is a large cavernous expanse
makes extrapolation from animal investigations to clini- that develops from the fusion of the trophoblastic lacunae
cal medicine tenuous. and the erosion of the decidua by the expanding blasto-
cyst, forming a huge blood sinus bounded by the chori-
onic plate and the decidua basalis (i.e., the maternal or
Vascular Architecture basal plate). Folds in the basal plate form septa that sepa-
rate the space into 13 to 30 anatomic compartments
Maternal
known as lobules. Each lobule contains numerous villous
Under the initial hormonal influences of the corpus trees that are also known as cotyledons or placentomes.
luteum, the spiral arteries of the uterus become elongated Although tightly packed with highly branched villous
and more extensively coiled. In the area beneath the trees, the intervillous space of the mature placenta can
developing conceptus, the compression and erosion of accommodate approximately 350 mL of maternal blood.
the decidua induces lateral looping of the already convo- Maternal arterial blood leaves the funnel-shaped spiral
luted spiral arteries,14 accessing the intervillous spaces. In arteries and enters the intervillous space. The blood
late pregnancy, the growing demands of the developing moves into the nearly hollow, low-resistance area, where
fetus use approximately 200 spiral arteries that directly villi are very loosely packed (the intercotyledonary space),
feed the placenta to handle a blood flow of approximately before entering another region of densely packed inter-
600 mL/min.14 The vasodilation required to accommo- mittent and terminal villi (Figure 4-3).15 The terminal villi
date this flow is the result of the replacement of the elastic represent the areas where placental exchange predomi-
and muscle components of the artery, initially by cyto- nates. After passing through this dense region, maternal
trophoblast cells and later by fibroid cells. This replace- venous blood collects between neighboring villous trees
ment reduces the vasoconstrictor activity of these arteries in an area called the perilobular zone.16 Collecting veins
and exposes the vessels to the dilating forces of the greater penetrate the maternal plate at the periphery of the
blood volume of pregnancy, especially at the terminal villous trees to drain perilobular blood from the intervil-
segments, where they form funnel-shaped sacs that enter lous space.
Chorionic plate
Chorionic villi
(secondary)
Intervillous space
Fetal
vessels Placental septum
Branch villi
Decidua basalis
Stratum compactum
Stratum spongiosum
FIGURE 4-3 ■ The relationship between
Myometrium the villous tree and maternal blood flow.
Arrows indicate the maternal blood flow
from the spiral arteries into the intervil-
lous space and out through the spiral
Anchoring villus veins. (Modified from Tuchmann-Duplessis
(cytotrophoblast) After delivery, the decidua H, David G, Haegel P. Illustrated Human
detaches at this point Embryology. Volume 1. Embryogenesis.
New York, Springer Verlag, 1972:73.)
4 The Placenta: Anatomy, Physiology, and Transfer of Drugs 59
Intervillous space
Syncytiotrophoblast
Fetal capillary
Syncytiotrophoblast
FIGURE 4-4 ■ Left, Cellular morphology of two ter- Fetal sinusoid
minal villi. Right, Higher magnification of
the boxed region exhibiting the placental barrier Hofbauer cell
between fetal and maternal blood. (Redrawn from
Cytotrophoblast
Kaufmann P. Basic morphology of the fetal and mater- Intervillous
nal circuits in the human placenta. Contrib Gynecol space
Obstet 1985; 13:5-17.)
Cell-free fetal DNA has been shown to be present in efflux of water across the placenta that affects fetal intra-
the plasma of pregnant women.23 This discovery has vascular volume and perfusion. Maternal hyperglycemia30
facilitated the development of a range of noninvasive and hypoxemia31 are examples of derangements that can
diagnostic investigations, including tests for fetal sex alter regional fetal blood flow, probably through vascular
assessment, fetal rhesus D blood group genotyping, fetal mediators. Endothelium-derived relaxing factors, espe-
chromosomal aneuploidy detection, and other genetic cially prostacyclin32 and nitric oxide,33 are important in
abnormalities.24 the control of fetoplacental circulation. Hypoxia-induced
fetoplacental vasoconstriction is mediated by a reduction
in the basal release of nitric oxide.34 This vasoconstrictor
Hormonal Function activity is functionally similar to that found in the lung
A sophisticated transfer of precursor and intermediate (i.e., hypoxic pulmonary vasoconstriction) and allows
compounds in the maternal-fetal-placental unit allows optimal fetal oxygenation through redistribution of fetal
placental enzymes to convert steroid precursors into blood flow to better-perfused lobules.31 The placental
estrogen and progesterone. This steroidogenic function vasculature constricts in response to graded hypoxia.35
of the placenta begins very early in pregnancy; by 35 to
47 days after ovulation, the placental production of estro-
gen and progesterone exceeds that of the corpus luteum
Transport Mechanisms
(i.e., the ovarian-placental shift).25 Substances are transferred across the placenta by one of
The placenta also produces a wide array of enzymes, several mechanisms.
binding proteins, and polypeptide hormones. For
example, the placenta produces human chorionic gonad- Passive Transport
otropin, human placental lactogen (a growth hormone
also known as human chorionic somatomammotropin), The passive transfer of molecules across a membrane
and factors that control hypothalamic function.25 This depends on (1) concentration and electrochemical differ-
ability to produce proteins and steroid hormones allows ences across the membrane, (2) molecular weight, (3)
the placenta to influence and control the fetal lipid solubility, (4) degree of ionization, and (5) mem-
environment.26 brane surface area and thickness. This process requires
no expenditure of cellular energy, with transfer driven
principally by the concentration gradient across a mem-
Regulation of Placental Blood Flow brane. Simple transmembrane diffusion can occur either
through the lipid membrane (e.g., lipophilic molecules
Maternal Blood Flow
and water) or within protein channels that traverse the
The trophoblastic invasion and functional denervation of lipid bilayer (e.g., charged substances such as ions) (Figure
the musculoelastic lining of the spiral arteries may rep- 4-5).36,37 Drugs with a molecular weight less than 600
resent adaptive mechanisms to decrease vascular reactiv- daltons cross the placenta by passive diffusion.38
ity and promote vasodilation. These alterations allow the
spiral arteries to vasodilate as much as 10 times their Facilitated Transport
normal diameter, thereby lowering resistance for the
passage of blood through the intervillous spaces.27 Carrier-mediated adenosine triphosphate (ATP)–inde-
Maternal blood enters the intervillous cotyledon space pendent transport of relatively lipid-insoluble molecules
at a pressure of 70 to 80 mm Hg in an area that has rela- down their concentration gradient is called facilitated dif-
tively few villi.14 The pressure and velocity of blood flow fusion.36 Facilitated diffusion differs from simple diffusion
rapidly diminishes to approximately 10 mm Hg as the in several ways. Specifically, this mode of transfer exhibits
blood passes into an area of higher resistance created by (1) saturation kinetics, (2) competitive and noncompeti-
the densely packed villi of the placentome.18 tive inhibition, (3) stereospecificity, and (4) temperature
influences (e.g., a higher temperature results in greater
transfer). With simple diffusion, the net rate of diffusion
Fetal Blood Flow
is proportional to the difference in concentration
In contrast to maternoplacental blood flow, the gesta- between the two sides of the membrane. This rate limita-
tional increases in fetoplacental blood flow primarily tion is valid for facilitated diffusion only when transmem-
results from vascular growth rather than vasodilation of brane concentration differences are small. At higher
the villous beds. Fetal perfusion of the placenta is not concentration gradients, a maximum rate of transfer
classically autoregulated; the placental vasculature has no (Vmax) is reached; thereafter, further increases in the con-
innervation by the sympathetic nervous system. However, centration gradient do not affect the rate of transfer. The
the fetus can modulate fetoplacental perfusion in a rate of transfer is determined by the number of membra-
number of ways: (1) via endocrine effects of adreno- nous carrier protein complexes and the extent of interac-
medullin, (2) via net efflux/influx of water regulated by tion between the carrier and the substance undergoing
fetal blood pressure, and (3) via local autoregulatory transport.37 An example of facilitated diffusion is the
effects mediated by the paracrine vasodilators nitric oxide transplacental transfer of glucose.
and acetylcholine.28,29 Adrenomedullin release by the fetal A special type of facilitated diffusion involves the
adrenal glands assists in maintenance of tone in placental “uphill” transport of a molecule linked to another sub-
vessels. Fetal blood pressure changes cause net influx/ stance traveling down its own concentration gradient. As
4 The Placenta: Anatomy, Physiology, and Transfer of Drugs 61
Cm Cm Cm Cm Cm Intervillous space
Microvillous membrane
of trophoblast
ATP
a b c d e Syncytiotrophoblast
Basal membrane
of trophoblast
Basal lamina
f Fetal endothelial cell
Fetal capillary
FIGURE 4-5 ■ The transfer mechanisms used for the transfer of substances across the placental barrier: a, simple diffusion; b, simple
diffusion through channels; c, facilitated diffusion; d, active transport; e, endocytosis; f, substance available for transfer into fetal
circulation; Cm, intervillous concentration of substance at the trophoblastic membrane. (Modified from Atkinson DE, Boyd RDH, Sibley
CP. Placental transfer. In Neill JD, Plant TM, Pfaff DW, et al., editors. Knobil and Neill’s Physiology of Reproduction. 3rd edition. St. Louis,
Academic Press, 2006:2787-846.)
such, the transfer is not directly driven by cellular energy compounds from the fetus; it exists on the maternal side
expenditure. In most cases, sodium is the molecule that of the trophoblastic cell membrane of the placenta and
facilitates transport. For the membrane-bound carrier to prevents compounds such as methadone and saquinavir
transfer these molecules, both molecules must be bound (a protease inhibitor) from leaving the maternal blood,
to the carrier. This hybrid system is called secondary active thus limiting fetal exposure.40 Inhibition of these trans-
transport or co-transport.37 The transplacental transport of porter proteins (e.g., inhibition of P-glycoprotein by
amino acids appears to occur principally through second- verapamil) can significantly increase the fetal transfer of
ary active transport. Transporters may be affected by certain drugs, including midazolam, which is a substrate
disease states (e.g., preeclampsia) or signaling molecules for P-glycoprotein. DNA transcription of transporters
(e.g., elevated steroid levels).39 may be induced by drugs or disease states. Expression of
transporters may change with gestational age.41
Active Transport
Pinocytosis
Active transport involves the movement of any substance
across a cell membrane; the process requires cellular Large macromolecules (e.g., proteins that exhibit negli-
energy. In general, active transport occurs against a con- gible diffusion properties) can cross cell membranes via
centration, electrical, or pressure gradient. the process of pinocytosis (a type of endocytosis). Pino-
Like facilitated diffusion, active transport requires a cytosis is an energy-requiring process in which the
protein membrane carrier that exhibits saturation kinet- cell membrane invaginates around the macromolecule.
ics and competitive inhibition.36 However, unlike second- Although the contents of pinocytotic vesicles are subject
ary active transport, the movement of a substance against to intracellular digestion, electron microscopic studies
its concentration gradient is directly linked to the hydro- have demonstrated that vesicles can move across the
lysis of high-energy phosphate bonds of ATP. The best cytoplasm and fuse with the membrane at the opposite
known example of primary active transport is the trans- pole. This appears to be the mechanism by which immu-
location of sodium and potassium through the sodium- noglobulin G is transferred from the maternal to the fetal
potassium adenosine triphosphatase (Na+/K+ ATPase) circulation.36
pump.
Active transport proteins include P-glycoprotein, Other Factors That Influence Placental Transport
breast cancer resistance protein, multidrug resistance
protein, and the sodium/multivitamin transporter, as well Other factors that affect maternal-fetal exchange include
as the many proteins involved in monoamine transport (1) maternal and fetal blood flow, (2) placental binding,
and xenobiotics.39 These transport proteins play an (3) placental metabolism, (4) diffusion capacity, (5) mater-
important role in protecting the fetus from foreign and nal and fetal plasma protein binding, and (6) gestational
potentially teratogenic compounds. Drugs may compete age (the placenta is more permeable in early pregnancy).42
with endogenous compounds of similar shape and charge Lipid solubility, pH gradients between the maternal and
for active transport.39 P-glycoprotein transports many fetal environments for certain basic drugs (“ion trap-
lipophilic drugs and antibiotics and removes cytotoxic ping”), and alterations in maternal or fetal plasma protein
62 PART II Maternal and Fetal Physiology
UBF
700 mL/min
UCBF
300 mL/min
UMBILICAL VEIN
PO2 = 28 mm Hg (3.73 kPa)
UTERINE VEIN PCO2 = 35 mm Hg (4.67 kPa)
PO2 = 33 mm Hg (4.40 kPa) pH = 7.37
PCO2 = 37 mm Hg (4.93 kPa) BE = - 4.50 mmol/L
pH = 7.35
BE = - 3 mmol/L
FIGURE 4-6 ■ The concurrent relationship between the maternal and fetal circulations within the placenta and the way this arrange-
ment affects gas transfer. These values were obtained from patients’ breathing room air during elective cesarean delivery. BE, base
excess; PO2, partial pressure of oxygen; PCO2, partial pressure of carbon dioxide; UBF, uterine blood flow; UCBF, umbilical cord blood
flow. (Blood gas data from Ramanathan S. Obstetric Anesthesia. Philadelphia, Lea & Febiger, 1988:27. Drawing by Naveen Nathan, MD,
Northwestern University Feinberg School of Medicine, Chicago, IL.)
concentrations found in normal pregnancy43 and other various species. The almost complete equilibration of
disease states (e.g., preeclampsia) may also alter placental maternal and fetal Po2 values suggests that a concurrent
transport. (or parallel) relationship between maternal blood and
fetal blood exists within the human placenta (Figure
4-6),18,46 although others have described a multivillous,
cross-current flow pattern.
Transfer of Respiratory Gases Much of the literature in this area is based on animal
and Nutrients studies. Because the functional anatomy of the placenta
in many mammals involves more layers than the human
Oxygen
placenta (e.g., the epitheliochorial placenta of the sheep
Our knowledge of oxygen transfer physiology in the pla- has three layers), results of animal models can only
centa is largely derived from the lung. The placenta must provide evidence for trends, not values, in humans.
provide approximately 8 mL O2/min/kg fetal body weight In humans, oxygen solubility is 10−4 M in plasma and
−2
for fetal growth and development, while adults only 10 M in hemoglobin; thus, 99% of the oxygen content
require 3 to 4 mL O2/min/kg at rest.44 As the “lung” for in blood is bound to hemoglobin. With an inspired
the fetus, the placenta has only one fifth the oxygen oxygen fraction of 1.0, the maximum maternal arterial
transfer efficiency of the adult lung.45 The human lung, Po2 was 425 mm Hg, but the fetal umbilical venous Po2
with a surface area of 50 to 60 m2 and a thickness of only was only 47 mm Hg, indicating a low diffusion capacity
0.5 µm, has a very large oxygen diffusion capacity; in of oxygen across the placenta.47 In addition, the placenta
comparison, the placenta has a lower diffusion capacity receives less than 50% of the fetal cardiac output, and
because of its smaller surface area of 16 m2 and a thicker blood returning from the placenta admixes with the non-
membrane of 3.5 µm. Furthermore, 16% of uterine oxygenated blood in the fetal inferior vena cava, thus
blood flow and 6% of umbilical blood flow are shunted limiting fetal arterial Po2.
through the placenta.18 Although some have called the human placenta “dif-
Oxygen transfer across the placenta depends on the fusion limited” because of the decreased ability of oxygen
membrane surface area, membrane thickness, oxygen to cross the intervillous membrane, the delivery of oxygen
partial pressure gradient between maternal blood and to the fetus is predominantly flow limited. Maternal
fetal blood, affinity of maternal and fetal hemoglobin, delivery of blood (i.e., oxygen) to the uterus is the pre-
and relative maternal and fetal blood flows. As physically dominant factor controlling fetal oxygen transfer. The
dissolved oxygen diffuses across the villous membranes, high fetal hemoglobin concentration (17 mg/dL) accounts
bound oxygen is released by maternal hemoglobin in the for the large oxygen content and the net delivery of large
intervillous space and diffuses across the placenta. Several quantities of oxygen to the fetus. Fetal hemoglobin has a
factors affect the fetal blood Po2 once it reaches equilibra- higher oxygen affinity and therefore a lower partial pres-
tion in the villi end-capillaries. First, the concurrent and sure at which it is 50% saturated (P50: 18 mm Hg) than
countercurrent arrangements of maternal and fetal blood maternal hemoglobin (P50: 27 mm Hg). This gradient
flow play a key role for placental oxygen transfer in produces a “sink” effect that enhances oxygen uptake by
4 The Placenta: Anatomy, Physiology, and Transfer of Drugs 63
fetal red blood cells, keeping fetal Po2 lower and promot- concentration gradient, stereospecific-facilitated diffu-
ing the transfer of additional oxygen across the placenta sion systems have been described with glucose transport-
(see Figure 5-7). The Bohr effect also augments the ers such as GLUT1 and GLUT3; the system is
transfer of oxygen across the placenta. Specifically, fetal- independent of insulin, a sodium gradient, or cellular
maternal transfer of carbon dioxide makes maternal energy.54 Insulin does not cross the placenta; however,
blood more acidic and fetal blood more alkalotic. These insulin receptors in the maternal side of the syncytiotro-
alterations of pH cause shifts in the maternal and fetal phoblast regulate nutrient transport through a signaling
oxyhemoglobin dissociation curves, further enhancing cascade involving the mammalian target of rapamycin
the maternal oxygen transfer to the fetus in what is complex (mTORC). Nutrient sensors for glucose, amino
termed the “double” Bohr effect. This accounts for 2% acids, oxygen, cytokines, growth factors, and energy
to 8% of the transplacental transfer of oxygen.48 levels stimulate mTORC1, a key sensing and signaling
The placenta normally has a 50% reserve for changes protein in the syncytiotrophoblast that regulates nutrient
in maternal or fetal blood flow by increasing venous transport and growth.55
extraction, a mechanism similar to that in adults. Based
on umbilical venoarterial difference, human fetal oxygen Amino Acids
uptake at term is 0.25 mmol/kg/min.49 The metabolic
activity of the placenta itself consumes up to 40% of the Concentrations of amino acids are highest in the pla-
oxygen uptake. Placental oxygen consumption is stable centa, followed by umbilical venous blood and then
even with changes in maternal blood pressure and Po2; maternal blood. The maternal-fetal transplacental trans-
30% of placental oxygen is used for protein synthesis and fer of amino acids is an active process that occurs princi-
almost 30% for Na+/K+ ATPase. The human placenta has pally through a linked translocation with sodium. The
a villous structure, which may be an adaptation for greater energy required for this transfer comes from the large
maternal flow and thus oxygen delivery, but at the expense sodium gradient established by the Na+/K+ ATPase pump,
of a smaller surface area and cross-current exchange resulting in increased intracellular concentrations of
mechanism.50 However, the placenta does change in amino acids, which then “leak” down their gradients into
response to chronic hypoxia found at high altitudes, with the fetal circulation. This transport mechanism may not
an increased capillary volume and decreased capillary apply to all amino acids and may be susceptible to inhibi-
thickness providing a near-doubling of the oxygen diffu- tors. Transport also occurs via transport exchangers of
sion capacity.51 amino acids on both maternal and fetal sides of the pla-
centa as well as facilitated diffusion. Pregnancies with
fetal growth restriction (also known as intrauterine
Carbon Dioxide
growth restriction) have reduced amino acid transport
The transfer of CO2 occurs through a number of with an inability to increase transport in spite of higher
different forms, including dissolved CO2, carbonic acid maternal levels of essential amino acids than occur in
(H2CO3), bicarbonate ion (HCO3−), carbonate ion healthy pregnancies.56
(CO32−), and carbaminohemoglobin. Equilibrium
between CO2 and HCO3− is maintained by a reaction Fatty Acids
catalyzed by carbonic anhydrase in red blood cells. The
Pco2 gradient between fetal and maternal blood (i.e., 40 Free fatty acids readily cross the human, but not ovine,
versus 34 mm Hg, respectively) drives fetal-maternal placenta. The essential fatty acids, linoleic and alpha-
transfer. Carbon dioxide is 20 times more diffusible than linolenic acid, must be transferred across the placenta.
oxygen and readily crosses the placenta,52 although dis- Lipid transfer to the fetus reaches a peak of 7 g/day at
solved CO2 is the form that actually crosses. The rapid term. The placental basal membrane has specific binding
movement of CO2 from fetal capillary to maternal blood sites for very low-density, low-density, and high-density
invokes a shift in the equilibrium of the carbonic anhy- lipoproteins. Lipase activity in the placenta is responsible
drase reaction (La Chatelier’s principle) that produces for converting triglycerides to nonessential fatty acids.
more CO2 for diffusion. The transfer of CO2 is aug- The placenta does not elongate fatty acid chains, whereas
mented further by the production of deoxyhemoglobin the fetus does. Fatty acid transport occurs primarily by
in the maternal blood, which has a higher affinity for CO2 simple diffusion; however, fatty acid–binding proteins
than oxyhemoglobin (the Haldane effect). The resulting (FABPpm, FAT/CD36, and FATP), which facilitate
affinity may account for as much as 46% of the transpla- transport, have been discovered. Nonessential fatty acids
cental transfer of carbon dioxide.46 Although a significant are albumin bound and may displace other protein-bound
fetal-maternal concentration gradient exists for HCO3−, substances.57
its charged nature impedes its transfer and contribution
to CO2 transport except as a source for CO2 production
through the carbonic anhydrase reaction.53 DRUG TRANSFER
Placental permeability and pharmacokinetics determine
Glucose
the fetal exposure to maternal drugs. Animal models (e.g.,
Simple diffusion alone cannot account for the amount pregnant ewes, guinea pigs) have been used to assess the
of glucose required to meet the demands of the placenta placental transport of drugs; however, interspecies differ-
and fetus. To assist the movement of glucose down its ences in placental anatomy and physiology limit the
64 PART II Maternal and Fetal Physiology
Da, dalton.
*The pH relative to the pKa determines the amount of drug that is ionized and un-ionized in both maternal and fetal plasma. Fetal
acidemia enhances the maternal-to-fetal transfer (i.e., “ion trapping”) of basic drugs such as local anesthetics and opioids.
†
The efflux transporter pumps substances in a fetal-to-maternal direction.
‡
Note: albumin concentration is higher in the fetus, and AAG concentration is higher in the maternal circulation.
* * *
0.0
Sufentanil Meperidine Morphine
TABLE 4-3 Opioid Transfer during In Vitro Perfusion of the Human Placenta
Clearance index, clearance drug/clearance antipyrine (a flow-limited reference compound); FTM, fetal-to-maternal (direction);
MTF, maternal-to-fetal (direction); placenta drug ratio, placenta drug concentration/g placental tissue/maternal drug concentration.
Data from non-recirculated experiments, using perfusate Media 199 without protein, with maternal flow 12 mL/min and fetal flow
6 mL/min.64,66,102,105,110
66 PART II Maternal and Fetal Physiology
minutes of maternal administration and a ratio of 2 at 60 rapid and symmetric maternal-fetal and fetal-maternal
minutes after maternal administration.97 Less lipophilic, transfers of alfentanil, with low placental drug uptake and
lorazepam requires almost 3 hours after administration rapid washout.64
for the F/M ratio to reach unity.98 Midazolam is more Maternal administration of sufentanil results in a high
polar, with an F/M ratio of 0.76 at 20 minutes after F/M ratio, 0.81. Compared with fentanyl, sufentanil has
administration. The F/M ratio of midazolam, unlike that higher lipid solubility and more rapid uptake by the
of other benzodiazepines, decreases rapidly; by 200 central nervous system, resulting in less systemic absorp-
minutes it is only 0.3.99 tion from the epidural space; lower maternal and umbili-
cal vein concentrations reduce fetal exposure and the
associated potential risk for neonatal respiratory depres-
Opioids sion.108 Human placental perfusion studies in vitro have
Meperidine has been associated with neonatal central confirmed the rapid transplacental transfer of sufentanil,
nervous system and respiratory depression. Intravenous which is influenced by differences in maternal and fetal
administration results in rapid transfer across the human plasma protein binding and fetal pH. High placental
placenta within 90 seconds after maternal administra- tissue uptake suggests that the placenta serves as a drug
tion.100 F/M ratios for meperidine may exceed 1.0 after 2 depot.65,66
to 3 hours; maternal levels fall more rapidly than fetal Remifentanil undergoes rapid placental transfer.
levels because of the mother’s greater capacity for metab- During cesarean delivery, average F/M ratios were 0.88
olism of the drug.101 This same time interval is associated when remifentanil was administered by intravenous infu-
with the greatest likelihood of neonatal depression, in sion (0.1 µg/kg/min) during epidural anesthesia114 and
part because of the active drug metabolite normeperi- 0.73 when it was given as a single bolus (1 µg/kg) at
dine. Human placental perfusion studies in vitro have induction of general anesthesia.115 Excessive maternal
demonstrated rapid placental transfer in both maternal- sedation without adverse neonatal effects has been
to-fetal and fetal-to-maternal directions with equal clear- reported with the use of remifentanil during labor;
ance profiles, minimal placental tissue binding, and no presumably, the rapid metabolism of remifentanil by
placental drug metabolism.102 As maternal levels fall, the nonspecific esterases (context-sensitive half-time of 3
meperidine and normeperidine will transfer from the minutes) results in minimal fetal exposure.116 When remi-
fetus back to the mother, correlating with the clinically fentanil was used for patient-controlled analgesia during
observed decrease in neonatal sedation 4 hours after labor, bolus doses of 0.5 µg/kg resulted in an F/M ratio
maternal administration. of approximately 0.5 and a 20% incidence of fetal heart
Morphine also rapidly crosses the placenta. One study rate changes.117 With continuous infusion of 0.33 µg/kg/
demonstrated a mean F/M ratio of 0.61, a mean umbilical min, the F/M ratio in plasma rapidly reached 0.1 to 0.3
venous blood concentration of 25 ng/mL, and a signifi- in sheep.116
cant reduction in the biophysical profile score (primarily The systemic administration of an opioid agonist/
as a result of decreased fetal breathing movements and antagonist for labor analgesia has been associated with
fewer fetal heart rate accelerations) within 20 to 30 few maternal, fetal, and neonatal side effects. Both butor-
minutes of maternal administration.103 Intrathecal admin- phanol and nalbuphine rapidly cross the placenta, with
istration of morphine results in a high F/M ratio (0.92), mean F/M ratios of 0.84 and 0.74 to 0.97, respec-
although the absolute fetal concentrations are less than tively.118,119 In one study, maternal administration of nal-
those associated with fetal and neonatal side effects.104 buphine resulted in “flattening” of the fetal heart rate
Human placental perfusion studies in vitro have demon- tracing in 54% of cases.119
strated that morphine, which is a hydrophilic compound,
exhibits membrane-limited transfer with a low placental
tissue content and a fast washout.105 Concurrent naloxone
Local Anesthetics
administration does not affect the placental transfer of Local anesthetic agents readily cross the placenta (see
morphine.106 Chapter 13). The enantiomers of bupivacaine cross the
Fentanyl and its analogues are administered via the placenta at the same rate as racemic bupivacaine.120
epidural, intrathecal, and intravenous routes. Fentanyl
has a high lipophilicity and albumin binding (74%).107
Maternal epidural administration results in an F/M
Muscle Relaxants
ratio between 0.37 and 0.57.108 During early pregnancy, As fully ionized, quaternary ammonium salts, muscle
fentanyl is rapidly transferred and may be detected not relaxants do not readily cross the placenta; however,
only in the placenta but also in the fetal brain.109 Perfu- single doses of muscle relaxants can result in detectable
sion of the human placenta in vitro results in rapid fetal blood concentrations. Maternal administration of
transfer in both maternal-to-fetal and fetal-to-maternal muscle relaxants for the induction of general anesthesia
directions, with the placenta acting as a moderate drug for cesarean delivery rarely affects neonatal muscle tone
depot.110,111 at delivery.
Despite a relatively low F/M ratio (0.30),112 maternal After a standard induction dose, succinylcholine is
administration of alfentanil has been associated with a not detectable in umbilical venous blood at delivery;
reduction of 1-minute Apgar scores when administered maternal doses larger than 300 mg are required before
to the mother immediately before the induction of anes- the drug can be detected.121 Neonatal neuromuscular
thesia.113 Perfusion of the human placenta in vitro shows blockade can occur when high doses are given repeatedly
68 PART II Maternal and Fetal Physiology
or when both the parturient and fetus are homozygous hypoglycemia, and respiratory depression.136 Although a
for atypical pseudocholinesterase deficiency.122 single dose of propranolol administered 3 hours before
The administration of nondepolarizing muscle relax- cesarean delivery has been shown to lead to an F/M ratio
ants results in low F/M ratios: 0.19 to 0.26 for pan- of 0.26,137 long-term administration during pregnancy
curonium,123-125 0.06 to 0.11 for vecuronium,125,126 0.16 results in F/M ratios greater than 1.0.138 Maternal admin-
for rocuronium,127 and 0.07 for atracurium.128 The F/M istration of atenolol and metoprolol leads to mean F/M
ratio may be the result of expedient fetal/neonatal blood ratios of 0.94 and 1.0, respectively.139,140
sampling; in a study in rats, the F/M ratio of vecuronium Labetalol, the most commonly used antihypertensive
nearly doubled as the induction-to-delivery interval during pregnancy, has a low F/M ratio of 0.38 with long-
increased from 180 to 420 seconds.126 No published study term oral administration, despite reports of mild neonatal
has investigated the placental transfer of the atracurium bradycardia.141,142 National data from Denmark showed
isomer cisatracurium. However, laudanosine, a metabo- that use of beta-adrenergic receptor antagonists during
lite of atracurium and cisatracurium, has an F/M ratio of pregnancy, including labetalol, approximately doubles
0.14.129 the risk for small-for-gestational-age preterm births and
Although nondepolarizing muscle relaxant transfer for perinatal mortality, even after adjusting for pre-
rates are low, the fetal blood concentrations increase over eclampsia.143 Preterm hypertensive women receiving
time.126 Fetal blood concentrations of nondepolarizing labetalol had no acute change in umbilical artery or fetal
muscle relaxants can be minimized by giving succinylcho- middle cerebral resistance indices of flow.144
line to facilitate intubation, followed by a nondepolariz- The ultra-short-acting beta-adrenergic receptor
ing muscle relaxant to maintain paralysis.124 antagonist esmolol has been used to attenuate the hyper-
tensive response to laryngoscopy and intubation. A mean
F/M ratio of 0.2 after maternal administration of esmolol
Anticholinergic Agents was observed in gravid ewes.145 However, a few cases of
The placental transfer rate of anticholinergic agents significant and prolonged fetal bradycardia requiring the
directly correlates with their ability to cross the blood- performance of emergency cesarean delivery have been
brain barrier. Atropine is detected in the umbilical cir- reported.146
culation within 1 to 2 minutes of maternal administration, Clonidine and methyldopa act through the central
and an F/M ratio of 0.93 is attained at 5 minutes.130 Sco- stimulation of α2-adrenergic receptors; studies have
polamine also crosses the placenta easily; intramuscular reported mean F/M ratios of 0.89147 and 1.17,148 respec-
administration results in an F/M ratio of 1.0 within 55 tively, for these agents. In concentrations likely to be
minutes.131 By contrast, glycopyrrolate is poorly trans- present in maternal blood during clinical use, magne-
ferred across the placenta, with maternal intramuscular sium and nifedipine, but not clonidine, produce fetal
administration resulting in a mean F/M ratio of only vasodilation in human placental perfusion studies in
0.22.132 Maternal intravenous administration of glycopyr- vitro.149 Phenoxybenzamine, an alpha-adrenergic recep-
rolate does not result in a detectable fetal hemodynamic tor antagonist, is commonly used to treat hypertension
response, whereas atropine and scopolamine may directly in patients with pheochromocytoma and has an F/M ratio
increase fetal heart rate. of 1.6 with long-term maternal administration.150
Direct-acting vasodilators are used for short-term
management of severe hypertension in pregnant women.
Anticholinesterase Agents Administration of hydralazine, which is often given to
Neostigmine, pyridostigmine, and edrophonium are lower blood pressure in preeclampsia, results in an F/M
quaternary ammonium compounds that are ionized at ratio of 1.0151 and causes fetal vasodilation in in vitro
physiologic pH and consequently undergo limited trans- studies.152 Hydralazine increased the umbilical artery
placental transfer.133 For example, maternal administra- resistance index, indicating vasodilation, in hypertensive
tion of neostigmine does not reverse atropine-induced women.144
fetal tachycardia. However, small amounts of these agents Sodium nitroprusside is lipid soluble, rapidly crosses
do cross the placenta, and fetal bradycardia after maternal the placenta, and can produce cyanide as a byproduct.153
administration of neostigmine and glycopyrrolate has Sodium thiosulfate, the agent used to treat cyanide toxic-
been reported.134 Because neostigmine may cross the pla- ity, does not cross the placenta in gravid ewes; it can be
centa to a greater extent than glycopyrrolate, the combi- used to treat fetal cyanide toxicity by lowering maternal
nation of neostigmine and atropine should be considered cyanide levels, thereby enhancing fetal-maternal transfer
for the reversal of nondepolarizing muscle relaxants in of cyanide.154
pregnant patients.134 Physostigmine crossed the pla- Glyceryl trinitrate (nitroglycerin) crosses the pla-
centa in 9 minutes and reversed the fetal heart rate effect centa to a limited extent, with an F/M ratio of 0.18, and
of scopolamine.135 results in minimal changes in fetal umbilical blood flow,
blood pressure, heart rate, and blood gas measurements
in gravid ewes.155 However, dinitrate metabolites found
Antihypertensive Agents in both maternal and fetal venous blood indicate the
Beta-adrenergic receptor antagonists have been com- capacity for placental biotransformation.156 Indeed, pla-
monly used as antihypertensive agents in pregnancy, cental tissue production of nitric oxide enhances the
despite early investigations noting an association uterine relaxation caused by nitroglycerin in vivo.157 In
with fetal growth restriction and neonatal bradycardia, one in vitro study, in which prostaglandin F2α was used to
4 The Placenta: Anatomy, Physiology, and Transfer of Drugs 69
create fetal vasoconstriction, the following order of nitro- measured by neonatal coagulation studies and the mea-
vasodilator compound potency was observed: glyceryl surement of radiolabeled heparin in fetal lambs.170 Low-
trinitrate ≥ sodium nitroprusside ≥ sodium nitrite molecular-weight heparin appears to have limited
(NaNO2) ≥ S-nitroso-N-acetylpenicillamine (SNAP) = placental transfer; maternal administration of enoxaparin
S-nitroso-N-glutathione (SNG).158 SNG and NaNO2 does not alter fetal anti-IIa or anti-Xa activity.171 Even
were significantly more potent under conditions of low when enoxaparin or fondaparinux (a pentasaccharide
oxygen tension. The antioxidants cysteine, glutathione, that selectively inhibits factor Xa) was given at doses
and superoxide dismutase significantly enhanced the used for acute thromboembolic therapy, human placental
vasodilatory effects of NaNO2 only.158 perfusion studies in vitro demonstrated no placental
Placental transfer of angiotensin-converting enzyme transfer.172,173 Several case reports discussed use of direct
inhibitors may adversely affect fetal renal function. Enal- thrombin inhibitors as early as 9 weeks’ gestation with
aprilat rapidly crosses the placenta, and its maternal successful delivery of normal neonates.174,175 Antiplatelet
administration in high doses resulted in a 20% reduction therapy (e.g., aspirin, clopidogrel) has been used suc-
in fetal arterial pressure in rhesus monkeys.159 cessfully in the first trimester in dual therapy for coronary
artery disease in the setting of drug-eluting stents.176
Abciximab, a glycoprotein IIb/IIIa platelet inhibitor, did
Vasopressor Agents not transfer across the in vitro perfused human placenta
Vasopressor agents are often administered to prevent or but did bind to the trophoblastic layer of the
treat hypotension during the administration of neuraxial placenta.177
anesthesia in obstetric patients. Ephedrine readily
crosses the placenta and results in an F/M ratio of
approximately 0.7.160 In an in vitro human perfusion
Drug Delivery Systems
model that required supraphysiologic doses to obtain any New drug delivery systems may influence drug transfer
effect, phenylephrine increased placental arterial pres- and distribution across the human placenta. Liposome
sure, but less so than ephedrine, whereas epinephrine, encapsulation, depending on the type and ionic charge,
norepinephrine, and methoxamine had no effect.161 can affect placental transfer; anionic and neutral lipo-
Ephedrine possesses 10 times greater lipid solubility somes increase placental transfer, whereas cationic lipo-
than phenylephrine, with F/M ratios of 1.1 versus 0.17, somes decrease placental transfer and placental tissue
respectively, in humans.162 Indeed, when either ephedrine uptake.178 Liposome encapsulation of valproic acid sig-
or phenylephrine was given during spinal anesthesia for nificantly reduces drug transfer and placental uptake.179
cesarean delivery, the ephedrine group had lower pH and
base excess, higher Pco2, and higher glucose, lactate, epi-
nephrine, and norepinephrine concentrations in umbili-
Disease States
cal arterial blood than the phenylephrine group.162 These Disease states, such as diabetes, may affect the placental
differences may be due to the beta-adrenergic agonist transfer of drugs. Glyburide, a second-generation sulfo-
effects of ephedrine in the fetus.162,163 nylurea, is partially dependent on a P-glycoprotein active
Cocaine, a common drug of abuse during pregnancy transport mechanism and demonstrates a lower F/M
(see Chapter 54), has potent vasoconstrictor activity. ratio (0.3) than the first-generation agents, even in the
Human placenta perfusion studies in vitro have demon- presence of a P-glycoprotein inhibitor.180 A high level of
strated the rapid transfer of cocaine in both maternal-to- protein binding (99.8%) may also contribute to the low
fetal and fetal-to-maternal directions; transfer is constant transplacental transfer of glyburide; when protein levels
over a wide range of concentrations.164 The active cocaine are reduced in vitro, higher transfer rates are observed.181,182
metabolites norcocaine and cocaethylene, but not the Some investigators have speculated that the thickened
inactive metabolite benzoylecgonine, are also rapidly placenta found in diabetic patients is a cause of low trans-
transferred across the placenta.165 Chronic maternal fer rates; however, no difference in maternal-fetal trans-
exposure to cocaine increases fetal concentrations; fer of metformin has been observed between placentas
however, they remain lower than maternal peak levels.166 from parturients with gestational diabetes and those from
In a study using the in vitro dually perfused human healthy parturients.183
placental lobule, fetal-side administration of vasocon- Gestational age may alter placental transfer, although
strictors was found to raise fetal placental perfusion pres- the direction of the alteration requires further evaluation.
sure, thus causing a shift of fluid from the fetus to the Although traditional belief holds that placentas from
maternal circulation.167 younger fetuses are more likely to transfer substances,
one study has demonstrated that methadone transfer is
30% lower in human preterm placentas than in term
Anticoagulants placentas.184 Dexamethasone and betamethasone, cor-
Anticoagulation therapy is often necessary during preg- ticosteroids that are often given to accelerate fetal lung
nancy. Maternal administration of warfarin in the first maturity, increase ABCB1 gene expression fourfold.
trimester results in placental transfer to the fetus, causing ABCB1 is an efflux transporter protein; hence increased
a higher rate of fetal loss and congenital anomalies.168 gene expression may increase fetal-maternal transfer of
After the first trimester, warfarin may be used in the substrate molecules.185
setting of stroke or mechanical heart valves.169 In con- Oxidative stress increases in preeclampsia, fetal growth
trast, heparin does not appear to cross the placenta, as restriction, and diabetes. New studies have shown that
70 PART II Maternal and Fetal Physiology
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129. Fodale V, Santamaria LB. Laudanosine, an atracurium and cisa- 153. Naulty J, Cefalo RC, Lewis PE. Fetal toxicity of nitroprusside in
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serum concentration and effect. Acta Anaesthesiol Scand 1989; maternal hemodynamic and metabolic effects of maternal nitro-
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C H A P T E R 5
Fetal Physiology
Mieke Soens, MD • Lawrence C. Tsen, MD
CHAPTER OUTLINE
Fetal life in utero differs significantly from postnatal life. this period, the composition of amniotic fluid is similar
The fetus relies completely on the mother and the pla- to fetal extracellular fluid, owing to the absence of keratin
centa for basic metabolic needs such as nutrient delivery, in the fetal skin. After this period, the volume of amniotic
gas exchange, acid-base balance, and electrolyte homeo- fluid is a function of production, from fetal urine (600 to
stasis. During gestation, the fetus gradually assumes the 1200 mL/day near term) and respiratory tract secretions
responsibility for many of the vital physiologic functions (60 to 100 mL/kg fetal body weight/day), and removal
that must be assumed after the abrupt transition to physi- through fetal swallowing (200 to 250 mL/kg fetal body
ologic independence at birth. Knowledge of fetal physiol- weight/day).3 Amniotic fluid volume is also influenced by
ogy, and the timing associated with these developmental intramembranous (between amniotic fluid and fetal blood
changes, is necessary for the optimal provision of analge- within the placenta) and transmembranous (between
sia and anesthesia during pregnancy and childbirth. amniotic fluid and maternal blood within the uterus)
pathways in both physiologic and pathophysiologic
states.4 Finally, the status of maternal hydration and the
FETAL ENVIRONMENT amount of decidual prolactin may alter the transfer of
amniotic fluid through fetal and maternal tissues.
Amniotic Fluid The composition of amniotic fluid undergoes more
marked variation than its volume.5,6 Keratinization of the
The fetus is surrounded by amniotic fluid, a complex fluid fetal skin is complete by 25 weeks’ gestation and decreases
that changes as the pregnancy progresses. Amniotic fluid the permeability of fetal tissues to water and solutes. The
serves a number of vital roles, including the facilitation impact of this process, coupled with the ability of the
of fetal growth, the provision of a microgravity environ- fetal kidneys to produce urine, results in increased amni-
ment that cushions the fetus, and the generation of a otic fluid concentrations of urea and creatinine, decreased
defense mechanism against invading microbes.1,2 The concentrations of sodium and chloride, and reduced
formation and maintenance of amniotic fluid is an intri- osmolality. A variety of carbohydrates, proteins, lipids,
cate process that depends on fetal maturation and mater- electrolytes, enzymes, and hormones, which vary in con-
nal hydration, hormonal status, and uteroplacental centration depending on the gestational age, are also
perfusion. present; some of these elements, particularly the amino
Amniotic fluid during early embryogenesis is princi- acids taurine, glutamine, and arginine, serve a nutritive
pally derived from maternal plasma by the passage of function for mitotic cells involved in trophoblastic growth
water and solutes through fetal membranous and placen- and placental angiogenesis.1 An abundance of growth
tal layers. Between 10 and 20 weeks’ gestation, the volume factors are found in amniotic fluid, including epidermal
of amniotic fluid increases in a predictable and linear growth factor, transforming growth factor-alpha,
manner from approximately 25 mL to 400 mL. During transforming growth factor-beta 1, insulin-like growth
75
76 PART II Maternal and Fetal Physiology
Plug of
First Trimester endovascular Second Trimester
trophoblast
Decidua
Interstitial Myometrium
trophoblasts
A B
FIGURE 5-2 ■ Invasion and remodeling of the spiral arteries by endovascular and interstitial extravillous trophoblasts. A, In the first
trimester, the terminal portion of the spiral artery is blocked by a plug of endovascular trophoblast. Early placental and embryonic
development occurs in a state of low oxygen tension, and nutrition at this early stage is derived from secretions from maternal
endometrial glands. B, After 10 to 12 weeks’ gestation, the endovascular trophoblast plug dissolves and the endovascular trophoblast
migrates into the myometrium, replacing endothelial cells, which undergo apoptosis. Maternal blood is now able to enter the inter-
villous space, the oxygen tension increases to 60 mm Hg, and nutrition changes from histotrophic to hemotrophic. (Modified from
Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006;
27:939-58.)
4.5
for oxygen than adult hemoglobin (see later discussion),
and a hemoglobin concentration higher than that of
adults (approximately 18 g/dL) result in a fetal arterial
blood oxygen content that is only marginally lower than 3.5
that in the adult, despite a lower oxygen tension.30
consumption occurs in the fetal myocardium and liver.42 prolapse is currently unknown. However, relatively small
Short-term exogenous lactate infusion in fetal lambs (suf- increases in temperature increase the sensitivity of the
ficient to lower the pH to 7.20) results in transient fetal fetal brain to hypoxic injury (see Chapter 10).55
bradycardia and increased fetal breathing movements but Although the fetus generates heat through high meta-
no other adverse effects.43 bolic activity, the ability of the fetus to generate heat
through thermogenic mechanisms is not developed until
the end of gestation and is largely inactive in utero.
Amino Acid and Lipid Metabolism Newborns are at high risk for rapid heat loss due to
The fetus uses amino acids for protein synthesis, growth, amniotic fluid evaporation and a sudden decrease in
and oxidation. Most maternal-to-fetal amino acid trans- ambient temperature.49 They are not capable of signifi-
fer occurs against a concentration gradient and involves cant heat production through shivering owing to their
energy-dependent transfer mechanisms. Under condi- small muscle mass. As a consequence, nonshivering ther-
tions in which fetal aerobic metabolism is decreased, mogenesis plays an important role in maintaining neona-
amino acid uptake by the placenta and fetus may be tal temperature. Nonshivering thermogenesis occurs in
reduced because it involves an expenditure of energy. brown adipose tissue, which is unique from other adipo-
Hypoxia results in a large reduction in nitrogen uptake cytes owing to the significant presence of mitochondria,
in fetal lambs.44 During maternal fasting, fetal amino acid fat vacuoles, sympathetic innervation, and blood vessels.
uptake does not change; however, enhanced fetal prote- In the mitochondria of brown adipose tissue, ATP pro-
olysis may occur, which subsequently results in amino duction is uncoupled from the oxidative process, resulting
acid oxidation or gluconeogenesis. in an increase in heat production and oxygen consump-
Lipid products are transferred from the mother to the tion.56 Nonshivering thermogenesis is inhibited in utero,
fetus. The fetus requires free fatty acids for growth, brain most likely owing to the presence of adenosine and pros-
development, and the deposition of body fat for postnatal taglandin E2, which have strong antilipolytic actions on
life. Fatty acids are transferred across the placenta by brown tissue.57-59 Inadequate oxygen levels and low levels
simple diffusion. Ketones are also transferred by simple of intrauterine catecholamines and thyroid hormones
diffusion; in humans, the maternal/fetal ketone ratio is may also inhibit nonshivering thermogenesis. The inhibi-
approximately 2.0.45 The fetus can use ketones as lipo- tion of nonshivering thermogenesis is believed to be ben-
genic substrates or as energy substrates in the brain, eficial to the health of the fetus, in that it allows for
kidney, heart, liver, and placenta.46 Beta-hydroxybutyrate conservation of fetal oxygenation and accumulation of
(fatty acid) metabolism can occur in the placenta, brain, brown adipose tissue.50
and liver during episodes of fetal hypoglycemia that
result from maternal fasting.46 Cholesterol synthesis
or free cholesterol diffusion does not appear to occur in FETAL CARDIOVASCULAR SYSTEM
the placenta.47 However, there is a significant correla
tion between maternal and fetal concentrations of The cardiovascular system is one of the first functional
lipoprotein(a), implying that diffusion of lipoprotein(a) organ systems in the developing fetus. The morphologic
may occur.47 development of the human heart, from its first appearance
as a heart tube to its development as a four-chambered
structure, occurs between 20 and 44 days’ gestation. Even
Thermoregulation before the development of the four-chambered heart, the
Intrauterine fetal temperature largely depends on mater- valveless heart tube generates unidirectional flow, typi-
nal temperature. However, owing to the high metabolic cally around 21 days’ gestation.
rate in the fetus, the net flow of heat is from the fetus to
the mother. When compared with the mother during the
third trimester, the fetus produces approximately twice as
Circulatory Pattern
much heat (on a weight-adjusted basis) and maintains a Fetal circulation differs significantly from the postnatal
temperature 0.5° C higher.48,49 This maternal-fetal differ- circulation. The fetal cardiovascular system is anatomi-
ence in temperature remains relatively constant and is cally arranged in such a way as to allow blood to bypass
referred to as the “heat clamp.”50 the lungs and provide maximal perfusion of the placenta,
The placental circulation is responsible for approxi- where gas and nutrient exchange occur. The fetal systemic
mately 85% of the heat exchange between the mother and circulation receives cardiac output from both the left and
fetus. The remaining 15% is dissipated through the fetal the right ventricle, with the ventricles working in parallel.
skin and transferred through the amniotic fluid and the In contrast, during postnatal life, the left and right circu-
uterine wall to the maternal abdomen.51 As a consequence, lations are separated and the ventricles work in series.
fetal temperature may be rapidly affected by changes in Fetal blood flow is characterized by three anatomic
umbilical blood flow; fetal temperatures rise quickly on communications between the left and right circulations:
occlusion of umbilical blood flow in both baboons and the ductus venosus, the foramen ovale, and the ductus
sheep.52,53 In humans, fetal temperatures increase during arteriosus (Figure 5-4). Oxygenated blood travels from
uterine contractions, which may be a result of intermit- the placenta through the umbilical vein to the ductus
tent obstruction of umbilical cord blood flow.54 Whether venosus, which connects the umbilical vein with the
this rise in fetal temperature contributes to acute hypoxic- inferior vena cava, thus bypassing the portal circulation
ischemic brain damage in the setting of umbilical cord and the liver. At mid gestation, approximately 30% of the
5 Fetal Physiology 79
10
Blood Volume
Human fetal intravascular volume is approximately
110 mL/kg, which is higher than that in postnatal life.
FIGURE 5-4 ■ Oxygenated blood leaves the placenta via the fetal
umbilical vein (1), enters the liver where flow divides between However, approximately 25% of this blood volume is
the portal sinus and the ductus venosus, and then empties into contained within the placenta; the blood volume within
the inferior vena cava (2). Inside the fetal heart, blood enters the the fetal body is estimated to be approximately 80 mL/
right atrium, where most of the blood is directed through the kg.61,62 Fetal intravascular volume is regulated through
foramen ovale (3) into the left atrium and ventricle (4), and then
enters the aorta. Blood is then sent to the brain (5) and myocar-
a complex interplay between the fetal heart, kidneys,
dium, ensuring that these cells receive the highest oxygen and circulation and the placenta.63 The fetus can adapt
content available. Deoxygenated blood returning from the more quickly to changes in intravascular volume than
lower extremities and the superior vena cava (6) is preferentially the adult, owing to higher diffusion rates between fetal
directed into the right ventricle (7) and pulmonary trunk. The compartments.64
majority of blood passes through the ductus arteriosus (8) into
the descending aorta (9), which in turn supplies the lower Transplacental transfer of water from mother to fetus
extremities (10) and the hypogastric arteries (11). Blood returns depends on hydrostatic and osmotic pressures. The
to the placenta via the umbilical arteries for gas and nutrient hydrostatic pressure is determined by the difference in
exchange. A small amount of blood from the pulmonary trunk pressures between the maternal intervillous space or cap-
travels through the pulmonary arteries (12) to perfuse the lungs.
Arrows in this figure depict the direction and oxygen content
illaries and the fetal capillaries. The osmotic pressure is
[white (oxygenated), blue (deoxygenated)] of the blood in cir- mainly determined by the presence of plasma proteins
culation. (Drawing by Naveen Nathan, MD, Northwestern Univer- (i.e., colloid osmotic pressure). Transplacental water
sity Feinberg School of Medicine, Chicago, IL.) transfer is further regulated by angiotensin II. Adamson
et al.65,66 found that angiotensin II lowered the pressures
in fetal placental exchange vessels, thereby promoting
umbilical venous blood is shunted through the ductus fluid transfer from the maternal to the fetal circulation.
venosus; from 30 to 40 weeks’ gestation, this fraction The production of angiotensin II is under control of the
decreases to approximately 20%, although a significant renin-angiotensin-aldosterone system in the fetal kidneys.
increase can occur in response to hypoxia (see later dis- A reduction in fetal arterial pressure results in an increase
cussion).60 Once in the right atrium, oxygenated blood in fetal plasma renin activity, which results in subsequent
preferentially flows through the foramen ovale to the increases in angiotensin I and II. The resulting expansion
left atrium and left ventricle, before entering the aorta of intravascular volume augments fetal cardiac output
and the systemic circulation. This mechanism ensures the and arterial pressure.
delivery of well-oxygenated blood to the brain and the
heart, which are the two organs with the highest oxygen
requirements. The preferential shunting of ductus
Cardiac Development
venosus blood through the foramen ovale into the left During gestation the fetal heart grows quickly and adapts
atrium is related to the umbilical venous pressure and the to the continuously changing demands. The fetal myo-
portocaval pressure gradient. cardium grows primarily through cell division, whereas
80 PART II Maternal and Fetal Physiology
after delivery, cardiac mass increases as a result of cell Cardiac Output and Distribution
enlargement.67 This growth correlates with a pre-birth
transition from mononucleated cardiomyocytes, which In postnatal life, the right and left ventricles operate in
contribute to heart growth by hyperplasia, to binucleated series and their output is approximately equal; as a con-
cardiomyocytes, which contribute to heart growth by sequence, cardiac output is defined through measure-
hypertrophy. ments of output from either ventricle. However, in the
The number of cardiac myofibrils and the transition fetus, the systemic circulation receives blood from both
in the type of cardiac troponins that are present during the left and right ventricle in parallel (i.e., the sum of the
prenatal development can alter fetal heart contractility.68 right and left ventricular outputs, with the exception of
The change from fetal to adult troponin is associated a proportion of the right ventricular output that is deliv-
with decreased sensitivity of the contractile apparatus to ered to the fetal lungs). At mid gestation, the combined
calcium. A heightened calcium sensitivity is important ventricular output (CVO) is approximately 210 mL, and
in the early development of the fetal heart, when the it increases to approximately 1900 mL at 38 weeks’ gesta-
sarcoplasmic reticulum is immature.69 With advancing tion (500 mL/min/kg).73,78,79 During fetal life, the right
gestational age, ejection fraction declines but cardiac ventricular volume is greater than the left ventricular
output (per unit of fetal weight) does not change owing volume during both systole and diastole, but stroke
to increasing ventricular volume. The fetal heart rate volume does not differ significantly between the two
decreases over the course of gestation from 140 to 150 ventricles.70
beats per minute at 18 weeks’ gestation to 120 to 140 Fetal cardiac output is sensitive to changes in fetal
beats per minute at term.70,71 heart rate. As heart rate increases, cardiac output
increases. As fetal heart rate decreases, fetal stroke volume
increases only slightly, in part because of low fetal myo-
Ventricular Responses to Changes
cardial compliance. Although fetal bradycardia results in
in Preload and Afterload
an extended diastolic filling time, the stiff fetal cardiac
It is unclear whether fetal and adult hearts possess similar ventricles have limited ability to distend. Therefore, fetal
responses to preload and afterload. The adult heart bradycardia is associated with a marked drop in fetal
responds in accordance to the Frank-Starling curve, cardiac output.
which indicates that ventricular distention lengthens the The distribution of the CVO in near-term fetal lambs
diastolic fibers and results in augmented contractility. A and resting adult humans is shown in Figure 5-5. The
number of studies have indicated that the fetal heart has fetal lamb CVO is distributed to the placenta (41%),
a limited capacity to increase its stroke volume in response the bone and skeletal muscle (38%), the gastrointestinal
to an increase in preload (e.g., intravenous fluid infu- system (6%), the heart (4%), the brain (3%), and
sion).72,73 By contrast, other studies have observed that the kidneys (2%). In both fetal and adult animals,
the fetal heart can accommodate increases in preload and approximately equal volumes of blood are delivered to
afterload in a manner consistent with the Frank-Starling
curve.74,75 These seemingly contradictory findings may be
partially explained if the fetal heart functions in vivo near
the peak of the Frank-Starling curve. However, the left
ventricular stroke volume is known to double at birth,
which would not be in agreement with this hypothesis. A
more plausible explanation is that ventricular constraint, 700
arising from tissues that surround the heart (chest wall,
Organ Blood Flow (mL/min/100 g)
600
pericardium, and lungs), limits fetal ventricular preload
and overall cardiac function in utero. Relief of this con- 500
straint at birth, as a result of lung aeration and clearance
of liquid from the lungs, may then allow for an increase 400
in left ventricular preload and subsequent stroke volume
in the newborn.76 300
Studies investigating the effects of afterload on fetal
200
ventricular function have observed a significant decrease
in right ventricular stroke volume in response to 100
increases in arterial pressure.72 The same phenomenon
occurs in the left ventricle, although to a lesser degree. 0
In a study of fetal lambs, in which gradual constriction Brain Heart Lungs Gut Adrenals Kidneys
of the descending aorta was applied, stroke volume was Before reduction of uterine blood flow
maintained until high mean arterial pressures were Reduction of uterine blood flow to 50% of normal
achieved, after which decreases were observed. This
decrease in stroke volume in the presence of high mean
arterial pressure may represent the exhaustion of FIGURE 5-5 ■ Redistribution of combined ventricular output in
fetal lambs during hypoxemia caused by reduced uterine blood
“preload reserve,” which will typically allow the mainte- flow. (Modified from Jensen A, Roman C, Rudolph AM. Effects of
nance of stroke volume in the setting of increased reducing uterine blood flow on fetal blood flow distribution and
afterload.77 oxygen delivery. J Dev Physiol 1991; 15: 309-23.)
5 Fetal Physiology 81
oxygen-uptake organs (i.e., the placenta before delivery, carotid chemoreceptors. Dawes et al.86 concluded that the
the lungs after delivery) and the oxygen-consuming carotid chemoreceptors are important for postnatal respi-
organs. ratory control, whereas the aortic chemoreceptors are
The distribution of the CVO changes over the course more involved in the control of cardiovascular responses
of gestation and in certain conditions, such as hypoxia and the regulation of oxygen delivery. Central chemore-
and hypovolemia. Interpretation of CVO data should be ceptors, located in the medullar oblongata, appear to play
evaluated with the understanding that significant inter- little if any role in fetal circulatory responses.
species differences exist. For example, in humans the fetal The neural control of the fetal circulation is far more
lungs receive approximately 20% of CVO, whereas in the dependent on chemoreceptor-mediated responses than
fetal lamb the lungs receive 10% or less of CVO. In neural control of the adult circulation.87 Acute fetal
human fetuses at 10 to 20 weeks’ gestation, the brain hypotension often stimulates a reflex response, which
receives approximately 15% of CVO,80 but this fraction can include both bradycardia and vasoconstriction. Vaso-
may be increased during circumstances of decreased pla- constriction is dependent on increases in both sympa-
cental perfusion, acidosis, and increased Pco2. In the thetic autonomic activity and the rate of secretion of
rhesus monkey, the fraction of CVO devoted to cerebral several vasoactive hormones, including arginine vaso-
blood flow was observed to increase from 16% to 31% pressin, renin, angiotensin, and aldosterone. Fetal brady-
during a hypoxic challenge.81 cardia is most likely caused by activation of peripheral
chemoreceptors.87
Fetal Blood Pressure
Autonomic Nervous System
Fetal blood pressure increases with gestational age. Intra-
cardiac (intraventricular) pressure recordings in the The autonomic nervous system is present early in gesta-
human fetus suggest that systolic pressure increases from tion and plays a critical role in maintaining cardiovascular
15 to 20 mm Hg at 16 weeks’ gestation to 30 to homeostasis. In the fetal chick heart, evidence of cholin-
40 mm Hg at 28 weeks’ gestation.67 Substantial variation ergic innervation occurs as early as 3 days after fertiliza-
in blood pressure may be observed. The diastolic ven- tion (average incubation, 22 days). In the mammalian
tricular pressures undergo similar, albeit slower and heart, inotropic and chronotropic responses to adrener-
smaller increases, from 5 mm Hg or less at 16 to 18 gic agents have been measured as early as 4 to 5 weeks’
weeks’ gestation to 5 to 15 mm Hg at 19 to 26 weeks’ gestation,88 and the fetal myocardial pacemaker can be
gestation.67 inhibited at this time by the cholinergic agonists carba-
mylcholine and acetylcholine.89
In comparing the parasympathetic cholinergic and
Regulation of Fetal Circulation
sympathetic adrenergic nervous systems during gesta-
Fetal cardiovascular function continuously adapts to tion, the majority of studies indicate that the parasympa-
varying metabolic and environmental conditions through thetic system appears earlier (8 weeks’ gestation versus 9
regulation by the neurologic and endocrine systems. The to 10 weeks’ gestation),88,90,91 becomes more dominant as
predominant form of neuroregulation occurs in response pregnancy progresses, and is more functionally complete
to baroreceptor and chemoreceptor afferent input to at birth (Figure 5-6). As a result, the baseline fetal heart
the autonomic nervous system and through modulation rate is slower at term than at 26 weeks’ gestation. The
of myocardial adrenergic receptor activity. Thus, the administration of atropine can result in fetal tachycardia
autonomic nervous system functions to reversibly redi- by 15 to 17 weeks’ gestation, which occurs before fetal
rect blood flow and oxygen delivery as required. bradycardia can be demonstrated with the administration
Arterial baroreceptor function has been demonstrated of a beta-adrenergic receptor antagonist.88
in several different fetal animal models. The predomi- Both parasympathetic and sympathetic systems
nant baroreceptors are located within the vessel walls of undergo significant maturation during postnatal life, and
the aortic arch and at the bifurcation of the common full maturation of the vagal response is not observed until
carotid arteries. These receptors project signals to the 1 to 2 months after delivery.92-94 Similarly, although the
vasomotor center in the medulla, from which autonomic contractile response of the fetal vasculature is less func-
responses emanate. The baroreceptors are functional tional than the adult response, the fetal administration of
early in fetal development and undergo continuous adap- an alpha-adrenergic agonist can result in the redistribu-
tation to the increases in blood pressure observed over tion of blood flow away from the kidneys, skin, and
time.82 A sudden increase in fetal mean arterial pressure— splanchnic organs and toward the heart, brain, placenta,
as occurs with partial or complete occlusion of the umbil- and adrenal glands.95 At birth, the autonomic nervous
ical arteries—results in cholinergic stimulation and system can mediate a number of hemodynamic adjust-
subsequent fetal bradycardia. ments, including changes in heart rate and peripheral vas-
Peripheral chemoreceptors are present within the cular resistance, as well as a redistribution of blood flow.88
vessel walls of the aortic arch and at the bifurcation of the
common carotid arteries. In some animal species, periph-
eral chemoreceptors are transiently present in the adrenal FETAL PULMONARY SYSTEM
gland but disappear after birth.83 The fetal aortic chemo-
receptors are responsive to even small changes in arterial The lungs begin as small, saccular outgrowths of the
oxygenation,84,85 which contrasts to the less active fetal ventral wall foregut. Although sacculi with type I and II
82 PART II Maternal and Fetal Physiology
Vagal tone
140 140
15 20 25 30 35 40
Weeks of pregnancy
FIGURE 5-6 ■ The growing influence of the parasympathetic nervous system on fetal heart rate as gestation progresses. This para-
sympathetic activity is reversible with administration of atropine. (From Schifferli P, Caldeyro-Barcia R. Effects of atropine and beta-
adrenergic drugs on the heart rate of the human fetus. In Boréus LO, editor. Fetal Pharmacology. New York, Raven Press, 1973:264.)
pneumocytes and ventilatory capacity are present during by an abrupt surge in pulmonary blood flow, and the
the last trimester, true alveoli develop at approximately creation of alveolar surface tension are other mechanical
36 weeks’ gestation. The majority of alveolar develop- factors that can decrease pulmonary vascular resistance.104
ment occurs postnatally, within the first 6 to 18 months Finally, the relative predominance of vasodilators (e.g.,
of life, when further maturation of the microvasculature endothelium-derived nitric oxide, prostacyclin) versus
and the air-blood barrier occurs.96 vasoconstrictors (e.g., platelet activating factor) at
The pulmonary vasculature develops early in gesta- birth may also significantly decrease pulmonary vascular
tion, with continuous circulation being documented at 34 resistance.105-109
days’ gestation.97,98 The size and number of pulmonary The pulmonary surfactant system is one of the last
arteries and veins increases over time; however, vessel systems to develop before birth.110 Surfactant is a lipo-
reactivity to local and hormonal influences is not detect- protein complex (phospholipoprotein) that reduces and
able until after 20 weeks’ gestation.99,100 From 20 to 30 regulates the surface tension at the air-liquid interface
weeks’ gestation, an increase in the size of the pulmonary to prevent alveolar collapse and reduces the work associ-
vascular bed combined with a decrease in the pulmonary ated with breathing.111 Pulmonary surfactant is com-
vascular resistance results in an increase in pulmonary posed predominantly (> 90%) of lipids (i.e., phospholipids
blood flow (i.e., from 10% to 15% of the CVO to 25% and neutral lipids [primarily cholesterol]), with the
of the CVO). During this time, alterations in maternal remaining fraction being proteins.112,113 Surfactant assem-
oxygenation have no effect on the fetal pulmonary vas bly occurs in the endoplasmic reticulum and the Golgi
culature.80,99 However, after 30 weeks’ gestation, blood apparatus of the type II alveolar cells, and it is stored in
flow to the lung decreases slightly owing to a significant the lamellar bodies. The primary stimuli for surfactant
increase in pulmonary vascular resistance, diminishing secretion (i.e., exocytosis from the lamellar bodies) are
the fraction of CVO to approximately 20%. Contempo- signals from the autonomic nervous system (β2-adrenergic
raneously, the vasomotor tone and reactivity of the fetal receptor mediated) and mechanical factors (e.g., stretch-
circulation begins to respond to maternal hyperoxygen- ing of the basement membrane of alveolar type II
ation with a decrease in pulmonary vascular resistance cells with ventilation).114 Dipalmitoylphosphatidylcho-
and an increase in pulmonary blood flow.80,99 A study line, an important component of surfactant, is present
in near-term fetal lambs observed a 10-fold increase in in amniotic fluid and can be found in alveolar lavage
pulmonary blood flow when fetal oxygen tension was samples from human fetuses between 24 and 28 weeks’
increased from 24 to 46 mm Hg101; this finding empha- gestation.
sizes the importance of ventilation and oxygenation in The amount and composition of surfactant changes
the newborn to assist in the transition to postnatal over the course of gestation. For example, the ratio of
circulation. phosphatidylglycerol to phosphatidylinositol, as well as
The reduction in pulmonary vascular resistance at the ratio of lecithin to sphingomyelin, increases with
birth is also attributed to a number of mechanical and gestation and may be used as markers of fetal lung
molecular processes. In utero, the fetal lungs are filled maturity.115-117 Fetal surfactant production can be acceler-
with fluid to maintain an appropriate level of expansion ated by a number of factors, including glucocorticoids,
for normal pulmonary development.102 The expulsion of thyroid hormones, and autonomic neurotransmitters.
lung liquid, particularly with a vaginal birth, likely The maternal administration of glucocorticoids such as
decreases extraluminal pressure on the pulmonary vascu- betamethasone or dexamethasone has been associated
lature and leads to a decrease in pulmonary vascular with a 35% to 40% reduction in respiratory distress syn-
resistance.103 Breathing movements, shear stress created drome in preterm infants.118
5 Fetal Physiology 83
100
FETAL HEMATOLOGIC SYSTEM
90
Red blood cells, platelets, neutrophils, monocytes, and
80
macrophages are all derived from a common progenitor
cell.131 In the developing embryo, hematopoiesis occurs 70
at several anatomic sites in multiple waves. The first wave
HbO2 saturation (%)
2,3-DPG concentrations, fetal blood exhibits a lower reported in human neonates with congenital esophageal
oxygen tension at which hemoglobin is 50% saturated atresia.153
(P50). Hemoglobin F levels begin to decrease toward the
end of pregnancy, resulting in a corresponding increase
in the P50. At term, hemoglobin A accounts for approxi-
Meconium
mately 25% of total hemoglobin and the P50 is approxi- Meconium, which consists of water, intestinal secretions,
mately 19 mm Hg.142,143 squamous cells, lanugo hair, bile pigments, and blood,
Hemoglobin A levels begin to increase and 2,3-DPG first appears in the fetal intestine between 10 and 12
concentrations transiently increase above usual fetal and weeks’ gestation.154 By 16 weeks’ gestation, meconium
adult levels during the first few months of life. During moves into the colon.155 Between 14 and 22 weeks’ gesta-
this time, the affinity of neonatal blood for oxygen is tion, fetal colonic contents, as indicated by the presence
equivalent to that of the adult despite the persistence of of high levels of intestinal enzymes (disaccharidases, alka-
25% fetal hemoglobin.137,142,143 line phosphatase), appear in the amniotic fluid.156 After
22 weeks’ gestation, a subsequent decline in the concen-
tration of these gastrointestinal enzymes within the
FETAL GASTROINTESTINAL SYSTEM amniotic fluid is observed, which coincides with the
development of anal sphincter tone.156,157
The gastrointestinal tract develops from the primitive Meconium is continually cleared by fetal swallowing,
digestive tube, which includes the foregut, midgut, and leading to relatively clear amniotic fluid in the majority
hindgut. The foregut receives its vascular supply from the of pregnancies. The presence of meconium-stained
celiac axis and gives origin to the oral cavity, pharynx, amniotic fluid may therefore represent either decreased
esophagus, stomach, and upper duodenum. The midgut, meconium clearance or increased meconium passage,
which receives its vascular supply from the superior mes- which is observed in the presence of fetomaternal stress
enteric artery, develops into the distal duodenum, factors such as hypoxia and infection, independent of
jejunum, ileum, cecum, appendix, and transverse colon. fetal maturation.154 Meconium-stained amniotic fluid
The hindgut receives its vascular supply from the inferior occurs more frequently with advanced gestational age
mesenteric artery, and it differentiates into the descend- and is common in post-term pregnancies.158
ing colon, the sigmoid colon, and the upper two thirds Although many fetuses with meconium-stained amni-
of the rectum.144 Intestinal villi appear by 7 weeks’ gesta- otic fluid are born without adverse sequelae, meconium
tion, and active absorption of glucose and amino acids can have detrimental effects on fetal organs and the pla-
occurs by 10 and 12 weeks’ gestation, respectively.145 centa. Meconium may cause umbilical cord vessel con-
Peristaltic waves and gastrointestinal motility are initi- striction, vessel necrosis, and the production of thrombi,
ated by 8 weeks’ gestation. Teniae, the three longitudinal which can lead to altered coagulation, cerebral palsy, and
ribbons of smooth muscle on the outside of the colon, neonatal seizures.159 In addition, meconium may reduce
appear by 12 weeks’ gestation and contract to produce the antibacterial properties of amniotic fluid by altering
the haustra (bulges) in the colon.146 In the small intestine, zinc levels.154 Fetal aspiration of meconium also may neu-
Auerbach’s and Meissner’s plexuses of parasympathetic tralize the action of surfactant, promote lung tissue
nerves provide motor and secretomotor innervation, inflammation through the activation of neutrophils, and
respectively; the two plexuses are present as early as 8 possibly result in meconium aspiration syndrome (see
weeks’ gestation.145 Aggregations of lymphoid nodules Chapter 9). Finally, in the presence of perinatal hypoxia,
(i.e., Peyer patches) develop by 20 weeks’ gestation in the meconium also may contribute to vascular hypertrophy
ileum.147 and possible pulmonary hypertension.154
30
10
1 2 3 4 5 6
O2 content (mM)
FIGURE 5-8 ■ The redistribution of cardiac output to the heart and central nervous system during hypoxemia in fetal lambs. Each
symbol represents a measurement from an individual fetal lamb. (Modified from Sheldon RE, Peeters LLH, Jones MD Jr, et al. Redis-
tribution of cardiac output and oxygen delivery in the hypoxic fetal lamb. Am J Obstet Gynecol 1979; 135:1071-8.)
nerve fibers. Although optimal pain processing requires After birth, neonates appear to be more sensitive to
myelination of pain pathways, cortical maturation, den- pain, with lower pain thresholds, poor discriminative
dritic arborization, and thalamocortical fiber synapto- abilities, and a greater tendency to exhibit central sensi-
genesis, it is unclear when nociception, the capacity to tization in response to later noxious stimuli than adults.
feel pain, develops within the fetus. As early as 18 weeks’ Early sensory experiences in the neonate can influence
gestation, human fetuses demonstrate pituitary-adrenal, the development of nociceptive pathways.191 Neonates
sympathoadrenal, and circulatory stress responses to and especially preterm infants who undergo numerous
noxious stimuli.180-182 In studies of intrauterine blood procedures in the neonatal intensive care unit and/or
transfusion in the human fetus, surgical needling of the surgery have been observed to demonstrate altered pain
intrahepatic vein (compared with needling of the insen- perceptions later in life.192 In the rodent model, tissue
sate umbilical cord) is associated with evidence of a injury in early neonatal life results in an increased mag-
stress response, including increases in plasma beta- nitude and duration of hyperalgesia after reinjury in later
endorphin and cortisol levels and a diminution in the life, compared with those with no early life pain experi-
middle cerebral artery pulsatility index.183 Administra- ence.191 Collectively, these observations have prompted
tion of fentanyl 10 µg/kg blunts this stress response to some investigators to conclude that noxious events in
intrahepatic needling.184 neonates, when pain pathways are still undergoing a
Near-infrared spectroscopy has demonstrated cortical learning or “tuning process,” may result in structural
activity in response to noxious stimuli in preterm neo- functional and behavioral alterations in adult pain pro-
nates born and studied as early as 25 weeks’ postmen- cessing. Some of these long-term consequences may be
strual age.185,186 Similarly, facial responses to painful attenuated by preemptive analgesia.193
stimuli (similar to those seen in adults) can be provoked The foregoing neuroanatomic and neurochemical evi-
in preterm neonates born and assessed as early as 25 dence, in addition to the well-characterized behavioral
weeks’ gestation, which suggests the development of and physiologic responses to pain, indicate that both the
functional pathways from the spinal cord to the brain.187,188 fetus and newborn infant have nociceptive pathways
However, the withdrawal from noxious stimuli or an capable of communicating nociceptive stimuli from the
increased release of stress hormones does not necessarily periphery to the cerebral cortex and regulating the
reflect an awareness of pain, because local spinal reflexes response via efferent inhibitory pathways. Current evi-
and hormonal release can occur without cortical involve- dence suggests that fetal nociception at the level of the
ment.189 The experience of pain is a conscious subjective cortex occurs after the midpoint of pregnancy (i.e.,
experience with emotional and affective components that between 24 and 30 weeks’ gestation). Of note, maternal
requires higher-level cortical processing. Nociceptive administration of general anesthesia does not guarantee
processing begins in the peripheral neurons, which relay the presence of fetal anesthesia or analgesia (see Chapter
signals through the spinothalamic tract, the thalamus, 7). For example, most infants are clearly awake and cry
and ultimately the cerebral cortex, where conscious per- loudly immediately after cesarean delivery during mater-
ception of pain occurs.190 nal administration of general anesthesia.
5 Fetal Physiology 87
KEY POINTS
• Amniotic fluid serves a number of vital roles, • The sympathetic nervous system at birth is not as
including the facilitation of fetal growth, the well developed as the parasympathetic nervous
provision of a microgravity environment that system; however, it plays an important role in the
cushions the fetus, and the generation of a hemodynamic adjustments at birth.
defense mechanism against invading microbes. • Although fetal fluid and electrolyte balance, as well
• The fetus depends on the mother and the placenta as acid-base homeostasis, are primarily regulated
for its basic metabolic needs, such as nutrient and maintained by the placenta, the fetal kidneys
delivery, gas exchange, and electrolyte and acid- play an important role in fetal development through
base homeostasis. amniotic fluid production.
• Fetal arterial blood Po2 ranges from 20 to • The pulmonary surfactant system is one of the last
30 mm Hg, and fetal development exists in a state systems to develop before birth. Surfactant
of relative hypoxia compared with adult oxygen assembly occurs in the type II alveolar cells,
tension. and components of surfactant are first
• Despite a lower fetal oxygen tension, the fetal detected between 24 and 28 weeks’ gestation.
arterial blood oxygen content is not much lower • Fetal hemoglobin has a greater oxygen affinity than
than that of the adult. This results from a higher adult hemoglobin, owing to a decreased interaction
oxygen-carrying capacity (hemoglobin concentration between hemoglobin F and 2,3-DPG. The P50
of 18 g/dL) and a higher affinity of hemoglobin F of fetal blood is significantly lower than that of
for oxygen, when compared with hemoglobin A. adult blood.
• The fetus produces approximately twice as much • Fetal hypoxemia leads to a significant redistribution
heat (on a weight-adjusted basis) and maintains a of cardiac output to the heart and the brain. This
temperature 0.5° C higher than the mother during results in both a global increase in cerebral blood
the third trimester. flow and a redistribution of blood flow within the
• The fetal circulation receives output from both fetal brain.
the left and the right ventricle, with the ventricles • Fetal swallowing plays an important role in
working in parallel. Systemic blood flow consists amniotic fluid homeostasis, and the swallowed
of the sum of the right and left ventricular outputs, fluid appears to provide nutritional support
with the exception of the small amount of blood for mucosal development within the
delivered to the fetal lungs by the right ventricle. gastrointestinal tract.
• Fetal blood flow is characterized by three important • The fetus has nociceptive pathways capable
communications between the left and right of communicating painful stimuli from the
circulation: the ductus venosus, the foramen ovale, periphery to the cerebral cortex. Current evidence
and the ductus arteriosus. suggests that fetal nociception at the level
• Acute hypotension in the fetus stimulates a reflex of the cortex occurs after the midpoint of
response, which includes both bradycardia and pregnancy (i.e., between 24 and 30 weeks’
vasoconstriction. gestation).
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PA RT I I I
Ostensibly, concern for the neonate began in 1861, when Ironically, one of Barcroft’s own students proved him
London physician W. J. Little published a paper entitled wrong. D. H. Barron, professor of physiology at Yale,
“On the influence of abnormal parturition, difficult suggested that Barcroft’s data had been skewed by the
labors, premature birth, and asphyxia neonatorum, on the conditions of his experiments, all of which had been con-
mental and physical condition of the child, especially in ducted on animals anesthetized for immediate surgery.
relation to deformities.”1 Hailed as “an original field Barron and his colleagues developed methods to sample
of observation,” Little’s paper was among the first to fetal blood in awake, unstressed animals. Under these
identify antepartum asphyxia as the cause of problems in circumstances, they observed no deterioration in the
the neonate. fetal environment until the onset of labor. Oxygen satura-
Almost half a century passed, however, before clini- tion, hemoglobin concentration, and pH remained stable
cians developed a sustained interest in fetal oxygenation. and normal.3
This development came through the influence of Sir Barcroft’s data have had the greatest impact on clinical
Joseph Barcroft and his book Researches on Prenatal Life.2 practice. Virtually all current methods of fetal monitoring
A professor of physiology at Cambridge University, grew out of the belief that oxygen availability is the single
Barcroft was already highly respected for his studies of most important factor influencing the well-being of the
respiration when this book was published. newborn. However, Barron’s studies affected physiolo-
From his laboratory studies, Barcroft discovered a gists, who began to study the mechanisms that main-
progressive decrease in fetal oxygen saturation during tained the stability of the intrauterine environment in the
the last half of pregnancy. He attributed this finding to presence of increasing fetal demands.
the fetal demands for oxygen, which slowly increased REFERENCES
until the capacity of the placenta was exhausted. Barcroft 1. Little WJ. On the influence of abnormal parturition, difficult
compared the fetus to a mountaineer climbing Mt. labours, premature birth and asphyxia neonatorum, on the mental
Everest, in that the oxygen environment of the fetus and physical condition of the child, especially in relation to deformi-
became progressively less dense. He suggested that the ties. Trans Obstet Soc Lond 1862; 3:293-344.
term fetus faced either asphyxia in utero or escape 2. Barcroft J. Researches on Prenatal Life, Vol. I. Springfield, IL:
Charles C Thomas, 1947.
through the initiation of labor. Barcroft’s depiction of 3. Barron DH. The environment in which the fetus lives: lessons
the fetal environment disturbed clinicians who were learned since Barcroft in prenatal life. In Mack H, editor. Prenatal
already well aware of the additional stress imposed Life: Biological and Clinical Perspectives. Detroit: Wayne State
by labor. University Press, 1970:109-28.
C H A P T E R 6
CHAPTER OUTLINE
Obstetric care providers have two patients, the mother Term, defined as the period from 37 weeks’ (259 days’) to
and the fetus. Although assessment of maternal health is 42 weeks’ (294 days’) gestation, is the optimal time for
relatively straightforward, assessment of fetal well-being delivery. Both preterm births (defined as delivery before
is far more challenging. Several tests have been developed 37 weeks’ gestation) and post-term births (delivery after
to assess the fetus during pregnancy, including some that 42 weeks’ gestation) are associated with increased peri-
are recommended for all pregnancies (e.g., ultrasonogra- natal and neonatal morbidity and mortality. Evaluation
phy for pregnancy dating) and others that are reserved of fetal growth, efficient use of screening and diagnostic
only for women with pregnancy complications (e.g., tests, appropriate initiation of fetal surveillance, and
middle cerebral artery Doppler velocimetry in pregnan- optimal timing of delivery all depend on accurate dating
cies with isoimmunization). In addition, a limited number of the pregnancy.
of fetal interventions are employed to improve fetal A number of clinical, biochemical, and radiologic tests
outcome, including some that are used frequently, such are available to determine gestational age (Box 6-1).1,2
as maternal corticosteroid administration, and others that Determination of gestational age is most accurate in early
are used much more rarely, such as intrauterine fetal pregnancy, and the estimated date of delivery (EDD)
procedures. A review is presented here of the tests avail- should be established at the first prenatal visit. Embryo
able to assess fetal well-being in both low- and high-risk transfer dating in women undergoing in vitro fertilization
pregnancies and of the fetal therapies used during the (IVF) is the most accurate clinical dating criterion.
antepartum period. Among women with regular menstrual cycles who con-
ceive spontaneously, if the first day of the last menstrual
period (LMP) is known and if uterine size is consistent
PRENATAL CARE IN LOW-RISK with dates by clinical examination, then Naegele’s rule
(subtract 3 months and add 7 days to the LMP) can be
PREGNANCIES used to determine the EDD. Menstrual dating is known
Determination of Gestational Age to be inaccurate in women taking oral contraceptives,
in women who conceive in the immediate postpartum
The mean duration of a singleton pregnancy is 280 days period, and in women who have irregular menstrual
(40 weeks) from the first day of the last normal menstrual cycles or a history of intermenstrual bleeding. Moreover,
period in women with regular 28-day menstrual cycles. clinical examination of uterine size can be inaccurate in
95
96 PART III Fetal and Neonatal Assessment and Therapy
Clinical Criteria Commonly Used With the use of transvaginal ultrasonography, an intra-
BOX 6-1 uterine pregnancy can typically be confirmed at a serum
to Confirm Gestational Age
hCG level of 1500 to 2000 mIU/mL.11 Failure to confirm
• Reported date of last menstrual period (estimated due an intrauterine sac at these hCG levels should raise con-
date can be calculated by subtracting 3 months and cerns about an abnormal pregnancy (e.g., ectopic preg-
adding 7 days to the first day of the last normal men- nancy, missed abortion) and requires further evaluation.
strual period [Naegele’s rule]) or date of assisted repro- A fetal pole and cardiac activity should be visible at a
ductive technology (intrauterine insemination or
serum hCG concentration of approximately 1700 mIU/
embryo transfer)
• The size of the uterus as estimated on bimanual exami- mL (5 to 6 weeks) and 5400 mIU/mL (6 to 8 weeks),
nation in the first trimester, which should be consistent respectively. The EDD derived from ultrasonographic
with dates evaluation should be used when there is a 5- to 7-day
• The perception of fetal movement (“quickening”), discrepancy from LMP dating in the first trimester.11
which usually occurs at 18 to 20 weeks in nulliparous In the first trimester, the fetal crown-rump length
women and at 16 to 18 weeks in parous women (CRL) is the most accurate determinant of gestational
• Fetal heart activity, which can be detected with a non- age (± 3 to 5 days). In the second trimester, the biparietal
electronic fetal stethoscope by 18 to 20 weeks and with diameter (BPD) and length of the long bones (especially
Doppler ultrasonography by 10 to 12 weeks femur length) are the ultrasonographic measurements
• Fundal height; at 20 weeks, the fundal height in a
used most often to determine gestational age. Of these,
singleton pregnancy should be approximately 20 cm
above the pubic symphysis (usually corresponding to the BPD is the more accurate indicator with a variation
the umbilicus) of ± 7 to 10 days.12 Two large clinical studies of approxi-
• Ultrasonography, involving crown-rump length mea- mately 50,000 pregnancies demonstrated that a second-
surement of the fetus during the first trimester, or fetal trimester BPD measurement, when used instead of
biometry (biparietal diameter, head circumference, menstrual dating to establish the EDD, resulted in a
and/or femur length) during the second trimester significant increase in the number of women who deliv-
ered within 7 days of their due dates and a 60% to 70%
Data from American College of Obstetricians and Gynecologists. reduction in the number of pregnancies continuing post
Antepartum fetal surveillance. ACOG Practice Bulletin No. 9.
Washington, DC, 1999 (reaffirmed 2009); and American College of term.13,14 After 26 weeks’ gestation, the variation in the
Obstetricians and Gynecologists. Management of postterm pregnancy. BPD measurement is greater (± 14 to 21 days), thereby
ACOG Practice Bulletin No. 55. Washington, DC, 2004 (reaffirmed making it less valuable in estimating gestational age.12
2009). Both femur length and humerus length correlate strongly
with the BPD and gestational age and are sometimes
used for additional confirmation.15 By contrast, because
women with a high body mass index (BMI), uterine abdominal circumference (AC) reflects fetal nutritional
fibroids, or a multifetal pregnancy. For these reasons, status and growth, it is less accurate than either BPD
reliance on standard clinical criteria alone to determine or femur length. All fetal biometric measurements are
the EDD will lead to an inaccurate diagnosis, with a subject to some degree of error, so a number of tech-
tendency to overestimate gestational age.3-6 One study niques have been used to predict gestational age more
reported that reliance on LMP alone leads to a false accurately. Serial determinations of gestational age at 2-
diagnosis of preterm birth and post-term pregnancy in to 3-week intervals may be more accurate than a single
one fourth and one eighth of cases, respectively.7 Use of determination in the third trimester to confirm dating
other historic factors (e.g., the date of the first positive and eliminate the possibility of fetal growth restriction.
pregnancy test result or the first perceived fetal move-
ments [“quickening”]) and physical findings (e.g., the
date when fetal heart sounds are first audible) may help
Routine Ultrasonography
obstetric providers determine the EDD more accurately Routine early ultrasonography significantly improves the
(see Box 6-1). accuracy of gestational age dating.3-6,16-19 Early ultraso-
Most early pregnancy tests involve the identification nography can also detect pregnancy abnormalities (e.g.,
and quantification of human chorionic gonadotropin molar pregnancy), major fetal structural abnormalities
(hCG), a hormone produced by the syncytiotrophoblast (e.g., anencephaly), and multiple pregnancy. Although
of the fetoplacental unit.8,9 Levels in the maternal circula- recommended in Europe, the practice of routine ultraso-
tion increase exponentially to a peak of 80,000 to nography for pregnancy dating has not been recom-
100,000 mIU/mL at 8 to 10 weeks’ gestation and then mended as a standard of prenatal care in the United
decrease to a level of 20,000 to 30,000 mIU/mL for the States.20,21
remainder of the pregnancy. Commercially available The usefulness of routine second-trimester ultraso-
hCG test kits can detect concentrations as low as 25 nography in all pregnant women remains a subject of
to 50 mIU/mL in serum or urine, which are typically debate. Early studies suggested an improvement in peri-
evident 8 to 9 days after conception. natal outcome with its use.17,22-25 For example, one pro-
Uncertainty in dating parameters should prompt spective clinical trial in Helsinki, Finland, randomly
ultrasonographic assessment of gestational age. Transab- assigned 9310 low-risk women either to a single screen-
dominal ultrasonography can identify an intrauterine sac ing ultrasonographic examination at 16 to 20 weeks’ ges-
in 94% of eutopic (intrauterine) pregnancies once the tation or to ultrasonography for obstetric indications
serum hCG concentration is 6000 mIU/mL or higher.10 only; a significantly lower perinatal mortality rate was
6 Antepartum Fetal Assessment and Therapy 97
found in the screening ultrasonography group (4.6 versus abdominal examination has several limitations (especially
9.0 per 1000 births, respectively).18 This difference was in the setting of a small fetus, maternal obesity, multiple
due in part to earlier detection of major fetal malforma- pregnancy, uterine fibroids, or polyhydramnios), it is safe,
tions (which prompted elective abortion) and multiple is well tolerated, and may add valuable information to
pregnancies (which resulted in more appropriate antena- assist in antepartum management. Palpation is divided
tal care) with the screening examination. As expected, into four separate Leopold’s maneuvers (Figure 6-1).
routine ultrasonography also led to improved pregnancy Each maneuver is designed to identify specific fetal land-
dating and a lower rate of induction of labor for post- marks or to reveal a specific relationship between the
term pregnancy.18 fetus and mother. The first maneuver, for example,
In contrast, a subsequent large multicenter random- involves measurement of the fundal height. The uterus
ized clinical trial involving 15,151 low-risk women in the can be palpated above the pelvic brim at approximately
United States (designated as the RADIUS study) con- 12 weeks’ gestation. Thereafter, fundal height should
cluded that screening ultrasonography did not improve increase by approximately 1 cm per week, reaching the
perinatal outcomes and had no impact on the manage- level of the umbilicus at 20 to 22 weeks’ gestation (Figure
ment of the anomalous fetus.19,26,27 Although this trial was 6-2). Between 20 and 32 weeks’ gestation, the fundal
adequately powered, it has been criticized for the highly height (in centimeters) is approximately equal to the ges-
selective entry criteria (by one estimate, less than 1% of tational age (in weeks) in healthy women of average
pregnant women in the United States would have been weight with an appropriately growing fetus. However,
eligible28) and the selection of primary outcomes (perina- there is a wide range of normal fundal height measure-
tal morbidity and mortality) that were inappropriate for ments. In one study, a 6-cm difference was noted between
the low-risk population studied. In addition, only 17% of the 10th and 90th percentiles at each week of gestation
major congenital anomalies were detected before 24 after 20 weeks.32 Moreover, maximal fundal height occurs
weeks’ gestation in the routine ultrasonography group, at approximately 36 weeks’ gestation, after which time
so the rate of elective pregnancy termination for fetal the fetus drops into the pelvis in preparation for labor.
anomalies was significantly lower than that in the Hel- For all of these reasons, reliance on fundal height mea-
sinki study. The skill and experience of the ultrasonogra- surements alone fails to identify more than 50% of fetuses
pher is also an important variable in these studies. with fetal growth restriction (also known as intrauterine
growth restriction).33 Serial fundal height measurements
by an experienced obstetric care provider are more accu-
Evaluation of Fetal Growth rate than a single measurement and will lead to better
Normal fetal growth is a critical component of a healthy diagnosis of fetal growth restriction, with reported sen-
pregnancy and the subsequent long-term health of the sitivities as high as 86%.34
child. Maternal weight gain during pregnancy is at best If clinical findings are not consistent with the stated
an indirect measure of fetal growth, because much of the gestational age, ultrasonography is indicated to confirm
weight gain during pregnancy is the result of fluid (water) gestational age and provide a more objective measure
retention. Earlier recommendations for weight gain in of fetal growth. Ultrasonography may also identify an
pregnancy were based on the Institute of Medicine (IOM)
guidelines published in 1990.29 In 2009, the IOM revised
their 1990 recommendations to include an upper limit of
weight gain for obese women (9 kg [20 lb]), and they
altered the lower limit of weight gain from 6.8 kg (15 lb)
to 5 kg (11 lb) (Table 6-1); they also recommended that
all women try to be within the normal BMI range when
they conceive.30
The size, presentation, and lie of the fetus can be
assessed with abdominal palpation. A systematic method
of examination of the gravid abdomen was first described
by Leopold and Sporlin in 1894.31 Although the A B
collagen vascular disorder). In practice, the distinction Despite the inaccuracy in the prediction of fetal mac-
between asymmetric and symmetric fetal growth restric- rosomia, an EFW should be documented by either clini-
tion is not particularly useful. cal estimation or ultrasonography in all high-risk women
Early and accurate diagnosis of fetal growth restriction at approximately 38 weeks’ gestation. Suspected fetal
coupled with appropriate intervention leads to an macrosomia is not an indication for induction of labor,
improvement in perinatal outcome. If fetal growth because induction does not improve maternal or fetal
restriction is suspected clinically and on the basis of ultra- outcomes and may increase the risk for cesarean deliv-
sonography, a thorough evaluation of the mother and ery.51 The American College of Obstetricians and Gyne-
fetus is indicated. Referral to a maternal-fetal medicine cologists (ACOG) recommends performance of an
specialist should be considered. Every effort should be elective cesarean delivery when the suspected birth
made to identify the cause of the fetal growth restriction weight exceeds 4500 g in a diabetic woman or 5000 g in
and to modify or eliminate contributing factors. Up to a nondiabetic woman.51,52,63
20% of cases of severe fetal growth restriction are associ-
ated with fetal chromosomal abnormalities or congenital Assessment of Fetal Well-Being
malformations, 25% to 30% are related to maternal con-
ditions characterized by vascular disease, and a smaller All pregnant women should receive regular antenatal care
proportion are the result of abnormal placentation. Other throughout their pregnancy, and fetal well-being should
causes of fetal growth restriction include exposure to be evaluated at every visit. Fetal heart activity should be
teratogens, alcohol, and substance abuse. In a substantial assessed and the fetal heart rate (FHR) estimated. A low
number of cases (>50% in some studies), the etiology of FHR (<100 bpm) is associated with an increased risk for
the fetal growth restriction remains unclear even after a pregnancy loss, although congenital complete heart block
thorough investigation.50 should be excluded. In the latter half of pregnancy, physi-
cal examination of the abdomen should be performed to
document fetal lie and presentation.
Fetal Macrosomia
Fetal movements (“quickening”) are typically reported
Fetal macrosomia is defined as an EFW (not birth weight) at 18 to 20 weeks’ gestation by nulliparous women and
of 4500 g or greater measured either clinically or by at 16 to 18 weeks’ gestation by parous women; the pres-
ultrasonography and is independent of gestational age, ence of fetal movements is strongly correlated with fetal
diabetic status, and actual birth weight.51 Fetal macroso- health. Although the mother appreciates only 10% to
mia should be differentiated from the large-for- 20% of total fetal movements,64-67 such movements are
gestational age (LGA) fetus, in whom the EFW is greater almost always present when she does report them.67
than the 90th percentile for gestational age. By defini- Factors associated with a diminution in perceived fetal
tion, 10% of all fetuses are LGA at any given gestational movements include increasing gestational age, smoking,
age. Fetal macrosomia is associated with an increased risk decreased amniotic fluid volume, anterior placentation,
for cesarean delivery, instrumental vaginal delivery, and and antenatal corticosteroid therapy. Decreased fetal
birth injury to both the mother (including vaginal, peri- movements may also be a harbinger of an adverse preg-
neal, and rectal trauma) and the infant (orthopedic and nancy event (e.g., stillbirth) that can be averted if detected
neurologic injury).52-56 Shoulder dystocia with resultant early. For these reasons, a subjective decrease in per-
brachial plexus injury (Erb’s palsy) is a serious conse- ceived fetal movements in the third trimester should
quence of fetal macrosomia; it is more likely in the setting prompt an immediate investigation.
of diabetes because of the larger diameters of the fetal Published studies support the value of fetal move-
upper thorax and neck. ment charts (“kick counts”) in the detection and preven-
Fetal macrosomia can be determined clinically (e.g., tion of fetal complications (including stillbirth) in both
Leopold’s maneuvers) or with ultrasonography, and these high- and low-risk populations.68-73 The normal fetus
two techniques appear to be equally accurate.57 Estimated exhibits an average of 20 to 50 (range of 0 to 130) gross
fetal weight measurements are less accurate in macroso- body movements per hour, with fewer movements during
mic fetuses than in normally grown fetuses, and factors the day and increased activity between 9:00 pm and 1:00
such as low amniotic fluid volume, advancing gestational am.74 Several different schemes have been proposed to
age, maternal obesity, and fetal position can compound determine the baseline fetal activity pattern for an indi-
these inaccuracies. Indeed, clinical examination has been vidual fetus after 28 weeks’ gestation and to evaluate
shown to underestimate the birth weight by more than activity patterns that may represent fetal compromise.
0.5 kg in almost 80% of macrosomic fetuses.58 For all One commonly used scheme (“count-to-10”) instructs
these reasons, prediction of fetal macrosomia is not par- the mother to rest quietly on her left side once each day
ticularly accurate, with a false-positive rate of 35% and a in the evening (between 7:00 pm and 11:00 pm) and to
false-negative rate of 10%.57,58 A number of alternative record the time interval required to feel 10 fetal move-
ultrasonographic measurements have therefore been pro- ments. Most patients with a healthy fetus will feel 10
posed in an attempt to better identify the macrosomic movements in approximately 20 minutes; 99.5% of
fetus, including fetal AC alone,59 umbilical cord circum- women with a healthy fetus feel this amount of activity
ference,60 cheek-to-cheek diameter,61 and subcutaneous within 90 minutes.75 Under this scheme, failure to appre-
fat in the mid humerus, thigh, abdominal wall, and ciate 10 fetal movements in 2 hours should prompt
shoulder.62 However, these measurements remain immediate fetal assessment. In one large clinical trial,
investigational. institution of this fetal activity monitoring scheme
100 PART III Fetal and Neonatal Assessment and Therapy
BOX 6-2 High-Risk Pregnancies all of these causes; however, those specifically associated
with uteroplacental vascular insufficiency should be iden-
MATERNAL FACTORS tified when possible. Antenatal fetal testing makes the
• Preeclampsia (gestational proteinuric hypertension) following assumptions: (1) pregnancies may be compli-
• Chronic hypertension cated by progressive fetal asphyxia that can lead to fetal
• Diabetes mellitus (including gestational diabetes) death or permanent neurologic handicap; (2) current
• Maternal cardiac disease antenatal tests can adequately discriminate between
• Chronic renal disease asphyxiated and nonasphyxiated fetuses; and (3) detection
• Chronic pulmonary disease of asphyxia at an early stage can lead to an intervention
• Active thromboembolic disease that is capable of reducing the likelihood of an adverse
FETAL FACTORS perinatal outcome.
Of interest, it is not clear whether any of these assump-
• Nonreassuring fetal testing (fetal compromise)
• Fetal growth restriction
tions are true, and nonreassuring fetal test results may
• Isoimmunization reflect existing but not ongoing neurologic injury.
• Intra-amniotic infection At most, 15% of cases of cerebral palsy are thought
• Known fetal structural anomaly to result from antepartum or intrapartum hypoxic-
• Prior unexplained stillbirth ischemic injury.75-78 Despite these limitations, a number
• Multiple pregnancy of antepartum tests have been developed in an attempt to
identify fetuses at risk. These include the nonstress test
UTEROPLACENTAL FACTORS
(NST), biophysical profile (BPP), and contraction stress
• Premature rupture of fetal membranes test (CST). Such tests can be used either individually or
• Unexplained oligohydramnios in combination. There is no consensus as to which of
• Prior classic (high vertical) hysterotomy
• Placenta previa
these modalities is preferred, and no single method has
• Placental abruption been shown to be superior.1
• Vasa previa
Antepartum Fetal Tests
All antepartum fetal tests should be interpreted in relation
to the gestational age, the presence or absence of con-
resulted in a significant increase in hospital visits, labor genital anomalies, and underlying clinical risk factors.79
induction, and cesarean deliveries, but also in a reduction For example, a nonreassuring NST in a pregnancy com-
in perinatal mortality from 44.5 to 10.3 per 1000 births.75 plicated by severe fetal growth restriction and heavy
Taken together, these data suggest that daily or twice- vaginal bleeding at 32 weeks’ gestation has a much higher
daily fetal “kick counts” should be performed after 32 predictive value in identifying a fetus at risk for subse-
weeks’ gestation in high-risk pregnancies. Currently quent neurologic injury than an identical tracing in a
there is insufficient evidence to recommend this practice well-grown fetus at 40 weeks, because of the higher preva-
in low-risk pregnancies. lence of this condition in the former situation. It should
be remembered that, in many cases, the efficacy of ante-
natal fetal testing in preventing long-term neurologic
PRENATAL CARE IN HIGH-RISK injury has not been validated by prospective randomized
PREGNANCIES clinical trials. Indeed, because of ethical and medicolegal
concerns, there are no studies of pregnancies at risk that
Approximately 20% of all pregnancies should be regarded include a nonmonitored control group, and it is highly
as high risk (Box 6-2). Because of the attendant risks to unlikely that such trials will ever be performed.
both the mother and fetus, additional efforts should be
made to confirm fetal well-being throughout such preg- Nonstress Test
nancies. In addition to the testing outlined previously,
high-risk pregnancies should be monitored closely and The fetal nonstress test, also known as fetal cardiotocog-
regularly by a multidisciplinary team, including subspe- raphy, investigates changes in the FHR pattern with time
cialists in maternal-fetal medicine and neonatology, if and reflects the maturity of the fetal autonomic nervous
indicated. system. For this reason, it is less useful in the extremely
premature fetus (< 28 weeks) before the autonomic
Goals of Antepartum Fetal Testing nervous system has matured sufficiently to influence
the FHR. The NST is noninvasive, simple to perform,
The goal of antepartum fetal surveillance is the early inexpensive, and readily available in all obstetric units.
identification of a fetus at risk for preventable neurologic However, interpretation of the NST is largely subjective.
injury or death. Numerous causes of neonatal cerebral Although a number of different criteria have been used
injury exist, including congenital abnormalities, chromo- to evaluate these tracings, most obstetric care providers
somal abnormalities, intracerebral hemorrhage, hypoxia, have used the definitions for FHR interpretation estab-
infection, drugs, trauma, hypotension, and metabolic lished in 1997 by the National Institute of Child Health
derangements (e.g., hypoglycemia, thyroid dysfunction). and Human Development (NICHD) Research Planning
Antenatal fetal testing cannot reliably predict or detect Workshop (Table 6-2).80 A 2008 NIH report summarized
6 Antepartum Fetal Assessment and Therapy 101
Data from the National Institute of Child Health and Human Development Research Planning Workshop. Electronic fetal heart rate
monitoring: research guidelines for interpretation. Am J Obstet Gynecol 1997; 177:1385-90.
terminology and nomenclature used in contemporary NST are interpreted as reactive or nonreactive. An FHR
clinical practice. This report described a three-tier system tracing is designated reactive if there are two or more
for FHR tracing interpretation: category I (normal), cat- accelerations of at least 15 bpm for 15 seconds in a
egory II (indeterminate), and category III (abnormal).81 20-minute period (Figure 6-3).80-82 For preterm fetuses
By definition, an NST is performed before the onset (<32 weeks’ gestation), an FHR tracing is designated as
of labor and does not involve invasive (intrauterine) mon- reactive if there are two or more accelerations of at least
itoring. The test is performed by recording the FHR for 10 bpm for 10 seconds.
a period of 20 to 40 minutes; the recording is then evalu- An NST is performed when formal documentation of
ated for the presence of periodic changes. The FHR is the fetal condition is necessary. Because most healthy
determined externally with use of Doppler ultrasonogra- fetuses move within a 75-minute period, the testing
phy, in which sound waves emitted from the transducer period for an NST should not exceed 80 minutes.83 The
are deflected by movements of the heart and heart valves. NST is most useful in cases of suspected uteroplacental
The shift in frequency of these deflected waves is detected insufficiency. A reactive NST is regarded as evidence of
by a sensor and converted into heart rate. The FHR is fetal health,84,85 but the interpretation of a nonreactive
printed on a strip-chart recorder running at 3 cm/min. A NST remains controversial. Determination of a nonreac-
single mark on the FHR tracing therefore represents the tive NST must consider the gestational age, the underly-
average rate in beats per minute (bpm) of 6 fetal heart ing clinical circumstance, and the results of previous
beats. The presence or absence of uterine contractions is FHR tracings. Only 65% of fetuses have a reactive NST
typically recorded at the same time with an external by 28 weeks’ gestation, whereas 95% do so by 32
tonometer. This tonometer records myometrial tone and weeks.79,86 However, once a reactive NST has been docu-
provides information about the timing and duration of mented in a given pregnancy, the NST should remain
contractions, but it does not measure intrauterine pres- reactive throughout the remainder of the pregnancy. A
sure or the intensity of the contractions. Results of the nonreactive NST at term is associated with poor
102 PART III Fetal and Neonatal Assessment and Therapy
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
FIGURE 6-3 ■ A normal (reactive) fetal heart rate (FHR) tracing. The baseline FHR is normal (between 110 and 160 bpm), there is
moderate variability (defined as 6 to 25 bpm from peak to trough), there are no decelerations, and there are two or more accelera-
tions (defined as an increase in FHR of ≥ 15 bpm above baseline lasting at least 15 seconds) in a 20-minute period.
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
FIGURE 6-4 ■ An “at risk” fetal heart rate (FHR) tracing. The baseline FHR is normal (between 110 and 160 bpm), but the following
abnormalities can be seen: minimal baseline FHR variability (defined as 0 to 5 bpm from peak to trough), no accelerations, and
decelerations that are late in character (start after the peak of the contraction) and repetitive (occur with more than half of the
contractions).
perinatal outcome in only 20% of cases. The significance A normal FHR tracing is defined as having a normal
of such a result at term depends on the clinical endpoint baseline rate (110 to 160 bpm), normal baseline variabil-
under investigation. If the clinical endpoint of interest is ity (i.e., moderate variability, defined as 6 to 25 bpm from
a 5-minute Apgar score less than 7, a nonreactive NST peak to trough), presence of accelerations, and absence
at term has a sensitivity of 57%, a positive predictive of decelerations. The FHR typically accelerates in
value of 13%, and a negative predictive value of 98% response to fetal movement. Therefore, FHR accelera-
(assuming a prevalence of 4%). If the clinical endpoint is tions usually indicate fetal health and adequate
permanent neurologic injury, a nonreactive NST at term oxygenation.80-82 At-risk FHR patterns demonstrate
has a 99.8% false-positive rate.87 recurrent late decelerations with absence of baseline vari-
Visual interpretation of the FHR tracing involves the ability, recurrent variable decelerations with absence of
following components: (1) baseline FHR, (2) baseline baseline variability, or substantial bradycardia with
FHR variability, (3) presence of accelerations, (4) pres- absence of baseline variability (Figure 6-4). Intermediate
ence of periodic or episodic decelerations, and (5) changes FHR patterns have characteristics between the two
of FHR pattern over time. The definitions of each of extremes of normal and at risk already described.80,81
these variables are summarized in Table 6-2.80,81 The Persistent fetal tachycardia (defined as an FHR
patterns are categorized as baseline, periodic (i.e., associ- > 160 bpm) may be associated with fetal hypoxia, mater-
ated with uterine contractions), or episodic (i.e., not asso- nal fever, chorioamnionitis (intrauterine infection),
ciated with uterine contractions). Periodic changes are administration of an anticholinergic or beta-adrenergic
described as abrupt or gradual (defined as onset-to- receptor agonist, fetal anemia, or tachyarrhythmia. Per-
nadir time < 30 seconds or > 30 seconds, respectively). sistent fetal bradycardia (FHR < 110 bpm) may be a
In contrast to earlier classifications, this classification result of congenital heart block, administration of a beta-
makes no distinction between short-term and long- adrenergic receptor antagonist, hypoglycemia, or hypo-
term variability, and certain characteristics (e.g., the defi- thermia (Table 6-3). However, it may also indicate fetal
nition of an acceleration) depend on gestational age (see hypoxia.80,81 Both tachyarrhythmias and bradyarrhyth-
Table 6-2).80,81 mias require immediate evaluation.
6 Antepartum Fetal Assessment and Therapy 103
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
A
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
B
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
C
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
D
FIGURE 6-5 ■ Components of baseline fetal heart rate (FHR) variability. A, Absence of variability. B, Minimal variability (0 to 5 bpm
from peak to nadir). C, Moderate variability (6 to 25 bpm from peak to nadir). D, Marked variability (> 25 bpm from peak to nadir).
6 Antepartum Fetal Assessment and Therapy 105
Data from Manning FA. Fetal biophysical assessment by ultrasound. In Creasy RK, Resnik R, editors. Maternal-Fetal Medicine: Principles
and Practice. 2nd edition. Philadelphia, WB Saunders, 1989:359.
240
210
180
FHR bpm
150
120
90
60
30
UA
100
12
75
mm Hg
8
50
kPa
25 4
0 0
FIGURE 6-6 ■ A positive contraction stress test (CST) result. There are at least three contractions in a 10-minute period. The baseline
fetal heart rate (FHR) is 130 bpm, there is minimal baseline FHR variability (defined as 0 to 5 bpm from peak to trough), and there
are decelerations that are late in character (start after the peak of the contraction) and repetitive (occur with more than half of the
contractions).
TABLE 6-6 False-Positive and False-Negative and transfer to a tertiary delivery center—should be con-
Rates for the Nonstress Test, sidered when Doppler findings are severely abnormal in
Biophysical Profile, and the setting of fetal growth restriction, regardless of ges-
Contraction Stress Test tational age. However, in the presence of a normally
grown fetus, it is unclear how to interpret such findings.
False-Negative For these reasons, umbilical artery Doppler velocimetry
False-Positive Rate (per 1000 should not be performed routinely in women at low risk
Test Rate (%) live births)* for fetal abnormalities. Appropriate indications include
Nonstress test (NST) 58 1.4 to 6.2 fetal growth restriction, cord malformations, unexplained
Biophysical profile (BPP): 0.7 to 1.2 oligohydramnios, suspected or established preeclampsia,
• Score 6/10 45 and, possibly, fetal cardiac anomalies.
• Score 0/10 0 Umbilical artery Doppler velocimetry has not been
Contraction stress test 30 0.4 to 0.6 shown to be useful in the evaluation of some high-
(CST) risk pregnancies, including diabetic and post-term
pregnancies, primarily owing to a high false-positive
*Data are presented as perinatal mortality rate within 1 wk of a
reactive NST, a BPP score of 8 or 10, or a negative CST after
rate.2,109-112 Thus, in the absence of fetal growth restric-
adjustments for congenital anomalies and known causes. tion, obstetric management decisions are not usually
Data from references 1, 84, 95, and 103. made on the basis of Doppler velocimetry findings
alone. New applications for Doppler technology include
the use of MCA peak systolic velocity for the noninvasive
Doppler velocimetry measurements reflect resistance to evaluation of fetal anemia resulting from isoimmuniza-
blood flow from the fetus to the placenta. Normally, tion. When severe anemia develops in a fetus, blood is
umbilical artery resistance falls progressively throughout preferentially shunted to the vital organs, such as the
pregnancy, reflecting the increase in number of tertiary brain, and the shunt can be demonstrated by an increase
stem vessels. Factors that affect placental vascular in MCA peak systolic flow velocity.113 This finding can
resistance include gestational age, placental location, help the perinatologist counsel affected patients about
pregnancy complications (e.g., placental abruption, pre- the need for cordocentesis and fetal blood transfusion.
eclampsia), and underlying maternal disease (chronic Doppler studies of other vessels (including the uterine
hypertension). artery, fetal aorta, ductus venosus, and fetal carotid arter-
Doppler velocimetry of umbilical artery blood flow ies) have contributed to our knowledge of maternal-fetal
provides an indirect measure of fetal status. Decreased physiology but as yet have resulted in few clinical
diastolic flow with a resultant increase in the systolic-to- applications.
diastolic (S/D) ratio suggests an increase in placental
vascular resistance and fetal compromise. Severely abnor- Multiple Modalities to Assess Fetal Well-Being
mal umbilical artery Doppler velocimetry (defined as
absence of or reversed diastolic flow) is an especially All standard tests to assess antepartum fetal well-being
ominous observation and is associated with poor perina- (i.e., NST, BPP, CST) are evaluated according to their
tal outcome in the setting of fetal growth restriction ability to predict the absence of fetal death during the
(Figure 6-7).104-108 The role of ductus venosus and/or 1-week period after the test. The false-negative rate
middle cerebral artery (MCA) Doppler velocimetry in (defined as a reassuring test result with a subsequent bad
the management of fetal growth restriction pregnancies outcome) and false-positive rate (an abnormal result with
is not well defined. Preparation for delivery—including a subsequent normal outcome) for each of these tests are
administration of corticosteroids for fetal lung maturity listed in Table 6-6.1,84,95,103 The false-negative rates for all
6 Antepartum Fetal Assessment and Therapy 107
Systole
Diastole
Absent
diastolic
flow
FIGURE 6-7 ■ Umbilical artery Doppler velocimetry. A, Normal waveform in the umbilical artery as shown on Doppler velocimetry.
Forward flow can be seen during both fetal systole and diastole. B, Absent end-diastolic flow. Forward flow can be seen during
systole, but there is no flow during diastole.
108 PART III Fetal and Neonatal Assessment and Therapy
Systole
FIGURE 6-7, cont’d ■ C, Reverse diastolic flow. Forward flow can be seen during systole, but there is reverse flow in the umbilical
artery during diastole, which is suggestive of high resistance to blood flow in the placenta.
three tests are relatively low. Because the NST has a high involves determination of fetal number, viability,
false-positive rate, some authorities consider it a screen- position, gestational age, and gross malformations. Pla-
ing test to identify fetuses requiring further assessment cental location, amniotic fluid volume, and the presence
with either a BPP or a CST. No method of fetal assess- of abnormal maternal pelvic masses can be evaluated as
ment is perfect, and clinical judgment plays a large role well.20 Most pregnancies can be evaluated adequately
in any management decision. with this type of examination alone. If the patient’s
history, physical findings, or basic ultrasonographic
results suggest the presence of a fetal malformation, an
SPECIAL TECHNIQUES FOR ultrasonographer who is skilled in fetal evaluation should
perform a targeted or comprehensive examination
ANTEPARTUM FETAL SURVEILLANCE (level II). During a targeted ultrasonographic examina-
Perinatal Ultrasonography tion, which is best performed at 18 to 20 weeks’ gestation,
fetal structures are examined in detail to identify and
Ultrasonography uses high-frequency sound waves (3.5 characterize any fetal malformation. Ultrasonographic
to 5 MHz for transabdominal transducers and 5 to markers of fetal aneuploidy (see later discussion) can be
7.5 MHz for transvaginal transducers) that are directed evaluated as well. In some situations, a limited examina-
into the body by a transducer, reflected by maternal and tion may be appropriate to answer a specific clinical ques-
fetal tissue, detected by a receiver, processed, and dis- tion (e.g., fetal viability, amniotic fluid volume, fetal
played on a screen. Increasing the wave frequency results presentation, placental location, cervical length) or to
in greater display resolution at the expense of diminished provide ultrasonographic guidance for an invasive proce-
tissue penetration. Interpretation of images requires dure (e.g., amniocentesis).
operator experience. Widespread clinical application of Current debate centers on identifying those patients
two-dimensional ultrasonography began in the 1960s who would benefit from an ultrasonographic evaluation
after pioneering work by researchers in the United States and determining what type of evaluation would be
and Great Britain.114 Although no deleterious biologic optimal. Advocates of the universal application of ultra-
effects have been associated with obstetric ultrasonogra- sonography cite the advantages of more accurate dating
phy, the rates of false-positive and false-negative diagno- of pregnancy (see earlier discussion) and earlier and more
ses based on the images are a major limitation. accurate diagnosis of multiple gestation, structural mal-
Perinatal ultrasonography can be classified broadly formations, and fetal aneuploidy (see later discussion).
into three types of examinations: basic, targeted (compre- Opponents of routine ultrasonographic examination view
hensive), and limited. The basic examination (level I) it as an expensive screening test ($100 to $250 for a basic
6 Antepartum Fetal Assessment and Therapy 109
examination) that is not justified by published research, trisomy) results primarily from nondisjunction during
which suggests that routine ultrasonography does not meiosis I, an event that occurs with growing frequency
change perinatal outcome significantly.19,26,27 Although in older women. Women of advanced maternal age (> 35
routine ultrasonography for all low-risk pregnant women years or older at EDD) are at higher risk for having a
is controversial, few would disagree that the benefits far pregnancy complicated by fetal aneuploidy and are rou-
outweigh the costs for selected patients. The ACOG20 tinely offered noninvasive prenatal screening as well as
has recommended that the benefits and limitations of an invasive diagnostic procedure, either amniocentesis or
ultrasonography should be discussed with all pregnant chorionic villus sampling (CVS). However, because only
women. 8% to 12% of all births occur in women age 35 and older,
First-trimester ultrasonography is indicated to at most 20% to 25% of all cases of trisomy 21 (Down
confirm an intrauterine pregnancy (i.e., exclude ectopic syndrome) would be identified if all women of advanced
pregnancy), confirm fetal viability, document fetal maternal age agreed to amniocentesis.118 Many older
number, estimate gestational age, and evaluate the mater- women are now opting for serum analyte screening for
nal pelvis and ovaries. fetal aneuploidy, which is equally accurate in older
Second-trimester ultrasonography is indicated in women.119 All women, regardless of age, should be offered
patients with an uncertain LMP date, uterine size larger aneuploidy screening during early gestation.117
or smaller than expected for the estimated gestational age,
a medical disorder that can affect fetal growth and devel- Second-Trimester Fetal Aneuploidy Screening
opment (e.g., diabetes, hypertension, collagen vascular
disorders), a family history of an inherited genetic abnor- Methods have been developed to help identify women at
mality, and suspected fetal malformation or growth high risk for fetal aneuploidy. The major focus of atten-
disturbance.20 Most patients undergo a detailed fetal ana- tion has been the detection of Down syndrome, because
tomic survey at 18 to 20 weeks’ gestation to screen for it is the most common chromosomal abnormality mani-
structural defects. An understanding of normal fetal phys- festing at term and because, unlike the less common
iology is critical to the diagnosis of fetal structural anoma- disorders trisomy 13 and 18, its diagnosis can be very
lies. Placental location should be documented with the difficult to make with ultrasonography. In all of these
maternal bladder empty, because overdistention of the screening tests, one or more serum analytes are used to
bladder or a lower uterine contraction can give a false adjust the a priori risk for fetal aneuploidy in a given
impression of placenta previa. If placenta previa is identi- pregnancy, which depends primarily on maternal age.
fied at 18 to 22 weeks’ gestation, serial ultrasonographic The maternal serum analytes used most commonly in
examinations should be performed to follow placental second-trimester aneuploidy screening protocols are
location. Only 5% of cases of placenta previa identified in maternal serum alpha-fetoprotein (MS-AFP), total or
the second trimester persist to term.115 The umbilical cord free β-subunit hCG (β-hCG), unconjugated estriol,
should also be imaged and the number of vessels, placen- and dimeric inhibin A (collectively known as the qua-
tal insertion, and fetal insertion should be noted. Evalua- druple or “quad” screen). Screening results are reported
tion of the amniotic fluid volume should also be done. In as positive or negative. If the adjusted risk for fetal aneu-
pregnancies at high risk for fetal cardiac anomalies or ploidy exceeds the age-related risk at age 35 or the rate
preterm birth, fetal echocardiography and cervical length of amniocentesis procedure-related pregnancy loss,
measurements, respectively, should be performed. which is currently defined as 1 in 300 to 500 (i.e., if the
The indications for third-trimester ultrasonogra- chance of finding a chromosomal abnormality on fetal
phy are similar to those for second-trimester ultrasonog- karyotype is higher than the risk of the invasive proce-
raphy. Fetal anatomic surveys and EFW become less dure), then genetic amniocentesis is recommended.120 If
accurate with greater gestational age, especially in obese all screen-positive women undergo amniocentesis and if
women or pregnancies complicated by oligohydramnios. the fetal karyotype analysis is successful in all cases, this
Fetal biometry and detailed anatomic surveys are still protocol can identify 60% of all Down syndrome cases
performed in late gestation, because certain fetal anoma- with a screen-positive (amniocentesis) rate of approxi-
lies (e.g., achondroplasia, duodenal atresia) may become mately 5%. Older women are more likely to be screen
evident for the first time during this period. Transvaginal positive but also have higher detection rates. In women
ultrasonographic measurement of cervical length (per- older than 35 years, this protocol identifies 75% of aneu-
formed to identify women at risk for preterm birth) is of ploid fetuses with a screen-positive rate of approximately
little use after 30 to 32 weeks’ gestation.116 25%.118,121,122
can be detected reliably by perinatal ultrasonography. However, the true application of the integrated screening
Approximately 50% of fetuses with Down syndrome test requires that the first-trimester test results, even if
appear structurally normal on ultrasonography.123 Several abnormal, be withheld from the patient until combined
major structural ultrasonographic abnormalities (e.g., with the second-trimester test results; this practice of
endocardial cushion defect) may be associated with withholding information has generated controversy, par-
trisomy 21 in more than 30% of cases.123-125 The clinical ticularly in the United States. To overcome this objec-
significance of an isolated “soft” ultrasonographic tion, sequential and contingent integrated screening tests
marker for Down syndrome in a low-risk population is have been developed, whereby the second-trimester test
unclear. is performed after disclosure of the first-trimester screen-
ing result or if the first test result is abnormal, respec-
tively. It remains unclear, however, whether the detection
First-Trimester Fetal Aneuploidy Screening
rates for these integrated tests are any better than those
First-trimester fetal aneuploidy screening is a more of the first-trimester screening test alone (see Table
recent development. The screening protocol involves the 6-8).129-132 Indeed, if the first-trimester aneuploidy screen
following three steps undertaken at 11 to 14 weeks’ gesta- result is negative (indicating low risk), the sensitivity of
tion: (1) maternal serum analyte screening for pregnancy- second-trimester serum analyte screening is reduced five-
associated placental protein-A (PAPP-A) and total or free fold.136 For this reason, many authorities suggest that no
β-hCG, (2) ultrasonographic assessment of nuchal trans- further aneuploidy screening be done if the first-trimester
lucency, and (3) genetic counseling.126 The measurement screen result is negative, with the exception of the second-
of free rather than total β-hCG provides a small statistical trimester fetal anatomic survey and possibly isolated
advantage without apparent clinical benefit.127 First- MS-AFP serum screening for open neural tube defects at
trimester aneuploidy screening appears to be as good as 15 to 20 weeks’ gestation.
second-trimester serum analyte screening in identifying In addition to the nuchal translucency measurement,
fetuses with Down syndrome.128,129 The serum analytes in absence of the nasal bone on first-trimester ultrasonog-
the first trimester associated with an increased risk for raphy has been correlated with Down syndrome.
Down syndrome include a decrease in PAPP-A (< 0.4 However, whether this ultrasonographic marker adds to
multiples of the median [MoM]) and an increase in free the predictive value of first-trimester risk assessment in
hCG (> 1.8 MoM). Nuchal translucency is defined as the either low- or high-risk populations has been ques-
fluid-filled space between the back of the fetal neck and tioned.137,138 At this time, the presence or absence of the
the overlying skin. Proper training and technique are nasal bone is not included in the first-trimester screening
needed to obtain this measurement. There is a correla- test.
tion between an increased nuchal translucency measure- Risk assessment for Down syndrome can be performed
ment and a risk for Down syndrome. in twin pregnancies using either first- or second-trimester
The advantage of first-trimester aneuploidy screening serum analyte measurements but is less accurate than in
is that it is performed early in pregnancy, allowing for singleton pregnancies.132 Such screening has not been
more counseling, the option of CVS, and early pregnancy validated for use in higher-order multiple pregnancies
termination if desired. The screening test most com- (triplets and up) or in multiple pregnancies with a nonvi-
monly used in Europe for identifying pregnancies at risk able fetus (either due to spontaneous demise or following
for Down syndrome is the “integrated” test, which com- a multifetal pregnancy reduction). In such cases, Down
bines first-trimester aneuploidy screening with second- syndrome risk assessment can be achieved using first-
trimester serum analyte screening into a single adjusted trimester nuchal translucency measurements only,
risk in the mid to late second trimester. The integrated although this is not a particularly good screening test and
test can identify 85% to 90% of fetuses with Down syn- has a lower sensitivity even than nuchal translucency
drome with a false-positive rate of 2% (Table 6-8).129-135 alone in singleton pregnancies.132
6 Antepartum Fetal Assessment and Therapy 111
β-hCG, beta-human chorionic gonadotropin; MS-AFP, maternal serum level of alpha-fetoprotein; NT, nuchal translucency; PAPP-A,
pregnancy-associated placental protein-A.
*Assuming a 5% false-positive rate.
†Assuming an 85% detection rate.
Data from references 128 and 130-132.
Definitive Diagnosis of Fetal assessing fetal lung maturity, to look for pathogenic bac-
Chromosomal Abnormalities teria for confirmation of an intra-amniotic infection, and
to obtain fetal cells for determination of fetal karyotype
Although an abnormal screening test result or the pres- or performance of specific genetic analyses.
ence of ultrasonographic abnormalities may signal an Cell culture with karyotype analysis typically takes 10
increased risk for Down syndrome or other chromosomal to 14 days, although a small chance exists that the cells
abnormality, the majority of fetuses with such findings will fail to grow, resulting in an inconclusive result. Fluo-
are chromosomally normal. To provide a definitive diag- rescence in situ hybridization (FISH) does not require
nosis, an invasive procedure is needed to obtain the fetal that the cells be cultured for any length of time, and its
karyotype; generally amniocentesis or CVS is used, results can be obtained within a few days. This technique
although in rare cases a cordocentesis is performed. uses a series of chromosome-specific fluorescent probes
All invasive procedures are associated with risks to the to analyze the metaphase spread in fetal cells to deter-
pregnancy. Risks common to all invasive procedures mine fetal gender and detect common trisomies (21, 18,
include the chance of bleeding, isoimmunization (espe- 13, X, and Y). It can also be used to identify chromosome
cially in women who are Rh negative), and infection. All deletions or duplications in pregnancies at risk for a spe-
women who are Rh negative should receive Rh0(D) cific genetic disorder because of a family history or suspi-
immune globulin before or after the procedure. Although cious ultrasonographic findings, such as the 22q11
the risk for vertical transmission of viral infections (e.g., deletion in DiGeorge’s syndrome.140-142 Although FISH
hepatitis B, hepatitis C, human immunodeficiency virus) is highly sensitive (trisomy present on FISH testing is
with invasive procedures is believed to be low,139 every invariably present in the fetus), it is not particularly spe-
effort should be made to avoid invasive procedures in cific, with a false-negative rate of approximately 15%.
such patients, especially if there is a high viral load in the For this reason, the American College of Medical Genet-
maternal circulation. ics (ACMG) and the American Society of Human Genet-
ics (ASHG) recommend that all FISH results be
confirmed by complete karyotype analysis.142
Amniocentesis
The most common indication for second-trimester
Amniotic fluid is composed of fetal urine, lung fluid, skin amniocentesis is cytogenetic analysis of fetal cells,
transudate, and water that is filtered across the amniotic although on occasion it is performed to determine amni-
membranes. It contains electrolytes, proteins, and des- otic fluid AFP levels and acetylcholinesterase activity for
quamated fetal cells (amniocytes). Sampling of amniotic the diagnosis of fetal open neural tube defects. Amnio-
fluid (amniocentesis) can be used to measure various centesis later in pregnancy is usually performed for non-
substances such as lecithin and sphingomyelin for genetic indications, such as (1) documentation of fetal
112 PART III Fetal and Neonatal Assessment and Therapy
pulmonary maturity prior to elective delivery before 39 aspiration of chorionic villi by means of a 16-gauge cath-
weeks’ gestation, (2) for amnioreduction in pregnancies eter inserted transcervically or a 20-gauge spinal needle
complicated by severe polyhydramnios, (3) to confirm inserted transabdominally into the placenta. The 15 to
preterm premature rupture of membranes (PROM) 30 mg of villous material collected can be examined in
(amniodye test), or (4) to exclude intra-amniotic two ways: (1) by direct cytogenetic analysis after an over-
infection. night incubation, which yields results in 2 to 3 days; and
Genetic amniocentesis typically involves the insertion (2) by longer-term culture followed by cytogenetic analy-
of a 22-gauge spinal needle through the maternal abdom- sis, which yields results in 6 to 8 days.154 To provide rapid
inal wall and into the uterine cavity at 15 to 20 weeks’ and accurate results, many centers report the results of
gestation. The procedure is now commonly performed both methods. The main advantage of CVS over amnio-
under ultrasonographic guidance, which allows the oper- centesis is that it allows for fetal karyotyping results in
ator to choose the safest site, preferably away from the the first trimester, thereby allowing decisions about preg-
fetal face and umbilical cord and when possible without nancy termination to be made earlier if chromosomal
passage of the needle through the placenta. The greatest abnormalities are detected. Moreover, although rare,
risk of amniocentesis is spontaneous abortion; however, certain genetic disorders (e.g., osteogenesis imperfecta)
the procedure-related pregnancy loss rate for genetic can be diagnosed antenatally only through analysis of
amniocentesis appears to be only 1 in 300 to 500.120,143-145 placental tissue.
Of interest, the pregnancy loss rate is not influenced by CVS is best performed between 10 and 12 weeks’
operator experience or needle placement through the gestation. CVS performed before 10 weeks’ gestation has
placenta145,146 but is higher in the presence of first- been associated with limb reduction defects,155,156 whereas
trimester bleeding or recurrent miscarriage, ultrasono- no such association exists if the procedure is performed
graphic demonstration of chorioamniotic separation, after 66 days’ gestation.157 Transabdominal CVS can also
discolored amniotic fluid at the time of the procedure, be performed in the second or third trimester and is a
and an unexplained elevation in MS-AFP.144,147 Whether reasonable alternative to cordocentesis for obtaining
this risk is higher in twin pregnancies is not clear. Tran- tissue for an urgent fetal karyotype.158
sient leakage of amniotic fluid can be seen in 1% to 2% The most common complication of CVS is vaginal
of procedures. This leakage usually stops after 48 to 72 spotting, which occurs in 10% to 25% of patients within
hours, infection is extremely rare (< 0.1% of cases), and the first few days after the procedure. Fortunately, the
the perinatal survival rate after mid-trimester fluid leakage bleeding is usually mild and resolves spontaneously with
may be as high as 90%.117,148-152 no long-term sequelae. The incidences of amnionitis
Compared with late second-trimester amniocentesis, (0.3%) and rupture of membranes (0.3%) after CVS
early amniocentesis (before 15 weeks’ gestation) is associ- do not differ significantly from those seen with late
ated with significantly higher procedure-related preg- amniocentesis and are significantly lower than those
nancy loss rates, ranging from 2.2% to 4.8%.148-151 This reported after early amniocentesis.157 As with amniocen-
rate is fourfold higher than that of late amniocentesis and tesis, the most serious complication of CVS is spontaneous
twice as high as that of CVS. Early amniocentesis has also abortion. CVS appears to be associated with a higher
been shown to be associated with higher rates of rupture risk for pregnancy loss than late amniocentesis; the
of membranes, club foot, and amniocyte culture failures procedure-related loss rate in CVS is reported as 1.0% to
(2% to 5%) than late amniocentesis.148-153 For these 1.5%.157,159-164 This rate is significantly higher (0.6% to
reasons, amniocentesis before 15 weeks’ gestation is not 0.8%) than that seen after late amniocentesis, with an
recommended. adjusted odds ratio of 1.30 (95% confidence interval [CI],
If early karyotyping is desired, CVS is preferred over 1.17 to 1.52).163 Factors that increase the procedure-
early amniocentesis (see later discussion). Amniocentesis related loss rate are operator inexperience, number of
in the third trimester is technically easier and is associ- needle passes, and a history of bleeding prior to the pro-
ated with fewer complications. If a late amniocentesis is cedure.163 By contrast, the risk does not appear to be
being performed for any reason (e.g., to confirm fetal increased in twin gestations or with the anatomic approach
pulmonary maturity), consideration should be given to used (i.e., transabdominal versus transcervical catheter
obtaining the karyotype if indicated, even though the placement).162,165 Some investigators have suggested that
pregnancy is too far along to be ended electively. the apparently higher pregnancy loss related to CVS
Amniocentesis in multiple gestations can be performed (compared with amniocentesis) is a function of the earlier
safely. Care must be taken to carefully map the fetal sacs gestational age at which the procedure is performed.120
so that the amniotic fluid for each fetus is sampled sepa- One complication unique to CVS involves the inter-
rately. A small amount of indigo carmine (3 to 5 mL) is pretation of the genetic test results. Because the fetus and
typically inserted into the first sac after the fluid is placenta both arise from the same cell, it is assumed that
sampled to ensure that the same sac is not sampled twice. the genetic complements of these two tissues are identi-
cal, but this is not always the case. Confined placental
mosaicism refers to the situation in which the karyotype
Chorionic Villus Sampling
of the chorionic villus is a mosaic (i.e., it contains two or
Like that of amniocentesis, the goal of CVS is to provide more populations of cells with different karyotypes,
fetal cells for genetic analysis, although in this case the usually one normal and one trisomic) but the karyotype of
cells are trophectoderm (placental) cells rather than the fetus is normal. The incidence of confined placental
amniocytes. The technique entails ultrasound-guided mosaicism may be as high as 1% to 2% with the direct
6 Antepartum Fetal Assessment and Therapy 113
cytogenetic analysis method, but most cases are not con- position, location of the cord insertion site within the
firmed by the long-term tissue-culture method,157,161 sug- placenta). A transient fetal bradycardia may occur during
gesting a methodologic error. For this reason, many the procedure, often resulting from unintentional place-
centers report only the long-term culture results. On ment of the needle into one of the umbilical arteries and
occasion, it may be necessary to repeat the fetal karyotype, leading to arterial vasospasm. Although this bradycardia
either with a second CVS or with amniocentesis, to invariably resolves, if the fetus is at a favorable gestational
resolve the dilemma. The reverse situation, in which the age (> 24 weeks), the procedure should be performed at
CVS result is normal but the fetus has aneuploidy (a false- a facility with the capacity to perform an emergency
negative result), has also been reported166 but is rare. It cesarean delivery. No consistent data or recommenda-
may occur from contamination with maternal cells or tions exist regarding the use of prophylactic antibiotics,
from inadvertent sampling of a twin placenta. tocolysis, and maternal sedation during cordocentesis.
particular fetal anomaly. For example, radiographic performed by a skilled and experienced sonologist at 20 to
imaging is superior to ultrasonography in evaluating the 22 weeks’ gestation in all pregnancies at high risk for a
fetal skeleton and may provide valuable information in fetal cardiac anomaly. Indications for fetal echocardiogra-
the evaluation of a fetus with a suspected bony dystrophy. phy include (1) pregnancies complicated by pregestational
At least 25 different forms of skeletal dysplasias are iden- diabetes mellitus, (2) a personal or family history of con-
tifiable at birth, 11 of which are lethal in the peripartum genital cardiac disease (regardless of the nature of the
period.175 Although some of these forms can be identified lesion or whether it has been repaired), (3) maternal expo-
from their unusual appearance on ultrasonography (e.g., sure to certain drugs (e.g., lithium, paroxetine),179 and (4)
cloverleaf skull and small thorax in thanatophoric dyspla- conception by in vitro fertilization (but not if the preg-
sia), the majority are difficult to identify. Timely radio- nancy was conceived through the use of clomiphene
graphic imaging may allow an experienced pediatric citrate or ovarian stimulation/intrauterine insemination
radiologist to more thoroughly evaluate the fetal skeleton alone).180
and determine the correct diagnosis. A simple maternal
abdominal radiograph may be all that is required, because Fetal Cells or DNA in the Maternal Circulation
ossification is sufficient by 20 weeks’ gestation to allow
good visualization of the fetal bones. To minimize the risks associated with invasive prenatal
Although computed tomography is best avoided in diagnosis (amniocentesis and CVS), improved noninva-
pregnancy because it exposes the fetus to ionizing radia- sive tests are being developed for fetal aneuploidy genetic
tion (albeit at small doses), MRI is regarded as safe. This testing. Fetal cells are known to be present in the mater-
latter technology relies on the interaction between an nal circulation throughout pregnancy at a concentration
applied magnetic field and the inherent nuclear magne- of approximately 1 fetal cell for every 10,000 to 1 million
tism of atomic nuclei within the patient’s tissues to gener- maternal cells.181 However, we do not currently have the
ate a high-resolution anatomic image. Because MRI is technology to isolate these cells with sufficient purity to
particularly good at visualizing soft tissue rather than develop a reliable prenatal test. Recent efforts have
bony structures, it is uniquely suited to the evaluation of focused on genetic analysis of cell-free DNA in the
fetal intracranial defects and the soft tissues of the mater- maternal circulation. It is now apparent that fetal DNA
nal pelvis (Figure 6-8).176,177 Although fetal motion arti- (most of which comes from the placenta) accounts for 3%
fact has previously been a major limitation in the use of to 10% of all cell-free DNA in maternal serum, and it
MRI, new ultrafast technology allows for rapid image may account for as much as 20% of cell-free DNA in
acquisition and has largely overcome this problem. women with preeclampsia or after major fetal-maternal
hemorrhage. Because of its relative abundance, purity,
and short half-life (precluding contamination from a
Fetal Echocardiography
prior pregnancy), high-throughput sequencing of cell-
Cardiac anomalies are the most common major congeni- free DNA provides new opportunities for noninvasive
tal defects encountered in the antepartum period. A four- prenatal testing.182 Several commercial tests are now
chamber ultrasonographic view of the heart during the available that rely on analysis of cell-free DNA in the
fetal anatomic survey at 18 to 20 weeks’ gestation detects maternal circulation to screen for fetal aneuploidy as
only 30% of congenital cardiac anomalies, although early as 10 weeks’ gestation. Recent publications have
the detection rate can be increased to 60% to 70% if the shown that such noninvasive prenatal testing can increase
outflow tracts are adequately visualized.178 Owing to the the detection rate for trisomy 21 (Down syndrome) to
number of congenital cardiac anomalies that would be approximately 99.8% with a 0.2% false-positive rate in
missed, however, fetal echocardiography should be high-risk pregnancies 183-186; these results have not yet
A B
FIGURE 6-8 ■ Magnetic resonance images of a fetus with holoprosencephaly. A, Sagittal view showing the proboscis (arrow).
B, Coronal view showing the single ventricle and fused thalami (arrow). (Reprinted from Wenstrom KD, Williamson RA, Weiner CP,
et al. Magnetic resonance imaging of fetuses with intracranial defects. Obstet Gynecol 1991; 77:529-32.)
6 Antepartum Fetal Assessment and Therapy 115
been validated in low-risk pregnancies. Because of the TABLE 6-9 Relationship between First-
small but finite false-positive rate, these tests should be Trimester PAPP-A Level at or
considered screening and not diagnostic tests, and con- below Fifth Percentile (0.42 MoM)
firmatory CVS or amniocentesis is still recommended and Risks of Adverse Pregnancy
before acting on a positive test. The detection of trisomy Outcomes
18 (98%) and trisomy 13 (65%) is also possible using this
technology.184,186 Adjusted 95% Confidence
An alternative approach under investigation for defini- Adverse Outcome Odds Ratio Interval
tive genetic testing is the isolation of trophoblast cells Spontaneous loss < 24 2.50 1.76-3.56
from the cervicovaginal discharge of women in early weeks
pregnancy.187,188 Provisional studies have isolated these Fetal death ≥ 24 weeks 2.15 1.11-4.15
cells from the maternal cervix with cervical canal lavage Preterm birth ≤ 37 weeks 1.87 1.61-2.17
at 7 to 10 weeks’ gestation187 or with the use of a brush- Preterm birth ≤ 32 weeks 2.10 1.59-2.76
type collection device at 5 to 12 weeks (the “genetic Pap Preeclampsia 1.54 1.16-2.03
smear”).188 With this technique, such cells have been iso- Gestational hypertension 1.47 1.20-1.82
lated in 86% (195/227) of samples by immunocytochem- Placental abruption 1.80 1.15-2.84
istry with trophoblast-specific antibodies, and results Fetal growth restriction 3.22 2.38-4.36
agreed with those of placental tissue karyotyping via CVS
in 95% (186/195) of cases.188 The ability to successfully MoM, multiple of the median; PAPP-A, pregnancy-associated
placental protein-A test.
collect trophoblast cells from the cervicovaginal dis- Data from Dugoff L, Hobbins JS, Malone FD, et al. First-trimester
charge of women in early pregnancy may provide a maternal serum PAPP-A and free beta-subunit human chorionic
simple, reliable, noninvasive, yet definitive genetic test gonadotropin concentrations and nuchal translucency are
for fetal aneuploidy in a singleton pregnancy with no risk associated with obstetric complications: a population-based
to the mother or fetus. screening study (the FASTER Trial). Am J Obstet Gynecol 2004;
191:1446-51.
TABLE 6-11 Special Circumstances Requiring Additional Fetal Surveillance during Pregnancy
Gestational Age at Which
Pregnancy-Related Condition Additional Testing Recommended Testing Should Be Started
Maternal Conditions
Chronic hypertension Growth scans q3-4 wk 24 weeks
Weekly NST ± AFV 32 weeks
Diabetes mellitus:
Pregestational diabetes Growth scans q3-4 wk 24 weeks
Weekly NST ± AFV 32 weeks
Gestational diabetes Growth scans q3-4 wk From diagnosis
Weekly NST ± AFV 36 weeks
Maternal obesity (body mass index > 30 kg/m2) Weekly NST ± AFV 36 weeks
Advanced maternal age Weekly NST ± AFV 38 weeks
Abnormal serum analyte screening result (maternal Growth scans q3-4 wk 24 weeks
serum level of alpha-fetoprotein [MS-AFP] > Weekly NST ± AFV 36 weeks
2.0 MoM; pregnancy-associated placental protein-A
[PAPP-A] < 0.4 MoM) with normal fetal karyotype
Prior unexplained preterm birth < 35 weeks Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 24 weeks to 32-34 weeks
Prior cervical cone biopsy Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 24 weeks to 32-34 weeks
Post-term pregnancy Twice-weekly NST and AFV 41-42 weeks
Isoimmunization Weekly middle cerebral artery 18-20 weeks
Doppler velocimetry
Uteroplacental Conditions
Chronic abruption Growth scans q3-4 wk From diagnosis
Weekly NST ± AFV 28-32 weeks
Uterus didelphys Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
Preterm premature rupture of membranes Daily NST From diagnosis
Growth scans q3-4 wk From diagnosis
Weekly AFV From diagnosis
Unexplained oligohydramnios Growth scans q3-4 wk From diagnosis
Weekly AFV From diagnosis
Weekly NST with AFV 32 weeks
Weekly UA Doppler velocimetry From diagnosis
Fetal Conditions
Twin pregnancy:
Dichorionic, diamniotic twin pregnancy Biweekly AFV 18-20 weeks
Growth scans q3-4 wk 24 weeks
Weekly NST with AFV 32 weeks
Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 22-24 weeks to 30-32 weeks
Monochorionic, diamniotic twin pregnancy Weekly AFV 16-18 weeks
Growth scans q3-4 wk 24 weeks
Weekly NST with AFV 28-32 weeks
Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 22-24 weeks to 30-32 weeks
Monochorionic, monoamniotic twin pregnancy Weekly AFV 16-18 weeks
Growth scans q3-4 wk 24 weeks
Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 22-24 weeks to 30-32 weeks
± Continuous fetal heart rate 24-26 weeks to delivery
monitoring
Twin pregnancy complicated by demise of one twin Weekly NST with AFV From diagnosis
Growth scans q3-4 wk From diagnosis
Higher-order multiple pregnancy (≥ triplets) Weekly AFV 16-18 weeks
Growth scans q3-4 wk 24 weeks
Weekly NST with AFV 28-32 weeks
Weekly to biweekly cervical length 16-18 weeks to 30-32 weeks
measurements
± Weekly to biweekly fFN 22-24 weeks to 30-32 weeks
6 Antepartum Fetal Assessment and Therapy 117
AFV, amniotic fluid volume; biweekly, every 2 weeks; fFN, fetal fibronectin; MoM, multiple of median; NST, nonstress test; UA, umbilical
artery.
are due to nonimmune causes, such as maternal infection TABLE 6-12 Fetal-Maternal Transfusion
(e.g., with parvovirus B19, cytomegalovirus, syphilis), Volume and Risk for Rh(D)
massive fetal-maternal hemorrhage, and fetal abnormali- Isoimmunization in an Rh(D)-
ties (e.g., congenital cardiac defects, fetal thalassemia, Negative Woman
twin-to-twin transfusion syndrome). Although the overall
perinatal mortality rate in the setting of hydrops fetalis Incidence at Risk for
exceeds 50%, the prognosis depends on the underlying Transfusion Volume Delivery (%) Isoimmunization (%)*
cause, severity, and gestational age. Unmeasurable 50 Minimal
Immune hydrops occurs when fetal erythrocytes < 0.1 mL 45-50 3
express a protein that is not present on maternal eryth- > 5.0 mL 1 20-40
rocytes. The maternal immune system can become sen- > 30 mL 0.25 60-80
sitized and produce antibodies against these “foreign”
proteins. These immunoglobulin (Ig) G antibodies can *Without Rh0(D) immune globulin.
cross the placenta and destroy fetal erythrocytes, leading Data from American College of Obstetricians and Gynecologists.
Prevention of Rh D alloimmunization. ACOG Practice Bulletin
to fetal anemia and high-output cardiac failure. Immune No. 4. Int J Gynaecol Obstet 1999; 66:63-70 (reaffirmed 2009);
hydrops is typically associated with a fetal hematocrit less and Moise KJ. Red blood cell alloimmunization in pregnancy.
than 15% (normal fetal hematocrit is 50%). The most Semin Hematol 2005; 42:169-78.
antigenic protein on the surface of fetal erythrocytes is
the D antigen of the Rhesus protein complex, also known
as Rh(D). Other antigens that can cause severe immune woman is Rh(D) negative, Rh(D) sensitization will not
hydrops are Kell (“Kell kills”), Rh(E), Rh(c), and Duffy occur. However, 60% of Rh(D)-negative women have
(“Duffy dies”). Antigens causing less severe hydrops are Rh(D)-positive fetuses, and exposure of these women to
ABO, Rh(e), Rh(C), Ce, k, and s. Lewis a and b (Lea, Leb) as little as 0.25 mL of Rh(D)-positive blood may induce
incompatibility can cause mild anemia but not hydrops, an antibody response. Because the initial immune
because this condition primarily results in production of response is production of IgM, the index pregnancy is
IgM antibodies, which do not cross the placenta (“Lewis rarely affected. However, immunization in subsequent
lives”). For identification of women at risk for isoimmu- pregnancies triggers an IgG response that crosses the
nization, every pregnant woman should undergo blood placenta and causes hemolysis. Risk factors for Rh(D)
type and antibody screening at the first prenatal visit and sensitization include a mismatched blood transfusion
again in the third trimester. (95% sensitization rate), ectopic pregnancy (< 1%), abor-
Sixty percent of cases of immune hydrops result from tion (3% to 6%), amniocentesis (1% to 3%), and preg-
ABO incompatibility; however, only Rh(D) isoimmuniza- nancy itself. Indeed, the sensitization rate is 16% to 18%
tion can be prevented. The Rh(D) antigen is expressed after a normal pregnancy without Rh0(D) immune globu-
only on primate erythrocytes and becomes evident by 38 lin administration, 1.3% with Rh0(D) immune globulin
days of intrauterine life. A mutation in the Rh(D) gene at delivery only, and 0.13% with anti-Rh0(D) immune
on chromosome 1 results in lack of expression of Rh(D) globulin at 28 weeks and again after delivery.193,194 The
antigen on circulating erythrocytes (Rh[D] negative). risk for isoimmunization depends on the volume of fetal-
This mutation arose in the Basque region of Spain, and maternal hemorrhage (Table 6-12). Passive immuniza-
the difference in prevalence of Rh(D)-negative individu- tion with Rh0(D) immune globulin can destroy fetal
als between the races likely reflects the amount of Spanish erythrocytes before they evoke a maternal immune
blood in their ancestry: Caucasian, 15%; African- response, thereby preventing sensitization. Therefore,
American, 8%; African, 4%; Native American, 1%; and Rh0(D) immune globulin should be given within 72 hours
Asian, less than 1%.193 If the fetus of an Rh(D)-negative of potential exposure; 300 µg given intramuscularly is
118 PART III Fetal and Neonatal Assessment and Therapy
adequate for exposure to as much as 30 mL of fetal whole this indication.109,110 Although the data are inconsistent,
blood or 15 mL of fetal red blood cells. there is a suggestion that antenatal testing at 40 to 42
Once isoimmunization has occurred, passive immuno- weeks’ gestation may be associated with improvements in
globulin is not useful. Such pregnancies should be perinatal outcome. In one retrospective study, women
observed closely for evidence of fetal compromise. Fetal with routine antenatal testing beginning at 41 weeks had
hemolysis results in release of bile pigment into the amni- lower rates of cesarean delivery for nonreassuring fetal
otic fluid, which can be quantified as a change in optical test results than women in whom testing was started at
density measured at wavelength 450 nm. Traditionally, 42 weeks (2.3% versus 5.6%, respectively; P < .01).202 In
the extent of hemolysis had been measured with serial addition, the group with delayed antenatal testing expe-
amniocenteses, with amniotic fluid optical density plotted rienced three stillbirths and seven other neonatal major
against gestational age; increased density (upper 80% of morbidity events, compared with none in the group who
zone 2 or zone 3 of the Liley curve) is associated with a had antenatal testing from 41 weeks (P < .05).202
poor prognosis,195,196 and prompt intervention is indi- In the post-term period, evidence of fetal compromise
cated. Measurements of peak systolic velocity in the fetal (nonreassuring fetal test results) or oligohydramnios
MCA by means of noninvasive Doppler velocimetry have (e.g., low amniotic fluid volume) should prompt delivery.2
now emerged as the best tool to accurately identify fetuses Oligohydramnios may result from uteroplacental insuf-
with severe anemia requiring urgent intervention, regard- ficiency or increased renal artery resistance and may pre-
less of the cause of the anemia.113,194,197 The sensitivity of dispose to umbilical cord compression, thus leading to
an elevated MCA peak systolic velocity (i.e., >1.5 MoM intermittent fetal hypoxemia, meconium passage, and
for a given gestational age) for predicting moderate to meconium aspiration. A uniform definition for oligohy-
severe anemia approaches 100%.113 Depending on gesta- dramnios has not been established; however, options are
tional age, these interventions may include immediate as follows: (1) a depth of less than 2 cm for the maximum
delivery or intrauterine blood transfusion. vertical fluid pocket; (2) amniotic fluid index less than
5 cm (i.e., < 5 cm for the sum of the depths in cm of the
largest vertical pocket in each of four uterine quadrants);
Post-Term Pregnancy and (3) product of length times width times depth of the
Post-term (prolonged) pregnancy is defined as any pregnancy largest pocket (in cm) less than 60. Adverse pregnancy
that continues to or beyond 42 weeks (294 days) from the outcomes (nonreassuring FHR tracing, low Apgar score,
first day of the last normal menstrual period or 14 days and neonatal intensive care unit admission) are more
beyond the best obstetric estimate of the EDD.2,198 The common when oligohydramnios is present. Frequent
prevalence of post-term pregnancy depends on the patient (twice-weekly) screening of post-term patients for oligo-
population (e.g., percentage of primigravidas, incidence hydramnios is important, because amniotic fluid can
of pregnancy complications, frequency of spontaneous become dramatically reduced within 24 to 48 hours. One
preterm births) and the local practice patterns (e.g., use of prospective double-blind cohort study of 1584 women
ultrasonographic assessment of gestational age, cesarean after 40 weeks’ gestation found that an amniotic fluid
delivery rates, use of labor induction). Approximately index less than 5 cm with no largest vertical fluid pocket
10% (range, 3% to 14%) of all pregnancies continue depth greater than 2 cm was associated with birth asphyxia
beyond 42 weeks, and 4% (range, 2% to 7%) continue and meconium aspiration, although the sensitivity for
beyond 43 weeks in the absence of obstetric intervention.2 adverse outcomes was low.203
Compared with delivery at 40 weeks, post-term pregnan-
cies pose significant risks to both the mother (including
higher risk for cesarean delivery, severe perineal injury,
Intrauterine Fetal Demise
and postpartum hemorrhage) and the fetus (including Intrauterine fetal demise (IUFD), also known as stillbirth,
stillbirth, fetal macrosomia, birth injury, and meconium is defined in the United States as demise of the fetus after
aspiration syndrome).2,198-201 The risks to the fetus can be 20 weeks’ gestation and prior to delivery.204-206 In Europe,
largely prevented by routine induction of labor for all only fetuses more than 24 weeks’ gestation are included.
low-risk pregnancies at 40 to 41 weeks’ gestation.2,199 The stillbirth rate in the United States diminished from
Post-term pregnancy is a universally accepted indica- 15.8 per 1000 total births in 1960 to 7.5 per 1000 births
tion for antenatal fetal surveillance,2 although the efficacy in 1990.205,206 However, it remains a vastly underappreci-
of this approach has not been validated by prospective ated clinical problem, with antepartum stillbirths account-
randomized trials. Options for evaluating fetal well-being ing for more perinatal deaths than either complications
include NST with or without amniotic fluid volume of prematurity or sudden infant death syndrome.207 Risk
assessment, BPP, CST, and a combination of these factors for stillbirth include extremes of maternal age,
modalities. There is no consensus as to which of these chromosomal disorders, congenital malformations, ante-
modalities is preferred, and no single method has been natal infection, multiple pregnancy, prior unexplained
shown to be superior.2 The ACOG has recommended IUFD, post-term pregnancy, fetal macrosomia, male
that antepartum fetal surveillance be initiated by 42 fetus, umbilical cord and placental abnormalities, and
weeks’ gestation at the latest, without making a specific underlying maternal medical conditions (e.g., chronic
recommendation about the type of test or frequency.2 hypertension, pregestational or gestational diabetes
Many investigators would advise twice-weekly testing mellitus, autoimmune disorders, inherited or acquired
with some evaluation of amniotic fluid volume at least thrombophilia).204,208,209
weekly. Doppler ultrasonography has no benefit in moni- Although older studies observed that approximately
toring the post-term fetus and is not recommended for 50% of cases of IUFD were unexplained, an aggressive
6 Antepartum Fetal Assessment and Therapy 119
Antenatal Corticosteroids births, but not all infants are at equal risk. The pulmonary
system is among the last of the fetal organ systems to
Respiratory distress syndrome (RDS) refers to respiratory become functionally mature. Thus, RDS is primarily,
compromise presenting at or shortly after delivery due to although not exclusively, a disease of preterm infants,
a deficiency of pulmonary surfactant, an endogenous with the incidence and severity highly dependent on ges-
detergent that serves to decrease the surface tension tational age. For example, RDS affects more than 80%
within alveoli, thereby preventing alveolar collapse. of infants younger than 28 weeks’ gestation and 10% to
Overall, neonatal RDS affects approximately 1% of live 15% of all infants weighing less than 2500 g.261,262 RDS
6 Antepartum Fetal Assessment and Therapy 121
remains a major cause of perinatal morbidity and mortal- pregnancy prior to fetal viability (i.e., before 23 to 24
ity in extremely preterm infants. In addition to gesta- weeks’ gestation) in which the fetus has a normal karyo-
tional age, a number of other factors influence the risk type and an isolated malformation that, if untreated, will
for RDS in a given fetus. For reasons that are not clear, result in fetal or neonatal demise. A detailed understand-
African-American ethnicity, female gender, preeclampsia, ing of the natural history of the malformation is essential
and intrauterine exposure to cigarette smoke are protec- when one is considering whether to recommend surgery.
tive against the development of RDS. Fetal surgery should not be attempted if the natural
In 1972, Liggins and Howie263 demonstrated that the history of the disorder is unknown or if the chances of
administration of a single course of two antenatal doses survival without in utero treatment are equal to or greater
of a corticosteroid (betamethasone) reduced the inci- than the risks of the procedure. The only two random-
dence of RDS by 50%. This original observation has ized controlled trials published to date in fetal surgery—
since been confirmed by a number of investigators.225,264-267 one on tracheal occlusion for the management of
A meta-analysis of 12 randomized controlled trials with congenital diaphragmatic hernia274 and the other on pre-
more than 3000 participants concluded that antenatal natal versus postnatal repair of myelomeningocele275—
administration of corticosteroids to women in preterm found little significant benefit to in utero surgery. Repair
labor reduced the incidence of neonatal RDS by 40% to of lesions that are not believed to be life threatening (e.g.,
60% and resulted in an improvement in overall sur- cleft lip and palate) should be deferred until after delivery
vival.225 In one study, a single course of antenatal corti- to minimize risks to the mother.
costeroids resulted in a threefold rise in the chance of Before in utero surgery can be recommended, a thor-
unaffected survival in neonates with a birth weight less ough evaluation must be performed to (1) precisely char-
than 1500 g.264 Certain steroids cross the placenta and acterize the defect, (2) exclude associated malformations,
induce cellular differentiation at the expense of growth. (3) perform a fetal karyotype analysis, and (4) eliminate
Type II pneumocytes in the lungs differentiate and begin the possibility that the condition can be treated using less
making pulmonary surfactant, which accounts for the aggressive technologies. Detailed counseling about the
decrease in risk for RDS, and endothelial cells lining the risks and benefits of the proposed procedure is required,
vasculature undergo cellular maturation and stabilization, and written informed consent is mandatory. Such a dis-
which explains the concomitant drop in incidence of cussion must include a detailed review of the risks to both
bleeding into the brain (intraventricular hemorrhage) or the fetus and the mother, including preterm PROM
gastrointestinal tract (necrotizing enterocolitis).265 Pred- (28% to 100%), preterm labor and delivery (> 50%),
nisone does not cross the placenta and therefore does not maternal pulmonary edema (20% to 30%), placental
have a similar protective effect. abruption (5% to 10%), chorioamnionitis and sepsis
The National Institutes of Health and the ACOG (< 5%), and maternal death (rare).242,244 Specific examples
have recommended that a single course of antenatal cor- of fetal surgical procedures are summarized in
ticosteroids, defined as either betamethasone (12 mg Table 6-15.
intramuscularly q24 h × two doses) or dexamethasone
(6 mg intramuscularly q12 h × four doses), be given after
23 to 24 weeks’ gestation to any pregnant woman in
whom delivery before 34 weeks’ gestation is threaten-
KEY POINTS
ing.266,267 There is as yet no proven benefit to antenatal
administration of corticosteroids after 34 weeks’ gesta- • Accurate determination of gestational age is
tion266,267 or between 32 to 34 weeks in the setting of essential for the management of pregnancy
preterm PROM,268 but this situation is largely due to complications and the effective use of
the absence of data in these subgroups. Although the antepartum fetal testing.
maximum benefit of antenatal corticosteroids is achieved
24 to 48 hours after the first injection, as little as 4 hours • Ultrasonography can be used to estimate
of treatment exerts some protective effect. This protec- gestational age, assess fetal growth, monitor
tive effect lasts for 7 days, after which further benefit is amniotic fluid volume, and detect and
unclear. Multiple (three or more) courses of antenatal characterize fetal anomalies.
corticosteroids have been associated with fetal growth • Appropriate fetal growth is strongly correlated
restriction, smaller head circumference, and (in animals) with fetal health and can be assessed either
abnormal myelination of the optic nerves; consequently, clinically or with ultrasonography. Inappropriate
multiple courses are not routinely recommended. If a fetal growth requires further evaluation.
threat of preterm delivery occurs more than 2 weeks after • Fetal movement charts (“kick counts”) can be
the initial course was completed, a rescue course of cor- used to confirm fetal well-being in both high- and
ticosteroids is recommended.269-273 low-risk populations. High-risk pregnancies may
require additional fetal monitoring such as the
nonstress test (NST), biophysical profile (BPP), or
Fetal Surgery contraction stress test (CST).
Fetal surgery has been proposed in selected cases to • A fetal karyotype can be obtained by chorionic
prevent progressive organ damage or to restore normal villus sampling, amniocentesis, or fetal blood
anatomy and fetal development (see Chapter 7). The sampling (cordocentesis).
ideal case for fetal surgery consists of a singleton
122 PART III Fetal and Neonatal Assessment and Therapy
16. Bennett KA, Crane JM, O’Shea P, et al. First trimester ultrasound
• Doppler velocimetry has advanced our screening is effective in reducing postterm labor induction rates:
understanding of maternal-fetal physiology, but a randomized controlled trial. Am J Obstet Gynecol 2004;
190:1077-81.
its role in confirming fetal well-being is unclear. 17. Waldenström U, Axelsson O, Nilsson S, et al. Effects of routine
• Additional radiologic imaging (especially magnetic one-stage ultrasound screening in pregnancy: a randomised con-
resonance imaging) may be used in selected trolled trial. Lancet 1988; 2:585-8.
18. Saari-Kemppainen A, Karjalainen O, Ylostalo P, Heinonen OP.
cases to better define fetal malformations. Ultrasound screening and perinatal mortality: controlled trial of
• A number of intrauterine therapies have been systematic one-stage screening in pregnancy. The Helsinki Ultra-
shown to improve perinatal outcome in selected sound Trial. Lancet 1990; 336:387-91.
cases, including antenatal corticosteroid 19. Ewigman BG, Crane JP, Frigoletto FD, et al. Effect of prenatal
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Cordostat grasping device for selective ligation of the umbilical
C H A P T E R 7
CHAPTER OUTLINE
Fetal therapy originated in 1963 with Sir William Liley’s during birth, while the uteroplacental unit remains
successful intraperitoneal blood transfusion to a fetus functional.
with erythroblastosis fetalis.1 This was followed by many Fetal surgery is reasonable only with informed consent
years of discouraging attempts to transfuse blood via and only if (1) the lesion is diagnosed accurately, (2) the
direct cannulation of fetal vessels through a small uterine lesion’s severity is assessed correctly, (3) the associated
incision.2 In 1981, after careful experimentation and anomalies that contraindicate intervention are excluded,
practice in sheep3,4 and rhesus monkeys,5 the first success- (4) the maternal risk is acceptably low, and (5) the neo-
ful human fetal surgery, a vesicostomy, was performed in natal outcome would be better with in utero surgery than
a fetus with bilateral hydronephrosis due to a lower with surgery performed after delivery. With all fetal sur-
urinary tract obstruction.6 gical procedures, an emphasis also must be placed on
Advances in prenatal diagnostic technology, particu- maternal welfare to guard against undue maternal risk.7,8
larly in the resolution of imaging, contribute to increas- Fetal surgical interventions can be broadly categorized
ing sophistication in diagnosis of fetal disorders, into three kinds of procedures, namely, open surgical
principally anatomic anomalies. Fetal therapy is largely procedures, minimally invasive procedures, and intrapar-
nonsurgical (e.g., administration of medications, nutri- tum procedures. Open surgical procedures involve
ents, blood, stem cells) (see Chapter 6). Some identified both maternal laparotomy and hysterotomy with use of
disorders are amenable to intrauterine fetal surgery, but pharmacologic agents to maintain uterine relaxation.
most anatomic malformations diagnosed in utero remain These procedures are typically performed near mid ges-
unsuitable for antenatal intervention. Prenatal diagnosis tation and entail greater maternal and fetal risks com-
of serious malformations (e.g., those that are uncorrect- pared with the minimally invasive techniques, including
able and incompatible with normal postnatal life) allows a significant risk for preterm premature rupture of mem-
the choice of pregnancy termination. Most correctable branes (PROM), preterm labor and delivery, uterine
malformations are best managed after delivery at term dehiscence, oligohydramnios, hemorrhage, pulmonary
gestation, but antepartum recognition allows time for the edema, and fetal mortality.9,10 In addition, after an open
coordination of appropriate prenatal and postnatal care, surgical procedure, a cesarean delivery is required for the
including transfer of peripartum care to an appropriate subsequent delivery and all future deliveries owing to the
medical center while the fetus is in utero rather than as a location of the hysterotomy and the associated risks for
newly delivered, fragile neonate. Some defects, especially uterine dehiscence or rupture. Open fetal surgical proce-
those that cause airway obstruction, can be treated with dures have been used to repair fetal myelomeningoceles,
an intrapartum intervention, in which the fetus under- resect congenital pulmonary airway abnormalities, and
goes repair of the defect and/or the airway is secured debulk sacrococcygeal teratomas.
128
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 129
Minimally invasive procedures involve either male fetuses or urethral obstruction in females. Other
endoscopic or percutaneous procedures guided by ultra- causes of fetal obstructive uropathy include obstruction
sonography, typically performed at mid gestation (e.g., at the ureteropelvic or vesicoureteric junction and a
intrauterine blood transfusion, fetoscopic laser coagula- number of complex disorders in females (e.g., cloacal
tion for twin-to-twin transfusion syndrome [TTTS]). plate anomalies). These uropathies are easily detected
They include a significantly lower risk for preterm labor by ultrasonography, which is often performed to investi-
and delivery than open procedures because they do not gate oligohydramnios from diminished fetal urine
require a hysterotomy, yet the risk for preterm PROM output. Severe obstructive lesions may lead to progressive
remains. renal dysplasia and dysfunction, bladder distention, and
The third kind of procedure involves a modification of oligohydramnios and ultimately result in devastating
cesarean delivery to allow intrapartum fetal therapy while developmental consequences, such as limb and facial
the fetus remains supported by placental gas exchange. deformities and pulmonary hypoplasia (Figure 7-1).13
These delivery techniques are termed EXIT procedures, Preterm delivery allows early urinary tract decompres-
for ex utero intrapartum therapy.11 EXIT procedures are sion ex utero, but fetal pulmonary immaturity limits the
most often employed (1) to secure the airway by endotra- efficacy of this approach. Early intrauterine intervention
cheal intubation, bronchoscopy, or tracheostomy or (2) to with placement of a vesicoamniotic shunt allows drainage
perform other fetal procedures while gas exchange con- of urine from the fetal bladder into the amniotic cavity,
tinues in the placenta (placental bypass). The EXIT pro- thereby decompressing the urinary tract. In animal
cedure enables the prevention of postnatal asphyxia in models, in utero relief of obstructive uropathy improves
newborns with lesions such as cystic hygroma, lymphan- dysplastic renal histology, restores normal urine flow and
gioma, cervical teratoma, and congenital syndromes, in amniotic fluid volume, and results in improved lung
whom securing an airway after birth can be problematic. growth and development.14 The applicability of these
The procedure is also used as a bridge to extracorporeal findings to human fetal obstructive uropathy remains
membrane oxygenation (ECMO) for a fetus with cardio- unclear and controversial.15
pulmonary disease at risk for postnatal cardiac failure or Vesicoamniotic catheter shunts have been used for
failure of adequate gas exchange in the lungs. intrauterine treatment of bilateral hydronephrosis since
Fetal surgery is a reasonable therapeutic intervention the early 1980s.16 These valveless, double-coiled cathe-
for certain correctable fetal anomalies with predictable, ters are placed percutaneously with ultrasonographic
life-threatening, or serious developmental consequences. guidance, with one coil being left in the urinary bladder
If untreated, these lesions can interfere with fetal organ and the other in the amniotic space. Common problems
development or result in cardiac failure; if corrected in associated with these catheters include (1) difficult place-
utero, irreversible organ damage and fetal demise may be ment, occlusion, and displacement; (2) fetal trauma, iat-
prevented. rogenic abdominal wall defects, and amnioperitoneal
leaking; and (3) preterm PROM, preterm labor, and
infection.17 Neonatal survival rates after fetal vesicoam-
INDICATIONS AND RATIONALE FOR niotic shunting (performed from the 1980s to 2001)
FETAL SURGERY varied from 50% to 90%, with approximately half of the
survivors having normal renal function.15,18,19 Currently
Bilateral Hydronephrosis–Obstructive a multicenter, randomized controlled trial is underway
Uropathy comparing the perinatal mortality and renal function of
fetuses with lower urinary tract obstruction treated by
Congenital obstructive uropathy occurs in approximately either vesicoamniotic shunting or conservative noninter-
0.1% of pregnancies.12 Congenital bilateral hydrone- ventional care.20
phrosis results from fetal urethral obstruction at the Fetal cystoscopy is a more recent treatment option
bladder outlet, most often by posterior urethral valves in that allows direct visualization of the fetal urethra.
Potter’s facies
Oligohydramnios Hypoplastic lungs
Flexion contraction
Type 4 cystic
Hydronephrosis dysplasia
Renal failure
FIGURE 7-1 ■ Developmental consequences of fetal
urethral obstruction. Obstructed fetal urinary flow Abdominal muscle
results in hydronephrosis, hydroureter, megacys- Hydroureter and deficiency syndrome
tis, oligohydramnios, and pulmonary hypoplasia. megacystis Prune belly
(Redrawn from Harrison MR, Filly RA, Parer JT, et al.
Management of the fetus with a urinary tract malfor-
mation. JAMA 1981; 246:635-9.)
130 PART III Fetal and Neonatal Assessment and Therapy
hydrops fetalis, pulmonary compression, and fetal or The specific cause of myelomeningocele remains
neonatal death.62 unknown. Animal models have demonstrated improved
neonatal neurologic function with fetal closure of the
defect in utero.67,68 The results associated with defect
Sacrococcygeal Teratoma closure support a “two-hit” disease model in which the
The prevalence of sacrococcygeal teratoma (SCT) is pathology is produced by failure of the fetal neural tube
approximately 1 in 20,000 to 40,000.63 Some fetuses with to form combined with prolonged exposure to the uterine
SCT undergo massive tumor enlargement, experience amniotic fluid.69 Mutations of the PAX3 gene and direct
hydrops fetalis and placentomegaly, and die in utero. cord trauma may also play a role in the pathophysiology
These tumors function as large arteriovenous fistulas, and associated with a myelomeningocele.70
fetal demise results from high-output cardiac failure. The 5-year mortality of myelomeningocele is approxi-
Management of these tumors requires close surveillance mately 8% for live births; if it is not corrected in utero,
because they can grow rapidly and reach a size as large as surgical closure must be performed within a few days
1000 cubic centimeters.63 Fetuses with large lesions are at after birth.71 Ventriculoperitoneal shunting is required in
risk for intrapartum dystocia or tumor rupture and hem- 85% to 90% of uncorrected cases; however, despite suc-
orrhage; these fetuses may require cesarean delivery. cessful shunting, permanent deficits such as central
Fetuses with lesions diagnosed before 30 weeks’ gestation hypoventilation, vocal cord dysfunction, and oromotor
have a poor prognosis but may benefit from surgical deb- and swallowing dysfunction can still occur from the asso-
ulking in utero; surgical techniques have not reached the ciated Arnold-Chiari malformation.72 The average intel-
necessary level of sophistication to allow complete resec- ligence quotient in myelomeningocele patients who
tion of lesions that deeply invade the pelvis. In utero radio- require ventriculoperitoneal shunting is 80 (low normal).73
frequency ablation and thermocoagulation have been The purpose of fetal surgery for myelomeningocele is
used to reduce the tumor blood supply, but the benefit to improve function later in life.69 Fetal surgery is primar-
remains unclear.64 Catheterization of a fetal hand or ily performed through an open fetal surgical technique.
umbilical cord vein for blood and crystalloid transfusion Preliminary results suggest that in utero repair success-
during tumor resection may be needed. To date, there has fully reverses the hindbrain herniation of the Arnold-
been no significant improvement in outcome with inter- Chiari II malformation, probably through normalization
vention in cases of SCT with hydropic fetalis. of cerebrospinal fluid flow, and decreases the need for
Some SCT cases are accompanied by “maternal mirror ventriculoperitoneal shunt placement before 1 year of
syndrome” or Ballantyne syndrome, a hyperdynamic state age.74 More recently, a randomized, prospective, multi-
(i.e., hypertension, peripheral and pulmonary edema) in center clinical trial completed between 2003 and 2010
which the maternal physiology mirrors the abnormal cir- examined the risks and benefits of open fetal surgery for
culatory physiology of the hydropic fetus.65 This syn- myelomeningocele repair compared with standard post-
drome is associated with a substantial increase in fetal natal repair in 183 patients.75 Open fetal repair reduced
mortality and maternal morbidity and requires aggressive the need for ventriculoperitoneal shunting and improved
management similar to that used for severe preeclampsia, motor function at 30 months of age, but increased the
a disease from which it must be distinguished. Platelet risk for preterm birth and a partial or complete uterine
count, aspartate aminotransferase, alanine aminotransfer- dehiscence. Two perinatal deaths occurred in each group.
ase, and haptoglobin are typically unaffected in maternal Table 7-2 displays a subset of outcome measures that
mirror syndrome and may serve as diagnostic clues to rule were significantly different between the prenatal and
out severe preeclampsia and HELLP (hemolysis, elevated postnatal repair groups. Further data from the trial will
liver enzymes, low platelets). Unfortunately, maternal include assessment of the long-term benefit from the
mirror syndrome typically does not resolve quickly, even prenatal intervention.
with rapid correction of the fetal pathophysiology, and A recent study of endoscopic intrauterine myelome-
severe maternal complications including pulmonary ningocele repair resulted in an extraordinarily high com-
edema occur in about 20% of cases.65 plication rate for both mothers and fetuses.76 Of the 19
study patients, three fetuses died intraoperatively and
another three procedures were stopped owing to severe
Myelomeningocele hemorrhage from the procedure. Although this interven-
Although not lethal, a myelomeningocele is a protrusion tion was associated with spinal segmental neuroprotec-
of the meninges and spinal cord through a congenital tion, it resulted in significantly more complications; the
defect in the vertebrae and overlying muscles and skin. It authors concluded that, pending further advances, this
can result in lifelong morbidity and disability, including technique is unsuitable as standard care.76
paraplegia, bowel and bladder incontinence, hydrocepha-
lus, Arnold-Chiari II malformation, and impaired cogni-
tion.66 Myelomeningocele has an incidence of about 1 in
Twin-to-Twin Transfusion Syndrome
2000 live births but is becoming less common owing to An abnormal connection of chorionic blood vessels in the
folate supplementation in the maternal diet. In addition, placenta between two monochorionic twins can result in
detection by ultrasonography and alpha-fetoprotein twin-to-twin transfusion syndrome (TTTS). TTTS
screening of maternal blood has allowed for earlier diag- complicates 10% to 15% of monochorionic pregnancies,
nosis (i.e., second trimester) and consideration of preg- usually manifests at 15 to 26 weeks’ gestation, and is
nancy termination. typically recognized at 20 to 21 weeks’ gestation.77,78
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 133
TABLE 7-2 Maternal and Fetal or Neonatal Complications for MOMS Trial Patients*
Prenatal (n = 78) Postnatal (n = 80) P
Maternal Outcomes
Chorioamniotic membrane separation 20 (26%) 0 < .001
Pulmonary edema 5 (6%) 0 .03
Oligohydramnios 16 (21%) 3 (4%) .001
Placental abruption 5 (6%) 0 .03
Spontaneous rupture of membranes 36 (46%) 6 (8%) < .001
Spontaneous labor 30 (38%) 11 (14%) < .001
Blood transfusion at delivery 7 (9%) 1 (1%) .03
Hysterotomy site thin, or partial or complete 27 (36%) N/A
dehiscence noted at delivery
Fetal Outcomes
Fetal bradycardia during repair 8 (10%) 0 .003
Mean gestational age at birth (weeks) 34.1 ± 3.1 37.3 ± 1.1 < .001
Mean birth weight (g) 2383 ± 688 3039 ± 469 < .001
Respiratory distress syndrome 16 (21%) 5 (6%) .008
*The table lists maternal and fetal/neonatal complications that were significantly different (P < .05) between the prenatal and postnatal
repair groups in the Management of Myelomeningocele Study (MOMS). Other outcomes were evaluated, but only those that were
different between the two groups are included. Data for each group are shown as both an absolute number and as a percentage.
Modified from Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl
J Med 2011; 364:993-1004.
Intertwin transfusion is common between monochori- TTTS is untreated, it carries a greater than 80% mortal-
onic twins and is usually balanced by the presence of ity with 15% to 50% risk for significant morbidity in
arterioarterial (AA) and venovenous (VV) connections; surviving neonates.83
the presence of AA connections is associated with a nine- A variety of therapeutic management techniques have
fold reduction in TTTS.79 By contrast, unidirectional been developed, including (1) serial amnioreduction to
and imbalanced blood flow through arteriovenous (AV) control polyhydramnios and reduce the risk for preterm
chorionic vessels results in TTTS. In normal fetoplacen- labor, (2) surgical septostomy to equalize amniotic pres-
tal vasculature, the umbilical artery branches at the pla- sures, (3) selective feticide to allow the other fetus to
centa surface and traverses and then descends into the survive, and (4) selective fetoscopic laser photocoagula-
tissue, where it further branches into capillary divisions tion (SFLP) of the vascular anastomoses between the
for gas and nutrient exchange. The arterial system is two twins. Serial amnioreduction was demonstrated to
“paired” with venous vasculature, which returns blood to improve placental perfusion and decrease the occurrence
the umbilical cord. In TTTS, the umbilical artery simi- of preterm delivery.84 In a retrospective review of 223
larly descends into the placenta and cotyledon, but rather twin sets with TTTS, amnioreduction resulted in an
than connecting with a paired vein it connects with a vein overall birth survival rate of 78%, with 65% of recipient
that transports blood to the other twin.80 twins and 55% of donor twins alive at 1 month of age.85
The twin serving as the recipient demonstrates poly- In a prospective randomized trial comparing serial amni-
cythemia, polyuria, polyhydramnios, and hypertrophic oreduction to septostomy, there was no difference in the
cardiomyopathy; this twin is at risk for hydrops fetalis and rate of survival between the two techniques.86 Septostomy
fetal death. The twin serving as the donor is typically is rarely used for treatment because the creation of a
hypovolemic, growth restricted, and pressed against the single amniotic sac can increase the risk for umbilical
endometrium in an oligohydramniotic sac (hence the cord entanglement.
designation “stuck” or “pump” twin) and often has a vela- The laser used for SFLP is typically inserted percuta-
mentous cord insertion; this twin is at risk for neonatal neously through an endoscope (≤ 2.0 mm diameter) into
renal failure, tubular dysgenesis and dysfunction, and the recipient twin’s amniotic sac. Maternal anesthesia is
high cardiac output hydrops fetalis. Diagnosis is cur- commonly managed with either neuraxial blockade or
rently based on ultrasonographic findings that focus on local anesthetic infiltration from skin to myometrium.
differences in fetal size or amniotic sac fluid volume, Fetoscope placement is determined by placental location
presence of cardiac dysfunction in the recipient twin, and is guided by ultrasonography. Vessels that cross the
umbilical cord size, and abnormal umbilical arterial flow dividing membrane separating the amniotic sacs are visu-
velocity.77,81 Twin size discordance is not always present alized, and abnormal connecting vessels are selectively
and is no longer considered necessary to confirm the coagulated with the laser.77,80 On occasion, based on ana-
diagnosis. For unclear reasons, fetuses with TTTS are at tomic constraints created by the location of the fetuses
risk for neurologic injury with white-matter lesions and and placenta, nonselective laser ablation is performed;
long term disability; poor neurodevelopmental outcomes however, this type of ablation is associated with higher
are associated with increased TTTS severity, delayed rates of intrauterine fetal demise.77,87 Ablation of all abnor-
therapeutic interventions, and preterm delivery.82 If mal connecting vasculature is not needed for success of
134 PART III Fetal and Neonatal Assessment and Therapy
the procedure.88 After completion of the SFLP, amniotic and preterm birth. If untreated, TRAP sequence is associ-
fluid may be removed to reduce the degree of polyhy- ated with a risk for intrauterine death of the pump twin
dramnios and possibly decrease the risk for preterm labor. exceeding 50%.95 Diagnosis is confirmed with ultrasono-
A 2004 randomized multicenter trial compared laser graphic demonstration of reverse flow to the acardiac twin
therapy to amnioreduction for treatment of severe TTTS via the umbilical artery. Cardiovascular failure in the
diagnosed between 15 and 26 weeks’ gestation.89 Rates of pump twin is the indication for intervention, and early
at least one twin survival were significantly higher in the diagnosis is beneficial for optimal treatment.
laser treatment group at both 28 days (76% versus 56%, The goal of therapy is to interrupt the vascular com-
P < .01) and 6 months of life (76% versus 51%, P < .01). munication between the two twins. In contrast to the
In addition, neurologic outcomes were better in the laser treatment of TTTS, treatment of TRAP sequence results
treatment group. A subsequent prospective study of a in the death of the anomalous nonviable fetus. Percutane-
large subgroup of survivors from this trial observed these ous endoscopic laser or radiofrequency coagulation of the
children for 6 years and found no additional change in umbilical cord and/or placental vascular anastomoses is
survival or long-term neurologic outcome from the origi- the most viable therapeutic option.96,97 Alternative thera-
nal 6-month data.90 A meta-analysis of studies published pies include sectio parva (selective cesarean delivery of one
between 1997 and 2007 noted that treatment of TTTS of multiple fetuses), percutaneous thrombosis of the acar-
with laser ablation resulted in a higher overall rate of fetal diac twin’s umbilical cord with coils or other thrombo-
survival than amnioreduction91; similar findings were genic material, and alcohol-impregnated suture cord
demonstrated in a Cochrane review of treatment for ligation. A retrospective review of 60 TRAP sequence
TTTS.92 cases from multiple European centers using endoscopic
A more recent variation of the SFLP technique laser coagulation noted overall survival rates approaching
requires vascular laser ablation in a specific sequence. 80% and a median gestational age of 37.4 weeks at deliv-
First, ablation occurs at the donor-to-recipient AV anas- ery.98 An additional study, using radiofrequency coagula-
tomoses, then at the recipient- to-donor AV anastomoses, tion in 26 TRAP sequence cases at a single U.S. medical
then at the AA superficial anastomoses, and finally at the center, demonstrated a 92% survival rate of the viable
VV superficial anastomoses. The order of the procedure twin with a mean gestational age of 35.6 weeks at deliv-
is designed to reduce the chance of hemodynamic com- ery.96 Both procedures are typically performed with infil-
promise and hypotension during the procedure in the tration of local anesthesia at the insertion site of the
donor twin93; however, it is associated with longer opera- ablation device, although neuraxial anesthesia has also
tive times and increased case difficulty, particularly with been used. The procedures are guided by ultrasonogra-
an anterior placenta. In a single-institution study of con- phy, and absence of flow to the nonviable acardiac twin
secutive SFLP for treatment of TTTS, twins treated with is confirmed with Doppler imaging at the end of the
this sequence had better survival rates than twins whose procedure and again 12 to 24 hours later.
SFLP procedure was performed without a specific
sequence.93 A prospective multicenter trial found a sig-
nificantly improved 30-day survival of both fetuses and
Congenital Heart Defects
improved donor survival with this sequential technique The most commonly performed closed fetal cardiac
when compared with a cohort control group.94 intervention for a congenital heart defect is an aortic
The most common complication of SFLP is preterm valvuloplasty for mid-gestational aortic stenosis with
PROM with subsequent preterm labor and delivery. evolving hypoplastic left heart syndrome. Technical
Other possible complications include placement of the success as high as 75% has been reported using an angio-
trocar through the placenta, hemorrhage, and possible plasty balloon over a guidewire inserted percutaneously
membrane perforation resulting in limb entrapment and through an access cannula.99 Approximately 40% of suc-
ischemia.77 In conclusion, trial results and meta-analyses cessful cases result in aortic regurgitation and minimal
provide evidence that SFLP results in superior outcomes subsequent left ventricular growth; however, the physiol-
than amnioreduction for the treatment of TTTS. Further ogy of the left ventricle improves and leads to improved
research is needed to determine optimal techniques and aortic and mitral valvular growth. In about 30% of the
timing of interventions for the treatment of TTTS. successful cases, biventricular circulation is present at
birth. Other congenital heart defects that may benefit
from antepartum closed fetal cardiac intervention include
Twin Reversed Arterial (1) hypoplastic left heart syndrome with an intact or
highly restrictive atrial septum and (2) evolving hypoplas-
Perfusion Sequence tic right heart syndrome with pulmonary atresia or ste-
In monozygotic twins, one twin can also perfuse the other nosis without a ventricular septal defect.100,101
by retrograde blood flow though AA anastomoses. Twin More complex congenital cardiac defects that might
reversed arterial perfusion (TRAP) sequence affects 1% benefit from open repair have only been repaired in
of monozygotic twins and 1 in 30 triplets. Inadequate animal models and require fetal extracorporeal circula-
perfusion of the recipient twin via retrograde flow results tory bypass; the use of fetal cardiac bypass induces a
in the development of a lethal set of anomalies that catecholamine-mediated fetal stress response that
include acardia and acephalus. The normal (“pump”) twin increases vascular resistance and cardiac afterload and is
perfuses both itself and the nonviable twin and is at risk poorly tolerated by the immature fetal myocardium. Fetal
for high-output congestive heart failure, polyhydramnios, cardiac bypass can also result in severe placental
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 135
dysfunction when the high-capacitance, low-resistance management (see Chapter 2) and must take an active role
placenta is incorporated as the oxygenator, resulting in as a member of the multidisciplinary team. Imaging
endothelial dysfunction and leukocyte and complement studies should be reviewed for placental location, ana-
activation. After fetal cardiac bypass, increases in placen- tomic information about the congenital lesion, and esti-
tal vascular resistance, reduced blood flow, impaired gas mated fetal weight.
exchange, and fetal acidosis are frequently observed.102,103 Unlike other surgical procedures performed during
Correction of complex congenital cardiac defects, either pregnancy in which the fetus is an innocent bystander
open or closed, requires careful anesthetic and pharma- (e.g., maternal appendectomy), fetal surgery involves two
cologic strategies for myocardial protection. surgical patients. This requires the anesthesiologist to
balance the anesthetic needs of both patients, as well as
control uterine tone throughout the perioperative period.
SURGICAL BENEFITS AND RISKS Complete uterine relaxation is necessary during open
fetal surgical procedures.
The primary goal of intrauterine fetal surgery is to Maternal analgesia and anesthesia can involve local
improve neonatal outcomes over that of surgery per- infiltration, intravenous sedation, neuraxial anesthesia,
formed after a preterm or term delivery. The intrauterine general anesthesia, or a combination of these techniques,
environment supports rapid wound healing (i.e., without depending on the procedure, location of the placenta, and
scarring before mid gestation),104 and the umbilical cir- maternal co-morbidities. Fetal analgesia and anesthesia
culation meets nutritional and respiratory needs without can be achieved via placental transfer of anesthetic agents
outside assistance. The poorly developed fetal immune given to the mother, via direct fetal intravenous or intra-
surveillance system may facilitate certain invasive proce- muscular administration of agents, or by a combination
dures. However, continued refinement of surgical and of these methods. An appropriate method of fetal moni-
anesthetic techniques, reduction of maternal and fetal toring and the potential requirement for fetal intravenous
risk, and appropriate clinical trials for each intervention access or fluid resuscitation should be determined preop-
must occur before fetal surgery can be performed on a eratively. The operative team should be prepared for
more routine basis for a given congenital anomaly. emergency situations such as maternal hemorrhage, fetal
Serious maternal complications from intrauterine fetal deterioration requiring aggressive intrauterine resuscita-
surgery are relatively uncommon. Maternal risks include tion (e.g., fetal epinephrine administration), and/or deliv-
blood loss, infection, placental abruption, and pulmonary ery and resuscitation of the viable newborn infant.110
edema secondary to tocolytic therapy and fluid overload
from absorption of significant amounts of pressurized
crystalloid uterine irrigation during fetoscopic tech- Anesthesia for Minimally Invasive and
niques.105,106 Open fetal surgery involves a hysterotomy
that is not in the lower uterine segment, and therefore
Percutaneous Procedures
all future deliveries must occur via a cesarean procedure. Local anesthetic infiltration of the abdominal wall is suf-
Maternal welfare must always be emphasized.7 ficient to reduce maternal discomfort for many percuta-
The fetal risks of intrauterine surgery remain rela- neous procedures (e.g., amniocentesis, cordocentesis,
tively high. The most common postoperative complica- intrauterine blood transfusion, needle aspiration of cysts,
tions are fetal central nervous system injuries, postoperative shunt placement into the fetal bladder or thorax, SFLP
amniotic fluid leaks, membrane separation, preterm for TTTS). Supplemental maternal analgesia and anx-
PROM, and preterm labor and delivery. Preterm delivery iolysis can be achieved by maternal administration of an
accounts for significant morbidity and mortality among opioid, a benzodiazepine, or a low-dose propofol infu-
fetuses that might otherwise have benefited from the sion, which may confer some fetal immobility and anal-
therapeutic interventions. Chorioamniotic membrane gesia via placental transfer.111 However, when larger
separation can cause amniotic bands, umbilical cord needles or multiple attempts are necessary for percutane-
strangulation, and fetal demise.107 Improved techniques ous procedures or a minilaparotomy, maternal comfort
for sealing the membranes are being devised, including can be difficult to achieve with local infiltration, even
different surgical techniques, fibrin glue, and intra- when supplemented with sedation. In these circum-
amniotic injection of platelets and cryoprecipitate.108,109 stances, neuraxial anesthesia is recommended.77,91 General
anesthesia is rarely necessary for percutaneous proce-
dures unless placental location makes the procedure sig-
ANESTHETIC MANAGEMENT nificantly challenging or uterine exteriorization is needed.
Fetal movement may be hazardous for the fetus in cases
Fundamental considerations for the anesthetic manage- of intrauterine transfusion, cord blood sampling, or tho-
ment of fetal surgery are similar to those for nonobstetric racic shunt placement, because displacement of the needle
surgery during pregnancy (see Chapter 17). Maternal or catheter may lead to trauma, bleeding, or compromise
safety is paramount. Anesthesiologists must participate in of the umbilical circulation. Placental transfer of mater-
preoperative maternal assessment and exclude women nally administered opioids and benzodiazepines can
when their perioperative risk is not acceptably low given reduce fetal movement89 but cannot ensure fetal immobil-
the potential fetal benefit. To ensure both maternal ity for more stimulating procedures. A randomized con-
and fetal safety, the anesthesiologist must understand trolled trial of the use of a maternal remifentanil infusion
the physiologic impact of pregnancy on anesthetic (0.1 µg/kg/min) demonstrated improved fetal immobility
136 PART III Fetal and Neonatal Assessment and Therapy
and operating conditions during fetoscopic surgery, when should be prepared to emergently provide general anes-
compared with maternal administration of diazepam.112 thesia if required.
Fetal immobility can be safely achieved with direct fetal Tocolysis typically is unnecessary after cordocentesis
intramuscular or umbilical venous administration of pan- or intrauterine transfusion. For more invasive percutane-
curonium or vecuronium (0.3 mg/kg intramuscularly or ous procedures (e.g., shunt catheter placement, endo-
0.1 to 0.25 mg/kg intravenously) using ultrasonographic scopic techniques), some fetal surgery groups administer
guidance. The onset of fetal paralysis occurs in 2 to 5 prophylactic tocolytic agents.
minutes, with an approximate duration of 1 to 2 hours.113
For procedures that can cause noxious stimulation to the
fetus, such as shunt catheter placement or cardiac septo-
Anesthesia for Open Fetal Surgery
plasty, an opioid (e.g., fentanyl 10 to 20 µg/kg) can be When corrective fetal surgery or an intrauterine proce-
administered to the fetus intramuscularly or intrave- dure requires surgical access through a hysterotomy,
nously.114,115 When general anesthesia is employed, pla- general anesthesia is typically administered. Unique con-
cental transfer of a volatile halogenated agent is usually siderations for open fetal procedures include the need for
sufficient to immobilize and anesthetize the fetus. profound uterine relaxation, intraoperative fetal moni-
The fetal surgical team should be prepared for treat- toring, fetal anesthesia or analgesia, and postoperative
ment of fetal compromise with immediate availability maternal analgesia and uterine tocolysis (Table 7-3).
of appropriate doses of atropine and epinephrine. The In addition, significant maternal and fetal blood loss
obstetric team should be prepared to perform an emer- may occur, and the anesthesiologist must be prepared
gency cesarean delivery if the gestational age is compat- to achieve maternal and fetal resuscitation. A high con-
ible with extrauterine viability. The anesthesiologist centration of a volatile halogenated agent is typically
Preoperative Considerations
• Complete maternal history and physical examination
• Fetal work-up to exclude other anomalies and imaging studies to determine fetal lesion, placental location, and estimated
fetal weight
• Maternal counseling by multidisciplinary team and preoperative team meeting
• Lumbar epidural catheter placed and tested
• Prophylactic premedications for aspiration and tocolysis
• Blood products available for potential maternal and fetal transfusion
• Sequential compression devices on lower extremities for thrombosis prophylaxis
CO2, carbon dioxide; FIO2, fraction of inspired oxygen; IM, intramuscular; IV, intravenous.
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 137
administered to provide both maternal and fetal anesthe- muscle relaxant is usually not needed owing to the pro-
sia as well as uterine relaxation; adequate uterine relax- found depth of anesthesia but may be used to improve
ation may require greater than twice the minimum operative conditions. The intrauterine location and posi-
alveolar concentration (MAC) of a volatile halogenated tion of the fetus is confirmed with ultrasonography just
agent.116 before hysterotomy to optimize the incision location.
Preoperatively, the mother receives agents for aspira- Before uterine incision, it is important to achieve an
tion prophylaxis and uterine tocolysis (e.g., rectal indo- increased end-tidal concentration of the volatile haloge-
methacin) and an epidural catheter is placed for nated agent to provide both fetal anesthesia and uterine
postoperative analgesia. Minimal doses of preanesthetic relaxation (typically ≥ 2 MAC). Fetal well-being can be
and adjuvant anesthetic agents are given to allow signifi- assessed with pulse oximetry, ultrasonography for FHR
cant doses of a volatile halogenated agent to be adminis- monitoring, echocardiography to assess fetal ventricular
tered to achieve effective uterine relaxation; this approach contractility, and electrocardiography (ECG).
may also reduce the occurrence of hypotension. The The uterus is assessed both visually and by palpation
patient is placed in the supine position with left uterine for contractions or increased tone; further tocolysis can
displacement. After administration of 100% oxygen and be achieved with the administration of additional haloge-
denitrogenation of the lungs, a rapid-sequence induction nated agent (≤ 3 MAC) or intravenous nitroglycerin as
of general anesthesia with cricoid pressure and endotra- an infusion or in small boluses (50 to 200 µg).121 Use of
cheal intubation is performed. Fetal heart rate (FHR) and desflurane at 1.5 MAC with supplemental intravenous
umbilical cord blood flow are often monitored with ultra- propofol and remifentanil has provided adequate uterine
sonography during induction. relaxation in one retrospective study.122 For circumstances
Initially, anesthesia is maintained with a low concen- in which volatile halogenated agents or general anesthe-
tration of a volatile halogenated agent while further sia must be avoided (e.g., family history of malignant
preparations for surgery are undertaken, including (1) hyperthermia), a spinal or epidural anesthetic can be used
obtaining additional maternal vascular access, (2) prophy- with an intravenous infusion of nitroglycerin in doses up
lactic antibiotic administration, (3) urinary bladder cath- to 20 µg/kg/min.121 This technique does not have a clear
eterization, and (4) ultrasonographic assessment of fetal advantage for fetal outcome and may be associated with
presentation and placental location. Medications to more morbidity. Nitroglycerin administration during
provide fetal analgesia (e.g., fentanyl 10 to 20 µg/kg), open fetal surgery has been associated with maternal pul-
immobility (e.g., vecuronium 0.3 mg/kg), and resuscita- monary edema.117,123 Fetal intraventricular and periven-
tion (atropine 0.02 mg/kg, epinephrine 1 and 10 µg/kg, tricular hemorrhage and cerebral ischemia can result
and crystalloid 10 mL/kg) are prepared in sterile labeled from changes in fetal cerebral blood flow, and concern
syringes; each syringe should contain a single weight- has been raised regarding the use of tocolytic agents,
based unit dose. Crossmatched blood should be available which may affect vascular tone.124
for maternal transfusion. In addition, O-negative, cyto- An opioid and a muscle relaxant are administered
megalovirus (CMV)-negative, irradiated, leukocyte- to the fetus intramuscularly, either before uterine inci-
depleted, maternally crossmatched blood should be sion with ultrasonographic guidance or after uterine
available for fetal transfusion. For open procedures that incision with direct vision. Some anesthesiologists
have a high risk for significant fetal blood loss (e.g., mass administer atropine at this time in an effort to prevent
resection), an intravenous catheter should be placed in opioid-induced fetal bradycardia; a muscle relaxant with
the fetus to provide access for blood and fluid transfu- vagolytic effects also can be chosen to minimize this type
sions. An arterial catheter should be placed for maternal of bradycardia. Further studies are needed to determine
blood pressure monitoring if uterine tocolysis with a the optimal anesthetic technique for ensuring maternal
nitroglycerin infusion is planned. Intraoperative maternal and fetal cardiovascular stability, optimal uteroplacental
intravenous fluids are restricted (< 2 L) to reduce the risk perfusion, and adequate fetal anesthesia to cause immo-
for postoperative pulmonary edema; some fetal surgery bility and blockade of the fetal stress response.
centers choose to limit fluids even further (< 500 mL), A small uterine incision is created remote from the
although no clinical trials have proven a benefit of fluid location of the placenta. A stapling device with absorb-
restriction in this setting.117 The use of tocolytic agents able synthetic copolymer (Lactomer) staples is used to
such as magnesium sulfate and nitroglycerin has been extend the incision to seal the membranes to the endo-
associated with maternal pulmonary edema in patients metrium and prevent excessive bleeding.125 During
undergoing fetal surgery. surgery, the exposed fetus and uterus are bathed with
A final discussion (i.e., surgical time-out), prophylactic warmed fluids. The intrauterine temperature is closely
antibiotic administration, and an increase in the concen- monitored to prevent fetal circulatory compromise asso-
tration of the volatile halogenated agent should occur ciated with hypothermia.126
before skin incision. Maternal blood pressure is main- When uterine closure is initiated at the conclusion of
tained with a mean arterial pressure within 10% of base- the procedure, a loading dose of magnesium sulfate is
line values and greater than 65 mm Hg; a phenylephrine administered (4 to 6 g intravenously over 20 minutes),
infusion provides titratable blood pressure control with followed by an intravenous infusion of 1 to 2 g per hour.
minimal changes in the fetal acid-base status.118,119 Ephed- As magnesium potentiates neuromuscular relaxation,
rine or glycopyrrolate boluses also can be administered close monitoring of twitch recovery is needed if a non-
to maintain maternal heart rate and improve cardiac depolarizing muscle relaxant was administered. The vola-
output.120 Maternal administration of a nondepolarizing tile halogenated agent can be significantly decreased or
138 PART III Fetal and Neonatal Assessment and Therapy
discontinued after the magnesium sulfate bolus has been neuraxial anesthesia, typically combined with intravenous
administered. The epidural analgesia can be initiated and nitroglycerin infusion to achieve uterine relaxation, may
maternal anesthesia is maintained with additional fen- also be used. Multiple reviews of the surgical and obstet-
tanyl, nitrous oxide, and/or propofol. ric considerations associated with the EXIT procedure
Postoperative concerns include maternal and fetal have been published.132-134
pain, preterm PROM, preterm labor, infection, and a The conventional anesthetic approach is a modifica-
variety of potential fetal complications, including heart tion of the general anesthetic technique used for cesarean
failure, intracranial hemorrhage, constriction of the delivery. Preparation for fetal monitoring, airway man-
ductus arteriosus from indomethacin, and fetal demise. agement, fetal/neonatal resuscitation, and postdelivery
Postoperative maternal analgesia can be maintained with care should be completed before entering the operating
a continuous epidural infusion of a dilute solution of local room. A sterile pulse oximeter probe and an end-tidal
anesthetic and opioid for several days. Effective analgesia carbon dioxide indicator or gas analyzer are used for fetal
may help prevent postoperative preterm labor.127,128 monitoring during the procedure; basic ultrasonography
Intravenous opioids can also be used for analgesia; can be added to assess the fetal heart. Unit doses of atro-
however, decreased FHR variability may occur.129 pine, epinephrine, and calcium for intramuscular fetal
Management of postoperative preterm labor has been injection are transferred sterilely to the scrub nurse for
the “Achilles heel” of fetal surgery.7 Tocolysis is typically possible emergency intraoperative resuscitation. Supple-
provided by an infusion of magnesium sulfate for at least mental fetal anesthetic agents for intramuscular injection
24 hours; however, supplemental agents may include are also prepared and transferred to the scrub nurse (see
indomethacin, terbutaline, or nifedipine. Magnesium later discussion). A sterile ventilation bag with an air/
most likely competes with calcium at voltage-operated oxygen source and manometer is available for the fetus,
calcium channels, indomethacin blocks the synthesis of along with multiple endotracheal tube sizes and devices
prostaglandins, and beta-adrenergic agonists activate for fetal tracheal intubation. Catheters for intravenous
adenylate cyclase in the uterine muscle, thereby reducing access as well as crystalloid and blood (O-negative, CMV-
intracellular calcium levels. Frequently two tocolytic negative, leukocyte depleted, irradiated, maternally
agents are required to create uterine quiescence. Uterine crossmatched) should be available for fetal volume resus-
activity and FHR are monitored closely during the first citation if needed.
2 to 3 postoperative days. The fetus is evaluated postop- A maternal epidural catheter may be placed preopera-
eratively by ultrasonography, and if indomethacin is used, tively for postoperative analgesia. Anesthetic consider-
periodic fetal echocardiography is conducted to deter- ations for the mother are similar to those for cesarean
mine whether premature closure of the ductus arteriosis delivery but should also include large-bore intravenous
has occurred. access, availability of uterotonic agents and crossmatched
Patients recovering from open fetal surgery should blood, and the ability to quickly obtain invasive maternal
remain near the fetal treatment center after being dis- monitoring if needed.
charged. These patients are at high risk for preterm Techniques of induction and tracheal intubation do
PROM, preterm labor, infection, and uterine rupture. not differ from those typically used for cesarean delivery.
Unless preterm labor occurs, cesarean delivery is typi- Although techniques for maintenance of anesthesia vary
cally planned at 37 weeks’ gestation. between medical centers, administration of 2 to 3 MAC
of a volatile halogenated agent is often needed to achieve
Anesthesia for the Ex Utero Intrapartum and maintain adequate uterine relaxation. Occasionally,
nitroglycerin administered intravenously as a bolus dose
Treatment Procedure (50 to 200 µg) or as an infusion is required to obtain
Initially described as a method to remove the iatrogenic appropriate uterine relaxation. Fetal anesthesia from the
airway obstruction created for intrauterine treatment of halogenated agent transferred across the placenta can be
CDH, the EXIT procedure has evolved into a technique supplemented by direct fetal (intramuscular) administra-
useful for a number of fetal disorders that compress the tion of an opioid (fentanyl 5 to 15 µg/kg) and a paralytic
airway and/or render neonatal tracheal intubation diffi- agent (rocuronium 1 to 3 mg/kg or pancuronium 0.1 to
cult or impossible. It is also useful when resuscitation and 0.3 mg/kg); some practitioners also administer intramus-
surgical intervention are required immediately before cular atropine (20 µg/kg) to prevent fetal bradycar-
birth, while the fetus is still supported by the placentofe- dia.132,134 Intramuscular agents can be administered to the
tal circulation. Cases appropriate for an EXIT procedure fetus either before uterine incision with ultrasonographic
include (1) thoracotomy for congenital pulmonary airway guidance or after incision with direct visualization. Sig-
malformations and (2) tracheostomy and the removal of nificant variability in serum fentanyl concentrations
neck masses such as fetal teratoma. The use of an EXIT among fetuses has been documented in umbilical cord
procedure may also assist the transition to ECMO for blood during EXIT procedures,135 and similar variability
pulmonary insufficiency or the stabilization of conjoined may exist with muscle relaxants and other agents.
twins prior to separation.11,130,131 Similar to open fetal When adequate uterine relaxation has been achieved,
surgery procedures, sustained uterine relaxation and the placental location and edges are confirmed by intra-
delay of placental separation are necessary for a successful operative ultrasonography. Similar to open fetal proce-
EXIT procedure. dures, the uterine incision is extended with a stapling
Anesthesia for EXIT procedures is most commonly device to minimize blood loss. The fetal head and shoul-
performed with the use of general anesthesia, although ders are delivered in preparation for tracheal intubation.
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 139
For more extensive procedures, such as fetal thoracot- construct that can exist in the absence of physical stimuli
omy, or when there is fetal bradycardia suggestive of (e.g., phantom limb pain), and it includes emotional and
umbilical cord compression, the fetus can be completely affective components that require higher-level cortical
delivered and placed on the maternal chest and abdomen. processing. As such, although pain is commonly associ-
In an effort to maintain fetoplacental circulation, warmed ated with physical noxious stimuli, it is more than noci-
fluids are continuously irrigated into the uterine cavity ception or a simple reflex activity associated with a
and care is taken to avoid manipulation of the umbilical withdrawal response.146 Attempts have been made to cor-
cord. The warmed irrigant maintains fetal euthermia and relate pain with surgical stress; however, the physiologic
helps prevent decreased uterine volume, placental separa- responses are not equivalent and reductions in stress
tion, and spasm of the cord vessels. The fetus is initially hormones should not be interpreted as an indicator of
monitored with (1) a pulse oximeter probe placed on the adequate analgesia.147 The stress response is mediated
fetal hand, (2) periodic ultrasonography, and (3) direct primarily in the spinal cord, brainstem, and/or basal
visualization. ganglia, without involvement of the cortex. This distinc-
The duration of the fetal procedure can range from a tion acknowledged, pioneering studies of preterm neo-
few minutes (e.g., bronchoscopy or intubation) to several nates undergoing surgery with minimal anesthesia have
hours (e.g., neck or thoracic mass resection, tracheos- revealed circulatory, sympathoadrenal, and pituitary
tomy, or central intravascular access). Although the adrenal responses characteristic of stress (e.g., increased
majority of procedures require less than an hour, the release of catecholamines, growth hormone, glucagon,
anesthetic technique should be capable of providing cortisol, aldosterone, and other corticosteroids; decreased
maternal, fetal, and uteroplacental stability over several secretion of insulin).148,149 Administration of adequate
hours.136,137 Once surgery is completed and the trachea anesthesia in neonates blunts this stress response,150 and
secured, surfactant is given if indicated. Fetal oxygen attenuation of the stress response in preterm neonates has
saturation is typically 40% to 60% at this time138 but been associated with improved outcomes.151
increases significantly to above 90% with ventilation of In studies of intrauterine blood transfusion in the
the fetal lungs. Failure to achieve a fetal saturation of at human fetus, surgical needling of the intrahepatic vein
least 90% is an indication for the use of ECMO before (in contrast to the insensate umbilical cord) is associated
clamping the umbilical cord and delivering the fetus.139 with evidence of a stress response, including increases in
After the umbilical cord is clamped, the maternal anes- plasma beta-endorphin and cortisol concentrations and
thetic technique is altered to help achieve uterine tone decreases in the middle cerebral artery pulsatility index
and diminish the risk for postpartum hemorrhage.132,140 (determined by Doppler imaging). These responses,
This is accomplished by (1) substantially reducing the which may redistribute blood flow to vital organs, includ-
inspired concentration of the volatile halogenated agent; ing the brain,152 can be blunted by the administration of
(2) adding nitrous oxide, propofol, and/or an opioid to fentanyl 10 µg/kg.114 Human fetuses elaborate pituitary-
maintain anesthesia; (3) administering oxytocin and other adrenal, sympathoadrenal, and circulatory stress responses
uterotonic agents, if needed; and (4) initiating epidural to noxious stimuli as early as 18 weeks’ gestation.153-156
analgesia via the epidural catheter that was placed before During late gestation, fetuses can respond to environ-
surgery. mental stimuli such as noise, light, music, pressure, touch,
An alternative technique for EXIT procedures involves and cold.157
the use of neuraxial anesthesia.141-143 Although this Nerve terminals for the detection of touch, tempera-
approach avoids many of the risks associated with general ture, and vibration (not pain) are present deep within the
anesthesia, large doses of intravenous nitroglycerin (1 to human skin at 6 weeks’ gestation and become more
10 µg/kg/min) are often required to achieve adequate numerous and superficial (e.g., toward the skin surface)
uterine relaxation. Nitroglycerin can cross the placenta; by 10 weeks’ gestation.158 Immature skin nociceptors
however, a significant amount is metabolized at the pla- likely begin to emerge at 10 weeks’ gestation and are
cental interface, resulting in minimal fetal effects.121,143 If present by 17 weeks’ gestation159; in internal organs,
nitroglycerin is to be used at significant doses for a pro- nociceptors develop slightly later.
longed period, an arterial catheter is recommended and Peripheral nerve fibers that control movement grow
the patient should be observed for evidence of pulmonary into the spinal cord at about 8 weeks’ gestation. When
edema. Fetal analgesia and immobility can be achieved these fibers connect with nociceptors is unknown, but the
with fetal administration of intramuscular drugs (see timing of these connections is delayed when compared
earlier discussion); maternally administered intravenous with other sensory inputs in nonhuman, mammalian
remifentanil undergoes significant transfer across the pla- models. One human study suggested that nociceptive
centa and may serve as an adjuvant for fetal analgesia and nerve fibers do not enter the spinal cord before about 19
immobility.144,145 Prospective trials are necessary to delin- weeks’ gestation.160 The cerebral cortex develops after the
eate the advantages and disadvantages of these various fetal spinal cord and brainstem. Thalamocortical axons
anesthetic techniques for the EXIT procedure. reach the somatosensory cortex at 24 to 26 weeks’
gestation.146
The developing cerebral cortex consists of transient
Fetal Response to Surgical Stimulation fetal zones where neuronal proliferation, cell migration,
The subjective phenomenon of pain has not been, and apoptosis, axonal outgrowth, and synaptogenesis occur
perhaps cannot be, assessed adequately in human fetuses. according to a highly specific timetable (see Chapter 10).
Pain is a multidimensional, subjective, psychological Originating as a smooth layer without sulci and gyri, the
140 PART III Fetal and Neonatal Assessment and Therapy
cerebral cortex, like the thalamus, has no internal cellular associated with long-term adverse hormonal effects in
organization.158 The cortical subplate is a temporary young monkeys.174
structure that serves as a waiting and organizing zone for The exact onset of fetal sentience, the capacity to feel
various afferents destined for the cortex; it develops about pain, is unknown (see Chapter 5). Because of this uncer-
13 weeks’ gestation and recedes after 32 to 34 weeks’ tainty, it seems best to err on the side of administering
gestation. The insular cortex starts developing in humans adequate fetal anesthesia.175 Altogether, clinical observa-
at approximately 15 weeks’ gestation, with the cortical tions of fetal and neonatal behavior, information about
plate eventually developing into the six layers of the cere- the development of mechanisms of pain perception, and
bral cortex.161-163 studies of fetal and neonatal responses to noxious stimuli
The first fibers from the thalamus reach the subplate provide a compelling physiologic and philosophic ratio-
between 12 and 18 weeks’ gestation and remain until the nale for the provision of adequate fetal anesthesia, espe-
maturation of the cortical plate. The gestational age at cially after 24 to 26 weeks’ gestation. Noxious stimulation
which thalamic pain fibers reach the human cortex only during fetal life causes a stress response, which could have
can be estimated from histologic studies of other thala- both short- and long-term adverse effects on the develop-
mocortical circuits. Thalamic projections reach the visual ing central nervous system. Although the link between
subplate at 20 to 22 weeks’ gestation,162,164 the visual the stress response and pain is not always predictable, the
cortex at 23 to 27 weeks’ gestation,165 and the auditory threshold for pain relief is typically below that for stress
cortical plate at 26 to 28 weeks’ gestation.166 The subplate response ablation, and the stress response to noxious
becomes thinner in the insula and in areas of the brain stimulation is clear evidence that the fetal nervous system
where early cortical folding occurs. Extensive brain is reactive.176 Administration of fetal anesthesia has been
growth and maturation occur after 34 weeks’ gestation, the standard practice worldwide since the inception of
resulting in cortical sulci and gyri and an extensive fetal surgery more than 30 years ago.5,6,177,178 The impor-
network of pathways within the cortex and to the thala- tance of fetal immobility, cardiovascular homeostasis,
mus, midbrain, and spinal cord. Prior to the completion analgesia, and perhaps amnesia have always been empha-
of the thalamocortical system, the midbrain reticular sized in fetal surgery practice.
system is possibly responsible for pain awareness, as it is
for consciousness.162,167
Studies of fetal electroencephalograms (EEGs) at 24
Effects of Anesthesia on the Fetus
weeks’ gestation demonstrate electrical activity only 2% In fetal lambs, the concentration of halothane required
of the time, predominantly in 20-second bursts with to prevent movement in response to painful stimuli (1.0
periods of inactivity lasting up to 8 minutes. At 30 weeks’ MAC) is less than 40% of the concentration required in
gestation, EEGs begin showing patterns of wakefulness adult sheep.179 Despite rapid placental transfer of volatile
and sleep, but these are not concordant with fetal behav- halogenated agents, experiments in sheep models have
ior. By 34 weeks’ gestation, electrical activity is present shown that fetal concentrations of these agents remain
80% of the time, with more distinct wakefulness and lower than maternal concentrations for significant periods
sleep cycles similar to adult patterns. after maternal administration (Figure 7-3).180
Low levels of oxygenation in utero and endogenous Experimental studies of the fetal effects of maternal
neural inhibitors such as adenosine and pregnenolone administration of a volatile halogenated agent in sheep
may preclude optimal functioning of neural tissues and have not produced uniform results.180-183 Maternal admin-
networks.168 However, two studies using near-infrared istration of isoflurane and halothane resulted in variable
spectroscopy in preterm infants demonstrated differences changes in fetal blood pressure, heart rate, oxygen satura-
in cerebral oxygenation over the somatosensory cortex tion, cardiac output, and acid-base status. A retrospective
with noxious and non-noxious stimulation. This appears analysis of cardiac imaging from both open fetal cases and
to indicate that noxious information is at least transmit- EXIT procedures noted severe left ventricular systolic
ted to the infant cortex by 25 weeks’ gestation169,170; simi- dysfunction in the fetus with use of high concentrations
larly, preterm neonates also have demonstrated cortical of desflurane.122
evoked potentials after a heel lance.171 Maternal-fetal sheep studies, with no surgical stimulus
Although initial fetal reactions to nociceptive stimula- to either the mother or fetus, show that deep maternal
tion are purely reflexive, and cortical processes can occur inhalation anesthesia (> 2.0 MAC) results in progressive
only after thalamocortical connections have been com- fetal acidosis. By contrast, lower maternal inhalation
pleted, nociceptive stimuli can activate a number of anesthesia (1.0 MAC) also may be undesirable because it
subcortical mechanisms; moreover, stress responses may does not adequately block the fetal response to a painful
influence the maturation of both the thalamocortical stimulus, which includes increased fetal catecholamines,
pathways and the cerebral cortex. Although the data on vasoconstriction, and redistribution of fetal blood flow.184
the consequences of fetal exposure to stressful stimuli are However, the combined effect of adequate fetal anesthe-
incomplete, recognition should be given to the possibility sia with a halogenated agent, intrauterine manipulation,
that noxious stimuli, which can be attenuated or blocked and fetal stress on fetal cardiovascular stability and
by anesthesia, may be associated with adverse long-term regional blood flow remains unknown. Brief fetal expo-
neurodevelopmental consequences.172 For example, cir- sure to deep maternal inhalation anesthesia (i.e., 2.0 to
cumcision in nonanesthetized neonates has been associ- 3.0 MAC) does not appear significantly detrimental to
ated with increased pain responses to injections performed the fetus, with no fetal hypoxia, hypercarbia, or acidosis
6 months later173; in addition, fetal stress has been observed even after exposures of 2 hours if maternal
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 141
5
Direct oximetry (carotid) 200
0 180
∆DOx (%)
160
–5 140
–2.5 40
–5 20
–7.5 0
50
torr
100
45
90
40 80
70
160 Heart rate 60
SpO2 (%)
150 50
140
bpm
40
130
30
120
20
110
100 10
0 5 10 15 20 25 30 0
Time (sec)
120 150 180 210
Time (sec)
Umbilical occlusion
FIGURE 7-5 ■ Graphic representation of monitoring data from a
FIGURE 7-4 ■ Response to 5 seconds of umbilical cord occlusion fetus at 24 weeks’ gestation undergoing open diaphragmatic
in the fetal lamb. Direct oximetry and pulse oximetry are hernia repair. Top graph shows fetal heart rate (bpm) and
expressed as delta saturation (Tx − T0). (From Luks FI, Johnson bottom graph shows oxygen saturation (SpO2) detailed over a
BD, Papadakis K, et al. Predictive value of monitoring parameters in 2-minute period. The tracings demonstrate an acute decrease
fetal surgery. J Pediatr Surg 1998; 33:1297-1301.) in fetal heart rate (FHR) with an associated decrease in fetal
SpO2. The onset of the desaturation detected in the fetal hand
is delayed in relation to the onset of the bradycardia. Similarly,
the recovery in FHR precedes the onset of the rapid increase in
saturation. This pattern most likely represents a transport delay
improve fetal outcome without incurring substantive of the blood from the heart to the fetal hand. (From Rosen MA.
Anesthesia for fetal surgery. In Hughes SC, Levinson G, Rosen MA,
maternal risk. Well-organized, multidisciplinary, profes- editors. Shnider and Levinson’s Anesthesia for Obstetrics. 4th
sional, and comprehensive fetal treatment programs at edition. Philadelphia, Lippincott Williams & Wilkins, 2002.)
academic medical centers facilitate the sustained effort to
innovate new techniques, challenge dogma, and ensure
ongoing success. More collaborative clinical investigation
among international research centers will benefit these
efforts and guide the evolution of prenatal fetal therapy. likely future for fetal therapy. Endoscopic repair of
Advances in technology will continue to drive improve- myelomeningocele has already been attempted. Other
ment and availability of fetal intervention. For example, procedures with future potential include (1) placement of
dynamic tracheal occlusion for CDH rather than com- a cardiac pacemaker to restore sinus rhythm and improve
plete occlusion, using devices that have pressure-sensitive survival in fetuses with complete heart block or a cardiac
valves to allow egress of fetal lung fluid, may improve arrhythmia, when treatment is refractory to transplacen-
outcome by more closely imitating normal developmen- tal administration of medication; (2) repair of craniofacial
tal physiology and result in more normal lung function anomalies, gastroschisis, and cleft lip and palate; and (3)
than that seen with current techniques. corrections of skeletal anomalies by allogenic bone graft-
With continued advances and miniaturization of inva- ing. Innovations focused on tissue engineering, using
sive techniques and decreases in maternal and fetal risk, stem cells and gene therapies, are exciting possibilities for
fetal intervention for a wider variety of procedures is the future fetal therapy.
7 Anesthesia for Fetal Surgery and Other Intrauterine Procedures 143
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ence of infection or of nitroglycerin tocolysis after open fetal pared with cesarean delivery. Am J Obstet Gynecol 2002;
surgery. Am J Obstet Gynecol 1998; 179:925-33. 186:773-7.
118. Ngan Kee WD, Khaw KS, Tan PE, et al. Placental transfer and 141. Clark KD, Viscomi CM, Lowell J, Chien EK. Nitroglycerin for
fetal metabolic effects of phenylephrine and ephedrine during relaxation to establish a fetal airway (EXIT procedure). Obstet
spinal anesthesia for cesarean delivery. Anesthesiology 2009; Gynecol 2004; 103:1113-5.
111:506-12. 142. Benonis JG, Habib AS. Ex utero intrapartum treatment procedure
119. Ngan Kee WD, Lee A, Khaw KS, et al. A randomized double- in a patient with arthrogryposis multiplex congenita, using con-
blinded comparison of phenylephrine and ephedrine infusion tinuous spinal anesthesia and intravenous nitroglycerin for uterine
combinations to maintain blood pressure during spinal anesthesia relaxation. Int J Obstet Anesth 2008; 17:53-6.
for cesarean delivery: the effects on fetal acid-base status and 143. George RB, Melnick AH, Rose EC, Habib AS. Case series: com-
hemodynamic control. Anesth Analg 2008; 107:1295-302. bined spinal epidural anesthesia for Cesarean delivery and ex utero
120. Habib AS. Review article: a review of the impact of phenylephrine intrapartum treatment procedure. Can J Anaesth 2007; 54:
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natal outcomes in women undergoing cesarean delivery under 144. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil:
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121. Rosen MA, Andreae MH, Cameron AG. Nitroglycerin for fetal 1998; 88:1467-74.
surgery: fetoscopy and ex utero intrapartum treatment procedure 145. Fink RJ, Allen TK, Habib AS. Remifentanil for fetal immobiliza-
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96:698-700. procedure under combined spinal-epidural anaesthesia. Br J
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20:748-56. 947-54.
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Development of the primary afferent projection in human spinal 1983; 62:489-92.
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164. Hevner RF. Development of connections in the human visual to common anesthetic agents causes widespread neurodegenera-
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165. Kostovic I, Rakic P. Development of prestriate visual projections 187. Palanisamy A, Baxter MG, Keel PK, et al. Rats exposed to isoflu-
in the monkey and human fetal cerebrum revealed by transient rane in utero during early gestation are behaviorally abnormal as
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166. Krmpotic-Nemanic J, Kostovic I, Kelovic Z, et al. Development 188. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced
of the human fetal auditory cortex: growth of afferent fibres. Acta neuroapoptosis in the neonatal rhesus macaque brain. Anesthesi-
Anat (Basel) 1983; 116:69-73. ology 2010; 112:834-41.
167. Merker B. Consciousness without a cerebral cortex: a challenge 189. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral
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168. Mellor DJ, Diesch TJ, Gunn AJ, Bennet L. The importance of 190. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive
‘awareness’ for understanding fetal pain. Brain Res Brain Res Rev performance in children: no evidence for a causal relationship.
2005; 49:455-71. Twin Res Hum Genet 2009; 12:246-53.
169. Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ. Pain acti- 191. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents
vates cortical areas in the preterm newborn brain. Pain 2006; in neonates and young children. Anesth Analg 2007;
122:109-17. 104:509-20.
170. Slater R, Cantarella A, Gallella S, et al. Cortical pain responses in 192. Stratmann G. Review article: Neurotoxicity of anesthetic drugs in
human infants. J Neurosci 2006; 26:3662-6. the developing brain. Anesth Analg 2011; 113:1170-9.
171. Slater R, Worley A, Fabrizi L, et al. Evoked potentials generated 193. Rosen KG, Amer-Wahlin I, Luzietti R, Noren H. Fetal ECG
by noxious stimulation in the human infant brain. Eur J Pain 2010; waveform analysis. Best Pract Res Clin Obstet Gynaecol 2004;
14:321-6. 18:485-514.
172. Lowery CL, Hardman MP, Manning N, et al. Neurodevelopmen- 194. Kaneko M, Tokunaga S, Mukai M, et al. Application of a fetal
tal changes of fetal pain. Semin Perinatol 2007; 31:275-82. scalp electrode for continuous fetal heart rate monitoring during
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tion. Lancet 1997; 349:599-603. 195. Luks FI, Johnson BD, Papadakis K, et al. Predictive value of
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175. Glover V, Fisk N. Do fetuses feel pain? We don’t know; better to precede a decrease in fetal oxygen content. Gynecol Obstet Invest
err on the safe side from mid-gestation. BMJ 1996; 313:796. 1997; 44:26-31.
176. White MC, Wolf AR. Pain and stress in the human fetus. Best 197. Dickens BM, Cook RJ. Legal and ethical issues in fetal surgery.
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C H A P T E R 8
CHAPTER OUTLINE
The value of intrapartum obstetric interventions to assess sequelae. Fetal monkeys subjected to hypoxia in utero
and maintain fetal well-being has been scrutinized in suffer neurologic injuries similar to those seen in children
recent years. Old technologies have been reassessed, and who presumably suffered asphyxia in utero.7-9 Work with
new ones have been introduced. A rising cesarean deliv- rodent models has shown similar patterns of damage.10
ery rate, renewed interest in home birth, persistent cases Hankins et al.11 suggested that performance of elective
of fetal/neonatal neurologic injury, and excessive litiga- cesarean delivery at 39 weeks’ gestation (and avoidance
tion have prompted an ongoing search for methods to of a trial of labor) might result in an 83% reduction in
identify and intervene on behalf of the fetus at risk during risk for moderate or severe neonatal encephalopathy.
labor and delivery. Altogether, epidemiologic and experimental data suggest
that the fetus is at significant risk during labor and
delivery.
FETAL RISK DURING LABOR Some fetuses appear to be at greater risk for adverse
intrapartum events than others. Older studies report that
Historical epidemiologic data suggest that the fetus is at high-risk mothers constitute 20% of the pregnant popu-
increased risk for morbidity and mortality during labor lation, but their offspring represent 50% of the cases of
and delivery. In 1963, the British Perinatal Mortality perinatal morbidity and mortality.12 Various schemes to
Survey reviewed autopsy data for 1400 stillborn infants identify high-risk pregnancies have been published.13,14
and concluded that slightly more than 30% of these High-risk pregnancies include, but are not limited to,
losses resulted from intrapartum asphyxia.1 Neonatal out- women with (1) medical complications (e.g., hyperten-
comes in the industrialized world have improved over the sion, preeclampsia, diabetes, autoimmune disease, hemo-
past 40 years. A Canadian database identified approxi- globinopathy); (2) fetal complications (e.g., fetal growth
mately 80 intrapartum stillbirths per 120,000 live births restriction [also known as intrauterine growth restric-
from 1981 to 2002, a rate of 0.67/1000; some 11 of the tion], nonlethal anomalies, prematurity, multiple gesta-
infants were considered viable (i.e., not severely preterm tion, postdatism, hydrops); and (3) intrapartum
or anomalous), which indicated a preventable death rate complications (e.g., abnormal vaginal bleeding, mater-
of 0.09/1000.2 A Scottish study indicated that perinatal nal fever, meconium-stained amniotic fluid, oxytocin
deaths due to intrapartum anoxia in term, singleton, augmentation of labor). Owing to inadequate sensitivity,
cephalic infants declined significantly from 5.7 to poor positive predictive values, and the inability to modify
3.0/10,000 births between 1988 and 2007.3 Intrapartum outcomes related to risk factors, scoring systems for iden-
stillbirths are rare in developed countries, constituting tifying high-risk fetuses have not been shown to improve
less than 10% of all stillbirths. By contrast, in some devel- pregnancy outcomes.15 Lo et al.16 indicated that more
oping countries, as many as 50% of stillbirths occur intra- than half of infants with asphyxia had no clinical risk
partum.4 According to a World Health Organization factors. However, for low-risk parturients who wish to
report, intrapartum-related neonatal deaths account for avoid continuous monitoring during labor, scoring
almost 10% of deaths in children younger than 5 years systems may demonstrate some benefit.15 One strategy
of age.5,6 used in European centers for identifying high-risk partu-
Experimental models lend support to the hypothesis rients is fetal heart rate (FHR) tracing analysis at the time
that intrapartum events can have long-term neurologic of admission to the labor and delivery suite; if the FHR
148
8 Intrapartum Fetal Assessment and Therapy 149
tracing is abnormal, patients receive more intensive mon- 25% of fetuses may have antepartum and intrapartum
itoring.17 A meta-analysis of this approach observed an risk factors for neurologic injury.
increase in cesarean delivery rates but failed to demon- The ability of contemporary obstetricians to recognize
strate improvements in fetal and neonatal outcomes.18 and treat pregnancies at risk for hypoxia during labor is
The magnitude of risk for intrapartum fetal neuro- an evolving science. With the current understanding of
logic injury is a matter of some dispute. In 2003, the pathophysiology and the technology in current clinical
American College of Obstetricians and Gynecologists use, the extent to which obstetricians can prevent intra-
(ACOG) Task Force on Neonatal Encephalopathy and partum injury is unclear.26 It is hoped that the develop-
Cerebral Palsy concluded that 70% of these types of fetal ment of standardized, clearer definitions of intrapartum
neurologic injuries result from events that occur before injury, and new strategies and interventions that can
the onset of labor.19-21 Examples of antepartum events correct reversible pathophysiology, will lead to more
that may cause fetal neurologic injury include congenital precise identification and optimization of fetuses at risk.
anomalies, chemical exposure, infection, and fetal Efforts to understand placental physiology and patho-
thrombosis/coagulopathy. Only 4% of cases of neonatal physiology are central to the efforts to support the health
encephalopathy result solely from intrapartum hypoxia, of the pregnant woman and her fetus, both antepartum
an incidence of approximately 1.6/1000.19,20,22 The Task and intrapartum. The fetus depends on the placenta for
Force identified criteria that define an acute intrapartum the diffusion of nutrients and for respiratory gas exchange.
hypoxic event sufficient to cause cerebral palsy (Box Many factors affect placental transfer, including concen-
8-1).19,20,23 A recent study found that fetuses that under- tration gradients, villus surface area, placental permeabil-
went a sudden and sustained deterioration of the FHR ity, and placental metabolism (see Chapter 4). Maternal
and that subsequently had a diagnosis of cerebral palsy hypertensive disease, congenital anomalies, and intra-
demonstrated characteristics consistent with the criteria uterine infection are examples of conditions that may
developed by the ACOG Task Force.24 An additional case impair placental transfer.
series of sentinel events during labor (e.g., uterine rupture, One of the most important determinants of placental
cord prolapse, placental abruption, amniotic fluid function is uterine blood flow.27 A uterine contraction
embolus) resulted in a high rate of hypoxic-ischemic results in a transient decrease in uteroplacental blood
encephalopathy in surviving infants.25 Approximately flow. A placenta with borderline function before labor
may be unable to maintain gas exchange adequate
to prevent fetal asphyxia during labor. The healthy
fetus may compensate for the effects of hypoxia
Criteria That Define an Acute during labor.28,29 The compensatory response includes (1)
BOX 8-1 Intrapartum Hypoxic Event as decreased oxygen consumption, (2) vasoconstriction of
Sufficient to Cause Cerebral Palsy nonessential vascular beds, and (3) redistribution of
blood flow to the vital organs (e.g., brain, heart, adrenal
ESSENTIAL CRITERIA glands, placenta).30,31 Humoral responses (e.g., release of
1. Evidence of metabolic acidosis in umbilical cord arte- epinephrine from the adrenal medulla, release of vaso-
rial blood obtained at delivery (i.e., pH < 7.00, base pressin and endogenous opioids) may enhance fetal
deficit > 12 mmol/L) cardiac function during hypoxia.27 Prolonged or severe
2. Early onset of encephalopathy in an infant delivered hypoxia overwhelms these compensatory mechanisms,
at > 34 weeks’ gestation resulting in fetal injury or death.
3. Cerebral palsy of the spastic quadriplegia or dyskinetic
type
4. Exclusion of other identifiable causes
INTRAPARTUM FETAL ASSESSMENT
CRITERIA THAT SUGGEST INTRAPARTUM TIMING OF
INSULT Electronic Fetal Heart Rate Monitoring
1. Sentinel hypoxic event occurring immediately before
or during labor An optimal, yet practical method for assessing fetal health
2. Sudden, sustained bradycardia or absence of fetal during labor and delivery has not been developed. Most
heart rate variability with persistent late or variable contemporary methods include assessment of the FHR.
decelerations The FHR can be monitored intermittently with a simple
3. Apgar scores of 0-3 beyond 5 minutes of life DeLee stethoscope. Alternatively, either Doppler ultra-
4. Evidence of multisystem involvement within 72 hours sonography or a fetal electrocardiographic (ECG) elec-
of delivery trode can be used to monitor the FHR intermittently or
5. Early imaging study that shows evidence of acute,
nonfocal cerebral abnormality
continuously.
Experimental models have provided insight into the
Modified from the American College of Obstetricians and Gynecologists Task regulation of the FHR. Both neuronal and humoral
Force on Neonatal Encephalopathy and Cerebral Palsy. Neonatal factors affect the intrinsic FHR. Parasympathetic outflow
Encephalopathy and Cerebral Palsy: Defining the Pathogenesis and by means of the vagus nerve decreases the FHR, whereas
Pathophysiology. Washington, DC, American College of Obstetricians and sympathetic activity increases FHR and cardiac output.27
Gynecologists and the American Academy of Pediatrics, January 2003;
and MacLennan A. A template for defining a causal relation between Baroreceptors respond to increased blood pressure and
acute intrapartum events and cerebral palsy: international consensus chemoreceptors respond to decreased Pao2 and increased
statement. Br Med J 1999; 319:1054-9. Paco2 to modulate the FHR through the autonomic
150 PART III Fetal and Neonatal Assessment and Therapy
Cerebral cortex
Hypothalamus
Medulla oblongata
Cardioinhibitory center
FIGURE 8-1 ■ Regulation of fetal heart rate. (Drawing by Naveen Nathan, MD, Northwestern University Feinberg School of Medicine,
Chicago, IL.)
nervous system. Cerebral cortical activity and hypotha- 10-minute period averaged over 30 minutes; tachysystole
lamic activity affect the FHR through their effects on is defined as more than five uterine contractions within
integrative centers in the medulla oblongata (Figure a 10-minute period.32 An intrauterine pressure catheter
8-1).27 Both animal studies and clinical observations have may be used to measure the strength of uterine contrac-
helped establish a correlation between FHR and perinatal tions. In some cases, an intrauterine pressure catheter is
outcome. placed to determine the precise onset and offset of each
An electronic monitor simultaneously records the uterine contraction. Such information may be used to
FHR and uterine contractions. Use of an electronic distinguish among early, variable, and late FHR decelera-
monitor allows determination of the baseline rate and tions. In a nonblinded, randomized controlled trial,
patterns of the FHR and their relationship to uterine Bakker et al.33 observed no significant differences in
contractions. External or internal techniques can assess adverse neonatal outcomes with internal tocodynamom-
the FHR and uterine contractions (Figure 8-2). Doppler etry as compared with external monitoring of uterine
ultrasonography detects the changes in ventricular wall contractions in women in whom oxytocin was used for
motion and blood flow in major vessels during each induction or augmentation of labor.
cardiac cycle. The monitor calculates the FHR by mea- The following features of the FHR pattern can be
suring the intervals between fetal myocardial contrac- assessed: (1) baseline measurements, (2) variability (the
tions. Alternatively, an ECG lead attached to the fetal extent to which the rate changes both instantaneously and
scalp enables the cardiotachometer to calculate the FHR over longer periods), (3) accelerations, and (4) decelera-
by measuring each successive RR interval. Both external tions and their association with uterine contractions.
and internal methods allow continuous assessment of the
FHR. Baseline Fetal Heart Rate
The FHR is superimposed over the uterine contrac-
tion pattern. Uterine contractions can be monitored A normal baseline FHR is defined as 110 to 160 beats per
externally with a tocodynamometer or internally with an minute (bpm) and is determined by assessing the mean
intrauterine pressure catheter. The tocodynamometer heart rate over a 10-minute period rounded to incre-
allows determination of the approximate onset, duration, ments of 5 bpm.32,34 In general, term fetuses have a lower
and offset of each uterine contraction. A normal pattern baseline FHR than preterm fetuses because of greater
of uterine contractions in labor is five or less in a parasympathetic nervous system activity. Laboratory
8 Intrapartum Fetal Assessment and Therapy 151
Tocodynamometer
Transducer
Amplifier
Cardiotachometer
Ultrasound
2 Channel
system recorder
FHR UC
Leg plate
studies suggest that bradycardia (caused by increased variability reflects the presence of normal, intact path-
vagal activity) is the initial fetal response to acute hypox- ways from—and within—the fetal cerebral cortex, mid-
emia. After prolonged hypoxemia, the fetus may experi- brain, vagus nerve, and cardiac conduction system (see
ence tachycardia as a result of catecholamine secretion Figure 8-1).27 Variability is greatly influenced by the para-
and sympathetic nervous system activity.28 Changes in sympathetic tone, by means of the vagus nerve; maternal
baseline FHR may also be caused by fetal anatomic or administration of atropine, which readily crosses the
functional heart pathology, maternal fever and/or intra- placenta, can eliminate some variability. In humans, the
uterine infections, or maternally administered medica- sympathetic nervous system appears to have a lesser role
tions, such as beta-adrenergic receptor agonists (e.g., in influencing variability.27 Maternal administration of
terbutaline) or the anticholinergic agent atropine. the beta-adrenergic receptor antagonist propranolol has
little effect on FHR variability.27
During hypoxemia, myocardial and cerebral blood
Fetal Heart Rate Variability
flows increase to maintain oxygen delivery.35,36 However,
Fetal heart rate variability is the fluctuation in the FHR in severe hypoxemia, blood flow cannot increase
of 2 cycles or greater per minute.32,34 Previously, FHR sufficiently to maintain oxygen delivery and a loss of
variability was divided into short term (from one beat, or FHR variability is observed.27 The absence of FHR
R wave, to the next) and long term (occurring over the variability in an anencephalic fetus indicates the influence
course of 1 minute), but this distinction is no longer made of an intact central nervous system (CNS) in producing
because in clinical practice variability is visually assessed these patterns. In animal models, perfusion of the
as a unit (Figure 8-3). The presence of normal FHR CNS with calcium results in depolarization of
152 PART III Fetal and Neonatal Assessment and Therapy
240
210
180
150
120
90
60
30
100
75 12
50 8
25 4
A 0 0
240
210
180
150
120
90
60
30
100
12
75
50 8
25 4
B 0 0
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210
180
150
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30
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12
75
50 8
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C 0 0
240
210
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150
120
90
60
30
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75 12
50 8
25 4
D 0 0
FIGURE 8-3 ■ A, Normal intrapartum fetal heart rate (FHR) tracing. The infant had Apgar scores of 8 and 8 at 1 and 5 minutes, respec-
tively. B, Absence of variability in a FHR tracing. Placental abruption was noted at cesarean delivery. The infant had an umbilical
arterial blood pH of 6.75 and Apgar scores of 1 and 4, respectively. C, Early FHR decelerations. After a normal spontaneous vaginal
delivery, the infant had Apgar scores of 8 and 8, respectively. D, Late FHR decelerations. The amniotic fluid surrounding this fetus
was meconium stained. Despite the late FHR decelerations, the variability remained acceptable. The infant was delivered by cesarean
delivery and had an umbilical venous blood pH of 7.30. Apgar scores were 9 and 9, respectively.
8 Intrapartum Fetal Assessment and Therapy 153
240
210
180
150
120
90
60
30
100
75 12
50 8
25 4
E 0 0
FIGURE 8-3, cont’d ■ E, Variable FHR decelerations. A tight nuchal cord was noted at low-forceps vaginal delivery. The infant had
Apgar scores of 6 and 9, respectively. Numerical scales: Left upper panel margin, FHR in beats per minute; left lower panel margin,
uterine pressure in mm Hg; right lower panel margin, uterine pressure in kilopascal (kPa).
electroencephalographic (EEG) activity, which abolishes activity secondary to mild hypoxia. Early decelerations
FHR variability. are not ominous.
Clinically, the presence of normal FHR variability pre- Late decelerations begin 10 to 30 seconds after
dicts early neonatal health, as defined by an Apgar score the beginning of uterine contractions and end 10 to
of greater than 7 at 5 minutes.37,38 In a case series of 30 seconds after the end of uterine contractions. Late
monitored fetal deaths, no fetus had normal variability decelerations are smooth and repetitive (i.e., they occur
immediately before demise.27 The differential diagnosis with each uterine contraction). Animal studies suggest
of decreased variability includes fetal hypoxia, fetal sleep that late decelerations represent a response to hypoxemia.
state, fetal neurologic abnormality, and decreased CNS The delayed onset of the deceleration reflects the time
activity that results from exposure to drugs such as needed for the chemoreceptors to detect decreased
opioids. oxygen tension and mediate the change in FHR by means
of the vagus nerve.28,39 Late decelerations may also result
from decompensation of the myocardial circulation and
Accelerations
myocardial failure. Unfortunately, clinical and animal
Accelerations are abrupt changes in the FHR above the studies suggest that late decelerations may be an oversen-
baseline. Beyond 32 weeks’ gestation, an acceleration is sitive indication of fetal asphyxia.28 However, the combi-
defined by a peak of at least 15 bpm above the baseline, nation of late decelerations and decreased or absent FHR
lasting at least 15 seconds. (Before 32 weeks’ gestation, a variability is an accurate, ominous signal of fetal
peak of 10 bpm above the baseline, lasting at least compromise.29,40,41
10 seconds, is required.34) A prolonged acceleration Variable decelerations vary in depth, shape, and
extends for at least 2 minutes; however, when greater duration. They often are abrupt in onset and offset. Vari-
than 10 minutes in duration, it is considered a change in able decelerations result from baroreceptor- or
baseline.34 Antepartum FHR accelerations can occur in chemoreceptor-mediated vagal activity. Experimental
response to fetal movement and typically are a sign of models and clinical studies suggest that umbilical cord
fetal well-being; their presence indicates a reactive non- occlusion, either partial or complete, results in variable
stress test. During the intrapartum period, the signifi- decelerations. During the second stage of labor, variable
cance of FHR accelerations is less clear.28,38 Although the decelerations may result from compression of the fetal
presence of accelerations generally precludes the exis- head. In this situation, dural stimulation leads to increased
tence of significant fetal metabolic acidosis, in some cases vagal discharge.42 The healthy fetus can typically tolerate
intrapartum accelerations may indicate a vulnerable mild to moderate variable decelerations (not below
umbilical cord. 80 bpm) without decompensation. With prolonged,
severe variable decelerations (< 60 bpm) or persistent
fetal bradycardia, it is difficult for the fetus to maintain
Decelerations
cardiac output and umbilical blood flow.42
Decelerations are typically classified as early, late, or vari- Sinusoidal and saltatory patterns are two unusual
able. Early decelerations occur simultaneously with FHR tracing results that may indicate fetal compromise.
uterine contractions and usually are less than 20 bpm The sinusoidal FHR pattern is a regular, smooth, wave-
below baseline. The onset and offset of each deceleration like pattern that may signal fetal anemia.27 Occasionally,
coincides with the onset and offset of the uterine contrac- maternal administration of an opioid can lead to a sinu-
tion (see Figure 8-3). In animal models, head compres- soidal FHR pattern. The saltatory pattern consists of
sion can precipitate early decelerations.28 In humans, excessive alterations in variability (> 25 bpm) and may
early decelerations are believed to result from reflex vagal signal the occurrence of acute fetal hypoxia; there is a
154 PART III Fetal and Neonatal Assessment and Therapy
weak association between this pattern and low Apgar suggested within the ACOG guidelines have some indi-
scores.27 rect support.53 Adherence to these standards for intermit-
tent auscultation may be difficult to achieve in the clinical
setting; in one study, only 3% of parturients met these
Limitations of Electronic Fetal Heart standards.54
Several hypotheses to account for the apparent failure
Rate Monitoring of intrapartum FHR monitoring to reduce the incidence
Despite laboratory and clinical data suggesting that FHR of cerebral palsy have been proposed and include (1) a
monitoring accurately reflects fetal health, controversy large proportion of the asphyxial damage begins before
exists regarding the ability of this assessment tool to the onset of labor; (2) catastrophic events (e.g., cord pro-
improve fetal and neonatal outcomes. First described lapse, placental abruption, uterine rupture) may not allow
more than 40 years ago, the use of continuous electronic sufficient time for intervention before neurologic damage
FHR monitoring increased dramatically to encompass occurs; (3) a larger proportion of very low-birth-weight
45% and 85% of the monitored deliveries by 1980 and infants survive and thus contribute to the numbers with
2002, respectively.32 Retrospective reports of continuous cerebral palsy; (4) infection is associated with abnormal
FHR monitoring associate its use with a lower incidence FHR patterns and the subsequent development of cere-
of intrauterine fetal demise, neonatal seizures, and neo- bral palsy, and it is unclear that early intervention offers
natal death.43-45 By contrast, the only consistent finding any benefit in such cases; and (5) the amount of asphyxia
from multiple case-control studies and more than a dozen required to cause permanent neurologic damage approxi-
prospective, randomized trials of electronic FHR moni- mates the amount that causes fetal death, leaving a narrow
toring (with control arms that employed intermittent window for intervention.55 The number of patients in
FHR auscultation46-48) is an increased rate of operative whom cerebral palsy develops from intrapartum asphyxia
delivery. In a meta-analysis of these trials, which included is probably quite small.55
more than 50,000 women from several continents, the Limitations of FHR monitoring include a poor posi-
incidence of 1-minute Apgar scores less than 4 and neo- tive predictive value in distinguishing between abnormal
natal seizures was decreased with the use of continuous FHR tracings and abnormal outcomes. Because of this
FHR monitoring.46-49 These results appear to suggest a imprecision, the ACOG recommended that abnormal
correlation between abnormal FHR tracings and fetal FHR tracings be described with the term nonreassuring
acidemia.41,50 An evaluation of the 2004 United States fetal status rather than fetal distress or birth asphyxia.56 In
birth cohort data suggested that the use of electronic one population-based study of California children with
FHR monitoring was associated with a significant cerebral palsy, FHR tracings were retrospectively
decrease in early neonatal and infant mortality, a decreased reviewed and compared with those of neurologically
risk for 5-minute APGAR scores less than 4 in low-risk normal children (i.e., control subjects). A markedly higher
pregnancies, and a lower rate of neonatal seizures in incidence of tracings with late decelerations and decreased
high-risk pregnancies.51 variability was found in children with cerebral palsy than
It remains unclear why prospective studies have not in the control subjects. However, of the estimated 10,791
confirmed greater benefit of the use of continuous elec- monitored infants weighing 2500 g or more who had
tronic FHR monitoring during labor; the intensity of these FHR abnormalities, only 21 (0.19%) had cerebral
intrapartum assessment and care may be partially respon- palsy, representing a false-positive rate of 99.8%.57 Later
sible. In prospective trials, women randomly assigned to case-control studies have yielded similar results.16,58 A
receive intermittent FHR auscultation were monitored by 2006 meta-analysis of 12 trials including 37,000 women
dedicated nursing staff who provided intensive intrapar- suggested that electronic FHR monitoring has resulted
tum care. By contrast, the historical cohort studies com- in a decrease in the occurrence of seizures but no change
pared patients who received continuous electronic FHR in the incidence of neonatal mortality or cerebral palsy.49
monitoring and intensive intrapartum care with patients The authors suggested that electronic FHR monitoring
who had intermittent FHR auscultation with nonintensive resulted in one cesarean delivery for every 58 women
nursing care. There are no published studies that ran- monitored and that 661 women would need to be moni-
domly assigned a group of patients to receive no FHR tored to prevent one neonatal seizure.49 Therefore, use
monitoring; however, the continued high rate of intrapar- of electronic FHR monitoring in combination with clini-
tum stillbirth in unmonitored births in the developing cal and laboratory assessments has been proposed to
world suggests that FHR assessment may be beneficial. enhance the prediction and perhaps the prevention of
Consistent with the findings of the prospective trials, severe asphyxia, but with poor specificity.16
the ACOG endorses the use of either intermittent aus- Further limitations of continuous FHR monitoring
cultation or continuous electronic FHR monitoring include (1) the poor intra-observer and inter-observer
during labor. In high-risk patients, the ACOG guidelines agreement despite the use of trained observers, (2) the
recommend that the obstetrician or nurse review the required continual presence of a nurse or physician to
electronic FHR tracing every 15 minutes during the first assess the FHR tracing, (3) the inconvenience for the
stage of labor and every 5 minutes during the second patient (e.g., confinement to bed and the application of
stage. For low-risk patients, the intervals may be length- monitor belts or a scalp electrode), and (4) the need to
ened to 30 minutes for the first stage and 15 minutes for archive the FHR tracings as legal documents.59-61
the second stage.52 The optimal interval for intermittent Despite little evidence for its efficacy, Parer and King62
FHR monitoring has not been studied, but the intervals have noted that obstetricians continue to rely heavily on
8 Intrapartum Fetal Assessment and Therapy 155
include moderate or thick meconium (suggesting recent saturation measurements are averaged every 45 seconds,108
passage and lower amniotic fluid volume) and abnormal and the human fetus typically demonstrates an oxygen
FHR tracings.91 The lung injury likely originates from saturation of 35% to 65%. Animal and human data
intrapartum fetal hypoxia.91,93,94 Oropharyngeal suction- suggest that metabolic acidosis does not occur until the
ing at delivery has not proved beneficial; randomized oxygen saturation has fallen below 30% for at least
controlled trials have suggested that vigorous newborns 10 minutes when measured with this device.110,111 Pulse
do not need aggressive airway cleansing with tracheal oximetry does not predict acidosis accurately in fetuses
intubation (see Chapter 9).91,95 Aggressive obstetric man- with severe variable decelerations during the second stage
agement of postdate pregnancies (i.e., avoidance of post- of labor.112 Moreover, the accuracy of fetal pulse oximetry
datism) has led to a substantial decrease in the incidence readings lower than 30% in human fetuses has been chal-
of meconium-stained amniotic fluid and meconium aspi- lenged.108,113 Fetal pulse oximetry used in conjunction
ration syndrome.92 with FHR monitoring appears to reduce the rate of cesar-
ean delivery for a nonreassuring FHR tracing; however,
this reduction is offset by an increased rate of cesarean
New Technologies for Fetal Assessment delivery for dystocia.114-116 The absence of an effect on
Because FHR monitoring provides only an indirect the overall cesarean delivery rate prompted the ACOG
measure of fetal oxygenation and acid-base status, alter- to withhold an endorsement of fetal pulse oximetry
native technologies, such as transcutaneous Po2, Pco2, pending further investigation of its use.109 A Spanish trial
and pH monitors have been developed to provide a more randomly allocated 180 women with nonreassuring intra-
direct assessment.96-98 However, the use of these monitors partum FHR tracings to receive further evaluation with
has been limited by technical difficulties in the applica- either ST waveform analysis or pulse oximetry; the inves-
tion of the probe(s), drift in the baseline readings, tigators observed a lower cesarean delivery rate in the ST
artifactual measurements, and difficulties in establishing waveform analysis group, with fewer low 1-minute
diagnostic criteria for intervention. APGAR scores and improved umbilical cord venous
ST waveform analysis of fetal electrocardiography blood pH measurements.117
is a technique proposed to enhance intrapartum fetal Proton magnetic resonance spectroscopy (1H
assessment. Fetal hypoxia induces changes in the ECG MRS) can obtain metabolic information from human and
morphology of the ST segment and T wave. ST wave- animal brains, and early investigations suggest an ability
form analysis enhances the specificity of FHR trac- to assess fetal brain oxygenation.118-120 1H MRS has proved
ings,99,100 but not the sensitivity.101 A 2006 meta-analysis useful in the evaluation of hypoxic-ischemic encepha-
of randomized controlled trials, accounting for almost lopathy and metabolic disorders in pediatric patients.
10,000 deliveries, of automatic ST waveform analysis (the This technique can also measure levels of the metabolites
STAN S21 system, Neoventa Medical, Göteborg, lactate, N-acetylaspartate, creatine, choline, and inositol
Sweden) demonstrated that a combination of FHR moni- in fetal and neonatal neural tissue. It has been applied
toring and ST waveform analysis reduced the risk for experimentally in a case series of fetuses with fetal growth
severe fetal acidosis and the incidence of neonates with restriction.121 Although these measurements can be cor-
encephalopathy.102-104 No differences in the rates of cesar- related with the level of tissue oxygenation, the clinical
ean delivery, 5-minute Apgar scores less than 7, or admis- use of this technique as a means of fetal assessment
sion to the NICU were observed.100,102,103,105,106 In a recent remains unclear.122
trial of 5600 parturients randomized to fetal observation Near-infrared spectroscopy (NIRS) has the poten-
with and without ST waveform analysis, Westerhuis tial to directly measure fetal tissue oxygenation.123 Trans-
et al.107 observed a lower rate of acidosis in the ST wave- abdominal NIRS has been used in research settings to
form analysis group but no other differences in outcome assess placental oxygenation.124 NIRS has gained some
(e.g., operative deliveries or hypoxic ischemic encepha- acceptance in assessing the effects of clinical interven-
lopathy). An unmasked, randomized controlled trial of tions on neonatal organ oxygenation at the bedside.
ST waveform analysis is currently being conducted to NIRS can detect changes in the ratio of reduced to oxy-
assess neonatal outcomes in 11,000 parturients within the genated cytochrome-c oxidase in the brain and in the
U.S. Maternal-Fetal Medicine Network. ratio of oxygenated to deoxygenated hemoglobin in the
Reflectance pulse oximetry has been adapted for blood perfusing the brain; the technique can also measure
assessment of fetal oxygenation. The U.S. Food and the total amount of hemoglobin in the tissue, thereby
Drug Administration (FDA) approved the Nellcor N-400 allowing an estimation of tissue blood perfusion.123 In
fetal pulse oximeter (Nellcor, Puritan Bennett, Pleasan- theory, NIRS offers the opportunity to determine whether
ton, CA) for use in the setting of a term, singleton fetus neurons are at risk for hypoxic damage; currently, the
at more than 36 weeks’ gestation with a vertex presenta- technique is being correlated with other measures of fetal
tion and a nonreassuring FHR pattern after rupture of well-being, such as periodic FHR changes and umbilical
membranes.108,109 The most commonly used probes are cord blood pH measurements at delivery. However,
held in place against the fetal head or cheek with pressure similar to fetal pulse oximetry, NIRS technology is
from the cervix. A reliable pulse oximetry signal can be limited by a frequent (approximately 20%) inability to
obtained in 60% to 70% of cases; however, environmen- obtain interpretable measurements and the need to cor-
tal factors and physiologic events (e.g., fetal scalp conges- relate the measurements with long-term neurodevelop-
tion, thick fetal hair, vernix caseosa, uterine activity, mental outcomes. As a consequence, NIRS remains a
movement artifacts) may affect the accuracy.109 The research rather than a clinical tool at this time.123
158 PART III Fetal and Neonatal Assessment and Therapy
TABLE 8-1 Various Intrauterine Resuscitative Measures for Category II or Category III Fetal Heart
Rate (FHR) Tracings or Both
Associated Fetal Heart Rate
Goal Abnormality* Potential Intervention(s)†
Promote fetal oxygenation Recurrent late decelerations Initiate lateral positioning (either left or right)
and improve Prolonged decelerations or Administer supplemental maternal oxygen
uteroplacental blood flow bradycardia Administer intravenous fluid bolus
Minimal or absent FHR variability Reduce uterine contraction frequency
Reduce uterine activity Tachysystole with category II or III Discontinue oxytocin or cervical ripening agents
tracing Administer tocolytic medication (e.g., terbutaline)
Alleviate umbilical cord Recurrent variable decelerations Initiate maternal repositioning
compression Prolonged decelerations or Initiate amnioinfusion
bradycardia If prolapsed umbilical cord is noted, elevate the
presenting fetal part while preparations are
underway for operative delivery
*Evaluation for the underlying suspected cause(s) is also an important step in management of abnormal FHR tracings.
†
Depending on the suspected underlying cause(s) of FHR abnormality, combining multiple interventions simultaneously may be
appropriate and potentially more effective than doing individually or serially (Simpson KR, James DC. Efficacy of intrauterine
resuscitation techniques in improving fetal oxygen status during labor. Obstet Gynecol 2005;105:1362-8).
From American College of Obstetricians and Gynecologists. Management of intrapartum fetal heart rate tracings. ACOG Practice Bulletin
No. 116, November 2010. (Obstet Gynecol 2010; 116:1232-40.)
Reports from the developing world indicate that, in some administration of a large bolus of a glucose-containing
cases, expeditious vaginal delivery may produce accept- solution is contraindicated.
able neonatal outcome.131 Alternative methods to decom- Fetal cardiac failure results in inadequate umbilical
press a prolapsed umbilical cord include the use of the blood flow and fetal hypoxemia and acidosis. Fetal
Trendelenburg position or an infusion of 500 to 700 mL anemia due to maternal isoimmunization, fetal hemoglo-
of 0.9% saline into the maternal bladder until an expe- binopathy, or fetal hemorrhage results in diminished fetal
dited delivery can occur.130,132,133 oxygen-carrying capacity. There are few options for the
Uterine contractions represent a much more common treatment of fetal cardiac failure or anemia during labor.
cause of umbilical cord compression and can manifest Standardization of FHR tracing interpretation and
as variable FHR decelerations or bradycardia. Oligohy- staged levels of intervention based on likely etiology will
dramnios is a risk factor for this type of cord compres- assist obstetric management. If intrapartum assessment
sion, and a change in maternal position or the use of suggests the presence of fetal compromise and fetal
saline amnioinfusion may be therapeutic. Amnioinfu- therapy is unsuccessful, the obstetrician should effect an
sion has been observed to reduce the frequency of severe expeditious, atraumatic delivery.
variable FHR decelerations and the incidence of cesarean
delivery and to increase the umbilical cord blood pH in
women with preterm premature rupture of membranes, KEY POINTS
oligohydramnios, or variable FHR decelerations during
labor.134,135 Systematic reviews have produced different • A normal FHR tracing accurately predicts fetal
conclusions as to whether prophylactic intrapartum amnio- well-being. An abnormal tracing is not very
infusion in patients with oligohydramnios is superior to specific in the prediction of fetal compromise.
therapeutic amnioinfusion in patients with both oligohy- Exceptions include the fetus with a prolonged
dramnios and FHR abnormalities.136,137 bradycardia or the fetus with late FHR
Initial studies suggested that in patients with thick, decelerations and absence of variability; both
meconium-stained amniotic fluid, amnioinfusion might suggest a high likelihood of fetal compromise.
decrease the incidence of meconium aspiration syndrome • Large, prospective, randomized studies have not
and fetal acidosis.138-140 However, meta-analyses of studies confirmed that continuous electronic FHR
suggest no benefit of amnioinfusion in the setting of monitoring confers substantial clinical benefit
meconium unless decelerations due to oligohydramnios over intermittent FHR auscultation as performed
are present.141-145 by dedicated labor nurses.
Saline amnioinfusion requires a dilated cervix, rup- • The specificity of FHR monitoring may be
tured membranes, and the placement of an intrauterine augmented by the use of fetal scalp stimulation,
catheter. Equipment that allows simultaneous saline fetal vibroacoustic stimulation, and fetal scalp
amnioinfusion and measurement of intrauterine pressure blood sampling. Pulse oximetry increases the
is preferred. Either normal saline or lactated Ringer’s specificity of FHR monitoring but does not
solution may be infused as a bolus or as a continuous reduce the rate of cesarean delivery.
infusion.146 The ideal rate of infusion has not been deter- • When possible, FHR resuscitation in utero is
mined, but a commonly used regimen consists of a bolus preferable to emergency delivery of an acidotic
of as much as 800 mL (infused at a rate of 10 to 15 mL/ fetus.
min) followed by either a continuous infusion at a rate of
3 mL/min or repeated boluses of 250 mL, as needed.146 • Saline amnioinfusion effectively prevents or
The necessity of either an infusion pump or a fluid relieves variable decelerations caused by
warmer has not been demonstrated.146 Alleviation of umbilical cord compression and may improve
abnormal FHR patterns generally requires 20 to 30 perinatal outcomes in patients with
minutes.146 oligohydramnios.
Although most studies suggest that amnioinfusion is
safe for the mother and fetus, some complications have
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C H A P T E R 9
CHAPTER OUTLINE
The transition from intrauterine to extrauterine life rep- training and certification program administered by the
resents the most important adjustment that a neonate will AAP. The NRP, which was originally sponsored by the
make. Occurring uneventfully after most deliveries, this AAP and the AHA in 1987, is designed to be appropriate
transition is dependent on the anatomic and physiologic for all personnel who attend deliveries. To ensure the
condition of the infant, the ease or difficulty of the implementation of current guidelines for neonatal resus-
delivery, and the extrauterine environmental conditions. citation, the AAP recommends that at least one NRP-
When the transition is unsuccessful, prompt assessment certified practitioner attend every delivery.3,4
and supportive care must be initiated immediately. Both the American Society of Anesthesiologists (ASA)
At least one person skilled in neonatal resuscitation and the American College of Obstetricians and Gyne-
should be present at every delivery.1 The resuscitation cologists (ACOG) have published specific goals and
team may include personnel from the pediatrics, anesthe- guidelines for neonatal resuscitation (Box 9-1).5 The ASA
siology, obstetrics, respiratory therapy, and nursing has emphasized that a single anesthesiologist should not
services. The composition of the team varies among insti- be expected to assume responsibility for the concurrent
tutions, but some form of 24-hour coverage should be care of both the mother and her child. Rather, a second
present within all hospitals that provide labor and delivery anesthesia provider or a qualified individual from another
services.1 A multidisciplinary team should participate in service should assume responsibility for the care of the
the process of ensuring that appropriate personnel and neonate, except in an unforeseen emergency.
equipment are available for neonatal resuscitation.1 In clinical practice, anesthesiologists often are involved
All personnel working in the delivery area should in neonatal resuscitation.6,7 Heyman et al.7 observed that
receive basic training in neonatal resuscitation to ensure anesthesia personnel were involved in neonatal resuscita-
prompt initiation of care before the arrival of the desig- tion in 99 (31%) of 320 selected Midwestern community
nated resuscitation team. The 2010 American Heart hospitals. In 13.4% of these hospitals, the individual who
Association (AHA) Conference on Cardiopulmonary administered anesthesia to the mother was also respon-
Resuscitation and Emergency Cardiovascular Care led to sible for the care of the neonate; in 6.8% of these institu-
the publication of updated guidelines for neonatal resus- tions, a second anesthesia provider typically assumed
citation.2 Changes in these guidelines reflected a review primary responsibility for the neonate. In a larger survey
of scientific evidence by members of the American of obstetric anesthesia workforce patterns within the
Academy of Pediatrics (AAP), the AHA, and the Inter United States, Bucklin et al.6 found that fewer anesthesi-
national Liaison Committee on Resuscitation. These ologists were involved in neonatal resuscitation in 2001
guidelines have been incorporated into the Neonatal than in 1981, with this practice occurring in less than 5%
Resuscitation Program (NRP), which is the standardized of cesarean deliveries.
164
9 Neonatal Assessment and Resuscitation 165
Optimal Goals for Anesthesia Care transitional circulation, to an adult circulation pattern
BOX 9-1 (which is in series) (Figure 9-1).10 In the fetus, blood
in Obstetrics:
from the placenta travels through the umbilical vein and
NEONATAL RESUSCITATION the ductus venosus to the inferior vena cava and the
right side of the heart. The anatomic orientation of the
Personnel other than the surgical team should be immedi- inferior vena caval–right atrial junction favors the shunt-
ately available to assume responsibility for resuscitation of ing (i.e., streaming) of this well-oxygenated blood
the depressed neonate. The surgeon and anesthesiologist are through the foramen ovale to the left side of the heart.
responsible for the mother and may not be able to leave her This well-oxygenated blood is pumped through the
to care for the neonate, even when a neuraxial anesthetic is
functioning adequately. Individuals qualified to perform
ascending aorta, where branches that perfuse the upper
neonatal resuscitation should demonstrate: part of the body (e.g., heart, brain) exit proximal to the
• Proficiency in rapid and accurate evaluation of the entrance of the ductus arteriosus.11 Desaturated blood
neonate’s condition, including Apgar scoring returns to the heart from the upper part of the body by
• Knowledge of the pathogenesis of a depressed neonate means of the superior vena cava. The anatomic orienta-
(acidosis, drugs, hypovolemia, trauma, anomalies, tion of the superior vena caval–right atrial junction
and infection) as well as specific indications for favors the streaming of blood into the right ventricle.
resuscitation Because fetal pulmonary vascular resistance is higher
• Proficiency in neonatal airway management, laryngos- than systemic vascular resistance (SVR), approximately
copy, endotracheal intubations, suctioning of airways, 90% of the right ventricular output passes through the
artificial ventilation, cardiac massage, and maintenance
of thermal stability
ductus arteriosus and enters the aorta distal to the
In larger maternity units and those functioning as high- branches of the ascending aorta and aortic arch;
risk centers, 24-hour in-house anesthesia, obstetric, and therefore, less well-oxygenated blood perfuses the lower
neonatal specialists are usually necessary. body, which consumes less oxygen than the heart
and brain.
Modified from a joint statement from the American College of Obstetricians At the time of birth and during the resulting circula-
and Gynecologists and the American Society of Anesthesiologists. Optimal tory transition, the amount of blood that shunts through
goals for anesthesia case in obstetrics. Approved by the American Society of
Anesthesiologists in October 2008. (See Appendix C for full document.)
the foramen ovale and ductus arteriosus diminishes and
the flow becomes bidirectional. Clamping the umbilical
cord (or exposing the umbilical cord to room air) results
Despite this relatively low incidence of primary in increased SVR. Meanwhile, expansion of the lungs
involvement, the anesthesiologist is often asked to provide and increased alveolar oxygen tension and pH result in
assistance in cases of difficult airway management or decreased pulmonary vascular resistance and subse-
when members of the neonatal resuscitation team have quently greater flow of pulmonary artery blood through
not yet arrived. The anesthesiologist should be prepared the lungs.12,13 Increased pulmonary artery blood flow
to provide assistance, provided that such care does not results in improved oxygenation and higher left atrial
compromise the care of the mother. A study of University pressure; the latter leads to a diminished shunt across
of Pennsylvania anesthesiology residency program grad- the foramen ovale. Increased Pao2 and SVR and decreased
uates from 1989 to 1999 revealed that, despite a desire to pulmonary vascular resistance result in a constriction
be certified in neonatal resuscitation, most anesthesiolo- of the ductus arteriosus.14,15 Together, these changes in
gists were not.8 vascular resistance result in functional closure of the
In a 1991 review of the ASA Closed-Claims Database, foramen ovale and the ductus arteriosus. This process
13% of obstetric anesthesia malpractice claims were does not occur instantaneously, and arterial oxygen satu-
related to neonatal resuscitation, including delayed or ration (Sao2) remains higher in the right upper extremity
failed tracheal intubation and an unrecognized esopha- (which is preductal) than in the left upper extremity and
geal intubation.9 Another review of obstetric anesthesia– the lower extremities until blood flow through the ductus
related lawsuits from 1985 to 1993 demonstrated that 12 arteriosus is minimal.16 Differences in Sao2 are usually
(17%) of the 69 cases involved claims of inadequate neo- minimal by 10 minutes and absent by 24 hours after
natal resuscitation by anesthesia personnel7; 10 of these birth. Provided that there is no interference with the
12 cases resulted in payment to the plaintiff. Written normal drop in pulmonary vascular resistance, both the
hospital policies should identify the personnel responsi- foramen ovale and the ductus arteriosus close function-
ble for neonatal resuscitation; obstetric anesthesia pro- ally, and the infant develops an adult circulation (which
viders should also maintain a high level of skill in neonatal is in series).
resuscitation. Persistent fetal circulation—more correctly called
persistent pulmonary hypertension of the newborn—
can occur when the pulmonary vascular resistance remains
TRANSITION FROM INTRAUTERINE TO elevated at the time of birth. Factors that may contribute
to this problem include hypoxia, acidosis, hypovolemia,
EXTRAUTERINE LIFE and hypothermia.13,17 Maternal use of nonsteroidal anti-
Circulation inflammatory drugs may also cause premature constric-
tion of the ductus arteriosus in the fetus and thus
At birth, the circulatory system changes from a fetal predispose to persistent pulmonary hypertension of the
circulation pattern (which is in parallel), through a newborn.18
166 PART III Fetal and Neonatal Assessment and Therapy
12
6 8
3
4
7
2
9
1
11
10
FIGURE 9-1 ■ Modification of blood flow patterns from the fetal (left), via the transitional (center), to the neonatal (right) circulation.
In the fetal circulation, oxygenated blood (white) from the placenta travels through the umbilical vein (1) into the ductus venosus
and the inferior vena cava (2). The majority of oxygenated blood passes through the patent foramen ovale (PFO) from the right
atrium to the left atrium (3) and ventricle (4), and distributes this blood to the brain (5). The deoxygenated blood (blue) from the
brain and upper extremities enters the superior vena cava, mixing with a small portion of the oxygenated blood in the right atrium,
before entering the right ventricle (RV, 7). The mostly deoxygenated blood is transported into the pulmonary artery where the
majority is diverted through the patent ductus arteriosus (PDA, 8) into the descending aorta (9), thereby bypassing the lungs. Some
blood enters the lower body (10), but the majority returns to the placenta via the umbilical arteries (11). A small amount of blood
from the pulmonary artery enters the lungs (12). During the transitional circulation, which occurs over a few days, the PFO closes,
diverting blood from the right atrium to the right ventricle. Closure of the PDA diverts deoxygenated blood through the pulmonary
arteries to the lungs. The neonatal circulation separates the oxygenated and deoxygenated blood flow pathways. (Drawing by Naveen
Nathan, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
gestation unless surfactant production has been stimu- weight, meconium aspiration, respiratory distress at
lated by chronic stress or maternal corticosteroid birth, hypothermia at birth, and group B beta-hemolytic
administration.25 streptococcal colonization of the maternal birth canal)
Stress during labor and delivery can lead to gasping have been observed to be strong predictors of the perfor-
efforts by the fetus, which may result in the inhalation of mance of neonatal sepsis evaluations, whereas maternal
amniotic fluid into the lungs.26 This event can produce fever and epidural analgesia have not.36 Confounding
problems if the stress causes the fetus to pass meconium variables may influence the findings of these types of
into the amniotic fluid before gasping. association studies; patients who choose either to receive
or not receive epidural analgesia may be inherently dif-
ferent. The incidence of actual neonatal sepsis is not
Catecholamines different in term infants whose mothers either did or did
Transition to extrauterine life is associated with a cate- not receive epidural analgesia.
cholamine surge, which may be necessary for the process
to be successful. In chronically catheterized sheep, cate-
cholamine levels begin to rise a few hours before delivery ANTENATAL ASSESSMENT
and may be higher at the time of delivery than at any
other time during life.27 Catecholamines have an impor- Approximately 10% of neonates require some level of
tant role in the following areas: (1) the production and resuscitation.2 The need for resuscitation can be pre-
release of surfactant, (2) the mediation of preferential dicted before labor and delivery with approximately 80%
blood flow to vital organs during the period of stress that accuracy on the basis of a number of antepartum factors
occurs during every delivery, and (3) thermoregulation of (Box 9-2).
the neonate. Preterm delivery increases the likelihood that the
neonate will require resuscitation. When a mother is
admitted with either preterm labor or premature rupture
Thermal Regulation of membranes, plans should be made for neonatal care in
Thermal stress challenges the neonate in the extrauterine the event of delivery. The antenatal assessment of gesta-
environment. Neonates raise their metabolic rates and tional age is based on the presumed date of the last
release norepinephrine in response to cold; this response menstrual period, the fundal height, and ultrasonographic
facilitates the oxidation of brown fat, which contains measurements of the fetus. Unfortunately, it may be dif-
numerous mitochondria. The oxidation results in non- ficult to assess gestational age accurately, because men-
shivering thermogenesis, the major mechanism for strual dates may be unknown or incorrect, the fundal
neonatal heat regulation.28 This process may lead to sig- height may be affected by abnormalities of fetal growth
nificant oxygen consumption, especially if the neonate or amniotic fluid volume, and ultrasonographic assess-
has not been dried off and kept in an appropriate ther- ment of fetal age is less precise after mid pregnancy. The
moneutral environment, such as a radiant warmer. assessment of gestational age is most accurate in patients
Thermal stress is an even greater problem in infants with who receive prenatal care in early pregnancy. An accurate
low fat stores, such as preterm infants or infants who are approximation of gestational age enables the health care
small for gestational age. An alternative method to elimi- team to plan for the needs of the neonate and to counsel
nate heat loss from evaporation is to provide an occlusive the parents regarding neonatal morbidity and mortality.
wrap rather than drying the infant. For infants born at These plans and expectations must be formulated with
less than 28 weeks’ gestation, the use of polythene wraps caution and flexibility, because the antenatal assessment
or bags is recommended to minimize heat loss.29,30 The may not accurately predict neonatal size, maturity, and/
maintenance of a neutral thermal environment (i.e., 34° or condition at delivery.
to 35° C) is recommended. However, in the neonate with A variety of intrauterine insults can impair the fetal
a perinatal brain injury, mild hypothermia therapy transition to extrauterine life. For example, neonatal
through selective head or whole body cooling is initiated depression at birth can result from acute or chronic
in the first 6 hours of life and may be neuroprotective in uteroplacental insufficiency or acute umbilical cord com-
the setting of hypoxia-ischemia.31,32 Hyperthermia may pression. Chronic uteroplacental insufficiency, regardless
worsen neurologic outcomes and should be avoided.2,33 of its etiology, may result in fetal growth restriction. Fetal
Hypothermia therapy, via selective head cooling or whole hemorrhage, viral or bacterial infection, meconium aspi-
body hypothermia, is continued for 72 hours after initia- ration, and exposure to opioids or other CNS depressants
tion. Consequently, if an infant is delivered at a center also can result in neonatal depression. Although random-
where hypothermia therapy is unavailable, passive cooling ized trials have not confirmed that fetal heart rate (FHR)
can be initiated by turning the radiant warmer off while monitoring improves neonatal outcome, a nonreassuring
awaiting infant transfer. FHR tracing is considered a predictor of the need for
Administration of epidural analgesia during labor is neonatal resuscitation.37
associated with an increase in maternal and fetal tempera- Studies have evaluated the use of fetal pulse oximetry
ture.34 Concern has been expressed that the temperature for the evaluation of fetal well-being during labor. This
elevation associated with intrapartum epidural analgesia technique involves the transcervical insertion of a flexible
might result in an increase in the frequency of neonatal fetal oxygen sensor until it rests against the fetal cheek.
sepsis evaluations.34,35 However, a number of variables A randomized trial found that use of the fetal pulse oxim-
(e.g., preeclampsia/hypertension, gestational age, birth eter in conjunction with FHR monitoring led to a
168 PART III Fetal and Neonatal Assessment and Therapy
Risk Factors Suggesting a Greater use of fetal pulse oximetry did not lead to an overall
BOX 9-2 reduction in the cesarean delivery rate.40
Need for Neonatal Resuscitation
Infants with congenital anomalies (e.g., tracheo-
ANTEPARTUM RISK FACTORS esophageal fistula, diaphragmatic hernia, CNS and
• Maternal diabetes cardiac malformations) may need resuscitation and car-
• Hypertensive disorder of pregnancy diorespiratory support. Improved ultrasonography allows
• Chronic hypertension for the antenatal diagnosis of many congenital anomalies
• Fetal anemia or isoimmunization and other fetal abnormalities (e.g., nonimmune hydrops).
• Previous fetal or neonatal death Obstetricians should communicate knowledge or suspi-
• Bleeding in second or third trimester cions regarding these entities to those who will provide
• Maternal infection care for the neonate in the delivery room to allow the
• Maternal cardiac, pulmonary, renal, thyroid, or neuro- resuscitation team to make specific resuscitation plans.
logic disease In the past, infants born by either elective or emer-
• Polyhydramnios
• Oligohydramnios
gency cesarean delivery were considered more likely to
• Premature rupture of membranes require resuscitation than infants delivered vaginally.
• Fetal hydrops Evidence suggests that repeat cesarean deliveries and
• Post-term gestation those performed for dystocia—in patients without FHR
• Multiple gestation abnormalities—result in the delivery of infants at low risk
• Discrepancy between fetal size and dates (i.e., last for neonatal resuscitation, especially when the cesarean
menstrual period) deliveries are performed with neuraxial anesthesia.3,4,41 Of
• Drug therapy (e.g., lithium carbonate, magnesium, interest, infants born by elective repeat cesarean delivery
adrenergic-blocking drugs) are at higher risk for subsequent respiratory problems
• Maternal substance abuse (e.g., transient tachypnea of the newborn) than similar
• Fetal malformation
• Diminished fetal activity
infants born vaginally. In addition, infants born by cesar-
• No prenatal care ean delivery after a failed trial of labor are at a higher risk
• Maternal age > 35 years for neonatal sepsis than similar infants born vaginally.42
Emergency cesarean delivery is considered a risk factor
INTRAPARTUM RISK FACTORS for the need for neonatal resuscitation.
• Emergency cesarean delivery
• Forceps or vacuum-assisted delivery
• Breech or other abnormal presentation NEONATAL ASSESSMENT
• Preterm labor
• Precipitous labor
• Chorioamnionitis Apgar Score
• Prolonged rupture of membranes (> 18 hours before
delivery) Resuscitative efforts typically precede the performance of
• Prolonged labor (> 24 hours) a thorough physical examination of the neonate. Because
• Macrosomia NRP instructions require simultaneous assessment and
• Category II or III fetal heart rate patterns treatment, it is important that the neonatal assessment be
• Use of general anesthesia both simple and sensitive. In 1953, Dr. Virginia Apgar,
• Uterine tachysystole with fetal heart rate changes an anesthesiologist, described a simple method for neo-
• Maternal administration of opioids within 4 hours of natal assessment that could be performed while care was
delivery being delivered.43 She suggested that this standardized
• Meconium-stained amniotic fluid and relatively objective scoring system would differenti-
• Prolapsed umbilical cord
• Placental abruption
ate between infants who require resuscitation and those
• Placenta previa who need only routine care.44
• Significant intrapartum bleeding The Apgar score is based on five parameters that are
assessed at 1 and 5 minutes after birth. Further scoring
Modified from Textbook of Neonatal Resuscitation. 6th edition. Elk Grove at 5- or 10-minute intervals may be done if initial scores
Village, IL, American Academy of Pediatrics and American Heart are low. The parameters are heart rate, respiratory effort,
Association, 2011:216. muscle tone, reflex irritability, and color. A score of 0, 1,
or 2 is assigned for each of these five entities (Table 9-1).
A total score of 8 to 10 is normal; a score of 4 to 7 indi-
reduction in the number of cesarean deliveries performed cates moderate impairment; and a score of 0 to 3 signals
due to a nonreassuring FHR tracing.38 However, this the need for immediate resuscitation. Dr. Apgar empha-
decrease was offset by an increased number of cesarean sized that this system does not replace a complete physi-
deliveries performed due to dystocia, raising the concern cal examination and serial observations of the neonate for
that the presence of the probe might predispose to dys- several hours after birth.45
tocia. As a consequence, the ACOG has recommended The Apgar score is widely used to assess neonates,
further study before fetal pulse oximetry is used routinely although its value has been questioned. The scoring
in clinical practice.39 A meta-analysis of five trials con- system may help predict mortality and neurologic mor-
cluded that there was some benefit to fetal pulse oximetry bidity in populations of infants, but Dr. Apgar cautioned
in the presence of a nonreassuring FHR tracing, but the against the use of the Apgar score to make these
9 Neonatal Assessment and Resuscitation 169
Parameter 0 1 2
predictions in an individual infant. She noted that the risk neonatal death was eight times higher in infants with a
for neonatal mortality was inversely proportional to the 5-minute Apgar score of 3 or less than in those with an
1-minute score.45 In addition, the 1-minute Apgar score umbilical arterial blood pH of 7.0 or less.63,64 In preterm
was a better predictor of mortality within the first 2 days infants, lower 5-minute Apgar scores were associated
of life than within 2 to 28 days of life. with younger gestational ages (i.e., mean score 6.6 ± 2.1
Several studies have challenged the notion that a low for infants born at 26 to 27 weeks’ and 8.7 ± 0.8 for
Apgar score signals perinatal asphyxia. In a prospective infants born at 34 to 36 weeks’ gestation).63,64 Similarly,
study of 1210 deliveries, Sykes et al.46 noted a poor cor- earlier studies found that preterm infants were more
relation between the Apgar score and the umbilical cord likely than term infants to have low 1- and 5-minute
blood pH. Other studies, including those of low-birth- Apgar scores, independent of neonatal oxygenation and
weight infants, have found that a low Apgar score is a acid-base status. Respiratory effort, muscle tone, and
poor predictor of neonatal acidosis, although a high score reflex irritability are the components of the score that are
is reasonably specific for excluding the presence of severe most influenced by gestational age.65
acidosis.47-53 By contrast, the fetal biophysical profile has The earlier the gestational age, the greater the likeli-
a good correlation with the acid-base status of the fetus hood of a low Apgar score, even in the presence of a
and the neonate (see Chapter 6).54 The biophysical profile normal umbilical cord blood pH. Preterm infants often
includes performance of a nonstress test and ultrasono- require active resuscitation efforts immediately after
graphic assessment of fetal tone, fetal movement, fetal delivery, and these manipulations may affect the compo-
breathing movements, and amniotic fluid volume.54 nents of the Apgar score. For example, pharyngeal and
Additional studies have suggested that Apgar scores tracheal stimulation may cause a reflex bradycardia,
are poor predictors of long-term neurologic impair- which affects the heart rate score.49 In addition, it is dif-
ment.55,56 The Apgar score is more likely to predict a poor ficult to judge respiratory effort during suctioning or
neurologic outcome when the score remains 3 or less at endotracheal intubation.
10, 15, and 20 minutes. However, when a child has cere- During cases of active neonatal resuscitation, the
bral palsy, low Apgar scores alone are not adequate evi- Apgar scores often are not assigned at the appropriate
dence that perinatal hypoxia was responsible for the times; rather, these scores may be assigned retrospec-
neurologic injury. tively. In these situations, the individual must rely on
The ACOG Task Force on Neonatal Encephalopathy recall of the infant’s condition at earlier times, introduc-
and Cerebral Palsy published criteria for defining an ing inaccuracy. Even if the scores are assigned at the
intrapartum event sufficient to cause cerebral palsy.57 An appropriate times, there may be disagreement among the
Apgar score of 0 to 3 beyond 5 minutes of age is not several individuals who are providing care for the infant.
included in the list of “essential criteria”; rather, it is one To avoid bias, Dr. Apgar recommended that someone not
of five criteria that “collectively suggest an intrapartum involved in the care of the mother assign the score.
timing (within close proximity to labor and delivery…) Although there is some appeal to the use of objective
but are nonspecific to asphyxial insults.”57-62 measurements (i.e., Sao2, heart rate) rather than subjec-
In a retrospective analysis of 151,891 singleton infants tive observations, it should not be inferred that the sub-
born at 26 weeks’ gestation or later between 1988 and jective components of the Apgar score (e.g., muscle tone)
1998, Casey et al.63 examined the relationship between are less important. There are some practical limitations
Apgar scores and neonatal death rates during the first 28 that may make objective measurements difficult to obtain
days of life. The highest relative risk for neonatal death (e.g., movement artifact with pulse oximetry).16 However,
was observed in infants with an Apgar score of 3 or less newer-generation pulse oximeters provide more accurate
at 5 minutes of age. The 5-minute Apgar score was a estimations of Sao2 (see later discussion).66
better predictor of neonatal death than the umbilical In summary, the usefulness of the Apgar score is still
arterial blood pH. In term infants, the relative risk for being debated more than 50 years after its inception.63,64
170 PART III Fetal and Neonatal Assessment and Therapy
The Apgar scoring system is used throughout the world, accurate if residual air bubbles are removed from the
but its limitations must be kept in mind. Low Apgar syringe.
scores alone do not provide sufficient evidence of perina- Historically, a normal umbilical cord blood pH mea-
tal asphyxia; rather, Apgar scores can be low for a variety surement was believed to be 7.2 or higher.74 However,
of reasons. Preterm delivery, congenital anomalies, neu- investigators have challenged the validity of this number,
romuscular diseases, antenatal drug exposure, manipula- given its lack of distinction between umbilical arterial and
tion at delivery, and subjectivity and error may influence venous blood despite clear differences in their normal
the Apgar score. measurements.75 One study noted that the median umbil-
ical arterial blood pH in vigorous infants (those with
5-minute Apgar scores of 7 or higher) was 7.26, with a
Umbilical Cord Blood Gas measurement of 7.10 representing the 2.5th percentile.76
Published studies suggest that the lower limit of normal
and pH Analysis umbilical arterial blood pH measurements may range
Umbilical cord blood gas and pH measurements reflect from 7.02 to 7.18 (Table 9-2).46,77-86 A number of factors
the fetal condition immediately before delivery and can may also influence the umbilical arterial blood pH mea-
be obtained routinely after delivery or measured only in surement. A fetus subjected to the stress of labor has
cases of neonatal depression. These measurements may lower pH measurements than one born by cesarean deliv-
be a more objective indication of a neonate’s condition ery without labor.83 Offspring of nulliparous women tend
than the Apgar score. However, there is a delay between to have a lower pH than offspring of parous women, a
obtaining the samples and completing the analysis; during difference that is likely related to a difference in the dura-
this interval, decisions must be made on the basis of clini- tion of labor.87
cal assessment. The ACOG67 has recommended that cord Some studies have suggested that preterm infants have
blood gas measurements be obtained in circumstances of a higher incidence of acidemia; however, later studies
cesarean delivery for fetal compromise, low 5-minute have observed that term and preterm infants have similar
Apgar score, severe growth restriction, abnormal FHR umbilical cord blood gas and pH measurements.78,79,87
tracing, maternal thyroid disease, intrapartum fever, and/ Preterm infants often receive low Apgar scores despite
or multiple gestations. the presence of normal umbilical cord blood gas and pH
The fetus produces carbonic acid (from oxidative measurements; therefore, the assessment of umbilical
metabolism) and lactic and beta-hydroxybutyric acids cord blood may be especially helpful in the evaluation of
(primarily from anaerobic metabolism). Carbonic acid, preterm neonates.
which is often called respiratory acid, is cleared rapidly by Physicians should use strict definitions when inter-
the placenta as carbon dioxide when placental blood flow preting umbilical cord blood gas and pH measurements.
is normal. However, metabolic clearance of lactic and Terms such as birth asphyxia should be avoided in most
beta-hydroxybutyric acids requires hours; thus, these cases.57 Acidemia refers to an increase in the hydrogen ion
acids are called metabolic or fixed acids. In the fetus, meta- concentration in the blood. Acidosis occurs when there is
bolic acidemia is more ominous than respiratory acidemia an increased hydrogen ion concentration in tissue.
because the former reflects a significant amount of anaer- Asphyxia is a clinical situation that involves hypoxia (i.e.,
obic metabolism. a decreased level of oxygen in tissue), damaging acidemia,
The measured components of umbilical cord blood and metabolic acidosis.
gas analysis are pH, Pco2, Po2, and HCO3−. Bicarbonate When acidemia is present, the type—respiratory,
(HCO3−) is a major buffer in fetal blood. The measure of metabolic, or mixed—must be identified (Table 9-3).
change in the buffering capacity of umbilical cord blood Metabolic acidemia is more likely to be associated with
is reflected in the delta base, which is also known as the acidosis than respiratory acidemia and is clinically more
base excess or deficit; this value can be calculated from significant. Similarly, mixed acidemia with a high Pco2,
the pH, Pco2, and HCO3−. Ideally, blood samples from an extremely low HCO3−, and a high base deficit is more
both the umbilical artery and vein are collected. Umbili- ominous than a mixed acidemia with a high Pco2 but
cal artery blood gas measurements represent the fetal only a slightly reduced HCO3− and a low base deficit.
condition, whereas umbilical vein measurements reflect Mixed or metabolic acidemia (but not respiratory acide-
the maternal condition and uteroplacental gas exchange. mia) is associated with an increased incidence of neonatal
Unfortunately, it may be difficult to obtain blood from complications and death.87 In their study of 3506 term
the umbilical artery, especially when it is small, as it is in neonates, Goldaber et al.88 noted that an umbilical arte-
very low-birth-weight (VLBW) infants. Caution should rial blood pH measurement less than 7.00 was associated
be used in the interpretation of an isolated umbilical with a significantly higher incidence of neonatal death.
venous blood pH measurement, which can be normal All neonatal seizures in their study occurred in infants
despite the presence of arterial acidemia. with an umbilical arterial blood pH less than 7.05. By
Proper blood sampling and handling are necessary. contrast, a short-term outcome study failed to show a
The measurements should be accurate, provided that (1) good correlation between arterial blood pH and the sub-
the umbilical cord is double clamped immediately after sequent health of an infant.53 In the previously discussed
delivery68-70; (2) the samples are drawn, within 15 minutes large study reported by Casey et al.,63 an umbilical arte-
of delivery,71 into a syringe containing the proper amount rial blood pH of 7.0 or less was a poorer predictor of
of heparin72; and (3) the samples are analyzed within the relative risk for neonatal death during the first 28
30 to 60 minutes.71,73 The Po2 measurement is more days of life than a 5-minute Apgar score of 3 or less.
9 Neonatal Assessment and Resuscitation 171
TABLE 9-2 Studies Reporting Umbilical Cord Arterial Blood Gas Measurements*
Study Sample Size pH PCO2 Bicarbonate Base Deficit PO2
Huisjes and Aarnoudse (1979) 80
852 7.20 ± 0.09
(7.02-7.38)
Sykes et al. (1982)46 899 7.20 ± 0.08 8.3 ± 4.0
(7.04-7.36) (0.3-16.3)
Eskes et al. (1983)81 4667 7.23 ± 0.07
(7.09-7.37)
Yeomans et al. (1985)77 146 7.28 ± 0.05 49.2 ± 8.4 22.3 ± 2.5
(7.18-7.38) (32.4-66.0) (17.3-27.3)
Low (1988)82 4500 7.26 ± 0.07 54.9 ± 9.9 15.1 ± 4.9
(7.12-7.40) (35.1-74.7) (5.3-24.9)
Ruth and Raivio (1988)86 106 7.29 ± 0.07 4.7 ± 4.0
(7.15-7.43) (−3.3-12.7)
Thorp et al. (1989)83 1694 7.24 ± 0.07 56.3 ± 8.6 24.1 ± 2.2 3.6 ± 2.7 17.9 ± 6.9
(7.10-7.38) (39.1-73.5) (19.7-28.5) (−1.8-9.0) (4.1-31.7)
Ramin et al. (1989)78 1292 7.28 ± 0.07 49.9 ± 14.2 23.1 ± 2.8 3.6 ± 2.8 23.7 ± 10.0
(7.14-7.42) (21.5-78.3) (17.5-28.7) (−2.0-9.4) (3.7-43.7)
Riley and Johnson (1993)84 3522 7.27 ± 0.07 50.3 ± 11.1 22.0 ± 3.6 2.7 ± 2.8 18.4 ± 8.2
(7.13-7.41) (28.1-72.5) (14.8-29.2) (−2.9-8.3) (2.0-34.8)
Nagel et al. (1995)85 1614 7.21 ± 0.09
(7.03-7.39)
*Data are presented as mean ± 1 SD and (−2 to +2 SD). Sample size pertains to cord arterial pH and not necessarily to other parameters.
Modified from Thorp JA, Dildy BA, Yeomans ER, et al. Umbilical cord blood gas analysis at delivery. Am J Obstet Gynecol 1996;
175:517-22.
However, 6264 infants were excluded from their study neonates with an umbilical arterial blood pH less than
because umbilical arterial blood gas measurements could 7.0. Ten percent of infants with an umbilical arterial base
not be obtained, and these infants had a higher incidence deficit of 12 to 16 mmol/L have moderate to severe com-
of neonatal death than those for whom blood gas mea- plications, which increases to 40% when the deficit is
surements were available (4.5 per 1000 versus 1.2 per greater than 16 mmol/L.67
1000, respectively). In a separate review of 51,519 term Abnormal FHR patterns and umbilical cord blood gas
deliveries, Yeh et al.89 found an increased risk for adverse measurements are not consistently correlated with poor
outcomes in infants with a pH less than 7.10, with the neonatal outcomes.37 In a longitudinal study that evalu-
lowest risk in infants with a pH between 7.26 and 7.30; ated outcomes at 6.5 years of age, Hafstrom et al.90 found
however, 75% of infants with neurologic morbidity had that infants with an umbilical arterial blood pH less than
a normal pH. Thus, it is important to remember that 7.05 but a normal examination at birth had outcomes that
neonates may suffer multiorgan system damage, includ- did not differ from those for matched infants with a
ing neurologic injury, even in the absence of low pH and normal umbilical arterial blood pH.
Apgar scores. As Dr. Apgar emphasized in 1962, the most important
According to the ACOG Task Force, an umbilical components of neonatal assessment are a careful physical
arterial blood pH less than 7.0 and a base deficit greater examination and continued observation for several
than or equal to 12 mmol/L at delivery are considered hours.45 Additional information can be gained from the
one part of the definition of an acute intrapartum hypoxic antenatal history, Apgar scores, and umbilical cord blood
event sufficient to cause cerebral palsy.57 The base deficit gas and pH measurements, provided that clinicians are
and bicarbonate (the metabolic component) values are aware of the proper methods of interpretation as well as
the most significant factors associated with morbidity in the limitations of these methods of assessment.
172 PART III Fetal and Neonatal Assessment and Therapy
Respiration and Circulation The pulse oximeter sensor should be applied to the
neonate’s right upper extremity, which receives preductal
There are some similarities between the initial assess- blood flow (see earlier discussion); because CNS blood
ment of the neonate and the initial assessment of an adult flow is also preductal, right upper extremity Sao2 mea-
who requires resuscitation. In both situations, the physi- surements provide a more accurate assessment of CNS
cian should give immediate attention to the ABCs of oxygenation.16 Sensor placement can be difficult on skin
resuscitation (i.e., airway, breathing, circulation). that is wet and covered with vernix caseosa; therefore, it
The normal neonatal respiratory rate is between 30 may be easier to place the sensor over the right radial
and 60 breaths per minute. Breathing should begin by 30 artery, especially in preterm infants.94
seconds and be regular by 90 seconds of age. Failure of Neonatal arterial blood sampling is technically diffi-
the neonate to breathe by 90 seconds of age represents cult and thus rarely obtained in the delivery room. Can-
either primary or secondary apnea, based on the neonatal nulation of the umbilical artery is useful in infants who
rhesus monkey asphyxia model.91 In this model, gasping will require frequent blood sampling. This procedure
motions were observed for approximately 1 minute often requires the use of microinstruments (especially in
immediately after delivery; this was followed by a preterm and VLBW infants) and the ability to monitor
1-minute period of apnea (primary apnea), then 5 minutes the infant when obscured from view by surgical drapes;
of gasping motions, and a final period of apnea (second- therefore, this procedure is usually performed in the
ary or “terminal” apnea). During primary apnea, but not neonatal intensive care unit (NICU).
secondary apnea, tactile stimulation of the newborn The normal neonatal heart rate may be greater than
monkey initiated breathing efforts. In addition, although 160 beats per minute (bpm) in the very early preterm
heart rate was low with both periods of apnea, a reduction neonate, but it should be within the range of 120 to
in blood pressure was observed only during secondary 160 bpm by 28 weeks’ gestational age. The heart rate can
apnea. With the onset of secondary apnea (approximately be determined in several ways. The clinician can lightly
8 minutes after birth), the pH was 6.8 and the Pao2 and grasp the base of the umbilical cord and feel the arterial
Paco2 measurements were less than 2 and 150 mm Hg, pulsations. (This method cannot be used in situations in
respectively. which the pulsations become difficult to feel, such as in
This experimental model illustrates two important an infant with a low cardiac output.) Alternatively, the
points. First, distinguishing primary from secondary clinician can listen to the apical heartbeat. When either
apnea is not possible unless blood pressure and/or blood of these two methods is used, the evaluator should tap a
gases and pH are measured. Second, by the time second- hand with each heartbeat so that other members of the
ary apnea has begun, blood gas measurements have dete- resuscitation team are aware of the rate. By contrast, the
riorated significantly. Therefore, during evaluation of the use of a pulse oximeter provides an audible heart rate,
apneic neonate, aggressive resuscitation must be initiated the additional benefit of Sao2 monitoring, and the ability
promptly if tactile stimulation does not result in the ini- to eliminate the need for an additional team member.
tiation of spontaneous breathing. Measurement of arterial blood pressure is not a prior-
Assessment of the adequacy of respiratory function ity during the initial assessment and resuscitation of the
requires comprehensive observation for signs of neonatal neonate.2 However, observation for signs of abnormal
respiratory distress. These signs include cyanosis, grunt- circulatory function is considered essential. These signs
ing, flaring of the nares, retracting chest motions, and include cyanosis, pallor, mottled coloring, prolonged
unequal breath sounds. The adequacy of respiratory capillary refill time, and weakness or absence of pulses in
function can also be assessed by the estimation of Sao2. the extremities. One of the causes of abnormal circula-
The reliability of pulse oximetry for the assessment of tory function is hypovolemia, which should be antici-
neonatal Sao2 was questioned initially because of con- pated in cases of bleeding from the umbilical cord or the
cerns about the accuracy of spectrophotometric assess- fetal side of the placenta or whenever a neonate does not
ments of fetal hemoglobin and the difficult signal respond appropriately to resuscitation. The hypovolemic
detection caused by the rapidity of the neonate’s heart neonate may exhibit not only signs of abnormal circula-
rate.92,93 The newer generation of pulse oximetry moni- tory function but also tachycardia and tachypnea. (Neo-
tors, which employ signal extraction and averaging tech- natal hypovolemia usually does not accompany placental
niques, are able to provide more reliable measurements, abruption, which may cause maternal bleeding or other
especially in the presence of poor perfusion, patient conditions associated with fetal asphyxia.)
movement, and ambient light artifacts.66,94
Pulse oximetry provides accurate estimates of Sao2
during periods of stability but may overestimate values
Neurologic Status
during rapid desaturation.95 In addition, the Sao2 (Spo2) The initial neonatal neurologic assessment requires only
measurements may fluctuate in the delivery room as a simple observation. The neonate should demonstrate evi-
result of the ongoing transition from the fetal to the dence of vigorous activity, including crying and active
neonatal circulation, and it may take more than 10 flexion of the extremities. Signs of possible neurologic
minutes to achieve a preductal Sao2 greater than 95% in abnormalities include apnea, seizures, hypotonia, and
a healthy term infant. Overall, the newer-generation unresponsiveness. Neonates should be assessed for physi-
pulse oximeters reliably provide continuous noninvasive cal signs of hypoxic-ischemic encephalopathy (Table 9-4).
Sao2 measurements and are useful for neonatal The stages of hypoxic-ischemic encephalopathy are asso-
monitoring.96-98 ciated with different outcomes: stage I, good; stage II,
9 Neonatal Assessment and Resuscitation 173
Modified from Eicher DJ, Wagner C. Update on neonatal resuscitation. J S C Med Assoc 2002; 98:115.
moderate; and stage III, poor.99 Although detailed neu- fetuses of different racial origin appear to mature at dif-
rologic assessment is performed after the neonate is ferent rates (i.e., black fetuses mature faster than white
transferred to the NICU, assessment of tone, baseline fetuses).107
heart rate, respirations, and reflex activity is part of both Another commonly used criterion for the estimation
the Apgar scoring system and the assessment for hypoxic- of gestational age is birth weight. Normal values for birth
ischemic encephalopathy and is made initially in the weight are published and readily available.108 Although
delivery room. birth weight may help physicians estimate the gestational
age of an otherwise healthy preterm infant, physicians
cannot rely on birth weight to provide an accurate esti-
Gestational Age mate of gestational age in an infant who suffered from
When assessing a very small neonate whose gestational intrauterine growth restriction or who is large for gesta-
age appears to be lower than that of viability, the evalu- tional age.
ator must consider whether it is appropriate to initiate Because of the potential for inaccurate gestational age
and maintain resuscitation efforts. The neonatal gesta- estimation in the delivery room, it is best not to use these
tional age is often assessed with the use of the scoring scoring systems to guide decisions regarding the initia-
systems described initially by Dubowitz et al.100 and sub- tion or continuation of neonatal resuscitation immedi-
sequently modified by Ballard et al.101 The Dubowitz ately after delivery. In most circumstances, the neonate’s
system makes use of an external score based on physical response to resuscitative efforts is the best indicator as to
characteristics, described previously by Farr et al.,102,103 whether further intervention is warranted.
and a neurologic score. The Ballard system uses simpli-
fied scoring criteria to assess gestational age. Ballard
et al.101 eliminated certain physical criteria such as edema NEONATAL RESUSCITATION
and skin color because of the unreliability of these criteria
in some clinical conditions. In addition, they abbreviated The equipment and medications needed for neonatal
the neurologic criteria on the basis of observations by resuscitation are listed in Box 9-3. Equipment, supplies,
Amiel-Tison.104 and medications should be checked regularly to ensure
The Dubowitz and Ballard scores are most accurate that all components are available and functional.
when used to estimate gestational age at 30 to 42 hours, Although previously published guidelines recom-
rather than during the first several minutes, after birth. mended suctioning of the mouth and nose after delivery
These scoring systems are also less accurate in very small of the head, the guidelines published in 2010 do not rec-
preterm infants. In one study of 100 preterm infants with ommend routine intrapartum oropharyngeal and naso-
birth weights less than 1500 g, agreement among ante- pharyngeal suctioning for infants born with either clear
natal measures of gestational age (e.g., last menstrual or meconium-stained amniotic fluid.2
period, ultrasonography determination) and postnatal Timing of cord clamping may vary by the gestational
measures (e.g., Dubowitz and Ballard scores) was poor.105 age and vigor of the infant. Current evidence suggests
Both scoring systems overestimated gestational age in that a delay in cord clamping for 1 minute after the deliv-
this subset of VLBW infants. Ballard et al.106 refined their ery of vigorous term infants improves iron stores through-
scoring system to provide a more accurate estimate of out early infancy.109 In vigorous preterm infants, a brief
gestational age in preterm infants (Figure 9-3). The new delay in cord clamping (30 seconds to 3 minutes) is asso-
Ballard score assesses physical criteria, such as eyelid ciated with improved blood pressure and a lower inci-
fusion, breast tissue, lanugo hair, and genitalia, and neu- dence of intraventricular hemorrhage110; no alterations
rologic criteria, such as wrist “square window.” (The in Apgar scores or need for delivery room resuscitation
square window assessment is performed by flexing the have been observed with this practice.111 In nonvigorous
infant’s wrist on the forearm and noting the angle between infants, regardless of gestational age, the benefits of
the hypothenar eminence and the ventral aspect of the delayed cord clamping may be outweighed by the need
forearm.) Although the new Ballard score may be more to promptly initiate resuscitation.
accurate than the older score for the assessment of After delivery is complete, the neonate is transferred
preterm infants, inconsistencies occur with all of these to the resuscitation area. The availability of sterile blan-
methods. Of particular interest is the observation that kets allows the individual performing the delivery to
174 PART III Fetal and Neonatal Assessment and Therapy
Neuromuscular maturity
–1 0 1 2 3 4 5
Posture
Square
window
(wrist) >90° 90° 60° 45° 30° 0°
Arm recoil
180° 140°-180° 110°-140° 90°-110° <90°
Popliteal
angle
180° 160° 140° 120° 100° 90° <90°
Scarf sign
Heel to ear
−5 22
Lanugo None Sparse Abundant Thinning Bald Mostly
areas bald
0 24
FIGURE 9-3 ■ Modified Ballard scoring system for clinical assessment of maturation in neonates. This scoring system was expanded
to include extremely preterm infants, and it was refined to improve the accuracy of assessment of more mature infants. (Modified
from Ballard JL, Khoury JC, Wedig K, et al. New Ballard score, expanded to include extremely premature infants. J Pediatr 1991; 119:418.)
remain sterile while transferring the infant; this issue The infant who is delivered preterm at less than 28 weeks’
is especially important during cesarean deliveries. The gestation should be placed in a polythene bag or wrap-
timing of delivery should be noted, assessment and ping to prevent heat loss.29,30 Hypothermia can result in
appropriate resuscitative measures should be continued, increased oxygen consumption and metabolic acidosis112
and Apgar scores should be assigned at the appropriate and leads to a significantly higher mortality rate among
intervals (Figure 9-4). preterm infants.113
The physician or nurse should place the infant beneath Selective cerebral hypothermia114 or whole-body
an overhead radiant warmer and promptly dry the skin hypothermia31,32 may protect against brain injury in the
of infants delivered at greater than 28 weeks’ gestation. asphyxiated infant. The use of intentional hypothermia
9 Neonatal Assessment and Resuscitation 175
therapy requires an NICU with defined protocols and nasopharynx. Vigorous nasal suctioning should be avoided
multidisciplinary support. When assessing an infant for because it can cause trauma to the nasal mucosa and
hypothermia therapy, the radiant warmer can be turned result in progressive edema and airway obstruction. The
off to allow passive cooling. With further assessment, if neonate is an obligate nasal breather; thus, choanal atresia
the criteria for hypothermia therapy are not met, the is a potentially lethal anomaly that requires immediate
infant can be warmed. Hyperthermia should be avoided attention. If this anomaly is present (as evidenced by
in all infants.2 failure of nasal passage of the catheter), the neonate
The neonate should be positioned in a way that allows should have an oral airway or endotracheal tube inserted
the airway to remain open, with the head in the “sniffing” and an evaluation performed for repair of the obstruc-
position (the neck flexed on the chest and the head tion. The classic clinical presentation for choanal atresia
extended on the neck, thereby aligning the oropharynx, is an infant with cyanosis and respiratory distress at rest
pharynx, and hypopharynx). Suctioning of the mouth and who becomes pink when crying.
nose with a bulb syringe may be necessary if secretions Tactile stimulation should be used if the neonate does
accumulate. not breathe immediately; this consists of gently rubbing
The neonate with a normal respiratory pattern, heart the back and flicking the soles of the feet. Tactile stimula-
rate, and color requires no further intervention. Often tion does not trigger respiratory efforts during secondary
the neonate has a normal respiratory pattern and heart apnea in the neonate. Therefore, if the neonate does not
rate but may not be pink. Acrocyanosis often persists for begin to breathe spontaneously after tactile stimulation,
several minutes after delivery and does not require inter- the evaluator should begin positive-pressure mask venti-
vention. However, an evaluation for choanal atresia can lation. If the neonate has an abnormally slow heart rate
be performed at this time with the gentle insertion of a (i.e., less than 100 bpm), positive-pressure ventilation
small suction catheter through each nostril into the should be performed until the heart rate rises to the
176 PART III Fetal and Neonatal Assessment and Therapy
TIMELINE
Term gestation? YES Routine care
Birth
Breathing or crying? Provide warmth
Good tone? Stay with
Clear airway if necessary
Mother
Dry
NO Ongoing evaluation
10 min 85-95%
HR below 100?
YES NO
Take ventilation
NO corrective steps
Postresuscitation
care
HR below 60?
YES
Consider intubation
Chest compressions
Coordinate with PPV
Take ventilation
Consider:
corrective steps
Hypovolemia
HR below 60? Intubate if
Pneumothorax
no chest rise
YES
IV epinephrine
FIGURE 9-4 ■ Algorithm for resuscitation of the newly born infant. HR, heart rate; PPV, positive-pressure ventilation; SpO2, oxygen
saturation. (Modified from Textbook of Neonatal Resuscitation. 6th edition. Elk Grove Village, IL, American Academy of Pediatrics and
American Heart Association, 2011:216. Figure by Naveen Nathan, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
normal range. Overzealous tactile stimulation (e.g., slap- performed initially with room air rather than 100%
ping the back) is not useful; it provides no advantage over oxygen.119 The current guidelines for neonatal resuscita-
the more moderate methods and can cause traumatic tion for term infants recommend the use of room air for
injury. Infants with labored or persistent cyanosis may assisted ventilation. In preterm infants, assisted ventila-
benefit from continuous positive airway pressure. tion should be initiated with an inspired oxygen concen-
High concentrations of oxygen (as opposed to ambient tration (Fio2) of 30% to 90% and should be guided by
air) can raise production of oxygen free radicals, which the response to resuscitation and the use of pulse oxim-
have been linked to hypoxia-reoxygenation injury.115 etry to assess oxygenation. The Fio2 should be lowered
Additionally, an association between neonatal oxygen as soon as possible to minimize the risk for retinopathy
supplementation and childhood cancer has been noted of prematurity and pulmonary toxicity. Sao2 measure-
with supplemental oxygen exposure for 3 minutes or ments of 85% to 92% are thought to be adequate and
longer.116 In two studies, term or near-term infants were appropriate for neonates of less than 34 weeks’ gesta-
randomly assigned to receive neonatal resuscitation with tion.117,118,120,121 A meta-analysis detected no significant
either room air or 100% oxygen; no major outcome differences in neurodevelopmental outcomes at 12 to 24
differences were observed.117,118 Subsequently a pooled months of age between infants resuscitated with either
meta-analysis of five trials, consisting of 1032 term or room air or 100% oxygen.122
near-term infants, showed a significantly lower mortality Positive-pressure ventilation must be performed cor-
rate with no evidence of harm when resuscitation was rectly to ensure that it is effective and does not cause
9 Neonatal Assessment and Resuscitation 177
barotrauma. A ventilation bag with a volume of 250 to visualization often is easier when cricoid pressure is
500 mL may be used. The circuit must contain a safety applied. The practitioner should hold the laryngoscope
pop-off pressure valve (e.g., at 35 cm H2O), a visible and apply cricoid pressure with the same hand. The
pressure gauge, or both. An oxygen flow rate of 5 to 10 L/ thumb and first two fingers hold the base of the laryngo-
min is adequate. Alternatively, a T-piece, which is a valved scope, the third finger rests on the mandible, and the
mechanical device, may be used; it allows more consistent fourth finger applies cricoid pressure. This technique
delivery of target inflation pressures and long inspiratory promotes gentleness during airway manipulation. The
times. The mask must be of appropriate size and shape distance from the gums to the larynx often is surprisingly
to ensure a good seal around the nose and mouth. A short. A common mistake is to advance the laryngoscope
variety of masks should be available to accommodate blade too deeply—past the larynx and into the esophagus.
infants of all sizes and gestational ages. For the infant When this error occurs, the larynx falls into view if the
with excessive occipital scalp edema (e.g., caput succeda- laryngoscope blade is withdrawn slowly to allow a second
neum), placing a small roll under the shoulders to allevi- attempt.
ate hyperflexion of the neck may be helpful. The diameter of the endotracheal tube should be large
During the first assisted breath, positive pressure at enough to allow adequate ventilation and insertion of a
30 cm H2O in term infants should be maintained for 4 suction catheter (if needed) but small enough to avoid
to 5 seconds at the end of inspiration to overcome the causing trauma and subsequent subglottic stenosis. The
surface tension of the lungs and open the alveoli.123 The ratio of internal diameter to gestational age should be
neonatal response to a large, rapid inflation of the lungs less than 0.1 (e.g., 3.0 mm tube/35 weeks’ gestation =
is a sharp inspiration of its own (Head’s paradoxical 0.09).128,129
reflex).124 Subsequent breaths should be delivered at a After tracheal intubation, positive-pressure ventilation
rate of 40 to 60 breaths per minute, with intermittent should be resumed by means of an appropriate circuit, as
inspiratory pauses to prevent the development of atelec- described earlier for mask ventilation. Assessment of
tasis. The maximum pressure generated should range proper tube placement is accomplished by listening for
between 20 and 30 cm H2O, with an inspiration-to- breath sounds in both axillae. Exhaled CO2 detection is
expiration ratio of approximately 1 : 1. In preterm infants, the recommended method for confirming placement of
whose lungs may be more easily injured, initial inflation the tube in the trachea.2 False-negative results can occur
pressures of 20 to 25 cm H2O may be adequate. If mask in situations in which the infant is correctly intubated,
ventilation is needed for longer than 2 to 3 minutes, the with the tube in the trachea, but pulmonary blood flow
stomach should be emptied with an orogastric catheter. is poor or absent. This may lead to unnecessary extuba-
Distention of the stomach with air can compromise respi- tion in critically ill infants. As noted previously, the Fio2
ratory function in the neonate. This maneuver should be should be reduced as soon as possible, especially in the
performed with care, because pharyngeal stimulation can preterm neonate. The addition of a pulse oximeter and
result in arrhythmias and apnea.125 an oxygen blender allows more targeted delivery of sup-
The adequacy of respiratory resuscitation can be mon- plemental oxygen to the preterm infant immediately after
itored from observation of its effect on heart rate; an birth. If the neonate is to remain intubated, a chest radio-
increase in heart rate is the first consistently reliable sign graph should be obtained to confirm the exact position
of effective oxygenation. By contrast, changes in color of the endotracheal tube. The skill and experience
occur slowly, are difficult to assess, and are a relatively required for correct tracheal intubation and effective bag-
poor index of successful resuscitation. and-mask ventilation may be lacking in providers who are
When the neonate’s heart rate is higher than 100 bpm, inexperienced with neonatal resuscitation; as a conse-
positive-pressure ventilation can be stopped, and the quence, the laryngeal mask airway (LMA) has been evalu-
infant can be reevaluated for spontaneous respiratory ated as a potential alternative airway device for neonatal
effort. If the neonate does not begin to breathe and if an resuscitation.130-132 The LMA is blindly inserted into the
opioid effect is the suspected etiology, administration of pharynx, and a cuff is inflated to provide a low-pressure
naloxone is not recommended. Naloxone can worsen the seal around the larynx. When evaluated in term infants
neurologic damage caused by asphyxia126,127 and can pre- requiring resuscitation at delivery, use of the LMA was
cipitate acute neonatal opioid withdrawal, including found to be highly successful and without complica-
seizure activity in cases of maternal opioid abuse. Assisted tions.130,131 The revised neonatal resuscitation guidelines
ventilation should be continued until resolution of the state that the LMA is an acceptable alternative means of
opioid effect rather than attempting to reverse it with establishing an airway in infants born at 34 weeks’ gesta-
naloxone. tion and greater and weighing over 2000 g; it can be used
If positive-pressure mask ventilation does not improve by appropriately trained providers when bag-and-mask
oxygenation (as reflected by an increase in heart rate), ventilation is ineffective or attempts at tracheal intuba-
prompt tracheal intubation is indicated. Tracheal intuba- tion have been unsuccessful.2
tion must be performed gently to avoid damage to the One cause of unequal breath sounds and eventual cir-
delicate neonatal neck and airway. The size of the neo- culatory collapse is a tension pneumothorax. Some physi-
nate’s head is large relative to that of its body; therefore, cians have recommended that providers of neonatal
the neonate is in the optimal position when it lies supine. resuscitation be skilled in needle aspiration of a tension
In most cases, it is not necessary to elevate or hyperex- pneumothorax.1 This maneuver is accomplished by place-
tend the neonate’s head during laryngoscopy. The neo- ment of a 22- or 25-gauge needle in the second intercos-
natal larynx is more anterior than that of the adult, and tal space in the midclavicular line (on the side where no
178 PART III Fetal and Neonatal Assessment and Therapy
breath or heart sounds are heard). Air will rush out of the Atropine is not recommended for use during neonatal
needle hub, thereby reducing the tension pneumothorax. resuscitation. Epinephrine is considered the drug of
In the vast majority of resuscitations, the neonate choice for the treatment of bradycardia.
responds to ventilatory support. Chest compressions are Calcium administration is not recommended for neo-
needed in only 0.03% of deliveries.133 Chest compres- natal resuscitation, unless it is given specifically to reverse
sions are indicated when the heart rate is less than 60 bpm the effect of magnesium (which may have crossed the
despite adequate ventilation with supplemental oxygen placenta from the mother to the fetus). Evidence suggests
for 30 seconds.2 that calcium administration causes cerebral calcification
The preferred method for providing chest compres- and decreases survival in stressed neonates.147
sions is with the thumbs of both hands and the hands Volume expanders must be given strictly according
encircling the chest.2,134 Pressure is applied over the to recommended dosage. A continuous infusion is dan-
sternum just below an imaginary line drawn between gerous in the neonate, because it can easily result in the
the nipples; pressure applied over the lower part of the administration of an excessive fluid volume. Fluid over-
sternum or xiphoid can injure the abdomen. The sternum load can cause hepatic capsular rupture, brain swelling in
should be compressed to approximately one third the the asphyxiated infant, or intracranial hemorrhage in the
anteroposterior dimension of the chest, and the compres- preterm infant. Fluids and medications can be adminis-
sion depth must be adequate to produce a palpable tered either intravenously (most commonly through the
pulse.2,135-137 The compression time should be slightly umbilical vein) or, if necessary, intraosseously.
shorter than the release time, particularly to improve The cannulation of the umbilical vein involves inser-
blood flow in the very young infant.138 Ventilation is tion of a soft catheter into the cut end of the vein (Figure
compromised if the chest is compressed simultaneously 9-5). The catheter is advanced until blood return is noted,
with the administration of positive-pressure ventilation. but no more than 2 cm past the abdominal surface. If
The recommended ratio of compressions to breaths is ongoing vascular access is required during the neonate’s
3 : 1.139,140 This pattern is given at a rate of 120 events per hospital course, the soft umbilical catheter can be
minute, with 90 chest compressions and 30 breaths advanced through the ductus venosus into the inferior
administered each minute. Respirations, heart rate, and vena cava. Care must be taken to avoid leaving the tip in
color should be rechecked every 30 seconds. Compres- an intermediate location because of possible hepatic
sions should be resumed until the heart rate is 60 bpm or damage if a high-osmolarity substance (e.g., improperly
higher. Positive-pressure ventilation with supplemental diluted sodium bicarbonate) were injected. Other com-
oxygen titrated to Sao2 should be continued until the plications of umbilical venous catheterization are hemor-
heart rate is higher than 100 bpm. rhage and sepsis. The prolonged absence of vascular
Medications are rarely required during neonatal access in critically ill neonates can lead to hypoglycemia,
resuscitation because most neonates who require resus- which in association with hypoxia, can increase the risk
citative measures respond well to satisfactory oxygen- for adverse neonatal outcomes.148
ation and ventilation alone.141 However, a variety of Intraosseous access is accomplished by insertion of a
pharmacologic agents should be available in the delivery 20-gauge needle into the proximal tibia approximately
room (see Box 9-3). Epinephrine (0.01 to 0.03 mg/kg 1 cm below the tibial tuberosity.149 This technique may
or 0.1 to 0.3 mL/kg of a 1 : 10,000 solution) should be be easier to perform for practitioners who have little
administered if the heart rate remains lower than 60 bpm experience with intravenous or umbilical neonatal cath-
after 30 seconds of adequate ventilation and chest com- eterization. Absorption from the neonatal bone marrow
pressions.2 Intravenous administration is the preferred into the general circulation occurs almost immedi-
route (via an umbilical venous line). While intravenous ately.150,151 This rapid absorption results from the prepon-
access is being established, intratracheal administration derance of red bone marrow over yellow bone marrow;
through an endotracheal tube may be considered; yellow bone marrow is less vascular and is the dominant
however, a larger dose of epinephrine (0.05 to 0.1 mg/ form of marrow after 5 years of age. Complications
kg) may be required. Administration of epinephrine is related to this technique are rare and include tibial frac-
especially important if the heart rate is zero. Epinephrine ture (which occurs more often in older children)152 and
raises the heart rate (the major determinant of neonatal osteomyelitis. The risk for infection is proportional to
cardiac output) and restores coronary and cerebral blood the duration of intraosseous infusion153-155; therefore, the
flow.142 needle should be removed after 1 to 2 hours and, if neces-
Sodium bicarbonate is used infrequently during sary, a more conventional route of access should be estab-
resuscitation. Because of its high osmolarity, this agent lished. Current guidelines state that intraosseous access
can cause hepatic injury at any gestational age and cere- should be used for medication administration or volume
bral hemorrhage in the preterm infant143,144; it may also expansion when venous access is difficult to achieve.2
compromise myocardial and cerebral function.145,146 It Volume expanders should be considered when the
should be given only during prolonged resuscitation and infant demonstrates signs of shock, such as pale skin, poor
when adequate ventilation and circulation have been perfusion, and weak pulse, or has not shown adequate
established. Arterial blood gas measurements and serum response to other resuscitative measures. Normal saline
chemistry determinations should guide the use of sodium and lactated Ringer’s solution are the preferred volume
bicarbonate. The current recommended dose is 1 to expanders, given initially at 10 mL/kg over 5 to 10
2 mEq/kg of a 0.5 mEq/mL solution given over at least minutes, with doses repeated as necessary after reassess-
2 minutes by slow intravenous push. ment for ongoing hypovolemia. Intravascular volume
9 Neonatal Assessment and Resuscitation 179
Correct Incorrect
FIGURE 9-5 ■ Cannulation of the umbilical vein. A 3.5F or 5F umbilical catheter with a single end-hole and a radiopaque marker
should be used. For emergency use, the catheter should be inserted into the vein of the umbilical stump until the tip of the catheter
is just below the skin level but free flow of blood is present. If the catheter is inserted farther, there is a risk for infusing solutions
into the liver and possibly causing damage. (Adapted from Textbook of Neonatal Resuscitation. 6th edition. Elk Grove Village, IL, American
Academy of Pediatrics and American Heart Association, 2011:216.)
should be assessed through evaluation of heart rate, capil- inhaled nitric oxide have been used for the treatment of
lary refill time, and color. If heavy blood loss is suspected, pulmonary hypertension associated with MAS and have
O-negative packed red blood cells may be used according been observed to reduce mortality rates.163-165
to the same dosage regimen.2 Red blood cells replete the Neonatologists have attempted to determine whether
oxygen-carrying capacity as well as the intravascular peripartum suctioning of the neonate’s airway reduces the
volume. O-negative blood should be available at all times risk for developing MAS. Gregory et al.162 published the
for emergency use during neonatal resuscitation. Placen- original study of 80 meconium-exposed neonates who
tal blood has been used for neonatal volume expansion,156 were born either vaginally or by cesarean delivery. All
but this practice is discouraged in most institutions infants underwent tracheal intubation and suctioning
because of the risks of infection or transfusion of clotted after delivery. In 34 infants, no meconium was observed
blood. Albumin administration is no longer recom- below the vocal cords; none of these infants demon-
mended, because it carries a risk for infectious disease and strated MAS. Meconium was noted below the cords in
has been associated with higher mortality.157 the remaining 46 infants, and MAS developed in a total
of 16 (35%) of these infants. These investigators con-
cluded that “all infants born through thick, particulate,
SPECIAL RESUSCITATION or ‘pea soup’ meconium should have the trachea aspirated
immediately after birth.”162 Subsequent studies docu-
CIRCUMSTANCES mented similar findings for all infants born through
Meconium Aspiration meconium-stained fluid,166 with a suggestion that earlier
suctioning could decrease the incidence of MAS.167
There has been significant interest in the management of However, additional investigators documented that
the neonate whose airway has been exposed to meconium- airway suctioning at birth does not prevent MAS and its
containing amniotic fluid. Meconium is present in the associated mortality168,169; these studies indicated that
intestinal tract of the fetus after approximately 31 weeks’ MAS was primarily a result of intrauterine events such as
gestation. Meconium-stained amniotic fluid is present in asphyxia or sepsis. Hypoxia induces pathologic changes
10% to 15% of all pregnancies; the incidence is higher in the pulmonary vasculature, which results in pulmonary
in post-term pregnancies. Intrapartum passage of meco- hypertension and respiratory distress after birth. The
nium may be associated with fetal stress and hypoxia.158,159 pulmonary damage is independent of meconium aspira-
Meconium aspiration syndrome (MAS) is defined tion; therefore, it is not prevented by the suctioning of
as respiratory distress in a neonate whose airway was meconium.
exposed to meconium and whose chest radiographic Murphy et al.170 examined the lungs of 11 neonates
study exhibits characteristic findings, including pulmo- who had MAS and died within 4 days of birth. Ten of
nary consolidation and atelectasis.160 Treatment of MAS these neonates also had a diagnosis of persistent pulmo-
often involves the use of positive-pressure ventilation and nary hypertension, and all had evidence of excessive mus-
is associated with a 5% to 20% incidence of pneumotho- cularization of the intra-acinar arteries, which is an
rax from pulmonary air leaks.161 In one study of 176,790 abnormal finding in the fetus or neonate.171,172 Meyrick
infants born between 1973 and 1987, the annual death and Reid173 demonstrated that chronic hypoxia (i.e., at
rate from MAS was as high as 6 per 10,000 live infants.162 least 4 weeks’ duration), but not acute hypoxia, results in
Extracorporeal membrane oxygenation (ECMO) and pulmonary vascular muscularization in an animal model.
180 PART III Fetal and Neonatal Assessment and Therapy
Murphy et al.170 concluded that the pathologic findings pulmonary hyaline membrane disease (also known as
in the 1- to 4-day-old human lung could not be explained neonatal respiratory distress syndrome) was the over-
by the postdelivery effects of meconium aspiration; a whelming obstacle to the attempted salvage of the very
more likely origin was the intrauterine maldevelopment preterm infant.
of the pulmonary vasculature. They suggested a potential Between 1970 and 2005, the proportion of infants
link between greater intestinal motility, passage of meco- weighing less than 1500 g at delivery rose from 1.17% to
nium, and precocious muscularization of the intra-acinar 1.5%; in 2009, the proportion stabilized at 1.45%.181 The
arteries. survival rate of these 500- to 1500-g infants has increased
A prospective study designed to assess the efficacy of to approximately 85%.181 Of these, 5% to 10% have what
routine tracheal suctioning of meconium to prevent MAS is characterized as cerebral palsy and 25% to 50% exhibit
indicated little or no benefit to this practice.174 Among behavioral and cognitive deficits that lead to important
the infants who underwent tracheal suctioning, four school problems (see Chapter 10).182,183 These VLBW
experienced MAS and two had laryngeal stridor. By con- infants constitute a tiny proportion of the birth popula-
trast, none of the infants who did not undergo suctioning tion, but they are at the highest risk for development of
had complications, suggesting that vigorous neonates cerebral palsy; infants weighing less than 1500 g at birth
who have begun breathing before transfer to the resusci- account for 25% of cases of this disorder.58
tation table may derive little or no benefit from tracheal Markers for brain injury affecting preterm infants are
suctioning and, in fact, may suffer some harm. germinal matrix intraventricular hemorrhage (IVH) and
A subsequent review of studies published between periventricular leukomalacia. The brain injury may occur
1980 and 1999 found that most cases of severe MAS were either as a consequence of the IVH and its sequelae or as
not causally related to meconium aspiration but rather an associated finding. The incidence of germinal matrix
resulted from intrauterine stress.175 The authors con- IVH in preterm infants declined from 35% to 50% in
cluded that severe MAS is a misnomer because, in most the late 1970s and early 1980s to approximately 15% in
cases, much more than meconium aspiration has contrib- the mid 1990s.184 Despite the decreased incidence of ger-
uted to the lung damage. The implication is that when minal matrix IVH, which is directly related to prematu-
severe MAS occurs, inadequate suctioning at delivery or rity,183 the overall burden of disability has sharply
during resuscitation should not be considered the cause; increased in recent years due to the proportion of very
therefore, other causes of intrauterine lung damage preterm infants who are surviving.184 Periventricular leu-
should be investigated. komalacia, which is the classic neuropathology associated
Amnioinfusion—the instillation of saline into the with hypoxic-ischemic cerebral white matter injury in the
amniotic cavity—has been used successfully for reduction preterm infant, commonly accompanies IVH.185
of cord compression in the presence of oligohydramnios The fragility of the immature subependymal germinal
during labor. It has also been proposed as a potential matrix predisposes the preterm infant to the develop-
treatment to reduce the incidence of MAS in infants born ment of IVH. The hemorrhage originates from the
to women with thick meconium staining of the amniotic endothelial cell–lined vessels that course through the
fluid. Potential benefits include (1) the reduction of germinal matrix in free communication with the venous
cord compression, thus alleviating fetal compromise and circulation (i.e., the capillary–venule junction). The
acidemia that contribute to MAS, and (2) the dilution mechanism of damage to these endothelial cells and to
or washing out of the meconium in the amniotic fluid. the integrity of these capillaries has been investigated in
A large multicenter randomized trial found no difference animal models186 and in human neonates by means of
in rates of MAS or other neonatal disorders with the use Doppler velocimetry.187
of amnioinfusion.176,177 Thus, the routine practice of Volpe,188,189 who has reviewed the theories of the
amnioinfusion for meconium-stained fluid alone is not pathogenesis of germinal matrix IVH, has concluded that
recommended.178 the pathogenesis is multifactorial; different combinations
Current guidelines do not recommend routine intra- of factors are relevant in different patients. The three
partum oropharyngeal and nasopharyngeal suctioning major categories in the pathogenesis of IVH are intra
before delivery of the infant’s head,2,179 given that a large vascular, vascular, and extravascular. Intravascular
multicenter randomized trial showed no benefit to this factors include fluctuating cerebral blood flow (CBF),
practice in term-gestation infants.180 After stabilization of which can result from respiratory disturbances in the
the infant, meconium may be gently cleared from the ventilated preterm infant with neonatal respiratory dis-
mouth and nose by means of a bulb syringe or a large tress syndrome187,190; increases in CBF186,191; increases in
suction catheter (e.g., 12F to 14F). cerebral venous pressure192; decreases in CBF followed
by reperfusion; and platelet and coagulation distur-
bances.193 Vascular factors include the tenuousness of
Preterm Infant the capillary integrity of the germinal matrix and the
The preterm neonate, especially the VLBW infant, is at vulnerability of the matrix capillaries to hypoxic-ischemic
higher risk for problems with multiple organ systems injury.194 Extravascular factors include deficient vascular
simply because of immaturity. During resuscitation, the support, excessive fibrinolytic activity, and a possible
physician should give special attention to the effect of postnatal decrease in extravascular tissue pressure.195
prematurity on the lungs and the brain. Before the addi- Of special interest in the discussion of antepartum and
tion of surfactant and high-frequency ventilation to the intrapartum care and neonatal resuscitation are the pos-
therapeutic armamentarium of the neonatologist, sible interventions that may prevent or lessen the severity
9 Neonatal Assessment and Resuscitation 181
of IVH. The best way to prevent germinal matrix IVH preserve cerebrovascular autoregulation in the preterm
is to prevent preterm birth. Infection and inflammation infant. The prevention of hypoxemia and hypercarbia is
are the most common identified causes of preterm birth essential, because they are both linked to pressure-passive
at the lowest relevant gestational age.196 Antenatal treat- cerebral circulation, which in turn leads to the develop-
ment of infections has not been proved to prevent preterm ment of IVH.212
labor or premature rupture of membranes58; however, Among infants who exhibit fluctuating CBF velocity,
prevention of infection, if possible, may be an important Pearlman et al.213 found that treatment with pancuronium
way to reduce the risk for IVH. Another intervention that bromide, which corrects this fluctuation, reduced both
lowers the incidence of IVH is the transportation of the the incidence and severity of IVH.213 Other clinical trials
preterm mother while the fetus is still in utero to a center have evaluated the efficacy of other pharmacologic agents
that specializes in the care of high-risk neonates.1 for the correction of fluctuating hemodynamic distur-
Various antenatal pharmacologic interventions bances. Studies of meperidine214 and fentanyl215 have
have been evaluated for the prevention of IVH. shown some benefit, but the side effects and need for
Clinical trials of antenatal maternal administration of prolonged ventilation associated with these agents must
phenobarbital197,198 and vitamin K199,200 have yielded con- be weighed against any potential benefits.
flicting results, and their routine use is not currently If the use of antepartum and intrapartum pharmaco-
recommended.58 logic prophylaxis against IVH becomes part of preterm
Corticosteroids are currently the most beneficial ante- delivery management, the practice of obstetric anesthesia
natal pharmacologic intervention for the prevention of for preterm patients will be directly affected. For example,
IVH. This effect was first noticed when obstetricians the conventional wisdom is that preterm infants are more
began giving betamethasone and dexamethasone to preg- sensitive than term infants to the effects of maternally
nant women to help accelerate fetal lung maturity. The administered agents such as analgesics216 and that this
mechanism behind this protection is thought to be effect is inherently deleterious. However, if this effect is
improved neonatal cardiovascular stability, which results found to protect the preterm infant brain from factors
in less hypotension and less need for blood pressure treat- that may lead to IVH (e.g., hemodynamic instability),
ment in these infants.201 Antenatal betamethasone admin- perhaps obstetric anesthesia providers will no longer
istration leads to lower placental vascular resistance and attempt to avoid the placental transfer of pharmacologic
higher placental blood flow.202 This improvement in pla- agents but will deliberately administer these agents to the
cental blood flow may decrease impairment of the preterm mother with the intent that they reach the fetus.
infant’s cerebral autoregulation. In addition, corticoste-
roids may stimulate the maturation of the germinal
matrix. There is consensus regarding the efficacy of a
Congenital Anomalies
single course of corticosteroids in patients at risk for Occasionally, neonatal resuscitation is complicated by
preterm delivery, but the risks and benefits of multiple congenital anomalies of the airway or diaphragm. These
courses of corticosteroids for women who remain unde- anomalies may manifest as respiratory distress, which
livered 7 days after the initial dose are still controversial. resolves only when appropriate resuscitation techniques
Obstetricians must balance the possible benefits of these are used. For example, neonates are obligatory nose
agents against their potentially deleterious effects on breathers. The diagnosis and management of choanal
neuronal and organ growth (see Chapter 34). stenosis and atresia include placement of an oral airway
Multiple studies have demonstrated a lower incidence or endotracheal tube until a definitive surgical procedure
of cerebral palsy in infants of mothers given magnesium can be performed.
sulfate for the treatment of preeclampsia or for tocoly- Other congenital anomalies that cause upper airway
sis203,204; subsequent studies have observed a similar obstruction include (1) micrognathia, as in Pierre Robin
benefit when magnesium has been given specifically sequence; (2) macroglossia, as in Beckwith-Wiedemann
for fetal neuroprotection.205-207 An ACOG committee syndrome or glycogen storage disease type II; (3) laryn-
opinion208 now recommends the administration of mag- geal webs; (4) laryngeal atresia; (5) stenosis or paralysis at
nesium sulfate to mothers in preterm labor. Maternal the level of the vocal cords; (6) subglottic stenosis; (7)
magnesium sulfate administration does not result in a subglottic webs; (8) tracheal agenesis; and (9) tracheal
decreased incidence of IVH, although the incidence of rings. Obstruction also can occur as a result of tumors
high-grade (grade III or IV) lesions may be reduced.209 such as subglottic hemangiomas. The presence of a cleft
Although some investigators have suggested that antena- palate may lead to difficulty with manual ventilation. In
tal exposure to magnesium sulfate results in a higher risk an infant with micrognathia or macroglossia, airway
for adverse neonatal outcomes,210 others have observed patency may be maintained if the neonate is kept in the
no association between umbilical cord blood magnesium prone position, which reduces posterior movement of the
concentration and the need for delivery room resuscita- tongue into the pharynx. If macroglossia is extreme, use
tion when magnesium was administered for neuroprotec- of an oral airway or a small nasogastric or orogastric
tion in anticipation of a preterm birth.211 suction catheter may be necessary to prevent complete
Postnatal interventions that may prevent IVH include obstruction of the pharynx by the tongue.
the avoidance of overly rapid infusion of volume expand- When respiratory distress and difficulty with bag-and-
ers or hypertonic solutions such as sodium bicarbon- mask ventilation are encountered, laryngoscopy should be
ate.143,212 The establishment of adequate ventilation is performed. The cause of the obstruction may be evident
the most beneficial immediate intervention that helps if it is supraglottic in location. Some supraglottic entities
182 PART III Fetal and Neonatal Assessment and Therapy
(e.g., laryngeal webs) may be treated successfully by postoperative hematocrit or duration of hospital stay.
passing an endotracheal tube through the obstruction and The EXIT procedure group also had a higher rate of
into the trachea. Subglottic lesions may require tracheos- superficial wound infection (15% versus 2%), but the
tomy. The help of an otolaryngologist may be invaluable incidence of endometritis was not different. A review of
during resuscitation of a neonate with congenital airway fetal and maternal outcomes after performance of an
obstruction. If there is antepartum evidence of such a EXIT procedure in 12 infants with a giant neck mass
condition (e.g., laryngeal stenosis), it is best to have an found that 11 infants survived and 10 had normal devel-
otolaryngologist present at the time of delivery.217 If opment. All of the six mothers who desired future preg-
obstruction is discovered after delivery, the resuscitator nancies subsequently had uncomplicated deliveries.223
should not hesitate to call for surgical assistance. Anesthetic considerations for the mother during an
Fetal neck masses such as cervical teratoma and lymph- EXIT procedure include those relevant to general anes-
angioma can lead to extrinsic airway compression. The thesia for the mother undergoing cesarean delivery or
resulting distortion of the airway can result in airway other surgical procedures during pregnancy (see Chap-
obstruction, and it may be difficult—if not impossible— ters 7, 17, and 26). Several volatile halogenated agents
to secure an airway in a timely fashion at delivery. These have been used for the EXIT procedure, including iso-
masses often are diagnosed before delivery because of the flurane, desflurane, and sevoflurane.219 The anesthetic
associated occurrence of polyhydramnios resulting from management for an EXIT procedure differs from that for
esophageal compression. In these rare cases, a multidis- a routine cesarean delivery in the following ways: (1)
ciplinary team should be assembled before delivery to general anesthesia is used much more often than neur-
assist in securing the airway. Leichty et al.218 described a axial anesthesia, (2) a greater depth of anesthesia is
way of providing the time necessary to secure an airway, achieved and maintained, (3) maximum uterine relaxation
known as the ex utero intrapartum treatment (EXIT) is desirable, (4) warm fluid is occasionally instilled into
procedure (see Chapter 7). An EXIT procedure delivers the uterus, and (5) a second anesthesiologist provides care
the fetal head and shoulders, but keeps the lower torso for the fetus.220
and umbilical cord intact within the uterus, thereby George et al.224 described an alternative approach for
maintaining placental perfusion and oxygenation. The the EXIT procedure with the use of combined spinal-
fetus can be given additional agents intramuscularly (fen- epidural anesthesia (1.5 mL of bupivacaine 0.75%,
tanyl, vecuronium, and atropine) to provide fetal analge- fentanyl 15 µg, and morphine 0.15 mg, administered
sia and to prevent movement and breathing. The FHR intrathecally, followed by placement of a multiorifice
and Sao2 are monitored continuously via a pulse oximeter epidural catheter). Supplemental oxygen was provided
probe attached to the fetal hand. The pediatric surgeon through a face mask at 6 L/min. Immediately before
can then perform direct laryngoscopy, rigid bronchos- uterine incision, the patients were given intravenous
copy, or tracheostomy if necessary. After establishment nitroglycerin 50 to 100 µg, followed by an infusion of
of the airway, the delivery of the infant is completed. nitroglycerin (0.5 to 1.5 µg/kg/min), allowing adequate
The EXIT procedure has been considered an option uterine relaxation for partial delivery of the infant’s head.
for fetuses with a number of congenital anomalies.219,220 Maternal hypotension occurred in two of the three
A common indication for the EXIT procedure is an women and required vasopressor administration. After
intrinsic airway obstruction. Intrinsic airway obstruction the infant’s airway was secured and the infant’s delivery
of the larynx or upper trachea (e.g., laryngeal web, sub- was completed, the nitroglycerin was discontinued at the
glottic cyst, tracheal atresia) can lead to retention of time of umbilical cord clamping.
bronchial secretions and subsequent pulmonary disten- Esophageal atresia and tracheoesophageal fistula
tion; this constellation of findings is often classified occur in 1 of every 3000 births.225 There are many varia-
as congenital high airway obstruction syndrome tions of these anomalies, the most common being esoph-
(CHAOS).219 Use of the EXIT procedure resulted in the ageal atresia with a distal tracheoesophageal fistula (80%
first long-term survival of a child with this syndrome.221 to 90% of cases). Neonates with a tracheoesophageal
The EXIT procedure also may be useful in conditions fistula are at increased risk for the pulmonary aspiration
such as severe congenital heart disease, in which the need of gastric contents through the fistula into the lung.
for emergency ECMO at birth is anticipated. The EXIT When the presence of a tracheoesophageal fistula is not
procedure allows for the placement of arterial and venous known antepartum, it should be suspected if bubbling
cannulas before umbilical cord clamping, thereby avoid- secretions are observed during spontaneous or bag-and-
ing an unstable period between the termination of pla- mask ventilation. Once a tracheoesophageal fistula is sus-
cental perfusion and the institution of ECMO. 219 Other pected, bag-and-mask ventilation should be discontinued,
possible indications for the EXIT procedure include the because its use may contribute to overdistention of the
resection of congenital cystic adenomatoid malforma- gastrointestinal tract with air, possibly leading to diffi-
tions and as a first step in separation procedures for con- culty in ventilation from impingement of the enlarged
joined twins with cardiovascular involvement. stomach on the diaphragm. A suction catheter should be
Noah et al.222 compared the short-term maternal out- placed in the esophageal pouch to facilitate the removal
comes of 34 patients who underwent the EXIT proce- of oral secretions. If mechanical ventilation is necessary,
dure between 1994 and 1999 with those in a control an endotracheal tube should be inserted with the tip
group who underwent nonemergency primary cesarean distal to the entrance of the fistula. This positioning can
delivery. The EXIT procedure group had a higher esti- be accomplished by performing an intentional right
mated blood loss, but there was no difference in the mainstem bronchial intubation followed by slowly
9 Neonatal Assessment and Resuscitation 183
Modified from Neonatal Resuscitation: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency
cardiovascular care. Pediatrics 2010; 126:e1400-1413.
withdrawing the tube until breath sounds are auscultated discontinuation of resuscitation in the delivery room.2
on the left; a lack of breath sounds over the stomach Extremes of prematurity (< 23 weeks’ confirmed gesta-
should then be confirmed. Percutaneous gastrostomy tion) and severe congenital anomalies (e.g., anencephaly,
placement may be necessary during resuscitation to facili- confirmed trisomy 13 or 18) are examples of circum-
tate decompression of the gastrointestinal tract. stances when non-initiation of resuscitation is considered
Congenital diaphragmatic hernia (CDH) occurs in appropriate. Because intrapartum confirmation of perti-
approximately 1 in 3000 live births.226 The mortality rate nent information may not be possible, it is recognized
from CDH is 30% to 60%. In 80% to 90% of cases the that initiation of resuscitation may occur and that its
CDH occurs on the left side and is the result of herniation discontinuation may then be appropriate after further
of the gut through the posterolateral defect of Bochdalek. information has been obtained and discussion with family
During formation of the lung, herniation of the gut into has occurred. In some cases, a trial of therapy may be
the thoracic cavity results in hypoplasia of the lung tissue appropriate, which does not always mandate continued
and pulmonary vasculature. This hypoplasia may be uni- support. In situations or conditions in which there is a
lateral, but often it is bilateral because of the shift in high rate of survival and acceptable morbidity (i.e., ≥ 25
mediastinal structures to the other side. CDH should be weeks’ gestation and most congenital malformations),
suspected when a neonate has respiratory difficulty and a resuscitation is generally indicated. For those situations
scaphoid abdomen; this abnormal abdominal shape results with a poor prognosis, including unlikely survival and
from the presence of abdominal contents in the thorax. potentially high morbidity (i.e., 23 to 25 weeks’ gesta-
During resuscitation of the neonate with CDH, bag- tion), the parents’ desires as to initiation of resuscitation
and-mask ventilation is contraindicated because it allows should be supported (Table 9-5).227
further distention of the gut, which would further impinge Discontinuation of resuscitation of an infant with car-
on the lung. Tracheal intubation is recommended, fol- diopulmonary arrest may be appropriate if spontaneous
lowed by the placement of a nasogastric or orogastric circulation has not occurred in 15 minutes. After 10
tube to ensure decompression of the gastrointestinal minutes of asystole, survival itself and survival without
tract. Ventilation should consist of low-positive-pressure severe disabilities are very unlikely.227-232
breaths to decrease the risk for causing a pneumothorax
on the side contralateral to the CDH. If a pneumothorax
does occur, it must be evacuated promptly. In the neonate, NEUROBEHAVIORAL TESTING
evacuation is accomplished initially by placement of a
22-gauge needle into the second intercostal space in the It is difficult to detect subtle neurobehavioral differences
midclavicular line and aspiration of air with an attached among neonates during the assignment of Apgar scores
stopcock and syringe. Severe pulmonary hypertension or the performance of the initial neurologic examination;
often accompanies CDH. Maintenance of euthermia, therefore, investigators have developed and studied
normoxia, and adequate systemic blood pressure pro- methods of documenting neonatal neurobehavioral status
motes pulmonary artery blood flow. (Table 9-6). In the past, the neonate was considered inca-
Whenever congenital anomalies of the respiratory pable of exhibiting higher cortical function. However,
tract are noted, the presence of other anomalies should investigators have noted that the term neonate is able to
be suspected. It is important to evaluate the neonate sense and respond to a variety of stimuli in a well-
promptly for cardiac malformations, especially if appro- organized fashion.233-235
priate resuscitative efforts are not successful. Echocar- In 1973, Brazelton236 described the Neonatal Behav-
diography is used to evaluate cardiac structures and ioral Assessment Scale (NBAS) with the following four
function. variables as key determinants of neonatal neurobehavior:
(1) various prenatal influences (e.g., infection); (2) the
maturity of the infant, especially its CNS; (3) the effects
ETHICAL CONSIDERATIONS of analgesics and anesthetics administered to the mother
before and during delivery; and (4) the effects of difficul-
The current neonatal resuscitation guidelines address ties encountered during delivery (e.g., trauma). The
the ethical considerations of non-initiation or NBAS was developed as a tool to detect neurobehavioral
184 PART III Fetal and Neonatal Assessment and Therapy
abnormalities that resulted from any of these four Amiel-Tison et al.238 examined inter-observer reliabil-
variables. ity and assessed the correlation of results between the
This scale consists of 47 individual tests with 27 evalu- NACS and ENNS. The inter-observer reliability was
ating behavior and 20 evaluating elicited or provoked 93% for the NACS and 88% for the ENNS. Approxi-
responses. The 47 tests can be completed in approxi- mately 92% of infants with high scores on the ENNS
mately 45 minutes. The NBAS evaluates the ability of the scored equally well on the NACS. However, the reliabil-
neonate to perform complex motor behaviors, to alter ity of NACS has been questioned239,240; Halpern et al.241
the state of arousal, and to suppress meaningless stimuli. examined 200 healthy term infants with the NACS and
The goal is to provide an extensive evaluation of neonatal found poor inter-observer reliability. In contrast, in 2002
cortical function and to detect subtle differences among Amiel-Tison242 reported her later experience with the
groups of infants. Habituation (i.e., the ability to suppress NACS and documented good inter-observer reliability.
the response to meaningless, repetitive stimuli) is consid- Anesthesiologists have used neurobehavioral testing to
ered an excellent indicator of normal early cortical document the effects of analgesic and anesthetic agents
function.233 and techniques on neonatal neurobehavior (see Table
In 1974, Scanlon et al.237 described the Early Neonatal 9-6); the American Academy of Pediatrics243 and the U.S.
Behavioral Scale (ENNS), which consisted of tests that Food and Drug Administration244,245 have recommended
were easy to perform and score quantitatively during the that these investigations be performed. A number of
neonatal period. The ENNS was developed primarily for studies have demonstrated transient, serum concentration–
the evaluation of the effects of maternal medications (e.g., dependent depression of neonatal neurobehavior with
analgesic and anesthetic agents) on neonatal neurobehav- the maternal administration of systemic agents (e.g.,
ior. The ENNS consists of (1) 15 observations of muscle meperidine, diazepam).246-248 However, in a NBAS exami-
tone and power, reflexes (e.g., rooting, sucking, Moro), nation that controlled for patient and labor and delivery
and response to stimuli (e.g., light, sound, pinprick); (2) characteristics, only decreased habituation was observed
11 observations of the infant’s state of wakefulness; (3) an in neonates born to mothers who had received intrave-
assessment of the ability of the neonate to habituate to nous meperidine.249 Similarly, maternal administration of
repetitive stimuli; and (4) an overall general assessment intravenous fentanyl appears to minimally affect neonatal
of neurobehavioral status. This test can be performed in NACS examinations.250
6 to 10 minutes. As is the case with many studies of systemic agents,
In 1982, Amiel-Tison et al.238 described the Neuro- studies of epidural anesthesia are often confounded by
logic and Adaptive Capacity Score (NACS) to differenti- variables that are difficult to control, such as different
ate neonatal depression secondary to maternally patient populations, varied durations of labor, and mul-
administered drugs from depression due to asphyxia, tiple drug administrations. Scanlon et al.237 introduced
birth trauma, or neurologic disease. Whereas the ENNS the ENNS in a study of the effect of maternal epidural
concentrates on the infant’s habituation ability, the NACS anesthesia on neonatal neurobehavior. The researchers
emphasizes motor tone as a key indicator of drug-induced concluded that epidural anesthesia was associated with
abnormal neurobehavior. The basis for this emphasis on lower ENNS scores because of decreased muscle strength
neonatal motor tone is explained as follows: unilateral or and tone. In this study, all patients who had received
upper body hypotonus may occur as a result of either epidural anesthesia were considered part of one group,
birth trauma or anoxia, but global motor depression is although 9 patients had received lidocaine and 19 had
more likely a result of anesthetic- or analgesic-induced received mepivacaine. Further investigation showed that
depression. A total of 20 criteria are tested in the areas epidural lidocaine, even when administered in larger
of adaptive capacity, passive tone (e.g., scarf sign), active doses for cesarean delivery, does not affect ENNS
tone (e.g., assessment of the flexor and extensor muscles scores.251 The difference in ENNS scores between the
of the neck), primary reflexes (e.g., Moro), and alertness. epidural and nonepidural groups noted in the earlier
The total possible score is 40, and a score of 35 to 40 is study237 was most likely related to the use of mepivacaine
considered normal. The NACS can be performed in 3 to rather than lidocaine.252 As was observed with lidocaine,
4 minutes. epidurally administered bupivacaine, 2-chloroprocaine,
9 Neonatal Assessment and Resuscitation 185
and etidocaine—when given for cesarean delivery—do received general anesthesia with ketamine 1 mg/kg fol-
not affect ENNS scores.251,253 Kuhnert et al.254 assessed lowed by 50% nitrous oxide. A third group received
NBAS scores in a group of infants exposed to either spinal anesthesia with tetracaine 6 to 8 mg. The ENNS
epidural lidocaine or 2-chloroprocaine. Although the evaluations were conducted at 4 to 8 hours of age and
investigators observed subtle changes in neurobehavior again at 24 hours. During the 4- to 8-hour examination,
in the group of infants whose mothers had received lido- infants in the spinal anesthesia group scored significantly
caine, they concluded that other variables (e.g., mode of higher on multiple components of the ENNS than did
delivery) are more likely to affect performance on neu- infants in either of the general anesthesia groups. At 24
robehavioral testing. hours, infants in the spinal anesthesia group scored sig-
Sepkoski et al.255 compared NBAS scores between two nificantly higher than those in the thiopental group in
groups of vaginally delivered infants. In one group, the alertness, total decrement score, and overall assessment.
mothers had received epidural bupivacaine, and in the Similarly, infants in the spinal anesthesia group scored
other group, the mothers had received no anesthesia or higher than those in the ketamine group in alertness and
analgesia. The infants in the epidural group showed less overall assessment. No significant differences existed
alertness, less orientation ability, and less motor function between the scores of the thiopental group infants and
maturity than the infants in the control group. However, the ketamine group infants.258 Palahniuk et al.270 observed
variables such as duration of labor, incidence of oxytocin similar results in a study that compared groups of infants
administration, and incidence of instrumental delivery whose mothers received either epidural anesthesia or
were not similar in the two groups. Earlier, Abboud general anesthesia for elective cesarean delivery. Infants
et al.256 performed ENNS examinations on vaginally whose mothers had received thiopental and nitrous oxide
delivered infants whose mothers had received epidural scored significantly lower in the alertness component of
bupivacaine. In this study, epidural administration of the ENNS than infants whose mothers had received epi-
bupivacaine did not affect the ENNS scores. The mater- dural lidocaine with epinephrine.
nal doses of epidural bupivacaine and the maternal venous Stefani et al.271 observed that subanesthetic maternal
and umbilical cord blood bupivacaine concentrations doses of enflurane or nitrous oxide did not affect neonatal
were similar to those noted by Sepkoski et al.255 neurobehavior (as assessed by ENNS and NACS) at 15
Abboud et al.256 also noted normal ENNS scores for minutes, 2 hours, and 24 hours of age. Abboud et al.272
infants whose mothers had received epidural lidocaine or obtained similar results from NACS examinations of
2-chloroprocaine. infants whose mothers had received subanesthetic doses
Critics of the ENNS and NACS claim that the evalu- of isoflurane.
ations are unable to demonstrate subtle differences in The long-term effects of perinatal exposure to either
neurobehavior that would be detected by the more com- general or neuraxial anesthesia at the time of cesarean
prehensive NBAS.257 However, although some differ- delivery compared with vaginal delivery appear limited.
ences have been observed in NBAS performance among In a population-based birth cohort, Sprung et al.273 found
groups of infants exposed or not exposed to local anes- that children exposed to either general or regional anes-
thetics, confounding variables have prevented clear con- thesia during cesarean delivery were not more likely to
clusions as to cause and effect. develop learning disabilities than children who were
Hodgkinson et al.258 observed that the subarachnoid delivered vaginally.
administration of tetracaine for cesarean delivery did not In summary, subtle changes in neonatal neurobehavior
adversely affect ENNS performance. Other studies have may result from factors such as antepartum maternal
indicated that NACS performance is not significantly drug exposure. Parent-infant bonding and the ability of
affected by the maternal epidural administration of the infant to breast-feed may be adversely affected by
opioids259-264 or epinephrine (in combination with a local these neurobehavioral changes.233 These transient effects
anesthetic).265-268 may seem trivial to some observers but important to
The effects of general anesthetic agents on neonatal others. With regard to the long-term neurologic outcome
neurobehavior have been evaluated by the ENNS and of individual infants, performance during neurobehav-
NACS. In a prospective, randomized study, Abboud ioral assessment may aid the observer in the formulation
et al.269 assessed NACS performance at 15 minutes, 2 of a prognosis. However, as demonstrated with Apgar
hours, and 24 hours of age in infants whose mothers scores, the prognostic value of an isolated test score is
received general, epidural, or spinal anesthesia for cesar- likely to be lower than the prognostic value of multiple
ean delivery. Women who underwent general anesthesia factors considered together during the overall assessment
received thiopental 4 mg/kg followed by enflurane 0.5% of an individual infant.
with nitrous oxide 50% in oxygen. Although the NACS
was lower at both 15 minutes and 2 hours of age in the
infants in the general anesthesia group than in the infants KEY POINTS
in the neuraxial anesthesia groups, no difference in NACS
results was noted at 24 hours of age. • The anesthesia provider attending the mother
Hodgkinson et al.258 used the ENNS to evaluate out- should not be responsible for resuscitation of the
comes among three groups of infants, all of whom were neonate. However, all anesthesia providers
delivered by elective cesarean delivery. One group of should be prepared to provide assistance during
women received general anesthesia with thiopental 4 mg/ neonatal resuscitation when it is needed.
kg followed by 50% nitrous oxide. A second group
186 PART III Fetal and Neonatal Assessment and Therapy
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36. Kaul B, Vallejo M, Ramanathan S, Mandell G. Epidural labor 62. Finster M, Wood M. The Apgar score has survived the test of
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201. Moise AA, Wearden ME, Kozinetz CA, et al. Antenatal steroids bined spinal epidural anesthesia for Cesarean delivery and ex utero
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C H A P T E R 1 0
CHAPTER OUTLINE
The detection and diagnosis of fetal and neonatal brain the internal and external milieu. Although such neurode
injury have been advanced by improvements in functional velopmental processes occur throughout the human life
imaging and the identification of potential biochemical span, the process is most robust and dynamic during the
markers. Evidence indicates that inflammatory mediators perinatal period.5 Much of our understanding of the pro
play an important role in the pathophysiology of fetal cesses that drive fetal brain development comes from
brain injury. Evidence also suggests that maternal admin studies in rodents and nonhuman primates.6 With recent
istration of magnesium sulfate before anticipated early advances in neuroimaging, it is now possible to study
preterm birth reduces the risk for cerebral palsy in surviv brain anatomy and assess neurobehavioral changes in the
ing infants. New data suggest that induced hypothermia human fetus.7
is beneficial for the treatment of neonatal hypoxic ische When pathways leading to orderly brain development
mic encephalopathy. Of specific concern to anesthesia are deconstructed, three major events appear critical
providers is rodent and nonhuman primate data that to the establishment of functional synapses. Neuronal
suggest that fetal exposure to anesthetic agents may have proliferation, migration, and cellular differentiation
harmful effects on neurogenesis and synapse formation occur in a preordained fashion to establish early neural
in the developing brain. Overall, however, little progress circuitry. These processes often overlap and occur at dif
has been made in reducing the incidence of neonatal ferent rates in different brain regions. Neurogenesis,
brain injury and cerebral palsy. a term that encompasses both neuronal proliferation and
subsequent survival, begins with neural stem/progenitor
cells in neurogenic niches such as the subventricular zone
FETAL BRAIN DEVELOPMENT and the subgranular zone of the dentate gyrus. These
neural progenitor cells undergo mitosis to generate
Generation of the various cell types that populate the immature neurons that migrate in a radial fashion and
developing brain, and the subsequent layering and orga laminate the cortex in an “inside-out” fashion.8 Interneu
nization, is a precisely regulated process encoded by rons, which comprise 10% to 15% of the total neuronal
genetic programs and modified by epigenetic influences.1-4 cells in the brain, originate from the ganglionic emi
Contrary to previous dogma, it is now well established nences in the developing brain.9 These newly generated
that the brain continuously evolves during ontogeny and interneurons, which play an indispensable role in circuit
that these processes are susceptible to subtle changes in inhibition, migrate in a tangential manner to populate
192
10 Fetal and Neonatal Neurologic Injury 193
distinct brain areas. Both forms of migration are guided migration.20-22 Alteration of this excitation-inhibition
by cell-intrinsic mechanisms as well as by structural balance is purported to be responsible for an array of
scaffolds and humoral mediators such as gamma- childhood neurodevelopmental disorders.
aminobutyric acid (GABA) and glutamate.10,11 Experimental studies reveal that the fetal blood-brain
In humans, neurogenesis starts and peaks at 5 and 25 barrier is morphologically well developed and function
weeks’ gestation, respectively, while neuronal migration ally competent at term.23 Convincing evidence confirms
is completed between 30 and 36 weeks’ gestation.12 that the endothelial tight junctions of the blood-brain
Between 20 and 40 weeks’ gestation, these processes are barrier are as effective in the term fetus as in the adult,
followed by the generation of an array of supporting glial although the exact time that blood-brain barrier compe
cells, such as astrocytes and oligodendrocytes.12 Concur tency is established in the human fetus is unknown. In
rently, synapse formation begins as early as the 10th week rodents, data suggest that the fetal blood-brain barrier is
of gestation and continues to increase gradually at a rate established between embryonic days 11 and 17 (term
of approximately 4% per week until the end of the second gestation is 22 days), a time period that corresponds to
trimester. After this phase, a robust and exponential approximately the late second and early third trimesters
increase in synapse formation (almost 40,000 synapses/ in humans.24
min) occurs between 28 weeks’ and term gestation.13
These processes, in conjunction with the onset of myelin
ation, result in a fivefold increase in brain volume and the CEREBRAL PALSY
appearance of morphologic features of the mature brain
such as sulci and gyri. By 24 weeks’ gestation the fetus History, Definitions, and Significance
has all the neural machinery necessary to perceive pain.14
Many clinicians recommend that appropriate measures In 1861, John Little, an orthopedic surgeon, first
should be taken to provide fetal analgesia during fetal described cerebral palsy in a report to the Obstetrical
surgical procedures from this point onward.15 Society of London. Described as a neonatal neurologic
Although the ontogeny of neurotransmitter systems disorder associated with difficult labor or birth trauma,
is less well studied, a wealth of animal and human data the disorder was known as Little’s disease until William
indicates that these systems appear very early in life, Osler coined the term cerebral palsy in 1888.25 A precise
before the phase of active synaptogenesis.12 The presence definition and classification of cerebral palsy has proved
of these neuromodulatory substances before synapse for elusive. In the forward to the “Report on the Definition
mation lends credence to the view that they serve a and Classification of Cerebral Palsy,” published in 2007
trophic role during early brain development, a role that in Developmental Medicine and Child Neurology, Peter
is distinct from their predominant role of facilitating syn Baxter25 wrote, “This [supplement] illustrates the diffi
aptic neurotransmission in the mature brain. Among culties inherent in trying to agree what we mean by the
these neurotransmitters, GABA remains the most widely terms we use and that a classification that suits one
studied (Figure 10-1).16 Although GABA has an inhibi purpose, such as a diagnostic approach, may not always
tory action in the mature brain, GABA serves an excit be ideal for others, such as therapy issues. Defining and
atory role during fetal brain development. The major classifying cerebral palsy is far from easy. We do need a
mechanism for this role reversal is the differential expres consensus that can be used in all aspects of day-to-day
sion of chloride ion transporters NKCC1 and KCC2; care and for future research on cerebral palsy.”
these transporters increase the intracellular concentra Today, cerebral palsy is defined as a nonprogressive
tion of chloride in developing neurons.17 On stimulation disorder of the central nervous system (CNS) present
of GABA receptors that are expressed in neural progeni since birth that includes some impairment of motor func
tor cells and immature neurons, chloride ions are actively tion or posture.25 Intellectual disability (formerly known as
extruded, causing membrane depolarization rather than mental retardation) may be present but is not an essential
the hyperpolarization seen in mature neurons. This diagnostic criterion. Various forms of cerebral palsy exist,
depolarizing effect of GABA decreases DNA synthesis with differences in pathology, pathophysiology, and
and inhibits proliferation of neural progenitor cells,18 potential relationships with intrapartum events. The
causes concentration- and time-dependent effects on literature on cerebral palsy is difficult to review and
neuronal migration,11 and plays a major role in activity- understand. Data from individual studies are difficult
dependent synapse formation.19 to compare because of variations in the duration of
The N-methyl-d-aspartate (NMDA)-subtype glu- follow-up, birth weight classifications, inclusion criteria
tamate receptors originate later than the GABA recep for congenital abnormalities, and exclusion criteria for
tors and remain functionally silent because of magnesium various causes of death. Terms such as hypoxic-ischemic
ion–induced channel blockade; thus, they play a limited encephalopathy of the newborn, newborn asphyxia, birth
role during early brain development. Dopaminergic, asphyxia, and asphyxia neonatorum are difficult to distin
cholinergic, and serotonergic systems develop concomi guish. Some authorities, including the American College
tantly and appear fully functional by the second of Obstetricians and Gynecologists (ACOG), have argued
trimester.12 Pharmacologic interventions (e.g., ethanol, that the term birth asphyxia should be abandoned.26
antiepileptic drugs) that act directly or indirectly on these Intrapartum events continue to receive the blame for
powerful neuromodulator systems induce long-lasting some cases of cerebral palsy. It is a widely believed theory
impairment of fetal brain development, mainly owing that an intrapartum reduction in fetal oxygen delivery
to impaired neurogenesis and/or altered neuronal may cause cerebral palsy, and early reports in primates
194 PART III Fetal and Neonatal Assessment and Therapy
Self-renewal/ MZ
proliferation
Asymmetric
division Interneuron
Maturation
Migration
CP
GAB
A
MZ
Interneuron GAB A
Immature
neuron Pyramidal
Immature neurons
A
neuron
AB
VZ SVZ
VZ
Radial glia
FIGURE 10-1 ■ Gamma–aminobutyric acid’s (GABA) role in regulating embryonic cortical development. During corticogenesis, inter-
neurons migrating in the subventricular zone (SVZ) can release GABA and activate GABAergic receptors on the radial glia, depolar-
izing these progenitors and decreasing their proliferation. Radial glia generate immature pyramidal neurons through asymmetric
division, and the migration of these immature neurons along the radial fibers is decreased by GABA signaling. As young neurons
assume their position in the cortex and begin to mature, GABA-mediated depolarization by the interneurons is required for the
development of dendritic arbors and excitatory synaptic inputs from other pyramidal neurons. MZ, marginal zone; VZ, ventricular
zone; SVZ, subventricular zone; CP, cortical plate. (From Wang DD, Kriegstein AR. Defining the role of GABA in cortical development.
J Physiol 2009; 587:1873-9.)
demonstrated that perinatal asphyxia could cause brain subset of 55 brain-damaged infants. These investigators
injury.27 Continuous electronic fetal heart rate (FHR) concluded, “We do not advocate the abandonment of the
monitoring, which has largely replaced intermittent FHR use of electronic fetal monitoring, but we do believe that
auscultation during labor, is believed to prompt the deliv it is yet to be proved to be of value in predicting or pre
ery of at-risk fetuses and thus reduce asphyxial events. venting neurologic morbidity.” A more focused applica
However, despite a higher incidence of cesarean delivery, tion of FHR monitoring may ultimately be found useful.
no reduction in the incidence of cerebral palsy has been For example, fetal inflammatory changes, which can be
observed since the widespread implementation of con associated with neurologic injury, may be associated with
tinuous electronic FHR monitoring during labor.28,29 characteristic FHR findings.36 Thus, electronic FHR
Further, among patients with new-onset late FHR decel monitoring provides incomplete data that should be
erations, an estimated 99% of tracings would be false evaluated in the clinical context in which is it used.
positive “if used as an indicator for subsequent develop Despite significant limitations in the use of intra
ment of cerebral palsy.”30 This information is probably partum electronic FHR monitoring, there is no doubt
surprising to the lay public and trial lawyers as well as to that it will continue to be used for the foreseeable
obstetricians; a survey of maternal-fetal medicine fellows future. In a review of medicolegal issues in FHR moni
showed that they, too, have greatly overestimated the toring, Schifrin and Cohen37 noted that despite its
diagnostic accuracy of FHR monitoring.30 limitations, “Monitoring deserves credit for reducing
Large randomized trials have not demonstrated better intrapartum death, one of the original rationales for its
fetal and neonatal outcomes with continuous electronic development.”
FHR monitoring than with intermittent FHR ausculta A 2008 workshop (sponsored by the Eunice Kennedy
tion.31,32 In an editorial citing observations made by Shriver National Institute of Child Health and Human
Schifrin and Dame,33 Friedman34 opined, “The absence Development, the ACOG, and the Society for Maternal-
of either suggestive or overtly ominous fetal heart rate Fetal Medicine [SMFM]) updated the definitions of
patterns is reliably reassuring.” Unfortunately, there is various types of FHR tracings to simplify interpretation
little objective evidence that reassuring FHR tracings for providers.38 As a result, a three-category system was
exclude the subsequent occurrence of cerebral palsy. In a developed. Category I FHR tracings provide the most
1993 review of published FHR monitoring studies, Rosen reassuring evidence of fetal well-being and strongly
and Dickinson35 could not identify FHR patterns that predict normal fetal acid-base status at the time of obser
were consistently associated with neurologic injuries. vation. Category III tracings are the most ominous; these
Moreover, no consistent FHR pattern was observed in a tracings predict abnormal fetal acid-base status at the time
10 Fetal and Neonatal Neurologic Injury 195
of observation and require prompt evaluation. Most FHR Epidemiology and Etiology
tracings are category II (indeterminate). Category II trac
ings are not predictive of abnormal fetal acid-base status, The causes of cerebral palsy are not known, but the
but they do not provide sufficient evidence to be classified varying forms suggest a multifactorial etiology. The Col
as either normal or abnormal; these tracings require con laborative Perinatal Project still represents one of the
tinued surveillance and reevaluation (see Chapter 8). largest studies of the antecedent factors associated with
Intrapartum events are responsible for some cases of cerebral palsy. The investigators in this study evaluated
cerebral palsy39; however, these cases are few. After exclu the outcomes of 54,000 pregnancies among patients who
sion of infants with significant congenital anomalies, delivered at 12 university hospitals between 1959 and
intrapartum events—including asphyxial insults—likely 1966. They evaluated more than 400 variables in a uni
account for only 5% to 8% of all cases of cerebral palsy variate analysis,44 which identified potential risk factors
at all gestational ages.40,41 In 1999, the International Task that were then subjected to a more rigorous multivariate
Force on Cerebral Palsy published a consensus statement analysis.45 Maternal age, parity, socioeconomic status,
summarizing criteria that are necessary and suggestive of smoking history, maternal diabetes, duration of labor, or
an intrapartum etiology for neurologic abnormalities use of anesthesia was not associated with cerebral palsy
(Box 10-1).42 In 2010, a proposed evidence-based neona in the univariate analysis. The factors most strongly asso
tal workup to confirm or refute allegations of intrapartum ciated with cerebral palsy in the multivariate analysis
asphyxia was published.43 were (1) maternal mental retardation, (2) birth weight of
2000 g or less, and (3) fetal malformations. Other factors
associated with cerebral palsy included (1) breech presen
tation (but not vaginal breech delivery), (2) severe pro
Criteria to Define an Acute teinuria (more than 5 g/24 h) during the second half of
BOX 10-1 Intrapartum Hypoxic Event as pregnancy, (3) third-trimester bleeding, and (4) a gesta
Sufficient to Cause Cerebral Palsy tional age of 32 weeks or less. There was a slight asso
ESSENTIAL CRITERIA (ALL FOUR MUST BE MET)
ciation between cerebral palsy and fetal bradycardia,
chorioamnionitis, and low placental weight. However,
1. Evidence of metabolic acidosis in fetal umbilical cord only 37% of the cases of cerebral palsy occurred in
arterial blood obtained at delivery (pH < 7 and base
deficit ≥ 12 mmol/L)*
patients with one or more of these identified risk factors.
2. Early onset of severe or moderate neonatal encepha Rosen and Dickinson46 reviewed studies from Europe,
lopathy in infants born at 34 or more weeks’ Australia, and the United States that were published
gestation between 1985 and 1990 and included data from 1959 to
3. Cerebral palsy of the spastic quadriplegic or dyskinetic 1982. The incidence of cerebral palsy ranged from 1.8 to
type† 4.9 (composite rate of 2.7) cases per 1000 live births. The
4. Exclusion of other identifiable etiologies, such as incidence of certain conditions in infants with cerebral
trauma, coagulation disorders, infectious conditions, palsy was as follows: birth weight less than 2500 g, 26%;
and genetic disorders diplegia, 34%; hemiplegia, 30%; quadriplegia, 20%; and
CRITERIA THAT COLLECTIVELY SUGGEST AN extrapyramidal forms, 16%.
INTRAPARTUM EVENT—WITHIN CLOSE PROXIMITY TO Two more recent studies from Australia reexamined
LABOR AND DELIVERY (E.G., 0 TO 48 HOURS)—BUT the risk factors for cerebral palsy. A large epidemiologic
ARE NONSPECIFIC TO ASPHYXIAL INSULTS study from 1998 noted an incidence of neonatal encepha
1. A sentinel (signal) hypoxic event occurring immedi lopathy of 3.8 per 1000 term births.47 The investigators
ately before or during labor identified preconception and antepartum factors that
2. A sudden and sustained fetal bradycardia or the were associated with neonatal encephalopathy (Box 10-2).
absence of fetal heart rate variability in the presence In the second study from 2011, the greatest risks for
of persistent, late, or variable decelerations, usually cerebral palsy included (1) preterm birth, (2) fetal growth
after a hypoxic sentinel event when the pattern was restriction (also known as intrauterine growth restric
previously normal tion), (3) perinatal infection, and (4) multiple gestation.48
3. Apgar scores of 0 to 3 beyond 5 minutes
4. Onset of multisystem involvement within 72 hours of
Upper respiratory tract and gastrointestinal infections
birth during pregnancy and instrumental (forceps or vacuum)
5. Early imaging study showing evidence of acute nonfo vaginal delivery were not associated with cerebral palsy.48
cal cerebral abnormality Evidence suggests that intrapartum factors alone are
associated with neonatal encephalopathy in less than 5%
*Buffer base is defined as the amount of buffer in blood available to of cases.47,49 These data, along with the recognition that
combine with nonvolatile acids. A buffer base of 34 mmol/L is most patients with identified risk factors do not have
equivalent to a whole blood base deficit of 12 mmol/L.
†
Spastic quadriplegia and, less commonly, dyskinetic cerebral palsy are
children with cerebral palsy, have led the majority of
the only types of cerebral palsy associated with acute hypoxic investigators to agree that most cases of cerebral palsy
intrapartum events. Spastic quadriplegia is not specific to cannot be predicted and that the identification of
intrapartum hypoxia. Hemiparetic cerebral palsy, hemiplegic pregnancy-related conditions contributes minimally to
cerebral palsy, spastic diplegia, and ataxia are unlikely to result the identification of patients at risk for having a child with
from acute intrapartum hypoxia.
From Nelson KB, Grether JK. Potentially asphyxiating conditions and cerebral palsy.
spastic cerebral palsy in infants of normal birth weight. Am J Obstet In 2000, the ACOG and the American Academy of
Gynecol 1998; 179:507-13. Pediatrics (AAP) convened the Neonatal Encephalopathy
196 PART III Fetal and Neonatal Assessment and Therapy
BOX 10-2
Risk Factors for Neonatal Peripartum Asphyxia and Cerebral Palsy
Encephalopathy
Asphyxia may be defined as insufficient exchange of
PRECONCEPTION FACTORS* respiratory gases.51 Although accurate, this definition
• Increasing maternal age does not include an index of severity or have any predic
• Mother unemployed, unskilled laborer, or tive value. Unfortunately, most studies have not used a
stay-at-home uniform definition of birth asphyxia.52-54
• No private health insurance In 1953, Dr. Virginia Apgar, an anesthesiologist, intro
• Family history of seizures duced her scoring system to identify newborn infants in
• Family history of neurologic disorders need of resuscitation and to assess the adequacy of sub
• Infertility treatment sequent resuscitation efforts.55 Although the Apgar score
ANTEPARTUM FACTORS* has also been used to identify infants at risk for cerebral
palsy, only a weak association has been found.56,57 In the
• Maternal thyroid disease
• Severe preeclampsia
Collaborative Perinatal Project, only 1.7% of children
• Bleeding in pregnancy with a 1-minute Apgar score of 3 or less developed cere
• Viral illness in pregnancy bral palsy.58 Among infants who weighed more than
• Postdates pregnancy 2500 g at delivery, the incidence of cerebral palsy was
• Fetal growth restriction 4.7% if the 5-minute Apgar score was 0 to 3 and 0.2% if
• Placental abnormalities the 5-minute Apgar score was at least 7. Among infants
who weighed less than 2500 g with the same 5-minute
*Significantly and independently associated with neonatal Apgar scores, the incidence of cerebral palsy was 6.7%
encephalopathy in multiple logistic regression analysis.
From Penning DH. Fetal and neonatal neurologic injury. In Chestnut DH,
and 0.8%, respectively. Among all infants, a higher inci
Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Anesthesia: dence of cerebral palsy was observed if the Apgar score
Principles and Practice. 4th edition. Philadelphia, Mosby, 2009. remained 3 or less for longer than 5 minutes. The inci
Information compiled from Badawi N, Kurinczuk JJ, Keogh JM, et al. dence of early neonatal death increased among those
Antepartum risk factors for neonatal encephalopathy: the Western infants with prolonged neonatal depression.
Australia case-control study. BMJ 1998; 317:1549-53.
Most infants who subsequently manifest evidence of
cerebral palsy have a normal 5-minute Apgar score. In
the Collaborative Perinatal Project, only 15% of the
and Cerebral Palsy Task Force. The resulting landmark infants in whom cerebral palsy later developed had a
report,49 which was released in 2003, was reviewed and 5-minute Apgar score of 3 or less, approximately 12%
endorsed by such groups as the U.S. Department of had a score of 4 to 6, and the remaining 73% had a score
Health, the National Institutes of Health, the SMFM, of at least 7.58 It must also be noted that preterm delivery
the Child Neurology Society, the March of Dimes is independently associated with a low Apgar score.
Birth Defects Foundation, the Society of Obstetricians Although most cases of cerebral palsy are not attrib
and Gynaecologists of Canada, and the Royal Australian uted to intrapartum insults, intrapartum asphyxia does
and New Zealand College of Obstetricians and Gynae occur and can have serious consequences. However, the
cologists. The Task Force extended the earlier interna degree of asphyxia necessary to produce irreversible CNS
tional consensus statement regarding the requirements injury is unclear. In some cases, an intrapartum insult that
for establishing a causal relationship between intra might have otherwise been innocuous might be superim
partum events and cerebral palsy (see Box 10-1).42 posed on subclinical chronic fetal compromise and result
The consensus statement led to several medicolegal in permanent injury.
conclusions42,49: Umbilical cord blood gas measurements are often used
1. The only types of cerebral palsy associated with to diagnose suspected asphyxia. However, the definition
intrapartum hypoxia are spastic quadriplegia and, of normal umbilical cord blood gas and pH measurements
less commonly, dyskinesia. remains unclear.51 In one study of 15,073 vigorous neo
2. Intellectual disability, learning disorders, and epi nates (arbitrarily defined as having a 5-minute Apgar
lepsy should not be ascribed to birth asphyxia unless score of 7 or more) conducted between 1977 and 1993,
accompanied by spastic quadriplegia. the median umbilical arterial blood gas measurements
3. No statements about severity should be made (with the 2.5th percentile in parentheses) were as follows:
before an affected child is 3 to 4 years of age, pH 7.26 (7.10), Po2 17 (6) mm Hg, Pco2 52 (74) mm Hg,
because mild cases may improve and dyskinesia and base excess −4 (−11) mEq/L.51 Only small differences
may not be evident until then. in median pH and other measurements were present
4. Intrapartum hypoxia sufficient to cause cerebral when infants were grouped according to gestational age.
palsy is always accompanied by neonatal encepha These data suggest that umbilical arterial blood pH in
lopathy and seizures. vigorous neonates can be as low as 7.10 and base excess
Phelan et al.50 subsequently confirmed that fetuses may be as low as −11 mEq/L.
that experienced a sudden and sustained deterioration of Although intrapartum events are most likely associ
the FHR, and that subsequently were found to have cere ated with a minority of cerebral palsy cases, clinical
bral palsy, demonstrated characteristics consistent with studies have attempted to define the associated extent and
the ACOG/AAP Task Force criteria50 for intrapartum duration of perinatal asphyxia. Fee et al.59 defined
asphyxial injury. asphyxia as an umbilical arterial blood pH of less than
10 Fetal and Neonatal Neurologic Injury 197
7.05 with a base deficit greater than 10 mEq/L; they cord arterial blood pH less than 7.00 was significantly
concluded that this threshold was a poor predictor of associated with important, biologically plausible, adverse
adverse neurologic outcomes. Goodwin et al.60 defined neonatal outcomes (i.e., neonatal mortality, hypoxic
asphyxia as an umbilical arterial blood pH of less than ischemic encephalopathy, intraventricular hemorrhage,
7.00; with the use of this definition, hypoxic ischemic periventricular leukomalacia, cerebral palsy).68 Unfortu
encephalopathy and abnormal neurologic outcome were nately, this relationship does not consider the role of
associated with acidemia. Goldaber et al.61 also observed previous or repetitive hypoxic episodes before the episode
greater neonatal morbidity and mortality among term in question and therefore cannot accurately pinpoint the
infants (birth weight > 2500 g) with an umbilical arterial time of injury. Fortunately, the human fetus is quite
blood pH of less than 7.00. robust, and episodes of intrauterine asphyxia usually yield
Low et al.62,63 also studied complications of intrapar a normal neonate. A much smaller number of fetuses
tum asphyxia in term and preterm infants. They devel experiencing such episodes die in utero. Blumenthal69
oped a complication score that expressed the magnitude concluded that there is a fine threshold between normal
of neonatal complications. Among term infants, the fre ity and death from asphyxia.
quency and severity of newborn complications increased The increased presence of nucleated red blood cells in
with the severity and duration of metabolic acidosis at the umbilical circulation at delivery has been proposed as
birth. Importantly, respiratory acidosis at birth did not a marker of the occurrence and timing of intrauterine
predict complications in newborns. Similar results were asphyxia.50,70,71 However, data from these investigations
noted for preterm infants delivered between 32 and 36 demonstrated considerable variability and were influ
weeks’ gestation. In contrast, in infants delivered before enced by birth weight and gestational age.72 Further
32 weeks’ gestation, complications were similar in the more, the timing of the injury may be difficult to
control and asphyxia (defined as umbilical arterial blood determine with confidence, because multiple episodes of
buffer base < 30 mmol/L) groups. When this scoring asphyxia may have occurred. In such cases, the nucleated
system was used in term infants, the threshold for moder red blood cell count may reflect and implicate only the
ate or severe newborn complications was an umbilical most recent, but possibly least important, event. Both
arterial blood base deficit of 12 mmol/L.63 nucleated red blood cell and lymphocyte counts appear
Relatively few studies have followed neurodevelop to undergo more sustained elevations in cases of antepar
mental examinations for a sufficient duration to make tum asphyxia than in cases of intrapartum asphyxia.49
meaningful conclusions about peripartum predictors
of neurologic injury. Nagel et al.64 performed such exam Chorioamnionitis, Fever,
inations in 30 children in whom umbilical arterial blood
pH was less than 7.00 at delivery, 28 of whom survived
and Cerebral Palsy
the neonatal period. Evaluation at 1 to 3 years of age An association between cerebral palsy and chorioamnio
detected 3 children who had experienced an episode nitis has been demonstrated in preterm infants and term
of hypertonia. The majority of children exhibited no infants of normal birth weight.73,74 An elevated maternal
major problems, with only 1 child displaying mild motor temperature is one sign of chorioamnionitis, but alone it
developmental delay. Another study examined neonatal is insufficient for the diagnosis. Other signs include, but
complications (neonatal death, grade 3 or 4 intraven are not limited to, maternal and fetal tachycardia, foul-
tricular hemorrhage, gastrointestinal dysfunction, and smelling amniotic fluid, uterine tenderness, and maternal
neonatal seizures) in 35 newborns with an umbilical arte leukocytosis. The diagnosis remains unproven until con
rial blood pH of less than 7.00 at delivery, 3 of whom firmed by placental culture or histologic examination.
died during the neonatal period.65 An umbilical arterial The mechanism by which chorioamnionitis is associ
blood base deficit greater than or equal to 16 mmol/L ated with cerebral palsy is unclear; however, inflamma
and a 5-minute Apgar score less than 7 had a sensitivity tory cytokines may play a role (see later discussion).75-77
and specificity for predicting adverse neonatal outcomes A landmark meta-analysis published in 2000 reported
of 79% and 81%, respectively. These investigators did that both clinical and histologic chorioamnionitis were
not perform any follow-up neurologic examinations after strongly associated with an increased risk for cerebral
the neonatal period.65 palsy and periventricular leukomalacia in both preterm
Because metabolic acidosis may be a predictor of com and term infants.78 In a 2010 meta-analysis, both histo
plications in newborns, the severity of intrapartum aci logic (pooled odds ratio [OR], 1.83; 95% confidence
dosis could be an important variable. Gull et al.66 studied interval [CI], 1.17 to 2.89) and clinical chorioamnionitis
a small cohort of 27 patients with terminal bradycardia (OR, 2.42; 95% CI, 1.52 to 3.84) were again found to be
who were delivered vaginally. Not surprisingly, the significantly associated with cerebral palsy.79
umbilical arterial blood base deficit was greater in infants Several studies have demonstrated a tendency for
with end-stage bradycardia than in controls. The loss of maternal temperature to rise after administration of epi
short-term FHR variability for more than 4 minutes dural analgesia during labor (see Chapter 37).80 Although
during terminal bradycardia correlated with the develop the mechanism of epidural analgesia–associated maternal
ment of metabolic acidosis. pyrexia remains unclear, fever due to epidural analgesia
The relationship between umbilical arterial blood base alone is not associated with cerebral palsy.81 Epidural
excess values and the timing of hypoxic injury has been analgesia has been blamed for the common obstetric
estimated in human and animal studies.67 In addition, in practice of antibiotic administration to mothers with
a 2010 systematic review and meta-analysis, an umbilical fever but no other evidence of chorioamnionitis. This
198 PART III Fetal and Neonatal Assessment and Therapy
practice may lead to unnecessary neonatal sepsis evalua reduction of fetal nutrient supply or altered maternal-
tions and antibiotic exposure.82 Rather than treat all fetal endocrine status.
women with pyrexia for presumed chorioamnionitis, Dysregulation of neuronal calcium transport appears
Mayer et al.83 correctly noted that physicians should to be the initial pathway by which cerebral hypoxemia
make an effort to differentiate true chorioamnionitis causes perinatal neuronal injury.89 Hypoxia-induced
from incidental maternal fever. These investigators found changes in the NMDA receptor increases cellular perme
that additional signs of chorioamnionitis were present in ability to calcium; such increases in intracellular calcium
all cases in which the diagnosis was later confirmed by trigger a variety of downstream effects, ultimately result
culture or pathologic examination. Neuraxial anesthesia ing in generation of free radicals, peroxidation of lipid
is not a risk factor for cerebral palsy.44 membranes, and nuclear fragmentation. It has long been
The mode of delivery has been examined as an inde recognized that developing oligodendroglia are highly
pendent risk factor for periventricular leukomalacia, vulnerable to excitotoxic injury in preterm infants.90
the most common form of ischemic brain injury in sur Altered maturation or premature oligodendrocyte death
viving preterm infants in whom cerebral palsy later devel can occur in areas of severe hypoxia-ischemia as a result
ops. In 99 women with chorioamnionitis who delivered of up-regulation of inflammatory cytokines by activated
between 25 and 32 weeks’ gestation, vaginal delivery had microglia, elevated glutamate levels, or depleted levels of
a significant association with periventricular leukomala the antioxidant glutathione. It is highly likely that a com
cia.84 Because the cesarean delivery group likely included bination of these mechanisms, modified by the nature
a substantial number of infants with nonreassuring FHR and duration of insults and gestational age, determine the
tracings, the better outcomes in these infants is striking. ultimate neurobehavioral phenotype.
Prospective trials are needed to confirm these retrospec
tive observations. Maternal Inflammation and
Fetal Brain Injury
Although the development of the fetal brain is encoded
PATHOPHYSIOLOGY OF by genetic programming, such programs remain highly
FETAL ASPHYXIA susceptible to environmentally induced epigenetic modi
fications and appear closely intertwined with maternal
Intrauterine Hypoxemia and immune and endocrine systems. Recent experimental and
the Fetal Brain epidemiologic studies reveal that maternal infection and
inflammation early in pregnancy can cause an array of
The fetus is exclusively dependent on the placenta for neurodevelopmental abnormalities in the offspring such
oxygen and nutrients; thus, acute and chronic conditions as schizophrenia and autism.91-94 Among maternal infec
that affect the placenta or the umbilical cord can deprive tions, chorioamnionitis is the best characterized and
the fetus of one or more of these vital resources. Recent thoroughly investigated model of perinatal neuroinflam
evidence from experimental animal models and humans mation. Although the exact contribution of maternal
suggest that both hypoxemic and inflammatory pathways inflammation to perinatal brain injury is obscured because
interact and augment fetal brain damage. of the association of chorioamnionitis with preterm deliv
The spectrum of neurologic injury in neonates de ery and hypoxic-ischemic encephalopathy, inflammatory
pends on the duration and gestational age at hypoxemic- experimental models have revealed much information on
ischemic insult. Acute hypoxemia during the early- to cytokine induction, their transport across the placenta
mid-gestational period in sheep affects the predominant and amniotic fluid, and subsequent activation of the fetal
neurodevelopmental events such as neurogenesis and immune system.
neuronal migration. Such hypoxemia causes the death of The exact mechanism by which maternal inflamma
cerebellar Purkinje cells and hippocampal pyramidal neu tion triggers a fetal immune response is likely multifacto
rons, as well as impaired neuronal migration.85 In con rial (Figure 10-2). Despite the presence of circulating
trast, acute hypoxemia in late gestation appears to spare immune cells as early as 7 weeks’ gestation in humans,
the hippocampus and cerebellum but causes neuronal antigen presentation is suboptimal because of reduced
death in the cerebral cortex and striatum.86 Furthermore, expression of the major histocompatibility complex class
acute perinatal anoxia causes long-term changes in den II on antigen-presenting cells. Furthermore, the T cells
dritic arborization and synaptic connectivity.87,88 are relatively immature. Therefore, maternally derived
Experimental models of chronic hypoxemia, based on humoral mediators seem credible candidates to initiate
restriction of placental mass or blood flow, demonstrate and perpetuate an inflammatory cascade across the pla
an array of completely different effects on the fetal brain. centa. This idea has gained traction with the identifica
Chronic placental insufficiency relatively spares the fetal tion of maternal interleukin-6 (IL-6) in the fetal
brain compared with other organ systems, although it circulation as early as the second trimester, suggesting the
results in reduced fetal brain weight. Overall, neurons possibility of transplacental transfer of proinflammatory
appear to survive chronic and mild hypoxemia; even cytokines.95 Proinflammatory mediators such as IL-6
minor behavioral changes appear to resolve fully by cause significant impairment of placental blood flow and
adulthood in animal models. It is not known whether fetal hypoxemia in animal models, dysregulate the barrier
these effects are mediated by hypoxemia per se, or function of both the placenta and the immature fetal
by other accompanying conditions such as chronic blood-brain barrier, trigger production of acute-phase
10 Fetal and Neonatal Neurologic Injury 199
Preterm birth
(ELGAN, LBWI) Fetal inflammatory response syndrome
(increased proinflammatory cytokines
in fetal brain)
FIGURE 10-2 ■ Probable mechanisms of fetal brain injury with in utero exposure to maternal inflammation. IL, interleukin; TNF, tissue
necrosis factor; LBWI, low birth weight infant; ELGAN, extremely low gestational age neonate. (From Burd I, Balakrishnan B, Kannan
S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol 2012; 67:287-94.)
proteins from the fetal liver, promote T-cell entry into prenatal inflammation alters fetal brain development at
the immature brain parenchyma, and disrupt the orderly the molecular, cellular, and circuit levels. Epidemiologic
patterning of the fetal cerebral cortex.91,93,96-99 The role of studies have shown a strong correlation between mater
inflammatory mediators in this phenomenon is rein nal infection/inflammation and neurodevelopmental
forced by the direct correlation that exists between plasma disorders such as schizophrenia and autism.92,105,106
levels of IL-6 and the severity of functional deficits in
offspring.100,101 In addition to IL-6, cytokines such as
IL-1β, IL-7, and IL-13 are up-regulated in the fetal brain
Animal Models of Fetal Asphyxia
after a prenatal immune insult, a phenomenon that sug Much of our knowledge of the fetal response to insuffi
gests collective activation of the innate fetal immune cient exchange of respiratory gases has been gained
response.102 through the use of animal models. However, the limita
Both microglia (the major resident macrophages in tions of these models must be acknowledged. Raju107
the developing brain) and the complement system have reviewed the various animal models of fetal brain injury.
been implicated as amplifiers of this immune response. At birth, sheep and guinea pig brains are much closer to
During normal fetal development, microglia invade and maturity than the human brain. In this regard, rat pup
colonize the fetal brain during the first and second and human brains are more similar to each other because
trimesters103 and are readily activated by proinflamma they both undergo significant extrauterine development
tory mediators such as IL-1β. Activated microglial cells (Figure 10-3).108 Nonetheless, the importance of this
either cause a direct cytotoxic effect on oligodendrocytes distinction has been challenged. Previously, investigators
and impair myelination or produce long-lasting altera relied mainly on morphologic milestones (e.g., the brain
tions in neuronal-glial crosstalk, resulting in impaired growth spurt) to compare species at different stages
synaptic function and subsequent neurodevelopmental of development. A computerized method attempted to
disorders.3,91,104 more accurately compare observations among 10 species
At the cellular level, numerous mechanisms are (including humans) by evaluating the mathematical
involved in propagating the prenatal immune response. relationships of more than 100 developmental events
Collectively, robust experimental evidence suggests that and factors (e.g., evolutionary, genetic, neurochemical,
200 PART III Fetal and Neonatal Assessment and Therapy
Factors Decreasing Oxygen fetal demise. Incomplete asphyxia may occur in any setting
BOX 10-3 in which oxygen delivery to the fetus is inadequate to
Transfer to the Fetus
meet all of its needs (e.g., brief and/or repeated episodes
ENVIRONMENTAL PO2 of partial umbilical cord occlusion, placental emboliza
• High altitude tion, or incomplete placental abruption). This latter cat
egory of asphyxia presumably contributes to the largest
MATERNAL CARDIOPULMONARY FUNCTION proportion of cases of cerebral palsy attributed to ante
• Cyanotic heart disease partum events. In these cases, the insult is not severe
enough to lead to immediate fetal death but can pro
O2 TRANSPORT BY MATERNAL BLOOD foundly affect fetal brain growth and development.
• Anemia Ongoing studies are attempting to determine whether
• Cigarette smoking there is a period of time in utero when the fetus is espe
PLACENTAL BLOOD FLOW cially vulnerable to neurologic injury.
• Hypertension
Using a primate model to perform seminal research
• Diabetes on the subject of perinatal brain injury, Myers27 identified
• Placental abruption two patterns of injury based on whether the fetus suffered
• Uterine contractions complete or partial asphyxia. True complete asphyxia was
demonstrated in fetal monkeys at term subjected to
PLACENTAL O2 TRANSFER varying durations (0 to 25 minutes) of complete asphyxia.
• Placental abruption These fetuses were resuscitated when possible, a proce
• Placental infarcts dure that often required the use of cardiac massage and
UMBILICAL BLOOD FLOW AND FETAL CIRCULATION epinephrine, and postmortem examinations revealed
extensive pathology in brainstem areas. In humans, such
• Umbilical cord occlusion
• Maternal heart disease
a severe intrauterine insult would most likely be incom
patible with extrauterine survival. If survival did occur,
O2 TRANSPORT BY FETAL BLOOD the infant would show obvious encephalopathy and mul
• Anemia tiorgan system dysfunction at birth. The second pattern
• Hemorrhage (i.e., partial asphyxia) is more relevant to the discussion
of human cerebral palsy. In studies of fetal monkeys sub
From Richardson B. The fetal brain: metabolic and circulatory responses to jected to partial asphyxia,128 some animals demonstrated
insufficient exchange of respiratory gases. Clin Invest Med 1993; cortical necrosis, subcortical white matter damage, and
16:103-14.
Mid-gestation
(3/5 hypoxia)
Late gestation
(5/8 hypoxia)
1 cm
FIGURE 10-4 ■ Composite diagram showing distribution of hypoxic injury in mid-gestational (top) and near-term (bottom) fetal lambs
at 3 days after 8 hours of arterial hypoxemia. Hypoxemia was produced by placing the pregnant ewe in a chamber with reduced
ambient oxygen. Each shading pattern represents an individual animal. The severity of injury is not indicated in this diagram. (From
Penning DH, Grafe MR, Hammond R, et al. Neuropathology of the near-term and midgestation ovine fetal brain after sustained in utero
hypoxemia. Am J Obstet Gynecol 1994; 170:1425-32.)
202 PART III Fetal and Neonatal Assessment and Therapy
basal ganglia damage. Although these two studies form Fetal Cerebral Responses
the core of our knowledge of perinatal brain injury in BOX 10-4
to Asphyxia
primates, there were relatively few animals in each exper
imental group, and considerable variation in response FETAL CEREBRAL METABOLISM
occurred. Some animals suffered no injury, whereas • Increased oxygen extraction
others could not be resuscitated. • Use of alternative energy sources
Several investigators have attempted to summarize the • Decreased growth
neuropathology of fetal and neonatal asphyxia.128-130 • Altered behavioral state
Volpe131 emphasized that the variation in neuropathology
after intrauterine asphyxia depends on the fetal gesta FETAL CEREBRAL O2 TRANSPORT
tional age. Volpe also proposed a framework for these • Redistribution of cerebral blood flow
variations. The principal sites of injury in preterm fetuses
From Penning DH. Fetal and neonatal neurologic injury. In Chestnut DH,
are the white matter (especially periventricular white Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Anesthesia:
matter) and the basal ganglia, whereas older fetuses dem Principles and Practice. 4th edition. Philadelphia, Mosby, 2009. Modified
onstrate injury primarily in the gray matter of the cortex from Richardson B. The fetal brain: metabolic and circulatory responses to
and cerebellum. insufficient exchange of respiratory gases. Clin Invest Med 1993;
Periventricular leukomalacia is the most common patho 16:103-14.
logic finding in preterm infants with brain injury.131 This
lesion is characterized by coagulative necrosis of the
white matter adjacent to the lateral ventricles and around Fetal Adaptive Responses
the foramen of Monro, especially at the external angle
of the lateral ventricles and the optic radiation.132 With The fetus takes advantage of several adaptive responses
long-term survival, the lesion may progress to a widening for survival and growth in the relatively hypoxemic intra
of the ventricles and hydrocephalus ex vacuo. Clinically, uterine environment; these adaptive changes to intra
periventricular leukomalacia may not be apparent at uterine hypoxemia vary between immature and mature
birth.129 Developing hydrocephalus may be detected fetuses. Fetal responses to asphyxia may be categorized
on computed tomography or ultrasonographic examina as an alteration of fetal metabolism or maximization of
tion. In more subtle cases, magnetic resonance imaging fetal oxygen transport (Box 10-4).124 Richardson139 defined
(MRI) may show decreased myelination (see later the oxygen margin of safety as the extent to which fractional
discussion).133 oxygen extraction can increase and fetal arterial Po2 can
The pathophysiology of periventricular leukomalacia decrease before tissue oxygen supplies are inadequate.
is unclear. Conventional wisdom has held that periven Regardless of the etiology of decreased oxygen delivery
tricular leukomalacia is an ischemic lesion unique to to the fetus, fetal oxygen consumption is maintained by
preterm infants.134 The insult is thought to occur in an increasing oxygen extraction until oxygen delivery is
arterial border zone perfused by end-arterial branches of approximately 50% of normal.140 Lower levels of tissue
the middle and posterior cerebral arteries. This border oxygen tension result in progressive metabolic acidemia
zone has been identified by DeReuck,134 who demon and a terminal decrease in oxygen consumption.139
strated periventricular arborizations between vessels Alterations in substrate use may affect the fetal
penetrating to the ventricles (i.e., ventriculopedal vessels) response to insufficient exchange of respiratory gases.
and between vessels arising from the ventriculochoroidal Unlike the adult brain, the fetal brain can use ketone
arteries (i.e., ventriculofugal vessels). Others have chal bodies and lactate as alternative energy sources.141 In
lenged DeReuck’s anatomic findings and have questioned gravid ewes, a reduction in uterine blood flow results in
whether periventricular leukomalacia is a purely ischemic reduced fetal glucose consumption.141 Current opinion
lesion.135,136 holds that hyperglycemia should be avoided in adult
White matter in the immature fetal brain may be at humans at risk for ischemia.142 Hyperglycemia may exac
increased risk for hypoxic-ischemic injury because of a erbate metabolic acidosis by providing substrate for
limited ability of its vessels to vasodilate.131 If this were anaerobic metabolism, which increases lactic acid pro
true, autoregulation would be precluded in situations duction. However, Vannucci and Mujsce,143 citing experi
of hypotension. However, at least one study has shown ments in neonatal rat pups, suggested that the immature
that blood flow to white matter actually may increase brain may respond differently and that glucose adminis
(relative to gray matter) during fetal asphyxia.137 Fetal tration may actually reduce hypoxic-ischemic brain
white matter may be more metabolically active than gray injury. These investigators did not consider earlier work
matter because of large numbers of actively myelinating by Blomstrand et al.,144 who studied the effects of hypoxia
cells.131 In situations of marginal oxygen supply, glia are in the anesthetized, exteriorized fetal lamb. In that study,
subsequently at greater risk for injury. One study has hyperglycemia accelerated the loss of somatosensory
suggested that immature astrocytes are more susceptible evoked potentials, the onset of metabolic acidosis, and
to ischemic death than mature astrocytes.138 Studies the reduction of cerebral oxygen consumption. Until
in fetal lambs have successfully produced pathologic these different observations are reconciled, the mainte
changes similar to those present in infants with periven nance of normoglycemia in utero appears prudent.
tricular leukomalacia.127 These models may help clarify During chronic hypoxemia, the fetus may also restrict
the mechanism of this common pathologic correlate of the use of energy derived from oxidative metabolism to
cerebral palsy in the preterm infant. maintain essential cellular processes. This may lead to
10 Fetal and Neonatal Neurologic Injury 203
decreased somatic growth and fetal growth restriction. behavioral state, and (4) responsiveness to external
Using an ovine model of asphyxia, Hooper145 detected stimuli. The Fetal Neurobehavioral Coding System
decreased incorporation of tritiated [3H]-thymidine (FENS) incorporates most elements of fetal behavior and
(which reflects decreased DNA turnover and, presum is a direct extension of the NICU Network Neurobehav
ably, decreased cell division) in fetal tissue. The decrease ioral Scale (NNNS) used for neonatal assessment.152
in incorporation of tritiated [3H]-thymidine was not Using ultrasonography, FENS analysis can identify spe
uniform in all tissues. The rates of DNA synthesis were cific behaviors in fetuses with growth restriction; com
maintained in most fetal tissues (including the fetal brain) pared with normally developing fetuses, fetuses with
but were greatly reduced in the lung, the skeletal muscle, growth restriction demonstrate a delayed appearance of
and the thymus gland. behavioral states, longer behavioral state transitions, and
The fetus can conserve additional energy by decreas disorganized behavioral patterns. These tests have been
ing breathing and gross body movements. Rurak and validated in other paradigms, including pregnancies that
Gruber146 demonstrated a 17% reduction in oxygen were complicated by maternal diabetes, substance abuse,
consumption in fetal lambs that were paralyzed by a and cigarette smoking.
neuromuscular blocking agent. Perceptible fetal move A recently developed, more comprehensive scale is the
ments represent an index of fetal health. Many obstetri Kurjak Antenatal Neurodevelopmental Test (KANET),
cians instruct their patients to count episodes of fetal which includes an assessment of eight fetal parameters
activity for specified periods and to consult them if related to fetal behavior, general movements, and other
fetal movements are decreased or absent (see Chapter 6). physical signs (e.g., head circumference, presence or
Fetal hypoxemia results in decreases in both activity and absence of overlapping cranial sutures, finger move
rapid eye movement (REM) sleep in fetal lambs. REM ments).153 However, these fetal assessment studies are
sleep states are associated with an increased cerebral time-consuming and require specific training to codify
metabolic rate for oxygen (CMRo2).113 Thus, during behaviors. In addition, because the brain structures
periods of fetal stress, reductions in fetal body move driving such behaviors have not been clearly identified,
ments or REM sleep lead to a significant decline in fetal it is difficult to understand the significance of differences
energy expenditure. in behavior, if any.
Oxygen deprivation typically results in a change in
and/or redistribution of fetal cardiac output.147 The mag
nitude of these changes depends on the mechanism and
Fetal Neuroimaging Assessment
severity of oxygen deprivation. Sheldon et al.148 demon In vivo MRI provides details of the architecture of the
strated that experimental fetal hypoxemia (produced developing brain beginning in the eighteenth gestational
by the administration of a decreased maternal-inspired week and can quantify brain growth and structural abnor
concentration of oxygen) resulted in greater blood flow malities.154 The use of more sophisticated techniques
to the brain, myocardium, and adrenal glands. In fetal such as MR tractography and functional fetal MRI is
lambs, a brief (4-minute) complete arrest of uterine and likely to enhance our understanding of normal brain
ovarian blood flow resulted in a decrease in blood flow development and thus facilitate identification of abnor
to all organs except the myocardium and adrenal glands.149 mal development. Until controlled trials demonstrate
adequate sensitivity, specificity, and positive predictive
power for these tests, their clinical potential is limited.
FETAL AND NEONATAL ASSESSMENT These potential advantages will need to be balanced
against the potential detrimental effects of ultrasonogra
Fetal Neurobehavioral Assessment phy and MRI on fetal neuronal development and
migration.155
With recent advances in the understanding of prenatal
brain development and imaging technology, there is con Neonatal Radiologic Diagnosis
siderable interest in monitoring and codifying fetal neu
rologic development and behavior to predict postnatal
of Cerebral Injury
neurodevelopment.150 The driving principle is that fetal MRI is a useful tool in the diagnosis of neonatal brain
behavioral patterns reflect complex interactions between injury.156,157 MRI can assist in the diagnosis of hypoxic
the maternal environment and primitive neuronal net ischemic encephalopathy in newborn infants,158 provide
work generators in the developing brain. There is an three-dimensional evaluations to determine the volume
overwhelming convergence of opinion that most neuro of gray matter and the extent of white matter myelination
developmental disorders have an intrauterine origin and (thus providing valuable insights into normal and abnor
that there is extensive neurobehavioral continuity from mal brain development),159 and estimate the timing of the
the fetal to the neonatal period.151 brain injury in patients with cerebral palsy.160 The pres
Although the assessment of high-risk pregnancies has ence of cerebral edema confirms recent-onset brain
included an analysis of certain aspects of fetal behavior, injury; edema develops 6 to 12 hours after injury and
until recently there have been no unified scales for assess resolves within 4 days.161 Unfortunately, the changes are
ment of fetal neurobehavior. Current fetal neurobehav subtle and the time frame of interest may extend before
ioral scales assess a variety of behaviors that can be or after the intrapartum period. Nonetheless, the infor
categorized into the four main domains described by mation can be quite helpful, and early imaging should be
DiPietro150: (1) heart rate, (2) motor activity, (3) existing performed in cases of suspected brain injury. There is a
204 PART III Fetal and Neonatal Assessment and Therapy
strong correlation between anatomic brain lesions trajectory are unclear. Only a few preclinical studies have
detected on MRI and specific types of cerebral palsy.161 addressed this question.169,170 Endogenous opioid systems
MRI is particularly sensitive in the detection of periven are active in the fetal brain, and the presence of their
tricular leukomalacia, although many children with this cognate receptors at critical sites during this period sug
MRI abnormality have clinically normal neurologic gests that these systems are intricately linked to early
development.162 neurodevelopment.171-174 Preclinical evidence suggests
New imaging techniques, such as diffusion tensor that opioid mechanisms play an important role in both
imaging and magnetic resonance spectroscopy, may offer early and adult neurogenesis by modulating neuronal
advantages over conventional MRI when performed early progenitor proliferation and differentiation.175-177 Of
(i.e., hours) after a hypoxic-ischemic insult. Diffusion concern, fetal rat exposure to morphine during the entire
tensor imaging detects the microscopic movement of second trimester alters offspring hippocampal develop
water particles in brain tissue. Magnetic resonance spec ment.178 However, animal studies of opioid abuse in preg
troscopy analyzes the signal of protons attached to mol nancy should not be extrapolated to peripartum opioid
ecules such as glutamate, glutamine, and lactate, among use in humans because of differences in the gestational
others.163 These methods, developed in rabbit164 and age as well as differences in drug dose and duration of
sheep165 models of intrauterine hypoxia, detect acute administration. Only focused studies will reveal the true
chemical changes in brain tissue and may accurately consequences of intravenous opioid administration for
predict motor outcome in preterm infants.166 Injury pat labor analgesia at term gestation.
terns detected with these methods are present for several
days and resolve over the next week, at which point the Neuraxial Techniques
chronic injury becomes visible with conventional MRI.
Identification of injuries shortly after birth with these Studies of neuraxial analgesia in labor usually focus on
newer techniques can support the hypothesis that an analgesic quality and obstetric and short-term neonatal
injury occurred within days of delivery.163 Thus, magnetic outcomes. To date, no randomized trials have evaluated
resonance spectroscopy and diffusion tensor imaging are the long-term effects of neuraxial analgesia on brain
powerful new tools for timing the occurrence and under development in offspring. Epidurally administered local
standing the pathophysiology of perinatal brain injury.163 anesthetics cross the placenta and enter the fetal circula
Cerebral ultrasonography remains a useful technique in tion. Golub179 randomized nonlaboring pregnant rhesus
the early neurologic neonatal assessment,167 especially for monkeys at term to receive epidural bupivacaine (total
the critically ill infant who might not be a candidate for dose of 1.2 mg/kg) or saline.179 No differences in specific
transfer to an MRI facility. cognitive deficits were identified between groups;
however, exposed offspring demonstrated a prolonged
increase in motor disturbance behaviors at 10 to 12
ANESTHESIA AND BRAIN INJURY months of age, suggesting that perinatal interventions
can alter postnatal behavioral ontogeny. In the only
Anesthetic agents have profound effects on brain metab human evidence to date, investigators examined the asso
olism and synaptic transmission. These effects may be ciation between the use of neuraxial labor analgesia and
direct or indirect and protective or harmful. the incidence of childhood learning disabilities in a
population-based birth cohort of children from Olmsted
County, Minnesota.180 The incidence of childhood learn
Labor Analgesia and the Fetal Brain ing disabilities was not associated with the use of neur
Labor analgesia usually entails administration of lower axial labor analgesia (adjusted hazard ratio, 1.05).180
concentrations of analgesic/anesthetic agents for a longer
duration than occurs during administration of anesthesia Inhalational Agents
for surgical procedures. Despite widespread use of anal
gesic and sedative drugs during labor, little attention has The use of inhalational anesthetic agents during labor
been paid to the neurodevelopmental consequences of and delivery became popular after the successful use of
antepartum and intrapartum fetal exposure to these chloroform by John Snow during Queen Victoria’s deliv
drugs. Because neurodevelopmental events at term are ery of Prince Leopold in 1853. Other inhalational agents
quite different from those that occur during the second were subsequently introduced, including nitrous oxide,
trimester, there is a need to design experimental studies trichloroethylene, cyclopropane, and methoxyflurane.
to investigate the effects of analgesic techniques and Although the use of halogenated agents has been sup
drugs administered during the third trimester of planted by widespread adoption of neuraxial techniques
pregnancy. for labor analgesia, nitrous oxide is still widely used in
many countries. Typically it is administered as 50%
nitrous oxide in oxygen using a blender device (e.g.,
Parenteral Opioids
Nitronox in the United States) or premixed in a single
Among systemic opioids used for labor analgesia, meperi cylinder (e.g., Entonox in the United Kingdom) (see
dine remains the most widely studied. Although it is well Chapter 22).
recognized that opioids cross the placenta and enter the Scientific studies of the fetal and neonatal effects of
fetal circulation,168 the long-term effects of peripartum inhalational analgesics are generally of limited quality.181,182
opioid exposure on the infant’s neurodevelopmental Available evidence suggests that inhalational anesthetic
10 Fetal and Neonatal Neurologic Injury 205
agents, including nitrous oxide, have minimal or no effect the potential long-term effects of maternal anesthesia on
on Apgar and neurobehavioral adaptation scores imme the fetal brain must be investigated in animal models.
diately after delivery.183,184 However, none of these studies However, given the considerable differences in neural
has evaluated long-term neurodevelopmental outcomes. maturation among species (Figure 10-5; see also Figure
This knowledge gap is critical, because robust evidence 10-3), and the duration of anesthesia exposure in relation
suggests that early-life neural reprogramming, following to the lifespan of the organism, these results should be
pharmacologic and inflammatory insults, affects behav interpreted with caution.190,191
ioral development later in life. Of concern is compelling The exact mechanisms by which anesthetic agents
animal evidence that anesthetic agents, when adminis impair early brain development are still under active
tered during a critical period of brain development, cause investigation.192 Anesthetic agent interactions with GABA
widespread neurodegeneration with subsequent learning, and the NMDA-subtype of glutamate receptors decrease
memory, and behavioral problems (see later discus activity-dependent synapse formation and cause apo
sion).185,186 Nitrous oxide, in particular, is now known ptotic neurodegeneration in multiple areas of the devel
to be a potent developmental neurotoxin in animal oping brain. These histopathologic changes have been
models, yet its effects (if any) on human neurodevelop well investigated, especially in the hippocampal forma
ment are unclear. tion, which is an area that is crucial for memory. Early
Epidemiologic evidence from young children receiv exposure to anesthetic agents affects long-term potentia
ing anesthetic agents appears to support the possibility tion in the hippocampus and affects spatial working
that anesthesia and surgery are associated with learning memory in animal models.185 These changes do not
disabilities and attention deficit disorders later in life.187 appear to be caused by direct cytotoxicity193 but rather by
Thus, although the pattern of nitrous oxide administra a combination of effects on both neuronal and non-
tion during labor is unlike its administration for surgical neuronal cells in the developing brain (Box 10-5).
anesthesia, the administration of nitrous oxide for labor Of specific concern are the effects of anesthetic agents
analgesia merits closer scientific scrutiny. on neurogenesis and synapse formation in the fetal brain.
Human neural ontogeny suggests that the second trimes
ter is a period of active fetal brain development, with
Maternal Anesthesia and the Fetal Brain neuroblast proliferation peaking between the 5th and
Despite the popularity of neuraxial techniques in 25th postmenstrual weeks. Because GABA and glutamate
obstetric anesthesia, many pregnant women continue to play a crucial role in these processes, there is concern
require general anesthesia for either pregnancy-related that prolonged and nonphysiologic modulation of the
or nonobstetric surgical procedures. The commonly used fetal GABA and glutamatergic systems, as might occur
anesthetic agents freely cross the placenta and reach the during second-trimester maternal anesthesia, might
fetal brain, causing fetal sleep or sedation. Obstetric anes affect neurogenesis, neuronal migration, and/or synapse
thesia research has focused primarily on the teratogenic formation.
effects of anesthetic agents administered during the In one of the first animal studies to simulate a clinically
first trimester (see Chapter 17) and the effects of anes relevant scenario,194 a single exposure to 1.4% isoflurane
thetic agents on neonatal behavior when administered (1 MAC [minimum anesthetic concentration]) for 4 hours
during cesarean delivery. Historically, the second trimes during the second trimester caused long-lasting impair
ter has been assumed to be a safe period for surgery ment of spatial working memory in rodent offspring.
and anesthesia, primarily because of a lack of targeted Although the exact mechanisms behind these behavioral
studies. However, during the past decade, extensive disturbances are unclear, other studies suggest that mid-
animal research has shown that anesthetic agents, when gestational exposure to isoflurane up-regulates the pro
administered during the phase of synaptogenesis, can apoptotic protein caspase-12, decreases overall synapse
induce a profound neurodegenerative response in the numbers in the fetal hippocampus, and down-regulates
developing brain and cause functional impairment in the plasticity-associated protein GAP-43.195,196 Similar
offspring.185,188 results have been reported in pregnant guinea pigs and
Human epidemiologic studies appear to support an macaques, suggesting that the fetal brain remains highly
association between early childhood exposure to anes susceptible to maternal mid-trimester anesthesia.197,198
thetic agents and subsequent functional impairment. Furthermore, isoflurane suppresses neurogenesis in
However, it is unclear whether these adverse outcomes rodents both in vitro as well as in vivo,199-201 causing a
result from the underlying disease, surgery, or anesthesia depletion of the neural stem cell pool. At least in vitro,
or a combination of these factors.187,189 A recent study this phenomenon appears to be dose dependent.201 At the
found evidence that repeated anesthesia exposures or a present time, the impact of reduced neurogenesis on
cumulative anesthesia exposure time greater than 2 hours behavioral deficits and the effect of anesthetic agents on
during early childhood was associated with a nearly neuronal migration remain unknown.
twofold increase in the incidence of learning disabilities When these studies are extended to the third trimes
and attention deficit hyperactivity disorder.189 Because ter, the results are mixed. In one rodent study, maternal
human synaptogenesis appears to begin during the third administration of 1.3% isoflurane for 6 hours during the
trimester, there is now serious concern that intrauterine third trimester had no effect on offspring neurodevelop
fetal exposure to these anesthetic agents may result in ment.202 However, these investigators performed another
similar functional impairment. Because there is no precise dose-response study in term rodents and found that
way to monitor human fetal brain development in utero, maternal administration of 3% isoflurane, but not 1.3%
206 PART III Fetal and Neonatal Assessment and Therapy
Birth
Rodent
0d 7d 14 d 22 d 14 d
Primate
0d 40 d 100 d 165 d 60 d
Human
0w 12 w 28 w 40 w 3y
FIGURE 10-5 ■ Time lines of major neurodevelopmental events in utero in rodents, nonhuman primates, and humans. Events are as
marked in the figure legend (d, days; w, weeks; y, years). Synaptogenesis is predominantly a postnatal event in rodents, unlike that
in primates and humans. (From Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth 2012; 21:152-62.)
McGowan and Davis205 affirmed the U.S. Food and brain.213 In particular, allopregnanolone has been shown
Drug Administration’s (FDA) conclusion207 that cur to exert neuroprotective effects in the fetal brain (see later
rently, “there [is] no scientific basis to recommend discussion).214
changes in clinical [anesthesia] practice.” They noted that
the “real enemy” includes “known and understood causes Humoral Mechanisms
of brain injury and death,” such as hypoxia and cardio
vascular collapse. They cautioned, “[W]e must not let our Published studies have extensively investigated the intri
enthusiasm for understanding the possible neurocogni cate and symbiotic relationship between the fetus and
tive risks of anesthetics … obscure our awareness of this maternal hormones throughout pregnancy. Much of our
enemy or prevent us from alleviating pain.”205 The FDA’s understanding comes from elaborate murine and primate
position was reaffirmed in March 2011.208 research models in which changes in maternal levels of
hormones closely parallel changes in the fetal plasma
and/or brain. Throughout pregnancy, there is a gradual
Fetal Neuroprotection rise in the levels of many maternal hormones such as
Throughout gestation, the fetus remains concealed, pro progesterone, estradiol, and oxytocin.215-217 At term or
tected, and nourished by a combination of maternal ana during labor the levels of these hormones are 40- to 100-
tomic and physiologic factors. For example, the amniotic fold higher than in the nonpregnant state.
fluid cushions the fetus against trauma, and the placenta Many of these hormones freely cross the placenta and
serves as a conduit to ensure a continuous supply of are transported to the fetal brain, where they profoundly
maternal nutrients to the developing fetus. Despite these influence neurodevelopment. For example, estradiol and
inbuilt protective mechanisms, the fetus remains vulner progesterone influence neural stem cell proliferation,
able to maternal insults such as infection and fever, drugs, modulate apoptosis and synaptogenesis in a region-
and acute changes in placental physiology. Among all specific manner, alter subcellular signaling mechanisms,
organ systems, the developing central nervous system and promote dendritic growth and spinogenesis through
appears to be most susceptible to such insults. Under specific receptor mechanisms.215,216 Estradiol, in particu
standing the developmental aspects of neuroprotective lar, prevents cell death in both neuronal and non-neuronal
mechanisms will therefore enable generation of targeted cell lines.
neuroprotective therapies. Maternal plasma oxytocin levels gradually increase
during pregnancy and reach a peak during the second
stage of labor. Oxytocin is of particular importance because
Role of the Placenta
it has significant effects on GABAergic signaling in fetal
One of the fundamental neuroprotective mechanisms is neurons. In a series of elegant experiments, investigators
the barrier function of the placenta. The placenta serves showed that oxytocin transiently switched the action of
as a conduit for chemical communication between the GABA on immature rodent fetal neurons from depolariz-
mother and the developing fetus; endocrine signals, ing to hyperpolarizing at term gestation.218 This finding
growth factors, and cytokines freely traverse the placenta, raises the possibility that oxytocin protects the fetal brain
which dynamically adapts to chronic changes in the during the stressful process of labor and delivery.219
maternal-fetal environment to preserve fetal growth and
viability.209,210 However, this function also allows transpla
cental transfer of an array of pharmacologically active NEUROPROTECTIVE THERAPIES
molecules either by passive diffusion or active trans
port.211 By virtue of its enzymatic machinery, the placenta Magnesium Sulfate and Cerebral Palsy
is capable of detoxification of some of these potentially
harmful chemicals, making it the first line of defense Until recently there was considerable controversy re
against potentially harmful environmental agents. garding the role of magnesium sulfate in preventing or
Although passive diffusion along a concentration gra possibly exacerbating fetal brain injury. Although some
dient is the most widely studied placental transport controversy remains, the publication of several large ran
mechanism, recent studies have elucidated the roles domized studies of the effect of antenatal maternal mag
of two important active transport molecules in the syn nesium sulfate administration on offspring outcome has
cytiotrophoblast, which actively extrudes xenobiotics: dramatically altered practice guidelines and clinical
phospho-glycoprotein (P-gp) and breast cancer resis practice.220-222 Although none of these studies demon
tance protein (BRCP).212 The activity of these transport strated significant improvement in the primary outcome,
ers varies with gestational age and certain pathophysiologic all showed reduced cognitive morbidity and none showed
conditions (e.g., preeclampsia, intrauterine infection) and any increase in pediatric morbidity or mortality associ
is influenced by the steroid hormones of pregnancy. ated with magnesium sulfate use for neuroprotection.
Thus, it is possible that placental permeability to certain In a placebo-controlled trial of women who were
drugs could depend on a complex interplay of several thought likely to deliver within 24 hours and before 30
factors. In addition to this barrier function, the human weeks’ gestation in New Zealand and Australia, Crowther
placenta secretes estrogen and progesterone in very high et al.220 reported a lower incidence of substantial gross
concentrations; these hormones, as well as others, even motor dysfunction (3.4% versus 6.6%; relative risk [RR],
tually enter the fetal circulation, where they serve as 0.51; 95% CI, 0.29 to 0.91) and combined death or sub
substrates for de novo neurosteroid synthesis in the fetal stantial gross motor dysfunction (17% versus 22.7%; RR,
208 PART III Fetal and Neonatal Assessment and Therapy
0.75; 95% CI, 0.59 to 0.96) in children whose mothers the loss of striatal neurons and oligodendroglia. This
were randomized to receive antenatal magnesium sulfate finding was associated with improved basal ganglia func
treatment. In another large trial from France, which tion after ischemia.
included women in preterm labor before 33 weeks’ gesta These and other experimental results prompted a
tion, a significant reduction in death and/or gross motor randomized clinical trial of whole-body hypothermia for
dysfunction was again identified in the children whose neonates with hypoxic ischemic encephalopathy.227 Eli
mothers received magnesium sulfate (25.6% versus gible neonates were older than 36 weeks’ gestational age,
30.8%; OR, 0.62; 95% CI, 0.41 to 0.99).221 A reduction had moderate or severe encephalopathy, and were admit
in death and/or motor or cognitive dysfunction (34.9% ted to the neonatal intensive care unit within 6 hours of
versus 40.5%; OR, 0.68; 95% CI, 0.47 to 0.99) was birth. Body temperature was lowered to 33.5° C for 72
observed in the magnesium-exposed offspring at 2 years hours in neonates randomized to hypothermia treatment.
of age.221 Finally, a randomized, controlled multicenter Death or moderate to severe disability at 18 to 22 months
trial in the United States found that fetal exposure to of age occurred in 44% of 102 infants in the hypothermia
magnesium sulfate within 24 hours of preterm delivery group, compared with 62% of 106 infants in the control
(between 24 and 32 completed weeks’ gestational age) did group (risk ratio, 0.72; 95% CI, 0.54 to 0.95; P = .01).
not reduce the combined risk for moderate or severe Although encouraging, these results are at odds with
cerebral palsy or death. However, fetal exposure to mag those from another large multicenter randomized trial.228
nesium sulfate reduced the risk for moderate or severe In an editorial attempting to reconcile these opposing
cerebral palsy among survivors (1.9% versus 3.5%; RR, results, several possible explanations were suggested.229
0.55; 95% CI, 0.32 to 0.95) and was associated with a Importantly, in the study that demonstrated no benefit,
decreased overall rate of cerebral palsy (4.2% versus cooling began later and more time was required to achieve
7.3%; P = .004).222 complete cooling, because head (not total body) cooling
Although the results are optimistic, it is difficult to was employed.228 Moreover, the study that showed no
compare these trials owing to differences in inclusion benefit with hypothermia may have included infants who
criteria, study interventions/dosages, and outcomes. were so severely affected that no therapy would have been
Nonetheless, after the publications of these trials, it has beneficial.228 This possibility highlights the importance
been concluded from meta-analyses that fetal exposure to of patient selection in these clinical trials.
magnesium sulfate may reduce the risk for cerebral palsy In 2012, the whole-body hypothermia investigators
without increasing the risk for neonatal death.223,224 published the results of follow-up evaluations of the orig
In 2010, the ACOG and the SMFM released a joint inal study subjects at 6 to 7 years of age. There was no
committee opinion that supported antenatal maternal difference in the combined primary outcome of death or
magnesium sulfate administration for fetal neuroprotec an IQ score less than 70 (47% versus 62%, P = .06)
tion, stating that the available evidence suggests that mag between the hypothermia group and the control group.230
nesium sulfate administered before anticipated early The hypothermia group had a lower incidence of death
preterm birth reduces the risk for cerebral palsy in surviv or severe disability (41% versus 60%, P = .03), but there
ing infants.225 Physicians electing to use magnesium was no difference in moderate or severe disability (35%
sulfate for fetal neuroprotection should develop specific versus 38%, P = .87). Attention-executive dysfunction
guidelines regarding inclusion criteria, treatment regi occurred in 4% of the hypothermia group versus 13% of
mens, concurrent tocolysis, and monitoring. The ACOG the usual care group (P = .19), and visuospatial dysfunc
and the SMFM have concluded that it is reasonable to tion occurred in 4% of the hypothermia group versus 3%
use a protocol based on one of the large randomized of the usual care group (P = .80).230 Thus, although there
trials220-222; magnesium sulfate should be offered to women was no significant difference in the primary outcome,
at high risk for anticipated preterm delivery (< 28 to 32 whole-body hypothermia decreased the incidence of
weeks’ gestational age) within 24 hours.220-222 A loading death and did not increase the rate of a low IQ score or
dose of magnesium sulfate 4 to 6 g should be adminis severe disability among survivors.
tered, followed by a maintenance infusion of 1 to 2 g/h for A 2013 meta-analysis of 11 randomized controlled
12 to 24 hours, at which point the risk for impending trials of hypothermia therapy, which included 1505 term
preterm delivery should be reassessed. If there is no longer and late preterm infants, concluded that the benefits
a concern for impending delivery, the magnesium sulfate of cooling on survival and neurodevelopment outweigh
should be discontinued and restarted with active labor or the short-term adverse effects.231 The authors advised
when delivery is again thought to be imminent. that hypothermia should be instituted in term and late
preterm infants with moderate-to-severe hypoxic isch
emic encephalopathy if identified before 6 hours of age.
Hypothermia Further trials are necessary to identify appropriate cooling
Some investigators have described improved outcomes techniques and to refine patient selection.
after the use of hypothermia in neonates at risk for
hypoxic ischemic encephalopathy. One group of investi
gators has described an experimental model of severe
Experimental Neuroprotection
intrauterine hypoxia in preterm fetal sheep, in which Perlman232 has reviewed various strategies for treating
asphyxia was produced by 25 minutes of complete umbil hypoxic-ischemic neonatal injuries, including administra
ical cord occlusion.226 Cerebral hypothermia (fetal extra tion of inflammatory mediator modulators, excitatory
dural temperature reduced from 39° to 29° C) decreased amino acid receptor agonists and antagonists, free radical
10 Fetal and Neonatal Neurologic Injury 209
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PA RT I V
FOUNDATIONS IN
OBSTETRIC
ANESTHESIA
Donald Caton, M.D.
As Simpson predicted, physicians used obstetric anesthe- intravenous opioids. They also performed many impor-
sia sparingly until patients forced the issue. A major tant studies on the use of regional anesthesia.
impetus came from early feminists. Suffragettes recog- For obstetricians, regional anesthesia had several
nized that they could not participate fully in the eco- advantages. First, it appeared to be safe and easy to
nomic and political life of the country unless they administer, a feature that was especially important because
were healthy. For this reason they made obstetric care, qualified anesthesiologists were in short supply. Second,
including anesthesia, part of their campaign for political regional anesthesia allowed obstetricians to make more
parity. liberal use of operative techniques for vaginal delivery
Early feminists had good reason to be concerned (e.g., episiotomy, use of forceps), which were just coming
about obstetric care. Despite many improvements in into vogue. No less important, regional anesthesia
medicine, maternal morbidity and mortality hardly appeared to satisfy the desires of women who wanted
changed between 1830 and 1930. Women were debili- more comfortable deliveries. These motives prompted
tated by the sequelae of poorly managed deliveries and the use of various regional blocks, including presacral,
exhausted by frequent pregnancies and management of paravertebral, spinal, lumbar epidural, and caudal epidu-
large families. Accordingly, feminists sought care by ral anesthesia. In conjunction with this clinical work,
obstetricians rather than by midwives, deliveries in hos- scientists studied the anatomy and physiology of uterine
pitals rather than at home, and adequate time for recu- function and childbirth pain, including the neurologic
peration before returning to their normal responsibilities. pathways involved in the perception of childbirth pain.
Other initiatives were construction of special maternity Our current practices of obstetric anesthesia, particularly
units, better instruction in obstetrics in medical schools, the emphasis on regional anesthesia, are a direct out-
and training of more obstetricians. growth of scientific studies and clinical trials that began
They also campaigned for obstetric anesthesia. during this period.1-4
Feminists and physicians alike believed that the pain of
childbirth, in and of itself, contributed to the disability REFERENCES
of women later in life. To improve the quality and avail- 1. Loudon I. Oxford: Clarendon Press, 1992: 172-233, 216-32,
220-3.
ability of anesthesia, feminists founded two organiza- 2. Barnett R. “The future of the midwife depends on her power to
tions: The National Twilight Sleep Association began in relieve pain”: the rise and fall of the Analgesia in Childbirth Bill
the United States just before the beginning of World War (1949). Int J Obstet Anesth 2007; 16:35-9.
I, and the National Birthday Trust Fund started in Great 3. Lewis J. Mothers and maternal policies in the twentieth century. In
Britain in 1928. Garcia J, Kilpatrick R, Richards M, editors. The Politics of Mater-
nity Care: Services for Childbearing Women in Twentieth-Century
Both organizations influenced the practice of obstetric Britain. Oxford: Clarendon Paperbacks, 1990:15-29.
anesthesia. Physicians explored new ways to manage the 4. Caton D. A century of spinals for childbirth. Int J Obstet Anesth
pain of childbirth, including the use of rectal ether and 2000; 9:149-50.
C H A P T E R 1 1
CHAPTER OUTLINE
FIGURE 11-2 ■ “Swiss cheese” diagram of near-miss event illustrating how numerous layers/barriers to harm were breached and
how these events almost resulted in permanent harm (permanent sterility) to the patient. See text for explanation.
sleep deprivation, there are no such limits on attending 5. Improve communication with patients.
physician work hours. Rothschild et al.11 found that the 6. Establish a partnership with patients to improve
risk for surgical complications was increased if attending safety.
physicians had slept less than 6 hours the night before 7. Make safety a priority in every aspect of practice.
the procedure. The IOM has defined medical error as a “failure of
Another ACOG committee opinion12 stated that pro- a planned action to be completed as intended, or the use
moting safety requires that all those in the health care of a wrong plan to achieve an aim.” Communication
environment recognize that the potential for errors exists problems are consistently identified as a leading cause of
and that women’s health care should be delivered in an medical errors in obstetrics,13 and the Joint Commission
environment that encourages disclosure and exchange of has found that although the majority of these events have
information in the event of errors, near misses, and multiple root causes, lack of effective communication
adverse outcomes. The ACOG12 has recommended the along with leadership and human factors are often the
following seven safety objectives: primary causes of sentinel events.14 Several of the 2012
1. Develop a commitment to encourage a culture of Joint Commission National Patient Safety Goals relate
patient safety. to error reduction on the labor and delivery unit (Box
2. Implement recommended safe medication 11-1).15 Departments of anesthesiology and obstetrics
practices. and gynecology should regularly review the national
3. Reduce the likelihood of surgical errors. patient safety goals established by the Joint Commission.
4. Improve communication with health care Hospitals are regularly surveyed to verify their compli-
providers. ance with these goals.
220 PART IV Foundations in Obstetric Anesthesia
Key Joint Commission National can significantly improve patient safety. Pronovost and
BOX 11-1 Freishlag19 eloquently described the operating room
Patient Safety Goals: 2012
environment when they stated that “operating rooms are
• Identify patients correctly (NPSG.01.01.01). among the most complex political, social, and cultural
• Use at least two patient identifiers when providing structures that exist, full of ritual, drama, hierarchy, and
care. too often conflict.” These authors concluded that poor
• Improve staff communication. Report critical results of teamwork contributes prominently to most adverse
tests and diagnostic procedures on a timely basis events, including those in the operating room.19
(NPSG.02.03.01).
• Get important test results to the right staff person
on time.
• Label all medications, medication containers, and
TEAMS AND TEAMWORK
other solutions on and off the sterile field in periopera-
tive and other procedural settings (NPSG.03.04.01). Health care should be considered a team activity. Teams
• Before a procedure, label all medications. take care of patients. Furthermore, health care teams
• Maintain and communicate accurate patient medica- operate in an environment characterized by acute stress,
tion information (NPSG.03.06.01). heavy workload, and high stakes for decision and action
• Obtain information on the medications the patient errors.20 Individuals have limited capabilities; when their
is currently taking when he or she is admitted. limitations are combined with organizational and envi-
• Compare the medication information the patient ronmental complexity, human error is virtually inevita-
brought to the hospital with the medications ordered ble.21 The labor and delivery unit is an exceedingly
for the patient by the hospital to identify and resolve
discrepancies.
complex environment. In fact, the labor and delivery unit
• Implement evidence-based practices for preventing requires intense, error-free vigilance with effective com-
surgical site infections (NPSG 07.01.01). munication and teamwork among various clinical disci-
• Use hand cleaning guidelines from the Centers for plines who, although working together, have probably
Disease Control and Prevention or the World never trained together. This group includes obstetricians,
Health Organization. Set goals for improving hand midwives, nurses, anesthesiologists and nurse anesthe-
cleaning. Use the goals to improve hand cleaning. tists, and pediatricians. The addition of trainees at all
• Prevent mistakes in surgery (UP.01.01). levels and in all disciplines enhances the potential for
• Make sure that the correct surgery is done on the communication error. Siassakos et al.22 suggested that
correct patient and at the correct place on the one of the most important components of effective train-
patient’s body.
• Pause before the surgery to make sure that a mistake
ing in obstetrics includes multiprofessional training and
is not being made. integration of teamwork training with clinical teaching.
A team consists of two or more individuals who have
NPSG, National Patient Safety Goal; UP, Universal Protocol. specific roles, perform independent tasks, are adaptable,
Summarized from the Joint Commission 2012 National Patient Safety and share common goals. Salas et al.23 have defined
Goals. Available at http://www.jointcommission.org/standards_ teamwork as a complex yet elegant phenomenon. It can
information/npsgs.aspx. Accessed November 2012.
be defined as a “set of interrelated behaviors, actions,
cognitions, and attitudes that facilitate the required task
work that must be completed.”23 Lack of teamwork has
been identified as a leading cause of adverse events in
Although those working in health care have made medicine. Team behavior and coordination, particularly
great efforts to reduce preventable patient harm,16 the communication or team information sharing, are critical
progress has not been as dramatic as necessary. Leape and for optimizing team performance.24 Baker et al.25 stated
Berwick, two “fathers” of the field of patient safety, sug- that to work together effectively, team members must
gested that the lack of progress following the release of possess specific knowledge, skills, and attitudes (KSAs),
the initial IOM report is due to the “culture of medi- including skill in monitoring each other’s performance,
cine.”17 They believe that this culture is deeply rooted, knowledge of their own and their teammates’ task respon-
both by custom and training, in autonomous individual sibilities, and a positive disposition toward working in a
performance. It remains possible that systematic and team. These authors have described characteristics of
appropriate use of medical simulation, along with other effective teams, which include team leadership, mutual
important changes to our systems, will facilitate the nec- performance monitoring, backup behavior, adaptability,
essary cultural changes and lead to improved patient shared mental models, communication, team/collective
safety. Labor and delivery units are no different than orientation, and mutual trust. Moreover, effective team
other medical care environments, and most still have performance in complex environments requires that team
many opportunities to change culture and practice to members hold a shared understanding of the task, their
optimize patient safety. Nabhan and Ahmed-Tawfik18 equipment, and their teammates (Table 11-1).26,27
suggested that the concept of patient safety in obstetrics Teamwork is essential for safe patient care. The IOM
is “not as strong as desirable for the provision of reliable suggested that team training and implementation of team
health care.” In many units a punitive culture still exists behaviors may improve patient safety.28 The Joint Com-
and results in suppression of error reporting, lack of mission has recommended a risk-reduction strategy for
proper communication, and failure of appropriate feed- decreasing perinatal death or injury. This strategy
back.18 Obviously, this culture needs to change before we includes the implementation of team training and mock
11 Patient Safety and Team Training 221
Feedback
FIGURE 11-3 ■ Adaptive team performance. (Modified from Salas E, Rosen MA, Burke CS, et al. The making of a dream team: when expert
teams do best. In Ericsson KA, Charness N, Hoffman RR, Feltovich RJ, editors. The Cambridge Handbook of Expertise and Expert Perfor-
mance. Cambridge, UK, Cambridge University Press 2006:439-456.)
leadership, followership, closed-loop communication, medical students, residents, attending physicians, nursing
critical language, standardized practice, assertive com- students, nurses, and midwives rarely learn or train to
munication, adaptive behaviors, and workload manage- work as teams.
ment. An adaptive team performance framework that The Liaison Committee on Medical Education
illustrates the relationship between variables, emergent (LCME), which is jointly composed of members of the
states, and the multiple phases of the team adaptation American Medical Association and the Association
cycle has been described by Salas et al.40 (Figure 11-3). of American Medical Colleges, has affirmed the impor-
Cultural factors may play a large role in team perfor- tance of teaching communications skills and teamwork.
mance. According to Salas et al.,27 these factors include For example, LCME standard ED19 states that “there
attitudes (especially as they relate to previous experiences must be specific instruction in communication skills as
with teams) and motivation. Although it has been sug- they relate to professional responsibilities, including
gested that an individual team member’s personality may communication with patients, families, colleagues, and
be counterbalanced by others, Janis41 suggested that other health professionals.”46 Teamwork needs to be not
openness, conscientiousness, and neuroticism are essen- only taught but also monitored. Box 11-2 summarizes
tial for individuals to succeed in command positions. best practices in team performance measurement for
Thomas et al.42 conducted a qualitative assessment of simulation-based training.
teamwork and suggested that factors that influence the Why is teamwork training important for labor and
ability to work together could be divided into three cat- delivery unit personnel? As previously noted, communi-
egories: provider characteristics (personal attributes, cation problems are consistently identified as a leading
reputation, expertise), workplace factors (staffing, work cause of medical error, and these problems can be
organization, work environment), and group influences addressed during team training. The 2000-2002 Confi-
(communication, relationships, and teamwork). These dential Enquiries into Maternal Deaths in the United
categories can be addressed, at least in part, by working Kingdom emphasized that “emergency drills for mater-
together in teams in a simulated environment and evalu- nal resuscitation should be regularly practiced in clinical
ating teamwork and human performance. Lyndon43 sug- areas in all maternity units.”47 That report listed six direct
gested that the application of human performance-based maternal deaths plus one late maternal death due to anes-
theory has demonstrated that “communication patterns, thesia. Esophageal intubation was the cause of three
team function, workload, and coping mechanisms affect maternal deaths. Each of these cases involved a trainee
both individual and group ability to identify evolving without immediate senior backup; and in two cases, cap-
problems and make appropriate management decisions nography was not used, which was in direct violation of
in complex decision-making situations.”43 mandatory monitoring requirements. In an accompany-
ing editorial, Ngan Kee48 stated, “This should give pause
for thought to all involved with training in obstetric anes-
Team Training thesia” [italics added].48 These reports remind us not only
Patient safety is “predicated on trust, open communica- of the need for appropriate supervision of trainees but
tion, and effective interdisciplinary teamwork.”44 It is also of the need to use simulation-based training for
often the interactions among health care workers that learning and practicing both crisis management and
determine whether a specific plan of care is effective or important techniques and procedures that are not fre-
ineffective.45 However, in the current environment quently encountered in clinical practice. Emergency
11 Patient Safety and Team Training 223
the obstetric service? The following case report by Sachs64 5. CRM training is designed systematically.
illustrates the need: 6. CRM is part of a learning organization’s strategy
A healthy 38-year-old woman needed emergency to promote patient safety and quality care.
cesarean delivery after a failed instrumental delivery. 7. Teamwork is rewarded and reinforced by the
At surgery, the uterus was found to be ruptured and health care provider.
the fetus was stillborn. After unsuccessful attempts 8. CRM training is evaluated at multiple levels for
to repair the uterus, the patient underwent a cesar- specific outcomes.
ean hysterectomy and required massive transfusion 9. CRM is supported by simulation or practice-based
and a 3-week hospital stay. approaches.
Was anyone at fault? According to the root cause 10. The health care provider is “ready” to receive
analysis, lack of teamwork on many levels played a sig- training.
nificant role in this patient’s hospital course. In particular, 11. The patient is part of the team.
Sachs64 reported that communication was poor and there 12. The team training is recurrent.
was a lack of mutual performance cross-monitoring, Some health care providers will benefit more than
inadequate conflict resolution, suboptimal situational others from CRM training and learning. For example,
awareness, and work overload. one study noted that physicians with poorer performance
at the beginning of CRM training showed greater
improvements after training.71
Crew Resource Management
Although relatively new to obstetrics, team drills have Disruptive Behavior
been successfully used in other areas of medicine, includ-
ing anesthesia, intensive care, and emergency medicine, Whereas miscommunication is common on the labor and
often using lessons learned from crew resource manage- delivery unit, some events are not caused by difficulties
ment (CRM) training. The human error aspects of many with communication but rather result from disruptive
air crashes are thought to include failure of communica- behavior by a team member. It is estimated that 3% to
tion, decision making, and leadership.65 In the airline 5% of physicians exhibit disruptive behavior.72 Disruptive
industry, CRM began as a program to train pilots to and intimidating behavior occurs frequently on labor and
reduce error by making better use of human resources delivery units and is observed in personnel of diverse
in the cockpit.66 CRM training has led to safety and per- disciplines, including obstetricians, anesthesia providers,
formance improvements beyond those produced by family practitioners, pediatricians, nurses, midwives, and
improvements in equipment and technology.5,65 administrators. In one survey, disruptive behavior was
Airlines use many tools to reduce human error; CRM reported on more than 60% of labor and delivery units
training is just one. Other tools include use of checklists, from personnel who responded to a questionnaire.73
standardized maintenance, ability to report errors without Disruptive behavior includes angry outbursts, rude-
disciplinary repercussions, and simulator training. Not all ness or verbal attacks, physical threats, intimidation,
of these, however, are easily adaptable to medicine. That noncompliance with policies, and sexual harassment. Dis-
said, Helmreich67 identified several lessons learned from ruptive behavior contributes to the nursing shortage,
CRM that can be applied to the practice of medicine. He near misses, and adverse occurrences. This behavior does
believes that errors in competence require technical not always involve physicians. Termed horizontal hostility,
training and that errors in decisions or communication it occurs among nurses as well, and includes rudeness,
require team training. Furthermore, Helmreich67 sug- verbal abuse, humiliating statements, unjustly critical
gested that adaptation of CRM to health care similarly statements, withholding information, and gossip.74 Dis-
requires the development of nonpunitive methods to ruptive behavior is not always effectively managed by
collect information on errors so that this information can the organization73 and should be considered when using
be used to evaluate team performance. It has been sug- simulation to improve team behaviors.
gested that elements of CRM that are useful in medical
settings include briefings, conflict resolution procedures, Options for Simulator Training in Obstetrics
and performance reviews.23 There is evidence that opera-
tor attitudes about teamwork, hierarchy, errors, and stress Both high-technology and low-technology approaches to
affect performance among aviators working together in simulation have been used for training labor and delivery
teams.68 Evidence also suggests that these attitudes are staff.54 Simulation centers often use high-fidelity simula-
relevant in the health care environment.69 tion with interactive computerized mannequins in a real-
Salas et al.70 suggested that CRM training will not be istic working environment (e.g., labor room or operating
effective or achieve its desired outcomes in health care room) that includes a full complement of working equip-
without the following 12 prerequisites: ment and staff.75 The mannequin is quite realistic; it has
1. The physicians must be “on board.” a pulse, heart and breath sounds, ventilatory movements,
2. The concept of teamwork becomes part of the and electrocardiographic and pulse oximetry tracings. All
“DNA” of the health care professional. vital signs can be adjusted via computer control, as can
3. CRM is supplemented by other teamwork-focused the ability to intubate or ventilate.75
training strategies. Not all simulation exercises and drills for obstetrics
4. The design, development, and delivery of CRM need to be performed in high-fidelity simulators. Some
are scientifically rooted. authors76 have argued that classroom training is a better
226 PART IV Foundations in Obstetric Anesthesia
option, particularly given the high cost77 and resources communication and allow recognition of potential areas
necessary for high-fidelity simulation. The inability to of weakness in obstetric care. We, as well as others,25,38,87
arrange for staff of several disciplines to be absent from believe that these are viable strategies to mitigate medical
the labor and delivery unit simultaneously often pre- errors. We also agree with Pearlman et al.,88 who stated
cludes the use of high-technology simulation and may that “we have the moral imperative as a specialty to fully
make on-site exercises more practical.54 engage in the identification of our own best practices, to
On the other hand, Gaba78 has countered that high- advance safety research in obstetrics and gynecology, and
fidelity simulation need not be cost-prohibitive and that to implement broadly those practices which are best.”
it provides the required “real-life” experience necessary In addition to better communication, team training,
for training in the management of complex real-life sce- and simulation-based education, several other changes to
narios. Morgan et al.79 reported an obstetric simulation our cultures and systems need to occur in order to sig-
model that included the participation of real surgeons nificantly improve patient safety on the labor and delivery
(rather than actors playing the role of surgeons). This was unit. These changes include:
the first published report of high-fidelity simulation of • Learning from our mistakes
obstetric team performance with anesthesia providers, • Changing the culture on the labor and delivery floor
nurses, and obstetricians involved in the hands-on man- to one of a “just culture”89
agement of obstetric crises. • Having buy-in and support from hospital leadership
Several options are available for teaching teamwork to implement the necessary changes
and crisis intervention in obstetrics. Multidisciplinary • Improving the care of the high-risk parturient so
obstetric simulated emergency scenarios (MOSES) was that every member of the team is more prepared and
developed by the St. Bartholomew Hospital Group in the working as a team member90
United Kingdom80 and involves participation of obstetri- • Improving and automating the collection of quality
cians, anesthesia providers, and midwives in team train- metrics, collecting appropriate data on outcomes,
ing on a high-fidelity simulator. MedTeams was developed and sharing the data with practitioners on a regular
by the U.S. Armed Forces and Dynamics Research Cor- basis91
poration. Originally employed in emergency depart- • Developing and implementing systems to reduce
ments,65,81,82 it has now been used for labor and delivery drug administration errors92,93
teams.33 The course consists of “train the trainer” ses- • Tearing down the silos so that we learn from
sions that focus on seven dimensions that are essential to each other’s mistakes and improvement processes,
teamwork. Behaviorally anchored rating scales (BARS) whether from department to department, hospital
are used to assess various key behaviors. Additionally, in to hospital, or country to country93
a 2006 review, Harris et al.83 discussed the challenges of The challenge for the next decade will be to implement
implementation of team training in an obstetric care these changes and test their effectiveness in improving
environment. patient safety.
Other evidence-based programs have emerged. Team-
STEPPS was developed by the U.S. Department of KEY POINTS
Defense and Agency for Healthcare Research and Quality
(AHRQ) as a team training and implementation toolkit.84 • Medical errors harm tens of thousands of
The program is adaptable, medically relevant, and based patients each year.
on findings from the science of team performance, and it • To err is human; therefore, systems should be
is applicable to training on labor and delivery units. developed to prevent or “catch” errors before
What is the evidence that team training and simula- the patient is harmed.
tion reduce errors and improve outcomes? Morey et al.65
reported that the MedTeams program reduced errors in • Poor communication among health care workers
the emergency department, and they observed a statisti- is the primary cause of sentinel events.
cally significant improvement in team behaviors. The • Teamwork is essential to safe patient care, and
clinical error rate in providers who received MedTeams team training may improve patient safety.
training decreased from 31% to 4%. Grunebaum et al.85 • Simulation-based training is an educational tool
implemented team training as well as other comprehen- that may improve responses to obstetric
sive patient safety changes to their obstetric practice and emergencies.
found that their interventions resulted in decreased com- • Adaptation of some elements of aviation crew
pensation payments and sentinel events. Clark et al.86 resource management training may improve
described implementation of a comprehensive redesign team performance in health care.
of patient safety processes that was associated with • Disruptive behavior interferes with safe patient
improved patient outcomes and a decline in litigation care and is observed in physicians as well as
rates. The authors of the report stressed that “every other members of the health care team.
member of the obstetric team should be not only empow-
ered but also required to intervene and halt any process
that is deemed to be dangerous.” This behavior can be REFERENCES
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11 Patient Safety and Team Training 227
2. Aiken LH, Clarke SP, Sloane DM, et al. Hospital nurse staffing and 29. The Joint Commission. Preventing infant death and injury during
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C H A P T E R 1 2
CHAPTER OUTLINE
The art and science of neuraxial anesthesia requires a body. The conus medullaris is attached to the coccyx by
thorough appreciation of neuroanatomy and the physi- means of a neural-fibrous band called the filum termi-
ologic effects imposed by medications commonly admin- nale, which is surrounded by the nerves of the lower
istered via the spinal and/or epidural route. The focus of lumbar and sacral roots, known as the cauda equina.
this chapter is to characterize the anatomic and technical Within the bony vertebral column are three membranes:
considerations for neuraxial anesthesia. The reader is the pia mater, the arachnoid mater, and the dura mater.
referred to Chapter 23 for a corresponding discussion of The pia mater is a highly vascular membrane that closely
the physiologic and untoward effects of neuraxial analge- invests the spinal cord. The arachnoid mater is a delicate,
sia in laboring women and to Chapter 26 for a discussion nonvascular membrane closely adherent to the third and
of neuraxial anesthesia for cesarean delivery. Successful outermost layer, the dura. The subarachnoid space,
administration and management of neuraxial anesthesia located between the pia mater and arachnoid mater, con-
requires well-developed technique moderated by sound tains (1) cerebrospinal fluid (CSF), (2) spinal nerves,
clinical judgment. (3) a trabecular network between the two membranes,
(4) blood vessels that supply the spinal cord, and
(5) lateral extensions of the pia mater—the dentate liga-
ANATOMY ments. The dura mater is a membrane composed of col-
lagen that encapsulates the spinal cord, the deeper
Neuraxial Anatomy meningeal layers, and the subarachnoid space. This layer
forms a connective tissue sheath along the vertical axis
The Spinal Cord, Spinal Canal, and Meninges
of the central nervous system (CNS) that is contiguous
The cephalad aspect of the spinal cord is continuous with with connective tissue covering the lateral extension of
the brainstem through the foramen magnum. The spinal spinal nerve roots as they exit the intervertebral foramina.
cord most often terminates as the conus medullaris at the The interface between the dural and arachnoid layers has
level of the lower border of the first lumbar vertebral been described as a potential space capable of expansion
229
230 PART IV Foundations in Obstetric Anesthesia
Epidural
Conus L1 space
medullaris
L2
Cauda
equina
L3
Ligamentum
flavum
Dura L4
mater
Epidural Ligamentum
space flavum
L5
Distal
dural sac B
S1
Internal filum
terminale S2
FIGURE 12-2 ■ A, Sagittal section of the epidural space demon-
strates that the contents of the epidural space depend on the
level of the section. B, Three-dimensional drawing of the epidu-
ral space shows the discontinuity of the epidural contents.
However, this potential space can be dilated by the injection of
fluid into the epidural space. (Redrawn from Stevens RA. Neur-
axial blocks. In Brown DL, editor. Regional Anesthesia and Analge-
sia. Philadelphia, WB Saunders, 1976:323).
Dura mater
Epidural space
Ligamentum flavum
Interspinous ligament
Supraspinous ligament
from the external occipital protuberance to the coccyx), and vena caval compression result in engorgement of the
subcutaneous tissue, and skin. Historically, some have epidural veins. Unintentional intravascular epidural cath-
described the ligamentum flavum as a single ligament. In eter cannulation and injection of local anesthetic are
actuality, however, it is composed of two curvilinear liga- more common in pregnant patients than in nonpregnant
ments that join in the middle and form an acute angle patients. In addition, the vertebral foraminal veins, which
with a ventral opening.3,6 Much like the epidural space, are contiguous with the epidural veins, are enlarged and
the ligamentum flavum is not uniform from skull to obstruct one of the pathways for anesthetic egress from
sacrum; indeed, it is not uniform even within a single the epidural space during administration of epidural
intervertebral space. The thickness of the ligamentum anesthesia. The enlarged epidural veins also may displace
flavum varies with vertebral level, body mass index, and CSF from the thoracolumbar region of the subarachnoid
age, as does the distance between the skin and the epidu- space, as does the greater intra-abdominal pressure of
ral space (Table 12-1).7,8 pregnancy; this displacement partly explains the lowered
dose requirement for spinal anesthesia in pregnant
women.9 Subarachnoid dose requirements are also
Anatomic Changes of Pregnancy affected by the lower specific gravity of CSF in pregnant
The normal anatomic changes of pregnancy affect the use patients than in nonpregnant patients.10
of neuraxial anesthesia techniques. Uterine enlargement The hormonal changes of pregnancy affect the peri-
vertebral ligamentous structures, including the ligamen-
tum flavum. The ligamentum flavum may feel less dense
and “softer” in pregnant women than in nonpregnant
TABLE 12-1 Distance from the Skin to the patients; thus, sensing the passage of the epidural needle
Epidural Space in 1000 Parturients through the ligamentum flavum may be more difficult. It
Distance (cm)
may also be more difficult for a pregnant woman to
Lumbar
achieve flexion of the lumbar spine. Progressive accen-
Interspace MEDIAN 5TH PERCENTILE 95TH PERCENTILE tuation of lumbar lordosis alters the relationship of
surface anatomy to the vertebral column. At least three
L1-2 4.23 3.12 6.33
changes may occur. First, a pregnant woman’s pelvis
L2-3 4.86 3.29 7.32
rotates on the long axis of the spinal column; thus, the
L3-4 4.93 3.57 7.44
line joining the iliac crests (Tuffier’s line) assumes a more
L4-5 4.78 3.25 6.75
cephalad relationship to the vertebral column (e.g., this
From Harrison GR, Clowes NWB. The depth of the lumbar imaginary line might cross the vertebral column at the
epidural space from the skin. Anaesthesia 1985; 40:685-7. L3 to L4 interspace rather than the L4 to L5 interspace).
232 PART IV Foundations in Obstetric Anesthesia
and motor function to the least extent. During spinal Suggested Resuscitation
anesthesia, local anesthetics act directly on neural tissue Equipment and Drugs That
in the subarachnoid space. Regression of anesthesia can BOX 12-1 Should Be Available During
be explained by the simple vascular uptake of local anes- Administration of Neuraxial
thetic from the subarachnoid space and spinal cord.14 Analgesia/Anesthesia
Epidural anesthesia has a much smaller zone of differen-
tial motor–sensory–sympathetic blockade; this difference DRUGS
suggests that the mechanism of epidural anesthesia must • Hypnotic-amnestic agents (propofol, ketamine, mid-
involve more than simple diffusion across the dura. For azolam)
many years, nerve fiber size was presumed to be the • Succinylcholine
primary determinant of susceptibility to local anesthetic • Ephedrine
blockade (i.e., smaller fibers are blocked more readily • Epinephrine
than larger fibers). However, later studies have shown • Phenylephrine
that the length of nerve fiber exposed to local anesthetic • Atropine
is as important as the size of the nerve fiber. Fink15 • Calcium chloride
hypothesized that the length of nerve fiber exposed to • Sodium bicarbonate
• Naloxone
local anesthetic affects the extent of the differential zone
of motor and sensory blockade. With spinal anesthesia, EQUIPMENT
the local anesthetic concentration required to block suf- • Oxygen source
ficient sodium channels to affect motor, sensory, and • Suction source with tubing and catheters
sympathetic function is less than that needed for the • Self-inflating bag and mask for positive-pressure ven-
better-protected nerves found in the epidural space; thus, tilation
a wider band of differential blockade occurs during spinal • Face masks
anesthesia than during epidural anesthesia. • Oral airways
The understanding of the mechanisms of spinal and • Laryngoscope and assorted blades
epidural anesthesia likely remains oversimplified. None- • Endotracheal tubes with stylet
• Eschmann stylet (bougie)
theless, it seems clear that spinal anesthesia results pri- • Qualitative carbon dioxide detector
marily from the effects of local anesthetic on the spinal
cord, whereas epidural anesthesia results from the effects
of local anesthetic on nerve tissue within both the epidu-
ral and subarachnoid spaces.
monitoring is necessary. The sensory level of analgesia
and the intensity of motor block are assessed after the
TECHNIQUE administration of the test and therapeutic doses of local
anesthetic. Subsequently, sensory level and motor block
Pre-procedural Considerations are assessed at regular intervals.
Neither the ASA nor the American College of Obste-
Monitoring
tricians and Gynecologists (ACOG) provides a specific
The American Society of Anesthesiologists (ASA) has recommendation as to whether continuous FHR moni-
published guidelines for administration of neuraxial anes- toring is necessary during performance of neuraxial anes-
thesia in obstetric patients (see Appendix A). Among thesia procedures. The ASA Task Force on Obstetric
other things these recommendations address (1) the Anesthesia16 has stated:
required presence of qualified anesthesia and obstetric
care providers, (2) immediate availability of resuscitation The fetal heart rate should be monitored by a qualified
medication and equipment (Box 12-1), (3) mandatory individual before and after administration of neuraxial
pre-procedural intravenous access, and (4) employment analgesia for labor. The Task Force recognizes that
and documentation of maternal vital signs and fetal heart continuous electronic recording of the fetal heart rate may
rate (FHR) monitoring. not be necessary in every clinical setting and may not be
During the initiation of neuraxial analgesia for labor, possible during initiation of neuraxial anesthesia.
all patients are monitored with an automatic blood pres-
sure cuff and a pulse oximeter to facilitate continuous The anesthesia provider cannot predict when hypoten-
assessment of the maternal heart rate and oxygenation. sion will occur during the administration of neuraxial
Maternal blood pressure is measured every 1 to 2 minutes anesthesia. In addition, there is concern that intrathecal
after the administration of the test and therapeutic doses administration of an opioid is associated with a higher
of local anesthetic for approximately 15 to 20 minutes, or incidence of nonreassuring FHR patterns than other
until the mother is hemodynamically stable. Subsequently neuraxial techniques (see Chapter 23).17 Thus, we believe
(during maintenance of neuraxial analgesia), maternal that continuous electronic FHR monitoring should be
blood pressure is measured every 15 to 30 minutes or performed both during (if possible) and after the admin-
more frequently if hypotension ensues. Continuous pulse istration of neuraxial analgesia in all laboring women. In
oximetry during maintenance analgesia is used in selected some cases, the mother’s position or maternal obesity
patients (e.g., patients with obstructive sleep apnea or precludes the use of an external Doppler device to
cardiovascular disease). Rarely, invasive hemodynamic monitor the FHR. In such cases (especially when there is
234 PART IV Foundations in Obstetric Anesthesia
concern regarding fetal well-being), it is helpful for the for informed consent, and they appreciate the opportu-
obstetric provider to place a fetal scalp electrode to nity to participate in decisions about their care.
monitor the FHR. Management of the pregnant patient occurs in a
unique clinical care environment in which the presence
of the patient’s spouse or family member must be
Informed Consent, Patient-Procedure Verification,
addressed. Most often, the dictates of local institutions
and Partner’s Presence
will establish whether a partner’s presence during neur-
Prior to initiation of neuraxial anesthesia, a pre-procedural axial labor analgesia is acceptable. However, hospital
verification process (i.e., “time-out”) is instituted as part policy may be vague enough that the discretion lies in the
of compliance with national patient safety recommenda- hands of the anesthesia provider. Intuition may suggest
tions from hospital accreditation organizations.18 The that a partner who remains present during the conduct
participation of the patient, the anesthesia care provider, of neuraxial analgesia may help alleviate the patient’s
and a third party such as a member of the nursing staff ongoing anxiety regarding the procedure. Conversely,
may lead to the discovery of concerns that should be the partner may be so apprehensive or disruptive that the
addressed before the initiation of neuraxial anesthesia. partner’s presence becomes counterproductive to the care
The risk of neuraxial procedures relates to (1) the physi- of the patient. Orbach-Zinger et al.24 randomized 84 nul-
cal instrumentation of the spinal axis and (2) physiologic liparous women to either presence or absence of their
changes associated with medication administration via partner during labor epidural catheter placement. Inter-
this anatomic route. Contraindications to needle or cath- estingly, patient and partner anxiety, as measured by a
eter placement include patient refusal or inability to validated anxiety questionnaire, were reduced when part-
cooperate, ongoing bleeding diathesis, infection either at ners were absent during the procedure.
the site of intended intervention or untreated systemic
blood-borne illness, and increased intracranial pressure Patient Positioning
predisposing to cerebral herniation. Contraindications to
injecting local anesthetics via the epidural or spinal route Pregnant women have an exaggerated lumbar lordosis,
include severe hypovolemia and allergy to local anesthet- and it is more difficult for them to flex the lumbar spine.
ics. It would be axiomatic that patient refusal presents an However, most pregnant women are young, and youth
absolute contraindication to an elective procedure. A usually allows sufficient flexibility to facilitate the inser-
thorough preoperative assessment of current fetal well- tion of a needle into the epidural or subarachnoid
being, maternal volume status, intrapartum systemic space. Whether the block is initiated in the lateral
opioid use, antibiotic administration for ongoing chorio- or sitting position is a matter of provider and patient
amnionitis or other infectious process, and a brief reitera- preference. Notable advantages of the lateral position
tion of known maternal disease states, including allergies, include (1) orthostatic hypotension is less likely and
will readily identify most of the major concerns that (2) the position often facilitates continuous FHR moni-
would render neuraxial anesthesia potentially hazardous. toring during placement of the epidural catheter. Vincent
The anesthesia provider should weigh the risks and ben- and Chestnut25 performed a study in which they observed
efits of neuraxial anesthesia for each patient. that neither the sitting nor the lateral position was
Informed consent should include a frank discussion consistently superior with regard to patient comfort.
about anesthetic procedures and risks. Surveys of post- However, pregnant women who preferred the left lateral
partum women have demonstrated that most parturients decubitus position weighed less and had lower body mass
want to know the possible complications of epidural indices than women who preferred the sitting position.
analgesia, even those that are rare.19,20 It is best to relay The sitting position is likely associated with a higher
this information before the onset of labor (e.g., during incidence of orthostatic hypotension and syncope.
antenatal classes),21 or early in the intrapartum period, However, the sitting position is preferred—and may be
although doing so is not always feasible. Some anesthesia required—in obese parturients, in whom identification
providers fear that distressed, desperate, or sedated par- of the midline is usually significantly easier in the
turients may not understand the discussion of anesthetic sitting position. Further, morbidly obese women may
procedures. However, adequacy of consent can be dem- experience hypoxemia when placed in the lateral decubi-
onstrated not only by documentation of information tus position.
provided to the patient but also by the lack of patient One study demonstrated a greater reduction in mater-
objection to a procedure and the cooperation provided nal cardiac output with maximal lumbar flexion in the
by the patient during the procedure.22 In a survey of lateral decubitus position than in the sitting position
North American anesthesiologists, Brull et al.23 found during identification of the epidural space in laboring
that a majority of clinicians did not disclose the most women.26 The researchers speculated that maximal
severe risks of central neuraxial anesthesia to their lumbar flexion in the lateral decubitus position results in
patients. Additionally, most anesthesiologists cited inac- concealed aortocaval compression. In contrast, they sug-
curate incidences of these complications. We do not find gested that the uterus falls forward (and thus does not
it difficult to explain the procedure and the risks of neur- cause aortocaval compression) when the patient assumes
axial analgesia to a laboring woman. The preanesthetic the sitting flexed position. They recommended that “the
evaluation allows the physician to communicate a sense tight fetal curl position be avoided,” especially when the
of concern and to demonstrate a commitment to the patient assumes the lateral decubitus position for identi-
patient’s care. Most laboring women understand the need fication of the epidural or intrathecal space.
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 235
Aortocaval compression must be avoided at all times. catheter (or perhaps an anatomic barrier within the epi-
The gravid uterus can occlude the inferior vena cava and dural space) than from patient position, particularly after
aorta when the parturient assumes the supine position.27-29 a bolus injection. Norris and Dewan34 observed that
This position may cause maternal hypotension30,31 and gravity did not augment the spread of anesthesia in
reduce uteroplacental perfusion,32 even in the absence of patients receiving epidural anesthesia for cesarean deliv-
anesthesia. Increased venous tone in the lower extremi- ery, and they concluded that posture does not need to be
ties helps overcome partial occlusion of the inferior vena manipulated to ensure adequate bilateral epidural anes-
cava in unanesthetized pregnant women. If maternal thesia. In at least two studies it was noted that the use
hydration is inadequate and if aortocaval compression is of the sitting position is not necessary for the develop-
not avoided, the onset of anesthesia-induced sympathetic ment of good sacral anesthesia when large volumes of
blockade may result in decreased venous return, cardiac epidural local anesthetic are given for cesarean deliv-
output, and uteroplacental perfusion.29 ery.34,36 However, Reid and Thorburn36 observed that use
Maternal position during placement of the epidural of the sitting position appeared to delay the spread of
catheter does not seem to affect the incidence of unin- anesthesia to the midthoracic dermatomes. In compari-
tentional dural puncture. However, adoption of the son with the bolus administration of epidural local anes-
lateral recumbent head-down position for epidural cath- thetic, the extent of blockade may be more gravity
eter placement may reduce the incidence of epidural dependent when the anesthetic is administered as a con-
venous puncture.33 tinuous infusion over a prolonged period.
When spinal or epidural anesthesia is performed with Some anesthesiologists contend that maternal position
the patient in a lateral position, the patient’s back should after epidural catheter placement affects the efficacy of
lie at, and parallel to, the edge of the bed, for at least two epidural analgesia, although this is a matter of some
reasons. First, the edge is the most firm section of the dispute. Beilin et al.37 observed that the placement of the
mattress. If the patient lies away from the edge of the laboring woman in the supine position with a 30-degree
bed, the patient’s weight will depress the mattress, and leftward tilt was associated with better epidural analgesia
the anesthesia provider must work in a “downhill” direc- than maintenance of the left lateral decubitus position. In
tion. Second, this position allows anesthesia providers to contrast, Preston et al.38 observed no difference in anal-
keep their elbows flexed, facilitating control of fine hand gesia and a significantly higher incidence of fetal brady-
and wrist muscle movements. The plane of the entire cardia with the supine wedged position than with the full
back should be perpendicular to the mattress. When lateral position.
asked to flex the lower back, patients typically roll the top Caudal anesthesia is used infrequently in modern
shoulder forward, an action that rotates the spine (which obstetric anesthesia practice. However, there remain
is undesirable) but does not flex the lower back. some circumstances in which a caudal technique is useful
Similarly, patients positioned sitting should have their and/or advantageous. It is a good choice for the second
feet supported by a stool with the backs of their knees stage of labor in selected patients in whom the lumbar
against the edge of the bed, a maneuver that helps posi- epidural approach is hazardous or contraindicated (e.g.,
tion the patient’s back closer to the anesthesia provider. fusion or instrumentation of the lumbar spine). In most
The shoulders should be relaxed symmetrically over the cases, caudal anesthesia can be successfully performed
hips and buttocks. Beds in obstetric units often break at with the patient in a lateral decubitus position.
the foot, and the split in the mattress encourages the
patient’s seat to slope downhill if she is straddling the Aseptic Technique
mattress split; this position will cause spine rotation and
may make the procedure more difficult. There appears to be a great degree of practice variation
When spinal anesthesia is performed, the patient’s among anesthesia providers with respect to aseptic tech-
posture relative to the baricity of the anesthetic solution nique during administration of neuraxial anesthesia.39-41
should be considered, because it influences the extent of This lack of consensus may result from an underapprecia-
blockade, the latency of blockade, and the incidence of tion of the gravity of infectious complications related to
hypotension. The incidence, timing, and extent of hypo- neuraxial anesthesia.42-44 Indeed the incidence of epidural
tension in the period immediately after initiation of the abscess and spinal meningitis is generally so low that
block depend on the type of block (e.g., spinal, epidural, many of the available recommendations are based
or combined spinal-epidural [CSE]), drug characteristics on evidence from other domains of infection control
(e.g., baricity, concentration), patient position during the (e.g., surgical wound site and central venous catheter–
procedure, and patient position in the period following related infection).45-47 Nonetheless, neurologic com
the procedure. For example, when spinal anesthesia is promise resulting from neuraxial infection can be a
initiated with a hyperbaric solution for instrumental devastating complication.
vaginal delivery, it often makes sense for the patient to Infection of the epidural space tends to result in the
be sitting to ensure the rapid onset of sacral anesthesia. formation of an abscess, most commonly formed by
Conversely, spinal anesthesia for cervical cerclage can be Staphylococcus aureus found in the epidermis of either
initiated with the patient in the steep lateral Trendelen- the patient or the anesthesia provider. In contrast, men-
burg position with a hypobaric anesthetic solution. ingitis associated with neuraxial procedures is most com-
Posture has less influence on the spread of epidural monly caused by Streptococcus viridans. Viridans species of
anesthesia.34-36 During epidural anesthesia, a unilateral streptococcus may reside in the oronasopharyngeal tract
block more likely results from the malposition of the of providers or patients or in the vagina. Potential routes
236 PART IV Foundations in Obstetric Anesthesia
of infection include the (1) epidural catheter track, Sprotte Whitacre Quincke Atraucan
(2) bloodstream, (3) equipment, and (4) injectate. A more
in-depth discussion of neuraxial infection is found in
Chapter 32.
Guidelines describing aseptic technique for regional
and neuraxial anesthetic procedures have been published
by professional anesthesiology organizations, including
the ASA, the Association of Anaesthetists of Great Britain
and Ireland, and the American Society of Regional Anes-
thesia and Pain Medicine.47-49 The following recommen-
dations deserve emphasis:
1. Given that the oropharyngeal and skin flora of the
anesthesia provider are implicated in many cases of
neuraxial infection, the provider should don a sur-
gical facemask and hat before initiation of spinal/
epidural anesthesia. Microbial sampling in laminar-
flow operating theaters has shown a 22-fold increase FIGURE 12-6 ■ Spinal needle assortment often used in parturi-
ents. Each needle is shown in an open-bevel view and an
in bacterial counts when a facemask and hat are not oblique orientation. The Whitacre and Sprotte needles have
worn.50 cone-shaped bevels, whereas the Quincke has a cutting bevel.
2. Washing hands with an alcohol-based antiseptic (Other sizes are available in some of these needle designs.)
solution is recommended because this has been
shown to be superior to antimicrobial soap.51
Jewelry (e.g., rings, watches) should be removed
before and sterile gloves worn after hand The primary equipment choice for spinal anes-
cleansing. thesia concerns the type and size of the spinal needle.
3. The patient’s skin should be decontaminated, Cutting-bevel needles (e.g., Quincke) are rarely used in
preferably with a chlorhexidine-in-alcohol solu- contemporary obstetric anesthesia practice because of the
tion.47 An abundance of evidence affirms the supe- unacceptably high incidence of post–dural puncture
rior bacteriocidal and bacteriostatic efficacy of headache associated with their use.55 Instead, non-cutting
chlorhexidine compared with povidone-iodine.46,52 needles (e.g., Whitacre, Sprotte, Gertie Marx) are used
If chlorhexidine is not available, then povidone- almost exclusively (Figure 12-6). Some anesthesia provid-
iodine with alcohol, rather than povidone-iodine ers refer to the non-cutting needles as “pencil-point
alone, is preferred.47,53 Of importance, the anesthe- needles.” It is now believed that the pencil-point needles
sia provider is encouraged to exercise patience in cause more trauma to the dura, which then results in a
allowing the antiseptic to dry, because a major more intense inflammatory response than occurs with
mechanism of antisepsis is the desiccating action of cutting-bevel needles. Presumably, the inflammation
alcohol. results in more rapid closure of the dural defect.56
Needle size must also be determined. Larger needles
offer a greater fidelity of tactile feedback as the anesthesia
Equipment and Placement provider traverses tissue planes of variable impedance
of Needle/Catheter when performing spinal anesthesia. Furthermore, larger
needles are more likely to withstand the high resistance
Spinal Anesthesia
encountered when contacting bone without bending or
The first equipment decision involves determining shearing. In general, the “ease-of-use” advantages associ-
whether to perform a single-shot or continuous tech- ated with larger needles must be balanced against a lower
nique. Continuous spinal anesthesia is not a new tech- incidence of post–dural puncture headache with smaller
nique; indeed, some physicians performed continuous needles. Most anesthesia providers use 25- or 27-gauge
spinal anesthesia more than 50 years ago. Currently, a non-cutting needles for routine spinal anesthesia in
large-bore epidural needle and catheter must be used for obstetric patients. However, anesthesia providers should
continuous spinal anesthesia, because the U.S. Food and make individual decisions based on their own skills, prac-
Drug Administration rescinded approval for the use of tice setting, and the patient. The urgency of the proce-
small-bore microcatheters in 1992.54 Therefore, the risk dure may also influence the choice of needle size. For
for post–dural puncture headache is significant. This example, a 27-gauge needle might be chosen for spinal
technique is useful after unintentional dural puncture with anesthesia for an elective procedure, and a larger (e.g.,
an epidural needle. In the morbidly obese patient, it may 22-gauge) needle might be chosen when the subarach-
be easier to manipulate and advance a rigid epidural noid space must be entered quickly because of severe fetal
needle than a more flexible spinal needle; thus the tech- compromise.
nique is useful for establishing continuous analgesia or With a small-gauge needle (i.e., 24-gauge or smaller),
anesthesia in this patient population, particularly when use of an introducer needle is preferable. The introducer
the need for anesthesia is urgent. However, for most needle engages the interspinous ligament and more accu-
obstetric patients, a single-shot technique is preferred for rately guides the trajectory of the smaller spinal needle
spinal anesthesia. than is possible with use of a small-gauge spinal needle
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 237
in a slightly upward angulation (relative to the perpen- approach is also easier to teach than the paramedian
dicular transverse plane). This may require that the approach, because it requires mental projection of the
needle be re-angulated accordingly. If bone is still anatomy in only two planes, whereas the paramedian
encountered despite all these considerations, it is likely approach requires appreciation of a third plane and esti-
that the needle tip is in fact not in the midline plane and mation of the depth of the subarachnoid space from the
is contacting the vertebral lamina. This may occur if the skin (Figure 12-10).
initial skin puncture is not in the midline, the needle tip Nevertheless, the paramedian approach is a useful
deviates from the midline as it is advanced, or the patient’s technique that allows for the successful identification of
spine is rotated (either from poor positioning or scolio- the subarachnoid or epidural space in difficult cases. The
sis). Clues that the needle tip is not midline include paramedian approach does not require that the patient
(1) the patient complaining of lateralizing pain, (2) lack fully reduce her lumbar lordosis. This approach exploits
of CSF flow despite appropriate needle depth, and (3) the the larger target that is available when the needle is
perception of “soft” or “mushy” tissue during needle inserted slightly off the midline.
advancement (paraspinous tissue) rather than the more A common error that is made with the paramedian
“rigid” ligamentous tissue, or even a false “pop” as the approach is the insertion of the needle too far off the
needle tip exits the interspinous ligament laterally into midline; the vertebral lamina then becomes a barrier to
paraspinous tissue. Much like the progressive modifica- needle insertion. With the paramedian approach, the pal-
tions described earlier for correct alignment in the pating fingers should again identify the caudad edge of
superoinferior plane, so too can these approaches be the more cephalad spinous process. A skin wheal is raised
employed for redirecting in the lateral plane (Figure 1 cm lateral and 1 cm caudad to this point; a longer
12-9). The novice is advised to make systematic changes needle is then used to infiltrate the deeper tissues in a
in a stepwise fashion, rather than indiscriminately chang- cephalomedial plane. This step contrasts to the midline
ing needle direction without first considering the ana- approach, in which the local anesthetic is not injected
tomic problem. beyond the subcutaneous tissue. The spinal introducer is
Once CSF is freely dripping from the needle hub, the then inserted 10 to 15 degrees off the sagittal plane in a
dorsum of the provider’s nondominant hand steadies cephalomedial direction, and the spinal needle is advanced
the spinal needle against the patient’s back while the through the introducer needle toward the subarachnoid
syringe with local anesthetic is attached to the needle. space. Another common error is to use an excessive ceph-
After aspirating to ensure the free flow of CSF, the anes- alad angle with initial needle insertion. When the needle
thesia provider injects the local anesthetic at a rate of is inserted correctly and contacts bone, it is redirected
approximately 0.2 mL per second. After completion of slightly cephalad. If bone is again encountered, but at a
the injection, some anesthesia providers again aspirate deeper level, the slight stepwise increase in cephalad
approximately 0.2 mL of CSF and reinject it into angulation is continued, and the needle is “walked” up
the subarachnoid space. This last step reconfirms the and off the lamina. As with the midline approach, the
needle location and clears the needle of the remaining characteristic feel of the ligamentum flavum and dura can
local anesthetic. The patient is then repositioned as be appreciated. The aim of the paramedian approach is
appropriate. to puncture the dura in the midline, even though the
For most patients, the midline approach is faster and needle is inserted off the midline. Use of the paramedian
less painful than the paramedian approach. The midline approach requires insertion of a greater length of needle.
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 239
A B
C D
FIGURE 12-9 ■ Troubleshooting contact with bony structures during needle placement. The gray needle represents the initial needle
trajectory; the blue needle represents the adjusted needle trajectory. A, Assuming correct midline needle placement, the needle
can be retracted slightly and angulated to overcome a spinous process. B, Alternatively, the needle may be “lifted” after slight
retraction while keeping the original trajectory constant. C, Assuming the needle is deviating from the midline plane and contacting
lamina, an action similar to that in A may be executed. D, Alternatively a stepwise lateral shift similar in concept to that shown in
B may correctly achieve midline alignment. (Drawing by Naveen Nathan, MD, Northwestern University Feinberg School of Medicine,
Chicago, IL.)
A B
C D
FIGURE 12-15 ■ Needle-through-needle combined spinal-epidural technique. A, The epidural needle is sited in the epidural space.
B, The long spinal needle is passed through the epidural needle and punctures the dura mater. The operator’s nondominant hand
stabilizes the spinal and epidural needles, and the spinal needle stylet is withdrawn. Cerebrospinal fluid is seen spontaneously drip-
ping from the spinal needle. C, The syringe is attached to the spinal needle, and the intrathecal dose is injected. D, The spinal needle
is withdrawn, and the epidural catheter is threaded through the epidural needle into the epidural space. (Drawing by Naveen Nathan,
MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
A B C
FIGURE 12-16 ■ Reasons for failure of the combined spinal-epidural technique. A, The spinal needle tents the dura but does not
puncture it. B, The spinal needle does not reach the dura. C, The spinal needle passes to the side of the dural sac. (Redrawn with
permission from Riley ET, Hamilton CL, Ratner EF, Cohen SE. A comparison of the 24-gauge Sprotte and Gertie Marx spinal needles for
combined spinal-epidural analgesia during labor. Anesthesiology 2002; 97:574.)
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 245
45o
Posterior superior iliac spine
30o
Sacral hiatus
15o
FIGURE 12-17 ■ The location of the sacral hiatus for caudal anesthesia is facilitated by the identification of the posterior superior iliac
spines. The posterior superior spines are marked, and a line drawn between them forms one edge of an equilateral triangle. If the
triangle is completed as illustrated, the sacral hiatus should underlie the caudad tip of the equilateral triangle. Once the sacral hiatus
is identified, the needle is inserted by insertion and withdrawal in a stepwise fashion from an initial 45-degree angle off the coronal
plane. In pregnant women, the needle eventually enters the caudal canal at an angle approximately 15 degrees off the coronal plane.
If the needle is placed properly, no subcutaneous “lump” develops after the injection of the local anesthetic solution. (Drawing by
Naveen Nathan, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
abandon the CSE technique and continue with epidural redirected so that the angle of insertion relative to the
anesthesia (if convinced that the epidural needle tip is in skin surface is decreased. In pregnant women, the final
the epidural space) or to reposition the epidural needle angle is approximately 15 degrees from a plane parallel
and reattempt the CSE technique. to the sacrum.
Accurate placement of the caudal needle is verified
Caudal Anesthesia primarily from the “feel” of the needle passing through
the sacrococcygeal ligament. An additional maneuver
Equipment for caudal anesthesia is similar to that used may help providers with less experience to verify correct
for lumbar epidural techniques, except that a needle with needle placement: Once the needle is believed to be
a lateral-faced opening is not needed. A blunt-tipped within the caudal canal, 5 mL of saline is rapidly injected
needle is satisfactory even when a catheter is used, because through the needle while the anesthesia provider’s other
the angle of needle insertion allows insertion of the hand is placed over the dorsum of the sacrum. If the
catheter. Successful administration of caudal anesthesia needle is placed correctly, no mass or pressure wave is
requires the accurate identification of the sacral hiatus. detected over the midline of the sacrum. Conversely,
The sacrococcygeal ligament (an extension of the liga- if the needle is malpositioned (often posterior to the
mentum flavum) overlies the sacral hiatus between the caudal canal), a fluid mass or pressure wave is felt by the
sacral cornua. Identification of the posterior superior iliac palpating hand.
spines facilitates the identification of the sacral cornua; The needle should be advanced only 1 to 2 cm into
the location of the sacral hiatus is approximated by using the caudal canal. Dural puncture or unintentional
the line between them as one side of an equilateral tri- intravascular cannulation is more likely to occur with
angle (Figure 12-17). Once the sacral hiatus is identified, deeper insertion. A test dose similar to that used during
the palpating fingers are placed on the cornua, the skin administration of lumbar epidural anesthesia should be
is anesthetized, and the caudal needle is inserted with the administered.
hub at an angle approximately 45 degrees from the skin.
A decrease in resistance is noted when the needle enters Ultrasonographic Guidance
the caudal canal. The needle is advanced until it contacts
bone (i.e., the dorsal aspect of the ventral plate of the Traditionally, surface anatomy visualization and palpation
sacrum). Next, the needle is withdrawn slightly and have been used to assess landmarks before initiation of
246 PART IV Foundations in Obstetric Anesthesia
the neuraxial procedure. This landmark-guided tech- and without ultrasonography. From the perspective of
nique is effective for the vast majority of patients and, as introducing trainees to the technique of neuraxial anes-
a consequence, the use of ultrasonography has not played thesia procedures, ultrasonographic imaging may yet play
as prominent a role in neuraxial anesthesia as it has in a more substantial educational role.
peripheral nerve blockade. There exist, however, unique How does pre-procedural ultrasonographic imaging
clinical circumstances in which immediate pre-procedural affect neuraxial anesthesia success for patients anticipated
imaging of epidural anatomy can be highly beneficial. to endure difficult needle placement? Chin et al.89 identi-
Such may be the case in patients with morbid obesity, fied 120 patients presenting for elective lower extremity
derangements of spinal anatomy such as scoliosis or orthopedic surgery who were predicted to endure diffi-
spinal stenosis, or a history of spinal instrumentation, and cult administration of spinal anesthesia. Their basis for
in patients in whom identification of specific vertebral qualifying these patients as “difficult” included a body
levels might be warranted (e.g., known preexisting disc mass index greater than 35 kg/m2 with nonpalpable
herniation or nerve root compression at a specific inter- spinous processes, the presence of moderate to severe
space). Unlike the use of ultrasonography for vascular scoliosis, or a history of spinal surgery involving excision
access and peripheral nerve block techniques, ultrasonog- of two or more lumbar spinous processes. These subjects
raphy for neuraxial techniques is not used in real time. were randomized to receive pre-procedural ultrasono-
Indeed, the real-time use of ultrasonography during graphic imaging of epidural anatomy or a conventional
administration of neuraxial anesthesia can be prohibi- landmark-based technique. The total number of attempts
tively cumbersome, is fraught with a tangible risk for required before successful dural puncture was twofold
violating aseptic technique, and raises unanswered ques- higher in the landmark control group than in the ultra-
tions about what untoward effects may result should sonography group. Although the average time spent
ultrasound coupling medium (gel) breach neuraxial struc- completing the spinal anesthesia procedure was longer in
tures. Most often ultrasonography is a pre-procedural the control group than in the ultrasonography group
tool to aid the operator in the assessment of needle (mean = 7.3 minutes versus 5.0 minutes, respectively), if
insertion site, needle angle, and estimated depth of the one accounted for the pre-procedural ultrasonographic
epidural space. examination, the total procedure time was shorter in the
It remains to be seen whether neuraxial ultrasonogra- control group (7.9 minutes versus 12.2 minutes).
phy can significantly impact the clinical success of neur- How accurately do pre-procedural ultrasonoanatomic
axial procedures, whether that is measured in terms of measurements correlate to the actual distance from the
time to completion of the spinal or epidural anesthesia skin to the epidural space? In general, although the cor-
procedure, or block success and patient satisfaction. relation is high, ultrasonographic measurements of neur-
Additionally, reductions in the incidence of complications axial anatomy may underestimate the true distance from
of neuraxial anesthesia, such as unintentional dural punc- skin to epidural space in the context of neuraxial proce-
ture, have yet to be realized. dures.88,90-92 The factors that influence the small disparity
In the obstetric population, four randomized con- between the two include (1) differences between the
trolled trials have explored outcomes related to block angulation of the imaging beam versus the angulation of
success using the traditional landmark-based technique the needle; (2) differences between the degree of exerted
versus the ultrasound-aided technique.85-88 Only one, pressure and skin compression of the ultrasound probe
however, divorced the unblinded ultrasonographer from versus the needle; (3) current lack of fidelity in the ability
those supervising the block and rendering assessments of of ultrasonography to discriminate between ligamentum
success.88 In this investigation,88 370 parturients receiving flavum, epidural space, and dura mater; and (4) operator
epidural labor analgesia were randomized to receive pre- dependency of typical onscreen measurement tools
procedural ultrasonographic imaging for determination such as digital calipers. In a general obstetric population,
of depth to epidural space or no imaging (control group). the mean difference between the needle depth and ultra-
The estimated depth to the epidural space was conveyed sonographic depth to the epidural space was 0.01 cm
to 15 first-year residents with little or no previous neur- (95% confidence interval, −0.67 to 0.69 cm),92 whereas
axial anesthesia experience, who performed the blocks in a second study by the same investigators in which
under the supervision of a staff anesthesiologist who was subjects were limited to obese parturients, the mean dif-
blinded to the group assignment. Obese patients were not ference was 0.3 cm (95% confidence interval, −0.7 cm to
excluded from this study, and there were no significant 1.3 cm).90
differences between groups in demographic factors. The A low-frequency (2- to 5-Hz) curvilinear probe allows
authors found a significant reduction in the number of visualization of neuraxial structures beneath the skin.
attempts needed to place the epidural catheter and in the Low-frequency waves are preferable owing to the requi-
need for catheter replacement in the ultrasonography site depth of penetration. The curvilinear array allows
group. There was no difference in the rate of uninten- enough ultrasonic scope to capture lateral structures such
tional dural puncture, although the study was underpow- as the transverse processes. The ultrasound beam can be
ered for assessment of this outcome. The calculated used to identify first the spinous processes if these are not
number of epidural catheter placements with ultrasonog- palpable, then the interspinous spaces, and, finally, liga-
raphy needed to avoid replacing one failed catheter mentous structures. The ligamentum flavum and dura
(number needed to treat) was 26. Of note, the residents mater are dense tissues and will appear hyperechoic
were not themselves randomized, nor were they tracked (white), like bone, whereas the less dense epidural and
according to the number of cumulative procedures with subarachnoid spaces will appear hypoechoic (black). A
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 247
variety of imaging planes are now well described. Trans- catheter. To prevent possible local anesthetic toxicity
verse and median sagittal as well as paramedian sagittal and high or total spinal anesthesia, the anesthesia pro-
approaches have been documented. The transverse- vider must recognize the unintentional intravenous
interlaminar view is likely to be of most use when attempt- or subarachnoid placement of the needle or catheter.
ing neuraxial procedures using the midline approach. On The purpose of the test dose is to allow early recognition
the other hand, the paramedian sagittal view may be of of a malpositioned catheter. The ideal test dose must
use if a paramedian approach is anticipated (Figure be readily available, safe, and effective. Its use should
12-18). With the median sagittal approach, the spinous have a high sensitivity (i.e., low false-negative rate) and
process will produce a shadow when the beam is placed a high specificity (i.e., low false-positive rate). The
directly over it, thus reducing the ability to appreciate intravascular and intrathecal test doses may be combined
any ligaments beyond it. (a single injection to test for both intravascular and
subarachnoid placement) or administered separately.
A negative response to an epidural test dose does not
EPIDURAL TEST DOSE guarantee the correct placement of the epidural catheter
in the epidural space, nor does it guarantee that the cath-
Epidural catheter placement may be complicated by eter is not malpositioned in a blood vessel or the sub-
blood vessel or dural puncture with the needle or arachnoid space. Rather, it decreases the likelihood that
SP
AP
TP
PVB
PVB
LFED
AP
TP
FIGURE 12-18 ■ Use of ultrasonography. A, Transverse spinous process view: A long, dark shadow is cast with little to no discernible
anatomy beyond the osseous tip of the spinous process (SP). B, Transverse interlaminar view: ultrasound waves propagate through
the interspinous ligament leading to signals partially reflected by the ligamentum flavum–epidural space–dura mater complex
(LFED). The rays that continue to transmit through this complex encounter the posterior wall of the vertebral body (PVB). Articular
(AP) and transverse processes (TP) can be seen as well. Continued
248 PART IV Foundations in Obstetric Anesthesia
FJ
PVB
LFED
PVB
FIGURE 12-18, cont’d ■ C, Paramedian view: a so-called sawtooth pattern may be seen as the lamina and facet joints (FJ) are captured
by this view, typically achieved 1 cm lateral to the midline sagittal plane. D, Paramedian view: by angulating the ultrasound probe,
the ultrasound waves may escape through the interlaminar and transforaminal “windows” and capture the ligamentum flavum-
epidural space-dura mater complex (LFED) as well as the posterior surface of the vertebral body (PVB). (Drawings by Naveen Nathan,
MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
the catheter tip is in a blood vessel or the subarachnoid heart rate of 20 beats per minute (bpm) within 45 seconds
space. was 100% sensitive and specific for intravascular injec-
tion in unpremedicated patients.95 An increase in systolic
blood pressure of between 15 and 25 mm Hg was also
Intravascular Test Dose observed. Some anesthesiologists have expressed con-
The ideal method for excluding intravenous placement cerns about the use of an epinephrine-containing test
of the catheter is controversial. Intravascular placement dose in laboring women. Intravenous epinephrine may
of the epidural catheter may occur in as many as 7% to cause a transient decline in uterine blood flow as a result
8.5% of obstetric patients.93 Failure to recognize intrave- of alpha-adrenergic receptor–mediated constriction of
nous placement of the epidural catheter and subsequent the uterine arteries (Figure 12-19).97-99
intravenous injection of a large dose of local anesthetic However, this decrease in uterine blood flow is tran-
may lead to systemic local anesthetic toxicity, with CNS sient and comparable to the decrease that occurs during
symptoms, seizures, cardiovascular collapse, and death.94 a uterine contraction. Youngstrom et al.100 noted that this
The most common intravascular test dose contains intravenous dose of epinephrine did not worsen fetal
epinephrine 15 µg. In normal volunteers, intravenous condition in acidotic fetal lambs. In healthy parturients,
injection of epinephrine 15 µg (3 mL of a 1 : 200,000 any transient effect of epinephrine on uterine blood flow
solution) reliably causes tachycardia.95,96 An increase in likely represents a less severe insult than systemic local
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 249
anesthetic toxicity. An epinephrine-containing test dose, epidural injection of 3 mL of 0.5% bupivacaine without
however, may not be appropriate in parturients with epinephrine. A study in laboring women compared the
severe hypertension or uteroplacental insufficiency. intravenous injection of epinephrine (10 to 15 µg) with
Some anesthesiologists argue that the epinephrine- that of saline; the sensitivity was 100%, the area under
containing test dose lacks specificity in laboring women. the receiver operator curve was 0.91 to 0.93, and the
The maternal tachycardic response to intravenous injec- negative predictive value was 100%.103 However, the
tion of epinephrine cannot always be distinguished from positive predictive value was 55% to 73%. The results
other causes of tachycardia (e.g., pain during a uterine suggested that if a positive heart rate response to
contraction) (Figure 12-20).101,102 an epinephrine-containing test dose occurs in 20% of
Cartwright et al.101 noted that 12% of laboring women patients, 5% to 9% of epidural catheters would be identi-
had an increase in heart rate of at least 30 bpm after fied incorrectly as intravascular and removed unnecessar-
ily. Colonna-Romano and Nagaraj104 concluded that the
intravenous injection of an epinephrine-containing test
dose results in “a sudden and fast acceleration in maternal
120
heart rate within one minute.” Thus, careful assessment
110
100
of the rate of increase in maternal heart rate may help
90
distinguish a contraction-induced increase in heart rate
from the effect of intravenously injected epinephrine,
UBFV (% baseline)
80
70 thereby improving the specificity of the epinephrine test.
60 It is unclear whether such an assessment is clinically prac-
EPI 0.2 µ g/kg
50 tical or will actually reduce the incidence of false-positive
EPI 0.5 µ g/kg
40 results.105
EPI 1.0 µ g/kg
30 LIDO and no EPI
Additionally, some anesthesiologists argue that the
20 LIDO and EPI 0.2 µ g/kg
epinephrine-containing test dose lacks sensitivity (the
10 ability to elicit a predictable increase in heart rate when
0 the catheter is intravascular). An increase in maternal
0 1 2 3 4 5
heart rate of 25 bpm occurring within 2 minutes of drug
Time since injection (minutes)
injection and lasting at least 15 seconds was observed in
FIGURE 12-19 ■ The effect of intravenous epinephrine (EPI), lido- only 5 of 10 laboring women who received intravenous
caine (LIDO), and lidocaine with epinephrine on uterine artery epinephrine 15 µg.106 Detection of intravenous epineph-
blood flow velocity (UBFV) in the pregnant guinea pig. The dose rine injection was improved when the authors retrospec-
of lidocaine was 0.4 mg/kg. Values are presented as mean ± tively defined a positive maternal tachycardic response as
standard error of mean (SEM) percentage of baseline. (From
Chestnut DH, Weiner CP, Martin JG, et al. Effect of intravenous
a 10-bpm increase above the maximum maternal heart
epinephrine on uterine artery blood flow velocity in the pregnant rate observed in the 2-minute period preceding the epi-
guinea pig. Anesthesiology 1986; 65:633-6.) nephrine injection. Others have confirmed that these
180
Fetal
160
Heart rate (bpm)
140
120
Maternal
100
80
60
100
UC Pressure (kPa)
12
10 80
8 60
6 40
4
2 20
0 0
FIGURE 12-20 ■ Heart rate of a laboring patient (maternal heart rate [MHR]), fetal heart rate, and uterine contractions (UC) are shown.
This tracing was obtained with the use of an FHR monitor with dual heart rate capacity. Note the variability of the MHR with uterine
contractions. An intravenous injection of bupivacaine 12.5 mg and epinephrine 12.5 µg was given (arrow). Note the marked increase
in MHR in response to intravenous injection of the test dose. The maternal tachycardia had a duration of approximately 40 seconds.
(From Van Zundert AA, Vaes LE, De Wolf AM. ECG monitoring of mother and fetus during epidural anesthesia. Anesthesiology 1987;
66:584-5.)
250 PART IV Foundations in Obstetric Anesthesia
*Test doses may be less sensitive in premedicated patients, patients treated with a beta-adrenergic receptor antagonist, pregnant
patients, and anesthetized patients.
†Weakness in hip flexion.
Modified from Yilmaz M, Wong CA. Technique of neuraxial anesthesia. In Wong CA, editor. Spinal and Epidural Anesthesia. New York,
McGraw-Hill, 2007:27-73.
revised criteria improve the sensitivity of the epinephrine- detected by the use of precordial Doppler ultrasonogra-
containing test dose in laboring women.103 These find- phy.112 (The external FHR monitor can be used for this
ings stress the importance of tracking the chronotropic purpose.) False-negative results may occur when small
variability that occurs in laboring patients during neur- volumes of air are injected through a multi-orifice epidu-
axial anesthesia procedures to reduce the risk for misin- ral catheter; thus, the air test is not a reliable test for
terpretation of the test dose. intravascular injection when multi-orifice epidural cath-
The usefulness of an epinephrine-containing test eters are used.113
dose also improves if additional information is obtained. Local anesthetic–induced symptoms of subclinical
For example, investigators administered intravenous CNS toxicity have also been evaluated as a means
bupivacaine 12.5 mg with epinephrine 12.5 µg or saline of recognizing the unintentional intravenous injection
to laboring women.107 They correctly identified the test of epidural medications. Colonna-Romano et al.114
solution in 39 of 40 women when they assessed maternal administered intravenous saline, lidocaine 100 mg, or
heart rate, blood pressure, uterine contractions, the 2-chloroprocaine 100 mg to laboring women. Observers
timing of the injection, the presence of analgesia, and blinded as to which substance was administered recorded
subjective signs and symptoms of intravascular injection the presence of CNS symptoms (i.e., dizziness, tinnitus,
(e.g., palpitations, lightheadedness, dizziness). The tachy- funny taste) after intravenous injection of local anes-
cardic response to intravenous epinephrine is not a reli- thetic. Lidocaine 100 mg was a reliable marker of intra-
able indicator of intravascular injection in patients who venous injection when the symptoms of tinnitus and
have received a beta-adrenergic receptor antagonist.95 funny taste were considered (sensitivity 100%; specificity
Other means of identifying intravascular placement 81%). 2-Chloroprocaine was less reliable (sensitivity
of an epidural catheter have been proposed and may 81% to 94%; specificity 69% to 81%). In a volunteer
be clinically useful in specific patients (Table 12-2). study, a dose of 1.5 mg/kg of 2-chloroprocaine was neces-
Intravenous administration of isoproterenol 5 µg consis- sary to produce a probability of 90% that the subject
tently results in tachycardia in pregnant women.108,109 would report symptoms of intravenous injection.115
Data from animals99,110 and noninvasive measurements in Administration of fentanyl 100 µg has been described
parturients109 suggest that isoproterenol is devoid of the as a test for intravenous injection.116 Morris et al.117 eval-
adverse effects of epinephrine on uterine blood flow, uated the accuracy and reliability of the fentanyl test
and limited neurotoxicity evaluations have not revealed dose in a double-blind study in which either intravenous
adverse effects.110,111 However, isoproterenol has not or epidural fentanyl 100 µg was administered to parturi-
been approved for epidural or intrathecal administration. ents, and the investigators sought evidence of the occur-
Given the lack of adequate information regarding poten- rence of sedation, dizziness, euphoria, and/or analgesia.
tial neurotoxicity, we do not recommend the use of iso- Dizziness was the most reliable symptom of intravenous
proterenol as an epidural test dose. fentanyl injection, with a sensitivity of 92% and a speci-
Leighton et al.112 have advocated the use of air as an ficity of 92%.
objective marker of intravascular injection. Intravenous Some situations reduce the reliability of subjective
injection of 1 or 2 mL of air through a single-orifice symptoms as a signal of intravenous injection of a drug.
catheter consistently produces changes in heart sounds as Tests that rely on the self-reporting of subjective
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 251
symptoms require clear communication with the patient epinephrine 15 µg and assessed patient perception of
and thus are less useful when the anesthesia provider and lower extremity warmth and heaviness, sensory loss to
patient speak different languages. Patient exhaustion pinprick, and ability to perform a straight-leg raise.
and/or prior opioid administration also may affect the Patients usually perceived warmth in their legs within 1
reliability of the test. minute of the intrathecal injection; however, impaired
Lastly, the epidural catheter design and speed of injec- straight-leg raise 4 minutes after an intrathecal test dose
tion may affect the reliability of the epidural test dose. injection was the only test that had a sensitivity of 100%
An epinephrine-containing test dose should be injected for intrathecal injection. The application of these data to
rapidly; otherwise rapid redistribution and metabolism of pregnant patients is unclear.
the drug decrease the actual dose administered to chro- Richardson et al.121 described the rapid onset (1 to 3
noreceptors. Multi-orifice epidural catheters have three minutes) of high levels of spinal anesthesia with motor
potential sites of exit for injected fluid or air, and the block and hypotension in five parturients who had
orifices may lie within two different body compartments. received a test dose of plain lidocaine 45 mg plus epi-
If injected too slowly, air or fluid preferentially exits the nephrine 15 µg. This solution is slightly hypobaric rela-
proximal orifice. The speed of injection used in clinical tive to CSF at body temperature; thus, the upright
practice typically exceeds that required to ensure that posture of these parturients during the injection may
fluid will exit all three orifices. In contrast, air must be have contributed to the high levels of spinal anesthesia.
injected at a much greater speed to ensure that it exits all The anesthesia provider must recognize the possible
three orifices; this speed is not practical for clinical use. range of responses to the dose of local anesthetic used to
The distal orifice is both the most difficult to test and the assess the position of an epidural catheter and should
one most likely to be positioned outside the epidural perform a careful assessment of sensory, motor, and
space.118 sympathetic function 3 to 5 minutes after administration
of the test dose before concluding that the intrathecal
test dose result is negative. Ropivacaine 15 mg is not a
Intrathecal Test Dose useful intrathecal test dose because the slow onset of
The intrathecal test dose should allow easy identification motor blockade precludes timely diagnosis of intrathecal
of subarachnoid (intrathecal) placement of the catheter injection.122 2-Chloroprocaine is the only local anes-
without causing high or total spinal anesthesia and thetic that can be used as a single, combined intravascu-
hemodynamic compromise. Bupivacaine (7.5 mg) and lar and intrathecal test dose; in most patients, 100 mg
lidocaine (45 to 60 mg) are the local anesthetics results in dense, but not total, spinal anesthesia after
most often used for an intrathecal test dose (see Table intrathecal injection and produces systemic signs of sub-
12-2; Figure 12-21).119,120 clinical toxicity (tinnitus, funny taste) after intravascular
In a study of older, nonpregnant patients receiving injection.
continuous spinal anesthesia for surgery, Colonna- The epidural injection of local anesthetic for the
Romano et al.120 used plain lidocaine 45 mg plus purpose of ruling out intrathecal or intravascular catheter
placement augments epidural analgesia and should be
considered in the calculation of the initial therapeutic
dose of local anesthetic. Several groups of investigators
100 demonstrated that the test dose enhanced the density of
Spinal epidural blockade and adversely affected the ability to
Epidural ambulate. A test dose containing lidocaine 45 mg/
90
epinephrine 15 µg adversely affected the ability to ambu-
Percent of patients
40
late when injected immediately before initiation of epi-
dural analgesia with 0.125% bupivacaine (18.75 mg) with
sufentanil (10 µg).123 Similarly, the same test dose inter-
30
fered with ambulation when administered immediately
after the intrathecal injection of bupivacaine 2.5 mg and
20 fentanyl 25 µg.124 Finally, a lidocaine 60 mg/epinephrine
15 µg test dose adversely affected the ability to ambulate
10 in women who received neostigmine 500 µg with sufen-
tanil 10 µg for initiation of analgesia.125
0– 3 4–6 7 – 9 1 0 – 12 1 3 – 15 > 15
Onset time of objective block (minutes)
Techniques to Minimize Local
FIGURE 12-21 ■ Percentage of pregnant patients who demon- Anesthetic Toxicity
strated objective evidence of anesthesia (defined as the loss of
sensation to pinprick) after epidural injection of 2 to 3 mL of No perfect test dose exists. Some anesthesia providers
hyperbaric 1.5% lidocaine with 1 : 200,000 epinephrine (light teal elect not to administer a test dose because it contributes
bars) (n = 250) or after intrathecal injection of 2 mL of hyperbaric to motor blockade.123,124 In addition, aspiration of a multi-
1.5% lidocaine with 1 : 200,000 epinephrine (dark teal bar) (n =
15). (From Abraham RA, Harris AP, Maxwell LG, et al. The efficacy orifice epidural catheter for blood has 98% sensitivity
of 1.5% lidocaine with 7.5% dextrose and epinephrine as an epidu- for detection of an intravascular location.67 Inadvertent
ral test dose for obstetrics. Anesthesiology 1986; 64:116-9.) intravascular injection of a solution containing a low
252 PART IV Foundations in Obstetric Anesthesia
because of its differential sensory blockade, long duration subsequent actions of opioids138 and bupivacaine,139
of action, low frequency of tachyphylaxis, and low cost. although this possibility is controversial.140
Anesthesia providers infrequently administer bupivacaine As in spinal anesthesia, epidural opioids work syner-
for cesarean delivery because of the risk for cardiac toxic- gistically with local anesthetics. Fentanyl 50 to 100 µg or
ity and maternal mortality after unintentional intravascu- sufentanil 5 to 10 µg is frequently added to an amide
lar injection of the drug. local anesthetic for both labor analgesia (allowing a lower
Ropivacaine has gained popularity as an agent for dose of local anesthetic and less motor block) and cesar-
epidural analgesia and anesthesia because it may result in ean delivery (resulting in a denser block with better
less cardiac toxicity and greater differential sensory blockade of visceral stimulation). Sodium bicarbonate
blockade than bupivacaine.130 may be added to lidocaine141 and 2-chloroprocaine142
Levobupivacaine also has a more favorable safety (1 mEq/10 mL local anesthetic) to decrease latency.
profile than bupivacaine. Clinical trials have shown
that ropivacaine and levobupivacaine have potency131
and analgesic qualities similar to those of bupiva-
Caudal Anesthesia
caine,132,133 with the probable exception of less motor The drugs used for caudal epidural anesthesia are identi-
nerve block.134 cal to those used for lumbar epidural block. However, a
Bupivacaine, ropivacaine, and levobupivacaine all have much larger volume (e.g., 25 to 35 mL) of local anes-
longer durations of action than lidocaine, and they may thetic solution must be administered to extend a caudal
be preferred over shorter-acting agents when a longer block for cesarean delivery or labor analgesia. Such large
duration of anesthesia or analgesia is desirable. They are volumes entail a greater risk for systemic local anesthetic
more commonly used for maintenance of epidural labor toxicity. Additionally, the caudal epidural space is highly
analgesia, whereas the shorter-acting agents are used for vascular, which further predisposes to intravasation of
epidural surgical anesthesia. Despite some variation drugs administered via this route.
among reports, published clinical studies suggest no
more than slight differences in onset and potency, and no
differences in quality or duration of neural blockade, COMPLICATIONS OF NEURAXIAL
among the three drugs. However, bupivacaine is more
cardiotoxic than the other agents in vitro and probably
TECHNIQUES
after unintentional intravascular administration.135 It Unintentional Dural Puncture
would seem prudent to use ropivacaine or levobupiva-
caine rather than bupivacaine when a bolus dose of a Unintentional dural puncture with an epidural needle
concentrated solution is being given. When administered occurs at a rate of approximately 1.5% in the obstetric
as a low concentration infusion, improved safety has not population.143 Approximately 52% of women will experi-
been demonstrated with ropivacaine and levobupivacaine ence a post–dural puncture headache after puncture with
compared with bupivacaine. an epidural needle (see Chapter 31). Techniques to mini-
The most popular choice of local anesthetic for epi- mize the incidence of unintentional dural puncture
dural anesthesia for cesarean delivery is 2% lidocaine include (1) identification of the ligamentum flavum
with epinephrine. The addition of epinephrine (5 µg/ during epidural needle advancement; (2) understanding
mL) causes a modest prolongation of the block. The the likely depth of the epidural space in an individual
major advantage of epinephrine is that it improves the patient; (3) advancement of the needle between contrac-
quality of epidural lidocaine anesthesia. Lam et al.136 have tions, when unexpected patient movement is less likely;
shown that epidural labor analgesia can be extended to (4) adequate control of the needle-syringe assembly
surgical anesthesia for cesarean delivery in 5.2 ± 1.5 during advancement of the needle; and (5) clearing the
minutes (mean ± SD) with the addition of bicarbonate needle of clotted blood or bone plugs. Norris et al.144
and fentanyl to 2% lidocaine with epinephrine. observed that post–dural puncture headache after unin-
Many anesthesia providers reserve 2-chloroprocaine tentional dural puncture was less likely to result in head-
for cases in which rapid extension of epidural anesthesia ache if the epidural needle bevel faced lateral rather than
for vaginal delivery or urgent cesarean delivery is neces- cephalad. In contrast, Richardson and Wissler145 found
sary. The onset of surgical anesthesia was several minutes no difference between the two orientations. An in vitro
faster with 2-chloroprocaine compared with lidocaine study using cadaver dura found that the fluid leakage rate
with freshly mixed epinephrine and sodium bicarbonate through dural tears was not dependent on the orientation
in the setting of urgent caesarean delivery after epidural of the dura relative to the needle bevel.146 We prefer to
labor analgesia.137 Therefore, when time is of the essence, insert the epidural needle with the bevel oriented in a
2-chloroprocaine is the drug of choice. Typically, in cephalad direction so that there is no need to rotate the
an emergency, a large volume of concentrated local needle bevel within the epidural space. Cephalad bevel
anesthetic solution is injected quickly. An additional orientation also increases the likelihood of successful epi-
advantage of 2-chloroprocaine in this situation is that dural anesthesia.147
it is rapidly metabolized by plasma esterases. Therefore, The management of unintentional dural puncture
the unintentional intravascular injection of a large depends on the clinical setting. If advancement of an
volume of 2-chloroprocaine may be less likely to have epidural needle results in dural trespass and the free flow
serious adverse consequences. A potential disadvantage of CSF is perceived in the barrel of the epidural syringe,
of 2-chloroprocaine is that it may interfere with the the anesthesia provider should halt advancement of the
254 PART IV Foundations in Obstetric Anesthesia
epidural needle and either remove the epidural needle if depends on the size of the hole, the lipophilicity of the
the plan is to resite the epidural catheter or replace the drug (highly lipophilic drugs cross quickly regardless of
stylet back into the lumen of the epidural needle to the presence of a hole, whereas water-soluble drugs cross
prevent further egress of CSF if the plan is to administer more quickly in the presence of a hole),151 and whether
intrathecal medication or perform a continuous spinal the drug is administered into the epidural space as a bolus
technique. Reinjection of CSF contained in the syringe or an infusion. Rapid bolus administration of medications
should not be entertained because there is a high likeli- through an epidural catheter in a patient with a known
hood that air will concomitantly be introduced into the dural puncture with a large-bore needle significantly
subarachnoid space and cause pneumocephalus. The risks increases the likelihood of high spinal anesthesia.
and benefits of administering an intrathecal dose of anes- Unfortunately, there is no reliable method to decrease
thetic should be considered. Although intrathecal admin- the risk for post–dural puncture headache once dural
istration of local anesthetic through the epidural needle puncture occurs. Obese patients appear to be at lower risk
will result in rapid analgesia for an uncomfortable patient, than lean patients for the development of headache.152 A
the rapid efflux of CSF may render the injectate ineffec- prophylactic blood patch (injection of autologous blood
tive. Additionally, spinal analgesia may mask paresthesias before removal of the epidural catheter and before onset
during subsequent attempts at neuraxial anesthesia. of a headache) does not reduce the risk for post–dural
Furthermore, spinal anesthesia may cause profound puncture headache.148,153
hypotension. If the patient is sitting, and likely to remain Occasionally, unintentional dural puncture is not rec-
so for the next few minutes, the anesthesia provider ognized until the epidural catheter is threaded and CSF
may struggle to manage two problems instead of one spontaneously appears at the proximal end of the cathe-
(i.e., a challenging neuraxial procedure and maternal ter, or the catheter aspiration or intrathecal test dose is
hypotension). However, rapid provision of analgesia may positive. Finally, an epidural catheter that has been cor-
enable the patient to better assume an optimal position rectly sited in the epidural space may migrate into the
without moving. One option is to administer intrathecal subarachnoid space. The most significant clinical threat
opioid, thus providing analgesia without the risk for in this scenario is the continued use of a large volume
hypotension. infusion of local anesthetic drug intended for epidural
The anesthesia provider has two options after unin- administration. Thus, during prolonged epidural labor
tentional dural puncture: site the epidural catheter within analgesia, the patient should be monitored for evidence
the subarachnoid space and use a continuous spinal anes- of high or dense neuraxial anesthesia.
thetic technique or site the epidural catheter in a different
interspace (i.e., starting afresh). Evidence is conflicting as Unintentional Intravascular
to whether the insertion of an epidural catheter through
the dural puncture site decreases the incidence of post–
or Subarachnoid Injection
dural puncture headache.148 Continuous spinal anesthesia The unintentional injection of large doses of local
is an attractive option if identification of the epidural anesthetics into the subarachnoid space can lead to
space has been difficult or if the anticipated duration of catastrophe. The rapid onset of high or total spinal anes-
epidural anesthesia or analgesia is relatively short (e.g., thesia results in profound hypotension, loss of conscious-
cesarean delivery, or vaginal delivery in parous women). ness, and apnea secondary to hypoperfusion of the brain
The major disadvantage of an intrathecal catheter is the stem. Prompt treatment necessitates assisted ventilation,
risk that it may be mistaken for an epidural catheter. volume resuscitation, and pharmacologic support of
Given that the local anesthetic dose required for epidural blood pressure. Administration of chronotropic agents
anesthesia is many times greater than that required for such as epinephrine may also be necessary if blockade of
spinal anesthesia, unintentional administration of an epi- cardiac sympathetic drive results in bradycardia. The
dural dose into the subarachnoid space will lead to total patient is at high risk for awareness in this setting, and
spinal anesthesia. Therefore, on a busy labor and delivery the judicious use of an amnestic agent such as midazolam
unit where multiple providers are giving anesthesia care, should be considered once cardiorespiratory stability has
it may be safer to use an epidural catheter rather than an been restored.
intrathecal catheter in women in whom prolonged anal- The incidence of intravascular catheter placement
gesia is anticipated. varies according to catheter type,33,65 patient popula-
Thus, the anesthesia provider may elect to initiate tion,154 and proper placement of the epidural needle
epidural anesthesia in another lumbar epidural inter- tip in the midline. Pregnant women are at higher risk
space. However, even if the attempt results in a correctly for unintentional intravenous cannulation due to the
placed catheter, the provider must be wary of an unex- engorgement of epidural veins. Intravascular injection of
pectedly high level of anesthesia after the epidural admin- a local anesthetic may initially result in altered sensorium,
istration of usual doses of local anesthetic.149,150 Leach and tinnitus, and perioral numbness. Higher blood concen-
Smith150 reported a patient who had an extensive block trations may result in seizures, and even higher concen-
after unintentional dural puncture and subsequent epidu- trations may cause dysrhythmias and cardiovascular
ral injection of bupivacaine. They presented radiologic collapse (see Chapter 13). Management of intravascular
evidence of the spread of local anesthetic from the epi- toxicity includes prompt institution of advanced cardiac
dural space to the subarachnoid space. The extent to life support (ACLS), gamma-aminobutyric acid (GABA)–
which a dural tear affects the movement of substances potentiating agents such as benzodiazepines to mitigate
from the epidural space to the subarachnoid space seizure activity, and the use of intralipid emulsion to
12 Spinal, Epidural, and Caudal Anesthesia: Anatomy, Physiology, and Technique 255
detoxify the patient. Several modifications have been of the location of the tip of the epidural catheter (pro-
made to the conventional ACLS protocol for the specific vided it is actually in the epidural space). If analgesia
treatment of local anesthetic-induced cardiac arrest.155 cannot be rescued with a second injection, the catheter
These include using small, judicious doses of intravenous should be removed and replaced at another interspace.
epinephrine for circulatory support (10 to 100 µg boluses The management of inadequate anesthesia is more
in adults), avoidance of vasopressin, and the use of amio- problematic during cesarean delivery. Failure of spinal
darone in place of local anesthetics for treatment of ven- anesthesia may result from the maldistribution of local
tricular arrhythmias. anesthetic within the subarachnoid space.162,163 If inade-
quate spinal anesthesia is noted before incision, the anes-
thesia provider may augment the block with additional
Inadequate Anesthesia local anesthetic by either performing a second spinal
Pain during anesthesia represents a higher proportion of anesthetic procedure or placing an epidural catheter.
obstetric malpractice claims than of nonobstetric claims.156 However, care must be taken if performing a second
During labor, inadequate epidural analgesia may result spinal anesthetic procedure. In the ASA Closed-Claims
from the inadequate extent of sensory blockade, nonuni- Project database, Drasner and Rigler162 identified three
form blockade, or inadequate density of blockade. When cases of cauda equina syndrome complicating spinal
called to evaluate breakthrough pain, the anesthesia anesthesia. In two cases, “failed spinal” anesthesia had
provider should first evaluate the extent of bilateral occurred, followed by a repeat injection of local anes-
sensory blockade in both the cephalad and caudad directions. thetic. The researchers recommended that anesthesia
Particularly if labor is progressing quickly, the extent providers determine the presence of anesthesia in the
of sacral blockade may not be adequate. In this case, sacral dermatomes before giving additional local anes-
epidural injection of a large volume of local anesthetic thetic into the subarachnoid space. Additionally, they
may improve sacral blockade. In contrast, if the extent of stated that if CSF was aspirated during the original pro-
sensory blockade is adequate but the patient is still expe- cedure, it should be assumed that local anesthetic was
riencing pain, the density of blockade may be insufficient. delivered into the subarachnoid space, and the total dose
In this case, the provider should reestablish and maintain of local anesthetic be limited to the maximum dose a
analgesia using a more concentrated solution of local clinician would consider reasonable to administer in a
anesthetic. single injection.162 If partial blockade is present (even
Why do some obstetric epidural anesthetics fail over if it is limited to the sacral dermatomes), the second
time? Collier157 administered epidural radiocontrast dye dose should be reduced accordingly. It may also be advis-
in 25 parturients reporting unsatisfactory analgesia. The able to perform the second procedure at a different inter-
two major causes of inadequate block in this small study space or make other changes to the original procedure
were transforaminal migration of the catheter tip and an (e.g., alter the patient’s position, use a local anesthetic
obstructive barrier in the epidural space. Total block with different baricity, or straighten the lumbosacral
failure usually results from failure to identify the epidural curvature).
space correctly or from malposition of the catheter tip If the patient complains of pain after incision, the
outside the epidural space (e.g., in a neuroforamen). A anesthesia provider must decide between the administra-
unilateral block may occur despite the use of good tech- tion of inhalation or intravenous analgesia and the
nique. Unilateral blocks can often be prevented by limit- administration of general anesthesia. Supplemental anal-
ing the length of catheter within the epidural space to gesia may be provided by giving 60% nitrous oxide in
3 cm or less. The problem with limited insertion of the oxygen, small incremental boluses of ketamine (0.1 to
catheter is that, in some patients, the catheter tends to 0.25 mg/kg), or small boluses of intravenous opioid.
migrate outward over time. (Patients undergoing surgery Supplemental infiltration of the wound with local anes-
remain still; by contrast, laboring women change position thetic is sometimes helpful, especially when spinal anes-
frequently.) Obese women seem to be at higher risk for thesia regresses near the end of an unexpectedly long
outward migration of the catheter tip. Prospective studies operation. The anesthesia provider must ensure that the
suggest that 4 to 6 cm is the optimal depth of epidural patient remains sufficiently alert to protect her airway. In
catheter insertion in laboring women.71,72,158 most cases, severe pain unrelieved by modest doses of
Whether catheter withdrawal in the setting of break- analgesic drug requires rapid-sequence induction of
through pain is beneficial is not clear. Beilin et al.159 com- general anesthesia followed by endotracheal intubation
pared catheter withdrawal followed by injection of local and general anesthesia.
anesthetic with injection of local anesthetic without cath- In some cases, inadequate epidural anesthesia results
eter withdrawal for the treatment of breakthrough pain. from failure to give a sufficient dose of local anesthetic
The ability to rescue analgesia was not different between or failure to wait a sufficient time after its administration.
the groups. Gielen et al.160 performed a radiologic study For example, after the epidural administration of 0.5%
in which they observed no consistent relationship between bupivacaine, approximately 20 minutes must pass to
catheter position and the asymmetric onset of sympa- achieve an adequate level of anesthesia, and additional
thetic blockade. Unilateral or patchy sensory blockade local anesthetic may be needed to achieve an adequate
likely results from the nonuniform distribution of local density of blockade. In urgent cases or in cases with a
anesthetic solution in the epidural space.161 Injection of a “missed” segment, local infiltration with a local anes-
large volume of dilute local anesthetic solution into the thetic often results in satisfactory anesthesia. Sometimes
epidural space usually corrects this problem, regardless it is difficult to separate the beneficial effect of the local
256 PART IV Foundations in Obstetric Anesthesia
infiltration from the beneficial effect of waiting for the the catheter with a sterile instrument, and reconnect it to
obstetrician to obtain, prepare, and inject the local anes- a new sterile connector. However, given the potential
thetic solution. Finally, the anesthesia provider should catastrophic consequences of neuraxial infection, we rec-
exercise caution when initiating spinal anesthesia after ommend replacing the catheter. Also, wire-embedded
failure of epidural anesthesia because of a greater inci- catheters cannot be cut.
dence of high spinal anesthesia in this setting.164 Presum-
ably, the large volume of local anesthetic within, or near,
the epidural space results in decreased lumbar CSF
volume, which predisposes to high spinal anesthesia. It KEY POINTS
may be advisable to reduce the dose of intrathecal local
anesthetic, particularly in the presence of partial epidural • Physiologic changes of pregnancy alter neuraxial
blockade. anatomy; alterations include accentuation of
lumbar lordosis, a “softer” ligamentum flavum,
and decreased space in the spinal canal due to
Equipment Problems vascular engorgement of epidural veins.
The frequency of major equipment malfunction is very • Physiologic changes of pregnancy cause a more
low during the administration of neuraxial anesthesia. pronounced response to neuraxial anesthesia–
Most anesthesia providers in the United States use dis- induced sympathetic blockade than is seen in
posable needles, and the plastic needle hubs are attached nonpregnant patients. These include higher
to the needles’ shafts with epoxy. Rarely, a needle breaks baseline sympathetic tone and aortocaval
at the hub-shaft junction.165 If a needle should break, the compression.
portion of the needle that remains in the patient should • Pregnant women, particularly those with
be removed, because it may migrate and cause injury. neuraxial blockade, should not be cared for in
An epidural or spinal catheter may shear and break off the supine position but rather in lateral tilt or in
if the catheter is withdrawn through a needle; thus an the full lateral position.
epidural or spinal catheter should never be withdrawn in • Correct patient positioning, equipment, and
this manner. Rather, if the catheter must be withdrawn, technique are important to the success and
the needle and catheter should be withdrawn as a unit. It safety of neuraxial techniques.
is also possible to break a catheter during attempts at • The midline approach is faster and less painful
removing it, although this is rare. If resistance to catheter than the paramedian approach to the epidural or
removal is encountered, the patient should assume a posi- subarachnoid space. However, the paramedian
tion that reduces lumbar lordosis, thereby lessening the approach may allow for the successful
kinking of the catheter between perivertebral structures. identification of the subarachnoid or epidural
If position change is not successful, the catheter should space in difficult cases.
be taped under tension to the patient’s back and left
• Use of a non-cutting (“pencil-point”) needle for
undisturbed for several hours. The catheter usually works
spinal anesthesia reduces the incidence of
its way out and is then easy to remove. Once the catheter
post–dural puncture headache.
has been removed successfully, it should be examined to
ensure that it has been removed completely. Complete • Combined spinal-epidural anesthesia has the
removal of the catheter should be documented in the advantages of both spinal anesthesia and epidural
medical record. anesthesia.
Rarely, catheters do break on removal. We favor • Approximately 20% to 30% less local anesthetic
aggressive attempts to remove broken spinal catheters. is required for epidural and spinal anesthesia in
However, it may be unnecessary to remove broken epidu- pregnant patients than in nonpregnant patients.
ral catheters; rather, in these circumstances, the patient • Multiple techniques (e.g., test dose, aspiration,
can be informed of the complication and observed over incremental dose injection) should be used to
time. The incidence of catheter migration or other reduce the incidence and risk for unintentional
delayed sequelae appears to be low. Computed tomogra- subarachnoid or intravascular injection, because
phy may help identify the precise location of a broken no one technique will completely exclude all
catheter.166 cases of malpositioned needles or catheters.
During use, an epidural catheter occasionally becomes
disconnected from the catheter connector. Options
include replacing the epidural catheter or reconnecting
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catheters. Anaesthesia 1988; 43:876-8. Analg 1989; 68:593-8.
119. Abraham RA, Harris AP, Maxwell LG, Kaplow S. The efficacy of 143. Choi PT, Galinski SE, Takeuchi L, et al. PDPH is a common
1.5% lidocaine with 7.5% dextrose and epinephrine as an epidural complication of neuraxial blockade in parturients: a meta-analysis
test dose for obstetrics. Anesthesiology 1986; 64:116-9. of obstetrical studies. Can J Anaesth 2003; 50:460-9.
120. Colonna-Romano P, Padolina R, Lingaraju N, Braitman LE. 144. Norris MC, Leighton BL, DeSimone CA. Needle bevel direction
Diagnostic accuracy of an intrathecal test dose in epidural analge- and headache after inadvertent dural puncture. Anesthesiology
sia. Can J Anaesth 1994; 41:572-4. 1989; 70:729-31.
121. Richardson MG, Lee AC, Wissler RN. High spinal anesthesia 145. Richardson MG, Wissler RN. The effects of needle bevel orienta-
after epidural test dose administration in five obstetric patients. tion during epidural catheter insertion in laboring parturients.
Reg Anesth 1996; 21:119-23. Anesth Analg 1999; 88:352-6.
122. Ngan Kee WD, Khaw KS, Lee BB, et al. The limitations of ropi- 146. Angle PJ, Kronberg JE, Thompson DE, et al. Dural tissue trauma
vacaine with epinephrine as an epidural test dose in parturients. and cerebrospinal fluid leak after epidural needle puncture. Anes-
Anesth Analg 2001; 92:1529-31. thesiology 2003; 99:1376-82.
123. Cohen SE, Yeh JY, Riley ET, Vogel TM. Walking with 147. Huffnagle SL, Norris MC, Arkoosh VA, et al. The influence of
labor epidural analgesia: the impact of bupivacaine concentration epidural needle bevel orientation on spread of sensory blockade
and a lidocaine-epinephrine test dose. Anesthesiology 2000; 92: in the laboring parturient. Anesth Analg 1998; 87:326-30.
387-92. 148. Apfel CC, Saxena A, Cakmakkaya OS, et al. Prevention of
124. Calimaran AL, Strauss-Hoder TP, Wang WY, et al. The effect of postdural puncture headache after accidental dural puncture: a
epidural test dose on motor function after a combined spinal- quantitative systematic review. Br J Anaesth 2010; 105:255-63.
epidural technique for labor analgesia. Anesth Analg 2003; 149. Hodgkinson R. Total spinal block after epidural injection into an
96:1167-72. interspace adjacent to an inadvertent dural perforation. Anesthe-
125. Roelants F, Mercier-Fuzier V, Lavand’homme PM. The effect of siology 1981; 55:593-5.
a lidocaine test dose on analgesia and mobility after an epidural 150. Leach A, Smith GB. Subarachnoid spread of epidural local
combination of neostigmine and sufentanil in early labor. Anesth anaesthetic following dural puncture. Anaesthesia 1988; 43:
Analg 2006; 103:1534-9. 671-4.
260 PART IV Foundations in Obstetric Anesthesia
151. Bernards CM, Kopacz DJ, Michel MZ. Effect of needle puncture administration of local anesthetic for women in labor. Anesthesi-
on morphine and lidocaine flux through the spinal meninges of ology 1998; 88:1502-6.
the monkey in vitro: implications for combined spinal-epidural 160. Gielen MJ, Slappendel R, Merx JL. Asymmetric onset of sympa-
anesthesia. Anesthesiology 1994; 80:853-8. thetic blockade in epidural anaesthesia shows no relation to epi-
152. Faure E, Moreno R, Thisted R. Incidence of postdural puncture dural catheter position. Acta Anaesthesiol Scand 1991; 35:81-4.
headache in morbidly obese parturients (letter). Reg Anesth 1994; 161. Hogan Q. Distribution of solution in the epidural space: examina-
19:361-3. tion by cryomicrotome section. Reg Anesth Pain Med 2002;
153. Scavone BM, Wong CA, Sullivan JT, et al. Efficacy of a prophy- 27:150-6.
lactic epidural blood patch in preventing post dural puncture 162. Drasner K, Rigler ML. Repeat injection after a “failed spinal”: at
headache in parturients after inadvertent dural puncture. Anesthe- times, a potentially unsafe practice. Anesthesiology 1991;
siology 2004; 101:1422-7. 75:713-4.
154. Bahar M, Chanimov M, Cohen ML, et al. The lateral recumbent 163. Rigler ML, Drasner K. Distribution of catheter-injected local
head-down position decreases the incidence of epidural venous anesthetic in a model of the subarachnoid space. Anesthesiology
puncture during catheter insertion in obese parturients. Can J 1991; 75:684-92.
Anaesth 2004; 51:577-80. 164. Furst SR, Reisner LS. Risk of high spinal anesthesia following
155. Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice failed epidural block for cesarean delivery. J Clin Anesth 1995;
advisory on local anesthetic systemic toxicity. Reg Anesth Pain 7:71-4.
Med 2010; 35:152-61. 165. Schlake PT, Peleman RR, Winnie AP. Separation of the hub from
156. Chadwick HS, Posner K, Caplan RA, et al. A comparison of the shaft of a disposable epidural needle. Anesthesiology 1988;
obstetric and nonobstetric anesthesia malpractice claims. Anesthe- 68:611-3.
siology 1991; 74:242-9. 166. Moore DC, Artru AA, Kelly WA, Jenkins D. Use of computed
157. Collier CB. Why obstetric epidurals fail: a study of epidurograms. tomography to locate a sheared epidural catheter. Anesth Analg
Int J Obstet Anesth 1996; 5:19-31. 1987; 66:795-6.
158. Beilin Y, Bernstein HH, Zucker-Pinchoff B. The optimal distance 167. Langevin PB, Gravenstein N, Langevin SO, Gulig PA. Epidural
that a multiorifice epidural catheter should be threaded into the catheter reconnection. Safe and unsafe practice. Anesthesiology
epidural space. Anesth Analg 1995; 81:301-4. 1996; 85:883-8.
159. Beilin Y, Zahn J, Bernstein HH, et al. Treatment of incomplete
analgesia after placement of an epidural catheter and
C H A P T E R 1 3
CHAPTER OUTLINE
Local anesthetics and opioids are often used for pain behave as weak bases. In its quaternary (i.e., “proton-
relief in obstetric practice. Local anesthetics may be used ated”) form, the terminal amine is the water-soluble
for infiltration anesthesia, peripheral (pudendal) nerve portion. The Henderson-Hasselbalch equation predicts
block, or neuraxial block, whereas opioids are adminis- the relative proportions of local anesthetic that exist in
tered both systemically and neuraxially. The physiologic the ionized and un-ionized form. The higher the pKB
changes that occur during pregnancy may affect the phar- (base dissociation constant) relative to physiologic pH,
macology of both local anesthetics and opioids. In turn, the smaller the proportion of drug that exists in the
these analgesic drugs may have effects on the mother and un-ionized form. All amide local anesthetics (with the
the fetus. exception of lidocaine) exist as stereoisomers because of
the presence of an asymmetric carbon adjacent to the
terminal amine.
LOCAL ANESTHETICS Clinical formulations of local anesthetics are prepared
as hydrochloride salts to increase their solubility in water.
Molecular Structure These solutions are usually acidic (i.e., pH of 4 to 6) to
enhance formation of the water-soluble quaternary amine
All local anesthetic molecules except cocaine contain a and to prevent oxidation of the epinephrine present in
desaturated carbon ring (aromatic portion) and a tertiary epinephrine-containing solutions.
amine connected by an alkyl chain (Figure 13-1). The
intermediate alkyl chain, by virtue of its ester or amide Chirality
linkage, is the basis for the classification of local anesthet-
ics as amino-esters (which are hydrolyzed by pseudo- With the exception of lidocaine, amide local anesthetics
cholinesterase) and amino-amides (which undergo are known as chiral compounds because they have
hepatic microsomal metabolism) (Table 13-1). The aro- a single asymmetric carbon adjacent to the amino
matic ring of the esters, which renders the molecule lipid group and thus exist in isomeric forms that are mirror
soluble, is a derivative of benzoic acid. The amide aro- images of each other. The direction in which the isomers
matic ring is a homologue of aniline. The tertiary-amine rotate polarized light distinguishes them as either dextro-
portion acts as a proton acceptor; thus, local anesthetics rotary (d) or levorotary (l) isomers. This distinction is
261
262 PART IV Foundations in Obstetric Anesthesia
important, because individual isomers of the same drug The reduction in systemic toxicity observed with
may have different biologic effects. As a rule, the levoro- administration of the levorotary isomers may be both
tary isomer of a drug has greater vasoconstrictor activity drug and concentration dependent. For example,
and a longer duration of action but less potential for one study in isolated guinea pig hearts noted that bupi-
systemic toxicity than the dextrorotary form.1 vacaine isomers lengthened atrioventricular conduction
In the past, single-isomer formulations were costly to time more than ropivacaine isomers did. In contrast to
produce; and for that reason, local anesthetics used clini- other measured variables, “atrioventricular conduction
cally (e.g., bupivacaine) have contained a racemic mixture time showed evident stereoselectivity” for bupivacaine at
of both the dextrorotary and levorotary forms of the the lowest concentration studied (0.5 µM) but only at
drug. However, with improved techniques of selective much higher concentrations for ropivacaine (> 30 µM).3
extraction, two commercially available single-isomer for-
mulations of local anesthetic are now available, ropiva-
caine and levobupivacaine. Levobupivacaine is the
Mechanism of Action
levorotary isomer of bupivacaine; it is currently not mar- At rest, the interior of a nerve cell is negatively charged
keted in the United States. Ropivacaine is a homologue in relation to its exterior. This resting potential of 60 to
of mepivacaine and bupivacaine, but, unlike these other 90 mV exists because the concentration of sodium in the
local anesthetics, it is formulated as a single levorotary extracellular space greatly exceeds that in the intracellular
isomer rather than as a racemic mixture. A propyl group space. The converse is true for potassium. Excitation
on the pipechol ring distinguishes ropivacaine from bupi- results in the opening of membrane channels, which
vacaine (which has a butyl group) and mepivacaine (which allows sodium ions to flow freely down their concentra-
has a methyl group).2 Thus, it is not surprising that the tion gradient into the cell interior. Thus, the electrical
physicochemical characteristics of ropivacaine are inter- potential within the nerve cell becomes less negative
mediate between those of mepivacaine and bupivacaine. until, at the critical threshold, rapid depolarization occurs.
This depolarization is needed to initiate the same
sequence of events in adjacent membrane segments and
for propagation of the action potential. Thereafter,
Aromatic Ester Intermediate Tertiary sodium channels close and the membrane once again
ring linkage alkyl chain amine becomes impermeable to the influx of sodium. The
negative resting membrane potential is reestablished as
O sodium is removed from the cell by active transport. At
R
the same time, potassium passively accumulates within
C O R N the resting cell.
Interference with sodium-ion conductance appears to
or R be the mechanism by which local anesthetics reversibly
inhibit the propagation of the action potential. Four
N C
major theories attempt to explain this effect. The most
prominent hypothesis is that the local anesthetic interacts
H O with receptors in the nerve cell membrane that control
Amide channels involved in sodium conductance.4 There may be
linkage more than one site at which local anesthetics bind to
sodium-channel receptors (Figure 13-2).
FIGURE 13-1 ■ Structure of the molecule of a local anesthetic.
R, alkyl group. (Modified from Santos AC, Pedersen H. Local anes-
The Meyer-Overton theory offers a second explana-
thetics in obstetrics. In Petrie RH, editor. Perinatal Pharmacology. tion for local anesthetic action. This hypothesis suggests
Cambridge, MA, Blackwell Scientific, 1989:373.) that the lipid-soluble portion of the local anesthetic
Extracellular
Space
Na+
FIGURE 13-2 ■ Local anesthetic access to the Channel
sodium channel. The uncharged molecule (LA-
NR2) diffuses most easily across the lipid mem-
brane and interacts with the sodium channel
at an intramembranous site. The charged mole-
cule (LA-NR2H+) gains access to a specific recep-
tor on the sodium channel in the intracellular Axoplasm
space. (Drawing by Naveen Nathan, MD, North-
western University Feinberg School of Medicine,
Chicago, IL.)
molecule expands the cell membrane and interferes with in cerebrospinal fluid (CSF) from women undergoing
rapid sodium conductance. A third possibility is that local cesarean delivery than in CSF from age-matched non-
anesthetics may alter the membrane surface charge, a pregnant controls. A higher pH increases the proportion
change that would inhibit propagation of the action of local anesthetic that exists as the base form and facili-
potential. Fourth, local anesthetics may displace calcium tates diffusion of the drug across nerve membranes.7
from sites that control sodium conductance.
Both the un-ionized and ionized forms of a local
anesthetic are involved in pharmacologic activity. The
Pharmacokinetics
un-ionized base, which is lipid soluble, diffuses through Pregnancy is associated with progressive physiologic
the cell membrane, whereas the charged form is much adaptations that may influence drug disposition (see
more active in blocking the sodium channel. Chapter 2). However, it is difficult to predict with cer-
tainty the effects of pregnancy on the pharmacokinetics
of an individual drug.
Pharmacodynamics
Pregnant women typically require smaller doses of local 2-Chloroprocaine
anesthetic compared with nonpregnant women for neur-
axial blockade. This effect may be evident as early as the 2-Chloroprocaine is hydrolyzed rapidly by plasma pseu-
second trimester.5,6 This difference has been attributed docholinesterase to chloroaminobenzoic acid and H2O.
to enhanced spread of local anesthetic due to epidural The in vitro half-life of 2-chloroprocaine in sera from
venous engorgement. However, mechanical effects alone men is less than 15 seconds.11 Although pregnancy is
do not account for the observation that the spread of associated with a 30% to 40% decrease in pseudocholin-
spinal and epidural analgesia in early pregnancy is similar esterase activity, the half-life of 2-chloroprocaine in
to that in pregnant women at term.5-7 In fact, pregnancy maternal plasma in vitro is 11 to 21 seconds. After epidu-
may also enhance neuronal sensitivity to local anesthet- ral injection, the half-life of 2-chloroprocaine in the
ics. For example, pregnancy increases median nerve sus- mother ranges from 1.5 to 6.4 minutes.12 The longer
ceptibility to lidocaine.8 In vitro studies demonstrated half-life after epidural administration results from con-
that the onset of neural blockade was faster, and lower tinued absorption of the drug from the injection site.
concentrations of bupivacaine were required to block Administration of 2-chloroprocaine to patients with low
vagal fibers, in pregnant rabbits than in nonpregnant pseudocholinesterase activity may result in prolonged
rabbits.9 local anesthetic effect and a greater potential for systemic
Hormonal and biochemical changes may be respon- toxicity.13
sible for the greater susceptibility to neural blockade
during pregnancy. For example, one study demonstrated Lidocaine
an enhanced effect of bupivacaine in isolated vagus fibers
from nonpregnant, ovariectomized rabbits who had The volume of the central compartment and the volume
received long-term (4 days) but not short-term exposure of distribution are greater in pregnant ewes than in
to progesterone.10 A higher pH and lower bicarbonate nonpregnant ewes.14,15 Bloedow et al.15 observed that the
and total carbon dioxide content have been demonstrated total body clearance of lidocaine was similar in the two
264 PART IV Foundations in Obstetric Anesthesia
groups of animals. They concluded that the elimination bupivacaine for cesarean delivery, PPX was detected in
half-life of lidocaine, which depends on the balance maternal plasma within 5 minutes and remained detect-
between volume of distribution and clearance, was longer able for as long as 24 hours.25 With the lower doses
in pregnant ewes.15 In contrast, Santos et al.14 concluded required for labor analgesia, PPX was found only if the
that the elimination half-life of lidocaine was similar in block was maintained with multiple reinjections during
the two groups of sheep because the total body clearance a period that exceeded 4 hours.26 Pregnancy may affect
of the drug was greater in pregnant animals than in non- metabolism of bupivacaine.22 For example, pregnant
pregnant animals. This discrepancy could result from women have higher serum PPX concentrations, but the
differences in the complexity of the surgical preparation unconjugated 4-hydroxy metabolite is not produced in
and the allowed recovery period. In pregnant women, the significant amounts. The reason for this finding is unclear
elimination half-life of lidocaine after epidural injection but may be related to the effects of hormonal changes
is approximately 114 minutes.16 on hepatic enzyme systems. Both progesterone and estra-
Lidocaine is metabolized to two active compounds, diol are competitive inhibitors of microsomal oxidases,
monoethylglycinexylidide (MEGX) and glycinexylidide whereas reductive enzymes are induced by progester-
(GX). Monoethylglycinexylidide can be detected in mater- one.24 Bupivacaine is bound extensively to AAG and
nal plasma within 10 to 20 minutes after neuraxial injec- albumin.27 This protein binding is reduced during late
tion of lidocaine, whereas glycinexylidide can be detected pregnancy in humans.28
within 1 hour of epidural injection but rarely after sub- Long-acting pipechol amide local anesthetics, such as
arachnoid injection.17,18 Urinary excretion of unchanged bupivacaine, are beneficial for neuraxial labor analgesia
lidocaine is negligible in sheep (i.e., < 2% of the adminis- because they produce a relative motor-sparing block as
tered dose) and is not affected by pregnancy.14 compared with other local anesthetics. The effective
The physiologic changes that occur during pregnancy dose in 50% of cases (ED50) for motor block after intra-
are progressive. However, little information is available thecally administered bupivacaine was lower in pregnant
about the pharmacokinetics of local anesthetics before than in nonpregnant women (3.96 mg and 4.14 mg,
term. In one study, total clearance of lidocaine was similar respectively).29
at 119 and 138 days’ gestation in gravid ewes (term is
148 days).19 Ropivacaine
Lidocaine is predominantly bound to alpha1-acid gly-
coprotein (AAG) in plasma.20 Pregnancy leads to a Pregnant sheep have a smaller volume of distribution
decreased concentration of AAG; thus, the free plasma and a slower clearance of ropivacaine than nonpregnant
fraction of lidocaine is higher in term pregnant women animals.24 However, the relationship between volume of
than in nonpregnant controls.20 The increase in the free distribution and clearance is such that the elimination
fraction of lidocaine occurs early in gestation and is half-life is similar in pregnant and nonpregnant animals.
progressive.21 After intravenous injection in laboratory animals, the
elimination half-life of ropivacaine is shorter than that of
bupivacaine.24,30 Similar findings have been described
Bupivacaine
after intravenous injection in nonpregnant human volun-
At least two studies compared the pharmacokinetics of teers.31 The shorter elimination half-life of ropivacaine
bupivacaine after epidural administration in pregnant and has been attributed to a faster clearance and a shorter
nonpregnant women.22,23 The absorption rate, the area mean residence time than for bupivacaine.24
under the concentration-time curve, and the elimination Peak plasma concentration (Cmax) after epidural admin-
half-life (12 to 13 hours) were similar in the two groups. istration of 0.5% ropivacaine and 0.5% bupivacaine for
The elimination half-life of bupivacaine after epidural cesarean delivery are similar (1.3 µg/mL and 1.1 µg/mL,
administration is much longer than that reported after respectively).32 The elimination half-life of ropivacaine is
intravenous injection, largely because the drug is con- 5.2 ± 0.6 hours, which is shorter than that for bupiva-
tinuously absorbed over time from the epidural space. caine, at 10.9 ± 1.1 hours. No difference in clearance
After intravenous injection, the volume of distribution between the two drugs has been noted.
of bupivacaine is lower in pregnant sheep than in non Like bupivacaine, ropivacaine is metabolized by
pregnant sheep.24 In contrast, ovine pregnancy is associ- hepatic microsomal cytochrome P450. The major
ated with a greater volume of distribution of lidocaine.14,15 metabolite is PPX, and minor metabolites are 3′- and
The differences in gestational effects on the volume of 4′-hydroxy-ropivacaine.33
distribution of the two local anesthetics may result from Ropivacaine is highly bound (approximately 92%) to
the greater binding of bupivacaine to plasma proteins plasma proteins but less so than bupivacaine (96%).34
during gestation (whereas the converse occurs with lido- Indeed, at plasma concentrations occurring during epi-
caine).24 In one study, urinary excretion of unchanged dural anesthesia for cesarean delivery, the free fraction
bupivacaine was not affected by pregnancy and was less of ropivacaine is almost twice that of bupivacaine.32 In
than 1% of the administered dose.22 Nonetheless, low sheep, pregnancy is associated with a greater binding of
concentrations of bupivacaine may be detected in the ropivacaine (and bupivacaine) to plasma proteins.24 In
urine of pregnant women for as long as 3 days after pregnant women undergoing epidural analgesia, the free
delivery.25 fraction of ropivacaine decreases as the concentration of
Bupivacaine undergoes dealkylation in the liver to AAG increases, up to the point at which the receptors are
2,6-pipecolyxylidide (PPX). After epidural injection of saturated.35 However, there is little correlation between
13 Local Anesthetics and Opioids 265
pregnancy did not reduce the doses required to cause of a large bolus of drug. Second, a potential for bias
convulsions after intravenous administration of mepiva- existed in the animal studies because randomization and
caine, bupivacaine, or lidocaine.51,73 Magnesium sulfate, blinding were not used in all studies and some relied
which is frequently used in obstetric practice, does not on historical controls.49-51 Third, it is unclear whether
affect the seizure-dose threshold of lidocaine.74 resuscitation in the reported clinical cases was accompa-
nied by prompt and effective relief of aortocaval
Cardiovascular Toxicity. In 1979, Albright66 alerted compression.75
anesthesiologists to several cases of sudden cardiovascular Nonetheless, bupivacaine remains a popular local
collapse after unintentional intravascular injection of anesthetic for obstetric anesthesia. In current practice,
bupivacaine and etidocaine in pregnant women. The fact heightened vigilance, use of an appropriate test dose, and
that cardiac arrest occurred concurrently with or shortly fractionation of the therapeutic dose have made epidural
after the onset of convulsions was especially disconcert- anesthesia a safe technique for use in obstetric patients
ing. Most of these cases were fatal, and subsequent con- (see Chapter 12). In a study of anesthesia-related mater-
troversy centered on whether resuscitation was instituted nal mortality, Hawkins et al.80 noted that the number of
promptly and effectively. Nonetheless, the U.S. Food and maternal deaths resulting from local anesthetic toxicity
Drug Administration (FDA) restricted the use of the decreased after 1984, the year that the FDA withdrew
highest concentration (0.75%) of bupivacaine in preg- approval for the epidural administration of 0.75% bupi-
nant women. vacaine in obstetric patients. However, LAST has been
Several physiologic changes that occur during preg- recognized for decades as an important potential cause
nancy place the parturient at higher risk for refractory of maternal mortality.81 In our judgment, adherence to
cardiac arrest than the nonpregnant patient. First, reduced the aforementioned clinical precautions—rather than the
functional residual capacity and a higher metabolic rate proscription against the epidural administration of 0.75%
increase the risk for and hasten the onset of hypoxemia bupivacaine—has been responsible for the lower number
during periods of hypoventilation or apnea. Second, of maternal deaths due to LAST. Anesthesia providers
aortocaval compression decreases the efficacy of closed- should be aware that intravenous injection of 0.25% and
chest cardiac massage in the supine position.75 Third, 0.5% bupivacaine can also cause LAST.
a large bolus of drug injected into an epidural vein The availability of single levorotary isomers of a local
might reach the heart rapidly through a dilated azygous anesthetic may be advantageous because these drugs have
system. However, none of these factors adequately a greater margin of safety than bupivacaine, with similar
explains why cardiac arrest and difficult resuscitation are blocking properties, although at a higher cost. From the
very rare in parturients intoxicated with lidocaine or standpoint of systemic toxicity, the use of these isoforms
mepivacaine.66,76 may be more beneficial in parturients undergoing cesar-
Results of laboratory studies of the effects of ean delivery, who require higher doses than administered
pregnancy on bupivacaine cardiotoxicity have been con- for analgesia during labor. Nonetheless, a greater margin
tradictory. Pregnancy-related hormones enhance the of safety with these new drugs should not be a substitute
cardiotoxicity and arrhythmogenicity of bupivacaine for proper technique.
in vitro.77,78 For example, the magnitude and severity
of bupivacaine-induced electrophysiologic changes are Treatment of Systemic Toxicity
greater in myocardium obtained from nonpregnant
rabbits treated with progesterone or beta-estradiol than Meticulous attention to good technique and adherence
in myocardium from untreated controls.77,78 The electro- to guidelines for maximum recommended dose are man-
physiologic effects of lidocaine are less pronounced than datory. (The use of a test dose to identify misplaced
those of bupivacaine, even in hormonally treated animals. injections is discussed in Chapter 12.) Incremental injec-
Studies conducted in vivo have been less conclusive. In tion of the therapeutic dose, careful observation of the
earlier investigations, significantly lower doses and plasma patient, and monitoring of vital signs usually provide
concentrations of bupivacaine, but not of mepivacaine early warning of an impending reaction. In mild cases,
or lidocaine, were required to produce circulatory col- discontinuation of the administration of drug, adminis-
lapse in pregnant sheep than in nonpregnant sheep.49-51 tration of supplemental oxygen, and maintenance of
However, a study involving a larger number of sheep and normal ventilation often limit the severity of the reaction.
more rigorous methods (e.g., randomization, blinding) In 2012, the American Society of Regional Anesthesia
failed to confirm that pregnancy enhances the cardiotox- and Pain Medicine developed a checklist for managing
icity of bupivacaine.69 LAST (Box 13-1). In patients who show signs of CNS
Progesterone does not increase myocardial sensitivity excitation, a small dose of an intravenous sedative-
to ropivacaine.79 Likewise, pregnancy does not enhance hypnotic drug with strong anticonvulsant properties such
the systemic toxicity of ropivacaine or levobupivacaine as a benzodiazepine (diazepam up to 5 mg or midazolam
in sheep.69 1 to 2 mg) or propofol (10 to 20 mg) may prevent pro-
Extrapolation of results of animal studies to obstetric gression to convulsions.82 In one study, prophylactic
anesthesia practice is difficult, for several reasons. First, administration of a benzodiazepine reduced the incidence
in the aforementioned sheep studies, the drug was admin- of both convulsions and mortality in mice intoxicated
istered by constant-rate intravenous infusion. In contrast, with amide local anesthetics.83 However, propofol should
in pregnant women intoxicated with bupivacaine, cardiac be avoided in patients with cardiovascular instability
arrest occurred after unintended intravascular injection because of its cardiovascular depressant properties.82
268 PART IV Foundations in Obstetric Anesthesia
to the use of different methodologies and different incidence of TNS did not differ from that of historic
species.93,94 It has been suggested that neurotoxicity was controls given 5% lidocaine.
caused by sodium metabisulfite, an antioxidant present in Interestingly, the exposure of frog sciatic nerve to lido-
the commercial formulation used in the reported cases.93 caine results in a progressive, irreversible loss of impulse
The pH of this formulation was between 2.7 and 4.0. In activity beginning at a concentration of 1%.101 The inves-
CSF rendered more acidic by 2-chloroprocaine, metabi- tigators in this study noted that “the range of lidocaine
sulfite generates sulfur dioxide, which is lipid soluble and that produces such changes in mammalian nerve awaits
can diffuse into the nerve cells.95 Intracellular hydration determination.”101 Meanwhile, it seems prudent to take
of sulfur dioxide generates sulfurous acid, which may the following precautions99,106:
cause profound intracellular acidosis and irreversible 1. Dilute the commercial 5% lidocaine for intrathecal
damage. injection as recommended by the FDA.
Subsequently, the manufacturer released another 2. Administer the lowest possible dose.
preparation of 2-chloroprocaine, which was free of bisul- 3. Avoid the use of hyperbaric lidocaine in clinical
fite but contained ethylenediaminetetraacetic acid conditions (e.g., obesity) or situations (e.g., the
(EDTA). This was followed by several reports of severe, lithotomy position) that may be associated with a
incapacitating paralumbar pain and spasm associated with higher incidence of TNS.
epidural injection of large volumes of drug.96 The etiol- Generally, if pencil-point, side-hole spinal needles are
ogy is unclear, although chelation of calcium by disodium used, it is recommended that the injection port should be
EDTA may result in a reduced tissue calcium concentra- directed cephalad. However, an epidemiologic survey did
tion and local tetany of the affected muscles. not implicate dose and needle bevel direction as factors
In a 2004 study, Taniguchi et al.97 suggested that that affect the risk for TNS.106 A meta-analysis of ran-
sodium bisulfite was the “scapegoat” for 2-chloroprocaine domized controlled trials comparing spinal lidocaine
neurotoxicity. They concluded that neurologic deficits with other local anesthetics (bupivacaine, prilocaine, pro-
associated with unintentional intrathecal injection of caine, and mepivacaine) found that the relative risk (RR)
2-chloroprocaine likely resulted from a direct effect of for development of TNS was higher with lidocaine than
the 2-chloroprocaine, not the sodium bisulfite. with the other local anesthetic agents (RR, 4.35; 95%
The current preparation of 2-chloroprocaine that is confidence interval [CI], 1.98 to 9.54).107 It has not been
marketed for epidural administration does not contain conclusively proven that TNS are manifestations of
EDTA or other preservatives. It is packaged in colored neurotoxicity.
vials to reduce the oxidation of the 2-chloroprocaine. Pregnancy may be associated with a reduced risk for
Low-dose, preservative-free 2-chloroprocaine (30 to TNS. Studies suggest that the incidence of TNS after
60 mg) is now being studied as a possible alternative to spinal anesthesia with lidocaine or bupivacaine is equally
lidocaine for spinal anesthesia.98 low (< 3%) in women having cesarean delivery and those
Lidocaine has been used for spinal anesthesia for more undergoing postpartum tubal ligation.108,109
than 50 years, in thousands upon thousands of patients,
with apparent safety. However, cauda equina syndrome, Allergic Reactions
sacral nerve root deficits, or transient neurologic toxicity
can occur after subarachnoid injection of lidocaine.99,100 True allergy to a local anesthetic is rare.110 Further,
Neurotoxicity of local anesthetics is concentration depen- anaphylactic and anaphylactoid reactions may be the
dent101 and is not unique to lidocaine.102,103 Some inves- result of additives such as methylparaben and metabisul-
tigators have speculated that slow injection of local fite.110,111 Clinical criteria are important in the diagnosis
anesthetic through a spinal microcatheter results in mal- because there is often a delay in obtaining confirmatory
distribution and pooling of high concentrations of hyper- laboratory data. The alleged allergy to a local anesthetic
baric lidocaine in the cauda equina area, resulting in can be substantiated in only 15% of patients by a history
neurotoxicity and cauda equina syndrome.99,100 of urticaria, bronchospasm, facial edema, and/or cardio-
Milder manifestations of neurotoxicity also may occur. vascular instability.112 Adverse reactions (e.g., CNS and
As early as 1954, mild, transient neurologic symptoms cardiovascular symptoms) may mimic hypersensitivity
were reported after spinal anesthesia with lidocaine.104 but may not actually be a result of hypersensitivity. These
Transient neurologic symptoms (TNS) (dysesthesia or symptoms may be caused by hyperventilation or vasova-
low back pain radiating to the buttocks, thighs, and gal syncope during injection of the drug, sympathetic
calves) have been observed in surgical patients even after stimulation (e.g., palpitations, tachycardia) from epi-
conventional (i.e., single-shot) spinal anesthesia with nephrine, or edema related to the injection itself
hyperbaric 5% lidocaine (see Chapter 32).100 In response (Box 13-2).
to concerns that intrathecal injection of hyperbaric 5% Some pregnant women claim to be allergic to “Novo-
lidocaine might be associated with TNS, in 1994 the caine” or “the caine” drugs. Obstetricians should refer
FDA Advisory Committee on Anesthetic Drugs recom- such patients to an allergist and an anesthesiologist for
mended that the injected drug concentration be reduced appropriate evaluation well before the expected date of
by dilution with an equal volume of either preservative- delivery. In many cases, a carefully obtained history
free saline or CSF. However, Pollock et al.105 reported excludes true hypersensitivity. If IgE-mediated hypersen-
that there was no difference in the incidence of TNS sitivity is suspected, patients should be referred to an
when spinal lidocaine 50 mg was diluted to 2%, 1%, or allergist for further evaluation. Phillips et al.111 recom-
0.5% solutions before administration and that the overall mended testing with skin prick or intradermal testing
270 PART IV Foundations in Obstetric Anesthesia
Modified from Bhole MV, Manson AL, Seneviratne SL, Misbah SA.
IgE-mediated allergy to local anaesthetics: separating fact from perception:
a UK perspective. Br J Anaesth 2012; 108:903-911.
10 mm in diameter, with or without a flare, arises within
10 minutes of injection and persists for at least 30
minutes.113 If provocative dose testing is completed
using appropriate positive (diluted histamine) and nega- without a reaction, the local anesthetic used and the final
tive (normal saline) controls. Intradermal testing is more dose given should be recorded; the patient (and the refer-
sensitive but is associated with a false-positive rate of 8% ring physician) should be informed that her risk for an
to 15%.110 If the skin testing is negative, subcutaneous adverse reaction to subsequent administration of that
provocative dose testing is a useful method to confirm drug and dose is no greater than that for the general
that the drug is safe to use clinically.111 Alternatively, if population.114,115
skin testing is positive, the testing sequence (skin testing
followed by provocative subcutaneous testing) should be Management of an Allergic Reaction. Pharmacologic
repeated with an alternative agent. therapy of a severe allergic reaction involves (1) inhibi-
The subcutaneous provocative test can be performed tion of mediator synthesis and release, (2) reversal of the
by any physician qualified to manage hypersensitivity effects of these mediators on target organs, and (3) pre-
reactions. Appropriate emergency equipment and drugs vention of the recruitment of other inflammatory pro-
(e.g., epinephrine, H1- and H2-receptor antagonists) cesses. In general, catecholamines, phosphodiesterase
should be immediately available for resuscitation. inhibitors, antihistamines, and corticosteroids have been
Although not mentioned in many protocols, establishing used for this purpose (Box 13-3).116 Higher doses of
intravenous access before testing seems prudent. The catecholamines may be required in a patient who has
back and the ventral aspects of the forearm are the pre- received sympathetic blockade. In addition, pregnancy
ferred sites for testing. Areas with abnormal skin color- itself decreases responsiveness to catecholamines.117
ation or dermographia should be avoided. A history of Despite its potential adverse effect on uterine blood flow,
recent treatment with antihistamines, salicylates, or cor- epinephrine remains the cornerstone of therapy for aller-
ticosteroids may alter the test results.113 gic reactions. In one reported case, a mother was treated
The following protocol has been proposed by successfully with epinephrine 100 µg without any appar-
Chandler et al.114 (Table 13-2) and has been used success- ent adverse effects on the newborn.118
fully in at least one published case.115 After a negative
needle-prick test, increasing volumes of undiluted local
anesthetic (typically 1% concentration) are injected sub- Effects on the Uterus and Placenta
cutaneously at 15-minute intervals. In patients with an Uterine Blood Flow
especially strong history of a severe reaction, the series
may be preceded by injection of diluted solutions (e.g., a The association of paracervical block anesthesia with fetal
1 : 100 solution, followed by a 1 : 10 solution). A fresh bradycardia has been attributed to the high concentration
syringe and a 30-gauge needle should be used for each of local anesthetic deposited in the vicinity of the uterine
subsequent injection. Additional refinements may consist arteries (see Chapter 24). Human uterine artery segments
of the use of both a negative control and a positive control obtained at the time of cesarean hysterectomy constrict
injection. A local anesthetic that is not in the same class when exposed to high concentrations of lidocaine,119
as the drug in question should be tested; if an ester is mepivacaine,119 or bupivacaine.120
suspected as the offending agent, testing should be per- These findings also have been confirmed in laboratory
formed with an amide agent, and vice versa. If possible, animals. Fishburne et al.121 observed a dose-related
the drug tested should be suitable for local infiltration decrease in uterine blood flow during uterine arterial
and for epidural and subarachnoid block. infusion of 2-chloroprocaine, lidocaine, or bupivacaine
The test is considered positive if there is a change in in gravid ewes. A 25% reduction in uterine blood
the patient’s clinical status or if a skin wheal more than flow occurred at the following calculated plasma
13 Local Anesthetics and Opioids 271
BOX 13-3 Management of Anaphylaxis anesthetics supports the view that clinical concentrations
of these drugs do not adversely affect the uterine vascu-
INITIAL THERAPY lature (see Chapter 3).127,128
• Stop administration of antigen. All local anesthetics can reduce uterine blood flow at
• Maintain airway with 100% oxygen. plasma concentrations that greatly exceed those occur-
• Discontinue all anesthetic agents. ring during the routine practice of obstetric anesthesia.121
• Start intravascular volume expansion: 2-4 L of There has been an added concern that the levorotary
crystalloid/colloid (25-50 mL/kg) to treat hypotension. isomers of local anesthetics, which produce vasoconstric-
• Give epinephrine: tion at clinical doses,129 may reduce uteroplacental perfu-
• 5-10 µg intravenously for treatment of hypotension; sion and adversely affect fetal well-being. It is reassuring
titrate as needed to note that ropivacaine, even at plasma concentrations
• 0.5-1.0 mg intravenously for treatment of cardiovas- that are almost two times greater than would be expected
cular collapse
to occur during clinical use, does not reduce uterine
SECONDARY TREATMENTS blood flow or affect fetal heart rate (FHR), blood pres-
• Catecholamine infusions (starting doses): sure, or acid-base measurements in pregnant sheep.122 In
• Epinephrine: 4-8 µg/min (0.05-0.1 µg/kg/min) humans, Doppler velocimetry studies have shown that
• Norepinephrine: 4-8 µg/min (0.05-0.1 µg/kg/min) ropivacaine has little effect on the uteroplacental or fetal
• Isoproterenol: 0.05-0.1 µg/min circulation when it is administered to provide epidural
• Antihistamines: 0.5-1.0 mg/kg of diphenhydramine anesthesia for cesarean delivery.127 Similarly, clinically
• Corticosteroids: 0.25-1.0 g of hydrocortisone; alterna- relevant plasma concentrations of levobupivacaine had no
tively, 1-2 g (25 mg/kg) of methylprednisolone adverse effect on uterine blood flow.122
• Bicarbonate: 0.5-1.0 mEq/kg in patients with persis-
tent hypotension or acidosis
• Airway evaluation (before extubation) Umbilical Blood Flow
From Levy JH. Anaphylactic Reactions in Anesthesia and Intensive Care. Fetal well-being also depends on the adequacy of
Stoneham, MA, Butterworth-Heinemann, 1992:162. fetal perfusion of the placenta. The regulatory mecha-
nisms that control flow through the umbilical vessels are
poorly understood. Lidocaine does not affect spiral strips
obtained from human umbilical artery segments at con-
centrations up to 5 µg/mL, but it produces relaxation in
concentrations of local anesthetic: bupivacaine, 7 µg/mL; concentrations from 30 to 900 µg/mL.130 Bupivacaine
2-chloroprocaine, 11.5 µg/mL; and lidocaine, 19.5 µg/ also does not constrict umbilical artery segments at
mL. However, when plasma local anesthetic concentra- clinically relevant concentrations of 0.3 and 1 µg/mL.130
tions mimic those that occur in ordinary clinical practice, At higher concentrations, the effect of bupivacaine
local anesthetics have no adverse effect on uterine blood appears to be biphasic. Constriction occurs at concentra-
flow.122-124 In pregnant ewes, uterine blood flow remained tions of 5 to 25 µg/mL, and relaxation occurs at concen-
unchanged during an intravenous infusion of lidocaine trations greater than 125 µg/mL.130,131 Hypercarbia but
or bupivacaine that resulted in plasma concentrations not hypoxemia lessens the contractile response of umbili-
of 0.81 to 4.60 and 1.5 to 2.0 µg/mL, respectively.122,124 cal vessels to bupivacaine in vitro.132
Similarly, intravenous injection of 2-chloroprocaine, 0.67 Decreases in umbilical blood flow of as much as 43%
and 1.34 mg/kg, did not reduce uterine blood flow veloc- accompany intravenous administration of lidocaine 4 mg/
ity in pregnant guinea pigs.123 kg in pregnant sheep.133 However, plasma concentrations
Pregnancy may enhance uterine vascular reactivity to of the drug were higher than would be expected with
local anesthetic agents. Isolated human uterine artery clinical use, and all ewes exhibited signs of CNS toxicity,
segments obtained from term parturients constrict at a which may reduce umbilical blood flow.
lower lidocaine concentration than uterine artery seg- Advances in noninvasive Doppler imaging have
ments from nonpregnant patients.119,125 Uterine artery facilitated clinical assessment of umbilical cord blood
sensitivity to local anesthetics increases as early as the flow velocity. The ratio of the systolic (S) peak to the
second trimester of pregnancy and may be related to an diastolic (D) trough of the umbilical artery waveform is
increase in estrogen levels.119,121 However, these studies used as a measure of vascular resistance. The S/D ratio
were performed before the recognition of the importance in the umbilical artery decreases during normal preg-
of intact vascular endothelium in the in vitro assessment nancy, and high ratios usually are associated with fetal
of vascular tone. compromise (see Chapter 6). Local anesthetics adminis-
The exact mechanism by which high concentrations tered for epidural anesthesia do not adversely affect the
of local anesthetics cause uterine artery vasoconstriction umbilical artery S/D ratio.134,135 In fact, labor epidural
(while causing dilation in other vascular beds) is unclear. analgesia with 1.5% lidocaine or 2% 2-chloroprocaine
This vasoconstriction may result from modulation of resulted in a decrease in the S/D ratio.134,135 This favor-
calcium-channel regulation because verapamil and nife- able change may have resulted from pain relief. Other
dipine ablate the response.125 Alternatively, local anes- investigators have noted no appreciable change or a slight
thetics may affect cyclic nucleotides and alter the ionic decrease in the S/D ratio after the epidural administra-
content and contractility of uterine vascular smooth tion of amide local anesthetics for elective cesarean
muscle.126 Clinical experience with the use of local delivery.127,128,136
272 PART IV Foundations in Obstetric Anesthesia
Uterine Tone and Contractility anesthesia for enhancing analgesia during labor or for
providing effective pain relief after cesarean delivery.
Changes in uterine tone and contractility may affect Lidocaine is a frequently used drug for epidural anesthe-
uteroplacental perfusion. Local anesthetics exert direct sia during cesarean delivery. In a recent study,149 epidural
effects on uterine smooth muscle. One study reported administration of 20 to 35 mL of epidural 2% lidocaine
that exposure to high concentrations of local anesthetic with fentanyl 1 hour before administration of extended-
in vitro led to contraction of human myometrial segments release epidural morphine increased the peak plasma
obtained at the time of cesarean delivery.137 These find- concentration(Cmax) of morphine when compared with
ings have been corroborated in laboratory animals.138 similar women who received a combined spinal-epidural
Further, Belitzky et al.139 observed that direct intramyo- (CSE) technique (intrathecal bupivacaine and fentanyl)
metrial injection of 1% procaine resulted in uterine with no epidural medication for cesarean delivery (see
hyperstimulation and fetal compromise in pregnant Chapter 28).
women. In all of these reports, the myometrium was
exposed to higher than normal concentrations of the
drug. In other studies, however, intravenous infusion of Potency of Bupivacaine, Ropivacaine,
lidocaine or bupivacaine that resulted in clinically rele-
vant plasma concentrations did not affect uterine tone or
and Levobupivacaine
uterine activity in pregnant ewes.122,124 In a recent study The levorotary compounds ropivacaine and levobupiva-
using electrohysterogram monitoring, levobupivacaine caine were developed because of the concerns about the
caused less uterine muscle relaxation after intramyome- safety of high doses of bupivacaine. Many studies have
trial injection in rats than did bupivacaine.140 addressed the question of relative potency among the
three drugs. Ropivacaine is approximately 10 times less
lipid soluble (N-heptane/buffer) than bupivacaine, a dif-
Drug Interactions with 2-Chloroprocaine ference that is important for two reasons.2 First, ropiva-
caine may penetrate more slowly into the large, heavily
and Lidocaine myelinated motor neurons, resulting in less motor block
Epidural 2-chloroprocaine may affect the efficacy of than occurs with bupivacaine. Second, the issue raises
other drugs administered in the neuraxis. Previous questions as to whether ropivacaine is equipotent to bupi-
administration of 2-chloroprocaine (even a test dose) may vacaine. Indeed, a higher dose of ropivacaine is required
reduce the quality and duration of analgesia produced by to produce a sensory and motor block comparable with
subsequent epidural injection of morphine or fen- that produced by bupivacaine after spinal injection.150,151
tanyl.141,142 Several hypotheses have been proposed for Similarly, the EC50 (the local anesthetic concentration at
this antagonism. The low pH of the 2-chloroprocaine which 50% of women have pain relief, also known as the
solution may result in acidification of the epidural space minimum local anesthetic concentration [MLAC]) of
and thus may favor formation of the poorly diffusible, epidural ropivacaine is almost twice as great as that of
charged form of the opioid. Second, it has been suggested epidural bupivacaine in laboring women.59 Critics of the
that 2-chloroprocaine (or its metabolite, chloroamino- use of EC50 data to compare potency argue that it pro-
benzoic acid) may act as a specific μ-opioid receptor vides no information on the shape and slope of the dose-
antagonist because a κ-opioid receptor agonist (e.g., effect relationship, which can vary with drug concentration,
butorphanol) is not antagonized by 2-chloroprocaine.141 and further, that it provides no information on the effec-
However, using an in vitro hippocampal slice model, tive clinical dose (ED95 [effective dose in 95% of cases]).152
Coda et al.143 concluded that 2-chloroprocaine opioid Studies of the EC50 of epidural levobupivacaine are
antagonism did not appear to act through a μ-opioid conflicting; one study found that levobupivacaine was
receptor. Third, a “window” may be caused by the rapid essentially equipotent to bupivacaine,70 whereas others
regression of 2-chloroprocaine before the onset of anal- suggest that ropivacaine and levobupivacaine have similar
gesia with epidural morphine.144 This mechanism is sup- potency.153,154 Levobupivacaine may have a greater motor-
ported by the results of a study145 in which women who sparing effect than bupivacaine when given for the initial
received spinal bupivacaine anesthesia for cesarean deliv- intrathecal injection. For example, in one study, none of
ery were randomly assigned to receive either epidural 37 women who received intrathecal levobupivacaine
morphine with 2-chloroprocaine or epidural morphine 2.5 mg (with sufentanil and epinephrine) had evidence of
with saline-placebo. There was no difference in post– motor block.155 In contrast, 13 of 38 (34%) women given
cesarean delivery epidural morphine analgesia between intrathecal bupivacaine 2.5 mg demonstrated a Bromage
the two groups; presumably the spinal bupivacaine pro- grade 1 motor block.
vided adequate analgesia until the onset of epidural mor- In obstetric anesthesia practice, the clinical effects of
phine analgesia.145 epidural levobupivacaine and ropivacaine are indistin-
2-Chloroprocaine also reduces the subsequent efficacy guishable from those of epidural bupivacaine for labor
of bupivacaine.146 Corke et al.147 suggested that chloro- analgesia.156 The choice of bupivacaine, levobupivacaine,
aminobenzoic acid is responsible for this effect. Admin- or ropivacaine does not affect the method of delivery or
istration of buffered 2-chloroprocaine does not prevent neonatal condition.156 For cesarean delivery, epidural
the antagonism of epidural bupivacaine.148 levobupivacaine 0.5% is virtually identical to epidural
The use of neuraxial opioids alone or in combination bupivacaine 0.5%.157 The levorotary isomers (ropivacaine
with local anesthetics has become ubiquitous in obstetric and levobupivacaine) may provide a greater margin of
13 Local Anesthetics and Opioids 273
PLACENTA PLACENTA
FIGURE 13-5 ■ Demonstration of how distribution of local anesthetics across the placenta may be predicted from differences in drug
protein binding in maternal and fetal plasma. Left, lidocaine (L); f, b, t, free, bound, and total drug concentrations, respectively.
Right, bupivacaine (B). Lidocaine umbilical cord–to–maternal plasma ratio (F/M) = 0.67; bupivacaine F/M = 0.20. (From Tucker GT,
Mather LE. Properties, absorption, and disposition of local anesthetic agents. In Cousins MJ, Bridenbaugh PO, editors. Neural Blockade in
Clinical Anesthesia and Management of Pain. 2nd edition. Philadelphia, Lippincott, 1988:95.)
placental microsomal fraction, presumably because of Fetal acidosis and hypoxemia result in circulatory adapta-
cholinesterase activity within the placenta.175 Placental tions that increase blood flow to vital organs (e.g., brain,
metabolism of para-aminobenzoic acid also has been heart, adrenal glands).194 The concentration of lidocaine
demonstrated.176 in these organs is higher in asphyxiated fetuses than in
healthy fetuses.163,194
Any drug that reaches the fetus undergoes metabolism
Teratogenicity and excretion. The term newborn has the hepatic enzymes
The teratogenicity of anesthetics is not an issue during necessary to metabolize local anesthetics.17,18,195-197 None-
parturition, but local anesthetics often are used for pro- theless, the elimination half-life of these drugs is longer
cedures during the first trimester of pregnancy. In vitro in the neonate than in the adult.196,197 The use of mepi-
studies have suggested that local anesthetics may have vacaine in obstetric epidural analgesia fell into disfavor
some adverse developmental effects. Even at low concen- after a report indicating that the elimination half-life of
trations, these agents have caused reversible reduction of the drug in the neonate was approximately 9 hours, or
cell division in tissue culture.177-182 However, structural three times as long as the neonatal half-life for lido-
anomalies have not been observed in intact animals.183-185 caine.198 It is ironic that it was later discovered that the
Mid-pregnancy administration of lidocaine or mepiva- neonatal elimination half-life for bupivacaine may be as
caine in rats has been associated with behavioral changes long as 14 hours.199
in the offspring.186,187 Morishima et al.197 compared the pharmacokinetics of
Extrapolation of laboratory findings to humans is lidocaine among adult ewes and fetal and neonatal lambs.
tenuous for several reasons. First, a drug may be terato- The metabolic (hepatic) clearance in the lambs was
genic in one species but not in others. Second, a 1-hour similar to that in adults, and renal clearance was greater
drug exposure in a pregnant rat (with a gestation of 21 than that in adults. Nonetheless, the elimination half-life
days) is excessive and not analogous to several hours of was more prolonged in the lambs. This latter finding has
clinical anesthesia during human pregnancy. Third, the been attributed to a greater volume of distribution in the
doses of local anesthetics used in animal studies greatly lamb. Thus, at any given time, a smaller fraction of lido-
exceed those administered for clinical anesthesia. Indeed, caine accumulated in the body is available for clearance
a large, multicenter study demonstrated that the risk for by hepatic metabolism. The greater renal clearance noted
congenital anomalies in humans was not increased by the in neonates is a result of decreased protein binding, which
administration of benzocaine, procaine, tetracaine, or increases the proportion of drug available to the kidneys
lidocaine during early pregnancy.188 However, a twofold for excretion.
increase in the incidence of congenital anomalies was The elimination half-life of local anesthetics in the
noted in infants whose mothers had received mepiva- fetus is similar to that in the adult because, unlike the
caine. The small number of patients who received mepi- newborn, the fetus can excrete drug across the placenta
vacaine in this study (n = 82) and the fact that no adverse back to the mother.90,197 With bupivacaine, this transfer
effects occurred with the use of other amide agents have may occur even though the total plasma drug concentra-
raised doubts about the validity of this observation.189 tion in the mother may exceed that in the fetus.90
Systemic Toxicity
Fetal and Neonatal Effects
In general, the neonate is more sensitive than the adult
Pharmacokinetics
to the depressant effects of drugs. However, the seizure
Local anesthetics, once transferred across the placenta, threshold for local anesthetics in the neonate appears to
are distributed in the fetus. Factors that influence tissue be similar to that in the adult.200
uptake of the drug include (1) fetal plasma protein Morishima et al.201 compared the relative CNS toxic-
binding, (2) lipid solubility, (3) the degree of ionization ity and cardiovascular toxicity of lidocaine in adult ewes
of the drug, and (4) hemodynamic changes that affect the and fetal and neonatal lambs. Greater doses (when calcu-
distribution of fetal cardiac output. The fetal plasma lated on a milligram-per-kilogram basis) were required
protein-binding capacity of local anesthetics is approxi- to elicit toxic manifestations in the fetus and neonatal
mately 50% that of maternal plasma.90,91,190 Thus, at any lamb than in the adult. However, the plasma concentra-
given total plasma concentration of local anesthetic, there tions of the drug associated with toxic manifestations
is greater availability of free drug in the fetus than in the were similar in the three groups of animals. The greater
mother.90,91,190-192 Studies have examined the distribution dose tolerated by fetuses than by neonates and adults was
of lidocaine in fetal tissues after an intravenous injection attributed to placental clearance of drug back to the
of the drug to animals.19,193 The higher concentration of mother and better maintenance of blood gas tensions
lidocaine in the liver, myocardium, and brain (compared during convulsions. In the neonate, a large volume of
with other fetal tissues) reflects rapid distribution of the distribution is most likely responsible for the high doses
drug to highly perfused tissues. The only organ in which of local anesthetic required to have toxic effects.
lidocaine concentrations in the fetus have been found to Studies of bupivacaine cardiotoxicity are inconsistent.
exceed those in the mother is the liver. This finding is In vitro, the sinoatrial node of neonatal guinea pigs was
not surprising, given the high lipid content of the fetal found to be more sensitive than that of adults to the
liver and the fact that it receives most of the blood return- cardiodepressant effect of bupivacaine.202 In contrast,
ing from the placenta by means of the umbilical vein.193 2-day-old piglets demonstrated greater resistance than
276 PART IV Foundations in Obstetric Anesthesia
older animals to the arrhythmogenic and CNS effects of preterm fetus, these factors primarily affect drugs that are
bupivacaine.203 highly bound to these proteins. Most local anesthetics,
however, exhibit only low to moderate degrees of binding
in fetal plasma.90,91
Fetal Heart Rate
The placenta efficiently eliminates fetal bilirubin.
Changes in FHR after administration of local anesthetics Thus, the hyperbilirubinemia of prematurity normally
are most often related to indirect effects such as maternal occurs in the postpartum period. Bupivacaine has been
hypotension and uterine tachysystole (see Chapter 23). implicated as a possible cause of neonatal jaundice.210,211
Local anesthetics probably have little direct effect on High affinity of the drug for fetal erythrocyte membranes
FHR, except perhaps after paracervical block. Rather, may lead to a decrease in filterability and deformability,
labor itself may be the single most important factor that which may render red blood cells more prone to hemo-
alters FHR patterns.204 Transient changes in FHR vari- lysis.211 However, increased bilirubin production has not
ability and an increase in the incidence of periodic decel- been demonstrated in newborns whose mothers received
erations have been observed during administration of bupivacaine for epidural anesthesia during labor and
neuraxial analgesia in laboring women.205,206 In contrast, cesarean delivery.212,213
in the absence of labor, FHR patterns are not affected Greater total body water in the preterm fetus results
even by the larger doses of local anesthetics required in a larger volume of distribution for drugs. Thus, to
during administration of epidural anesthesia for cesarean achieve equal blood concentrations, the immature fetus
delivery.204 The FHR changes noted in laboring women must receive a greater amount of drug transplacentally
were transient and did not affect the condition of their than the mature fetus.
newborns.205,206 In a recent study, investigators found no The diminished ability to metabolize or excrete drugs
significant difference in the number or type of fetal elec- associated with prematurity is certainly not a universal
trocardiographic ST-segment changes (ST-waveform phenomenon. One study of the pharmacokinetics of lido-
analysis [STAN] events) in women with a high-risk sin- caine in preterm newborns noted that plasma clearance
gleton gestation who received epidural analgesia for labor was similar to that in adults.196
when compared with a control group of women who did During anesthesia for preterm labor, concerns about
not receive epidural analgesia.207 drug effects on the newborn are far less important than
the prevention of asphyxia and trauma to the fetus.
Indeed, healthy preterm fetal lambs tolerated clinically
Neurobehavioral Tests
relevant plasma concentrations of lidocaine (e.g., approx-
Neurobehavioral tests have been developed to detect imately 1.5 µg/mL) as well as mature ones.19,214
subtle changes in organized behavior in the newborn.
These tests include the Brazelton Neonatal Behavioral Asphyxia
Assessment Scale (NBAS), the Early Neonatal Neurobe-
havioral Scale (ENNS), and the Neurologic and Adaptive Circulatory adaptations important for fetal survival
Capacity Score (NACS). All the tests are subjective and during asphyxia result in increased blood flow and oxygen
complex and lack specificity. delivery to vital organs (e.g., heart, brain, adrenal
Other perinatal factors appear to have a more impor- glands).194 Little information exists about the effects of
tant effect on neonatal test performance than the choice local anesthetics on these fetal responses. Adaptation to
of local anesthetic.208 Indeed, neurobehavioral tests have asphyxia was unaffected in mature fetal lambs exposed to
been shown not to be a reliable measure of drug effect in lidocaine.194 In contrast, lidocaine adversely affected
the newborn.209 asphyxiated preterm fetal lambs, which experienced a
further deterioration of acid-base status and a reduction
in cardiac output and blood flow to the brain and heart
Preterm Fetus and Newborn
(Figure 13-6).215 Also in asphyxiated preterm fetal lambs,
It has become axiomatic that the preterm infant is more exposure to bupivacaine reduced blood flow to vital
vulnerable than the term infant to the effects of analgesic organs; however, FHR, blood pressure, and acid-base
and anesthetic drugs. Causes of enhanced drug sensitivity measurements did not change.216
in the preterm newborn that have been postulated are as After performing an in vitro study using perfused
follows: (1) less protein is available for drug binding, (2) human placentas, Johnson et al.217 suggested that bupiva-
higher levels of bilirubin are present and may compete caine might be preferable to lidocaine in the presence of
with the drug for protein binding, (3) greater access of fetal acidosis because the greater maternal protein binding
the drug to the CNS occurs because of a poorly devel- of bupivacaine may limit its placental transfer. However,
oped blood-brain barrier, (4) the preterm infant has this methodology does not consider the potential for
greater total body water and less fat content, and (5) the greater fetal tissue uptake of bupivacaine (than of lido-
preterm infant has a diminished ability to metabolize and caine) because bupivacaine is more lipid soluble and more
excrete drugs. Unfortunately, few systematic studies have protein bound than lidocaine.
determined the maternal and fetal pharmacokinetics and In 1997, Santos et al.216 reported that the effects of
pharmacodynamics of drugs throughout gestation; nev- bupivacaine appeared less severe than those of lidocaine
ertheless, these deficiencies of the preterm infant may not in asphyxiated preterm fetal lambs. However, the lido-
be as serious as we have been led to believe. Although the caine data were generated in a separate experiment
plasma albumin and AAG concentrations are lower in the reported in 1989.215 There are inherent limitations in a
13 Local Anesthetics and Opioids 277
HO 2
3 1
Control
600
Asphyxia 4 CH3O
Asphyxia + 11 N
12 10 CH3O
lidocaine O
500 13 9 17
14 N CH3 CH2
5
Blood flow (mL/min/100 g)
15 OCH3
16
HO 6 8
400 7 OCH3
Morphine Papaverine
300
FIGURE 13-7 ■ Naturally occurring opioids: phenanthrenes (e.g.,
morphine) and benzylisoquinolines (e.g., papaverine).
200
HO 3 2
1
4
11
12 10
O
13 9 17
14 N CH3
5
15 16
O 6 8
7
Hydromorphone
OH
7 6
14 8
5
N 9 13
CH3
16 15 O
10 12
11
4
FIGURE 13-10 ■ Chemical structures of phenylpiperidine, meperi-
1 3 OH dine, and the 4-anilinopiperidine derivatives fentanyl, sufent-
2 anil, alfentanil, and remifentanil.
Morphine
V
Intermedial cell column
VI
(autonomic neurons) X
T1-L2 VII
S1-S4
VIII IX
Interstitial nucleus
IX
Flexors IXM
IX
model to continuously sample opioid concentrations in diffuse within the CSF in either a cephalad or a caudad
the epidural and intrathecal spaces. Using microdialysis direction. Both morphine and fentanyl have been shown
techniques, the investigators measured the redistribution to move rapidly within the CSF.244 Lipophilic drugs can
of morphine, alfentanil, fentanyl, and sufentanil out of also return to the epidural space by traversing previously
the epidural space. (These opioids were administered by mentioned structures.
epidural bolus injection.) Opioid concentrations were Ummenhofer et al.243 used a porcine model to inves-
measured over time in the epidural space, subarachnoid tigate intrathecal administration of opioids. These inves-
space, systemic venous plasma, and epidural venous tigators found that lipophilic opioids have a very large
plasma. Results suggested that there was a strong linear volume of distribution compared with hydrophilic drugs;
relationship between lipid solubility and mean residence the volume of distribution of sufentanil was 40 times
time, indicating that more lipid-soluble opioids spent a greater than that of morphine. The reason is sufentanil’s
longer time in the epidural space. Consequently, these extreme lipid solubility, with the drug rapidly leaving the
drugs partition themselves into the epidural fat with CSF and entering the epidural fat, from which it is
ongoing slow release back into the epidural space. Because absorbed systemically.245
of their long residence time in the epidural space, more The ultimate goal of neuraxial opioid administration
lipid-soluble drugs are found in lower concentrations is for the drug to penetrate the dorsal horn of the spinal
in the CSF (i.e., decreased bioavailability to opioid cord and activate μ-opioid receptors. A drug’s ability to
receptors in the dorsal horn). move from the CSF to the dorsal horn depends on its
Several human studies have evaluated whether epidur- physicochemical properties. Of the clinically relevant
ally administered fentanyl produces analgesia by a selec- opioids, morphine has the most favorable physicochemi-
tive spinal mechanism or by systemic absorption and cal properties to allow penetration of the dorsal horn of
redistribution. Results of studies of lipophilic opioids the spinal cord (i.e., gray matter). Because of its extreme
(administered by epidural infusion) have suggested that lipid solubility, sufentanil redistributes itself or partitions
low concentrations of lipophilic opioids are subject to itself on the superficial layer (i.e., white matter) of the
rapid vascular uptake from the epidural space or seques- spinal cord.243 Data suggest that the spinal bioavailability
tration in epidural fat, thereby limiting access to the of the hydrophilic drugs (e.g., morphine, hydromor-
spinal cord.237-239 However, other studies have suggested phone) is greater than that of hydrophobic opioids (e.g.,
the occurrence of a spinal effect when lipophilic opioids fentanyl, sufentanil).
are administered by epidural bolus injection240 or by epi- An extended-release formulation of morphine has
dural infusion of short duration.241 Ginosar et al.242 com- been developed to prolong the duration of a single epi-
pared the analgesic effects of epidural bolus injection and dural injection of morphine or obviate the need for a
epidural infusion of fentanyl in human volunteers. Study continuous catheter. Multivesicular liposomal prepara-
results suggested that epidural fentanyl infusion pro- tions gradually release morphine so that a larger epidural
duced analgesia by uptake into the systemic circulation dose can be administered, providing analgesia for up to
with redistribution to brain and peripheral opioid recep- 48 hours (see Chapter 28). Studies that have compared
tors. However, epidural bolus administration of fentanyl extended-release epidural morphine (EREM) 10 to
produced analgesia by selective spinal mechanisms. These 15 mg with conventional epidural morphine for provi-
results were consistent with previous reports that an epi- sion of analgesia after cesarean delivery have determined
dural fentanyl bolus results in a larger amount of fentanyl that EREM provided superior and prolonged analge-
in the epidural space than occurs at any time during an sia.246,247 The most recent American Society of Anesthe-
epidural infusion, leading to the greater availability of siologists Practice Guidelines for the Prevention,
drug to activate opioid receptors in the dorsal horn of the Detection, and Management of Respiratory Depression
spinal cord. Associated with Neuraxial Opioid Administration state
Although hydrophilic drugs (e.g., morphine) are that “the literature reports no significant difference in
subject to less systemic and epidural fat uptake than lipo- the frequency of respiratory depression when [EREM]
philic drugs, the transfer of the former into the CSF is is compared with conventional (i.e., immediate release)
an inefficient process because they have difficulty in epidural morphine.”248 However, in a study of patients
crossing the lipid bilayer of the arachnoid. However, undergoing cesarean delivery, Atkinson Ralls et al.149
despite these inefficiencies, morphine content in the observed that epidural administration of 20 to 35 mL of
spinal cord is significantly greater than lipophilic drug epidural lidocaine 2% with fentanyl 1 hour before admin-
(e.g., fentanyl) content,243 and morphine has much greater istration of EREM (8 mg) increased the mean (± SD)
bioavailability in the spinal cord than do fentanyl and peak plasma concentration (Cmax) in the EREM group
sufentanil.236,243 In summary, although morphine clearly (11.1 ± 4.9 ng/mL) compared with a group that received
produces analgesia via a spinal mechanism, the extent of a CSE anesthetic technique without epidural medication
spinal analgesia produced by the neuraxial administration (8.3 ± 7.1 ng/mL) (P = .038). Further, the EREM group
of fentanyl is less clear. had an increased incidence of vomiting, hypotension, and
After a drug reaches the subarachnoid space, either by use of supplemental oxygen. Patients who receive EREM
diffusion across the meninges or by direct injection into should be monitored at least once every hour during the
the CSF, its effects depend on its lipid solubility. All first 12 hours after administration and at least once every
opioids produce at least some analgesia by spinal-specific 2 hours for the next 12 hours (i.e., from 12 to 24 hours).248
mechanisms. Movement of these drugs within the CSF After 24 hours, monitoring should be performed at least
depends on their physicochemical properties. Drugs can once every 4 hours for a minimum of 48 hours. Increased
282 PART IV Foundations in Obstetric Anesthesia
intensity and duration of monitoring should be consid- administration of morphine compared with women
ered in patients at increased risk for respiratory depres- without the variant allele. In a second study, the variant
sion (e.g., obesity) or in the setting of concomitant allele was found to independently predict increased post-
administration of opioid analgesics or sedative-hypnotics operative morphine use in women undergoing cesarean
by other routes. Extra precautions should be taken when delivery.256
patients receive EREM within 1 hour of large doses The results of these studies are difficult to reconcile.257
of local anesthetic149 or when unintentional spinal admin- Although genetic components may influence patients’
istration occurs.249 responses to nociceptive stimuli, current evidence
In summary, the onset and duration of analgesia as suggests that genetic polymorphism in OPRM1 plays a
well as side effects produced by neuraxial opioid admin- minor role, if any, in opioid pain management.251,257 A
istration depend on the specific type of opioid receptor recent meta-analysis examining the 304A>G variant of
that is activated as well as the dose, lipid solubility, and OPRM1 failed to identify a strong association between
rate of movement and clearance of the opioid in the CSF. this variant allele and the response to opioids in different
clinical settings.251
Pharmacogenetics
Pain associated with labor and delivery is influenced by
Toxicity
a multitude of physiologic, psychosocial, and environ- Any agent that is injected into the epidural or subarach-
mental factors. However, genetic variations have also noid space should be administered with caution owing to
been suggested to alter a patient’s sensation, experience, the potential for neurotoxicity and permanent neurologic
and perception of pain. Recent advances in genomic damage. Although there is concern about injecting any
research have led to identification of more than 100 vari- type of medication into the neuraxis, the epidural space
ants (polymorphisms) in the μ-opioid receptor gene is more forgiving than the subarachnoid space (see
(OPRM1).250 Although inconsistent, results of some Chapter 32). In many cases, clinicians have injected med-
studies suggest that a single-nucleotide polymorphism ications that were not well tested in animal models. Yaksh
(SNP) in OPRM1 at position 118 (initially known as and Collins258 have urged careful administration of neur-
118A>G, now annotated 304A>G; rs1799971) may influ- axial drugs, stating that “studies in animals should precede
ence responses to opioid analgesics.251 The allelic fre- human use of spinally administered drugs.”
quency of the 304A>G polymorphism is population The most commonly administered neuraxial opioids
dependent; it is more common in Asians and less frequent in obstetric patients are preservative-free morphine, fen-
in whites and blacks. tanyl, and sufentanil. Preservative-free morphine is com-
The role of the 304A>G polymorphism has been mercially available for both epidural and intrathecal
investigated in obstetric anesthesia. Using both up-down administration. To evaluate preservative-free morphine
sequential allocation and random allocation methods, for potential neurotoxicity, Abouleish et al.259 examined
Landau et al.252 estimated the ED50 of intrathecal fen- the short- and long-term effects of intrathecal morphine
tanyl, administered as part of a CSE technique for labor injection in monkeys. The meninges, nerve roots, and
analgesia in nulliparous women with and without the dorsal root ganglia were examined macroscopically and
304A>G variant. The ED50 of intrathecal fentanyl in microscopically in both the study and the control groups.
women with the variant allele was lower than in women The researchers found no evidence of demyelination,
without the allele (1.5- to 2-fold difference). However, arachnoiditis, or necrosis in either group.
when Wong et al.253 investigated the effect of the 304A>G Fentanyl is also available in a preservative-free formu-
allele on the duration of intrathecal fentanyl labor anal- lation. Despite its widespread clinical use, few studies
gesia (25 µg), they found no significant difference in the have assessed the histologic, physiologic, or clinical evi-
duration of analgesia or in the treatment of breakthrough dence of neurotoxicity with spinally administered fen-
pain in women with the variant allele. Camorcia et al.254 tanyl. One in vitro study evaluated the effects of fentanyl
examined the effect of the 304A>G variant on the ED50 administration on nerve conduction.260 Histopathologic
of epidural sufentanil in nulliparous women. Similar to studies of isolated rabbit vagus nerve axons did not show
the findings of the Landau et al. study,252 the estimated localized nerve damage after nerves were bathed in an
ED50 was significantly lower in women with the variant isotonic solution of fentanyl. When axons were bathed in
allele (20.2 µg; 95% CI, 14.2 to 23.6) compared with a hypotonic solution of fentanyl, permanent conduction
women without the variant (25.2 µg; 95% CI, 23.2 to deficits were noted. However, in vivo, relatively large
26.4) (P = .03). doses of fentanyl would be required to create a hypotonic
The potential role of the 304A>G polymorphism in intrathecal environment.
influencing opioid analgesic requirements after cesarean Although no formal neurotoxicology studies have
delivery has been investigated in several studies. Wong evaluated sufentanil administration in humans, there are
et al.,253 in a mixed race/ethnicity population, found no clinical reports of neurotoxicity despite its widespread
no difference in duration of intrathecal morphine anal- use. In one study, sufentanil was administered to cats
gesia or need for supplemental analgesia in women car- through an indwelling intrathecal catheter over 5 days.261
rying the variant allele. In contrast, Sia et al.255 reported Sabbe et al.262 administered clinically relevant doses of
that Asian women with the variant allele had increased intrathecal sufentanil to dogs over several weeks and
breakthrough pain (as assessed by patient-controlled reported no histopathologic changes. In a sheep model,
intravenous morphine requirements) after intrathecal Rawal et al.263 demonstrated dose-dependent spinal cord
13 Local Anesthetics and Opioids 283
its use because of concern for QT-interval prolongation effects of ondansetron and dolasetron in the treatment
in association with droperidol administration. Intrave- of intrathecal morphine–induced pruritus. Study results
nous cyclizine 50 mg was shown to be superior to demonstrated that patients who received preemptive
dexamethasone 8 mg in reducing nausea after intrathe- 5-HT3–receptor antagonists reported significantly less
cal morphine administration for cesarean delivery.275 pruritus and pruritus of less severity during the first 8
Another systematic review of randomized controlled postoperative hours than patients who received placebo.
trials compared dexamethasone with placebo for the pre- The frequency of pruritus was reduced by 48% and
vention of postoperative nausea and vomiting in patients 70% for ondansetron and dolasetron, respectively, com-
receiving neuraxial morphine as part of a neuraxial tech- pared with placebo. A quantitative systematic review
nique.276 Results suggested that dexamethasone is an evaluated the efficacy of prophylactic 5-HT3 receptor
effective antiemetic agent, and doses used for antiemetic antagonists for the prophylaxis and treatment of neur-
prophylaxis enhanced postoperative analgesia compared axial opioid-induced pruritus. The investigators deter-
with placebo. mined that prophylactic 5-HT3 receptor antagonists did
not alter the incidence of pruritus compared with placebo
but did reduce the incidence of severe pruritus and the
Pruritus
need for therapy.274 Additionally, 5-HT3 receptor antago-
Pruritus is the most common side effect of neuraxial nists were efficacious for the treatment of established
opioid administration.264,277 Presentation is highly vari- pruritus.
able, but the incidence and severity seem to be dose Other treatments of intrathecal opioid–induced pruri-
dependent, especially with epidural opioid administra- tus include administration of intravenous naloxone (40
tion.278 Onset of the pruritus occurs shortly after analge- to 80 µg) or diphenhydramine (25 mg). Despite the
sia develops, and even small doses of intrathecal sufentanil probability that the pruritus is unrelated to histamine
may produce significant pruritus.279 Some observers have release, there may be some benefit from the modest
noted a segmental pruritus, especially with lipophilic sedation that follows diphenhydramine administration.
opioids. For example, patients often complain of perineal Administration of nalbuphine (2.5 to 5 mg intrave-
and truncal pruritus after intrathecal sufentanil injec- nously288,289 or 10 mg subcutaneously288,290) may also be
tion.264 Pruritus occurs more commonly with intrathecal helpful in reducing symptoms. The advantage of nalbu-
opioid administration than with epidural administration phine compared with naloxone is that it is less likely to
(in one study,271 41.4% versus 1.3%, respectively). The reverse neuraxial opioid analgesia.289 Although propofol
incidence and severity of pruritus may be reduced 10 to 20 mg was found effective for the treatment of
by administration of a lower dose of opioid279,280 or pruritus in several studies in nonobstetric patients, its
co-administration of the opioid with a local anesthetic.281 efficacy was no better than placebo in an obstetric study.291
Many patients do not complain about the pruritus and Regardless of the chosen treatment, pruritus can contrib-
appear asymptomatic; however, when questioned, they ute significantly to patient dissatisfaction and should be
acknowledge the symptom. treated promptly upon request.
Although the cause of opioid-induced pruritus is
unknown, it appears to be unrelated to histamine Hypotension
release.282 Some investigators have suggested that pruri-
tus results from a perturbation of sensory input resulting Decreased blood pressure was reported in early studies
from rostral spread of the opioid within the CSF to the that evaluated intrathecal opioid administration.264,269
trigeminal nucleus or subnucleus caudalis.282 Itch-specific Although hypotension occurs in 5% to 10% of parturi-
neuronal pathways may interact with pain pathways so ents who receive intrathecal opioids,264,269 the incidence
that continuing activity of the pain-processing system is higher when a local anesthetic or clonidine is added to
suppresses activity in the spinal itch-processing neurons. the opioid. Early reports suggested that hypotension was
Consequently, if pain is inhibited, pruritus can be due to a sympathectomy, but later work suggests that
unmasked (e.g., intrathecal morphine–induced pruritus). hypotension results from pain relief292 and decreased
Pruritus can also be inhibited by pain (e.g., antipruritic maternal levels of catecholamines, especially epineph-
effect of scratching).283 rine.293 Wang et al.294 demonstrated that intrathecal
The serotoninergic system may contribute to modula- opioids block the afferent information from A-delta and
tion of pain by providing a balance between nociception C-fibers to the spinal cord but that efferent nerve impulses
and anti-nociception in the network of pain-processing (e.g., sympathetic efferents) are not directly blocked.
neurons.284,285 The dorsal horn of the spinal cord and
the spinal tract of the trigeminal nerve are abundant in Respiratory Depression
5-HT3 receptors. Because morphine is known to activate
5-HT3 receptors by a mechanism independent of opioid All opioids can cause respiratory depression regardless of
receptors,286 it is postulated that morphine may directly their route of administration. When opioids are admin-
stimulate 5-HT3 receptors and may cause intrathecal istered either epidurally or intrathecally, the following
morphine–induced pruritus. Consequently, occupation factors affect the risk for respiratory depression: (1)
of 5-HT3 receptors by a 5-HT3–receptor antagonist choice of drug and its pharmacokinetics, (2) drug dose,
potentially prevents the pruritus. and (3) concomitantly administered CNS depressants.
Iatrou et al.287 performed a randomized, double-blind, The most important factor affecting the onset time of
placebo-controlled study to evaluate the prophylactic respiratory depression induced by intrathecal opioids
13 Local Anesthetics and Opioids 285
20
18
16
FIGURE 13-13 ■ Respiratory rate of an obstetric patient who received 5 mg of morphine after cesarean delivery and who experienced
delayed respiratory depression. (From Leicht CH, Hughes SC, Dailey PA, et al. Epidural morphine sulfate for analgesia after cesarean
section: a prospective report of 1000 patients [abstract]. Anesthesiology 1986; 65:A366.)
is lipid solubility.270 Respiratory depression may occur of respiratory depression in obstetric patients who have
within minutes after the administration of a lipophilic received the extended-release preparation.
opioid (e.g., fentanyl, sufentanil) because of rapid absorp- Although most cases of respiratory depression associ-
tion of the opioid from the CSF to lipophilic tissues.234 ated with sufentanil administration occur with larger
Its subsequent clearance and elimination are similar to doses, respiratory depression has also been reported with
those of the drug when injected intravenously; thus the as little as 10 µg of intrathecal sufentanil administered for
“time frame” for respiratory depression is short. In con- labor analgesia.300,301 Larger doses (e.g., 15 µg) have not
trast, hydrophilic drugs (e.g., morphine, hydromorphone) been found to produce better or more prolonged analge-
are associated with a delayed onset of respiratory depres- sia but do result in increased plasma opioid concentra-
sion. This potentially serious side effect occurs because tions and a higher risk for respiratory depression. In a
these hydrophilic opioids remain in the CSF for several female volunteer study, Lu et al.245 reported that doses of
hours. Although this characteristic improves the bioavail- intrathecal sufentanil larger than 12.5 µg did not produce
ability of these opioids, rostral migration and absorption a proportionate increase in intensity or duration of anal-
of the drug into the respiratory centers in the brainstem gesia. Similarly, there is little benefit to increasing the
can produce respiratory depression 6 to 12 hours after dose of intrathecal fentanyl beyond 25 µg when it is used
injection (Figure 13-13). as the sole agent for labor analgesia. These higher doses
The dose of opioid has also been shown to be (i.e., more than 10 µg of sufentanil or more than 25 µg
an important factor in the occurrence of respiratory of fentanyl) should not be used in routine clinical prac-
depression. The usual dose of intrathecal morphine for tice. Respiratory depression has been reported with as
analgesia after cesarean delivery is 0.1 to 0.2 mg. Not little as 100 µg of epidural fentanyl.302
surprisingly, an early report of respiratory depression Several case reports have implicated previous paren-
occurred after administration of intrathecal morphine teral administration of opioid as a contributing factor in
1 mg.295 In a dose-response study, Palmer et al.296 con- respiratory arrest associated with intrathecal sufentanil
cluded that there was little justification for giving more administration in laboring women.303,304 For example,
than 0.1 mg of intrathecal morphine for analgesia after Jaffee et al.305 reported a case of apnea and unresponsive-
cesarean delivery. In a dose-response study of epidural ness in a parturient who had received several doses of
morphine administration after cesarean delivery, investi- intravenous fentanyl in the 4 hours before intrathecal
gators concluded that the quality of analgesia increases sufentanil administration. Although the pregnancy-
as the dose of epidural morphine increases to 3.75 mg induced increase in respiratory drive continues through-
but that increasing the dose to 5 mg does not improve out labor and into the postpartum period and may provide
analgesia.297 some protection against respiratory depression, respira-
Studies in nonobstetric surgical patients suggest that tory depression is the most serious side effect of neuraxial
the risk for respiratory depression after the epidural opioid administration.
administration of EREM is also dose related.298,299 Carv- Practice guidelines from the American Society of
alho et al.247 compared EREM (10 mg) administration Anesthesiologists recommend that all patients who
with standard epidural morphine (4 mg) administration receive neuraxial opioids should be monitored for ade-
in healthy women undergoing cesarean delivery and quacy of ventilation (e.g., respiratory rate, depth of
found that EREM reduced opioid consumption for 48 respiration), oxygenation (e.g., pulse oximetry when
hours without significant risk for respiratory depression. appropriate), and level of consciousness.248 In patients
However, the authors cautioned that the study’s small who receive a single neuraxial injection of a lipophilic
sample size may not accurately reflect the true incidence opioid (e.g., fentanyl), monitoring should be continual
286 PART IV Foundations in Obstetric Anesthesia
100
80
40
21 Volunteers
2 Mg Ep. Morphine (n = 5)
4 Mg Ep. Morphine (n = 5)
20 10 Mg Ep. Morphine (n = 5)
10 Mg I.M. Morphine (n = 3)
10 Mg I.V. Morphine (n = 3)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (h)
Morphine
FIGURE 13-14 ■ Urodynamic effects of epidural (Ep.), intramuscular (I.M.), and intravenous (I.V.) morphine administration in male
volunteers. Depression of detrusor muscle function persisted for many hours after epidural morphine administration. This did not
occur with parenteral opioids and may represent a local spinal cause (i.e., opioid receptors). (From Rawal N, Mollefors K, Axelsson K,
et al. An experimental study of urodynamic effects of epidural morphine and of naloxone reversal. Anesth Analg 1983; 62:641-7.)
for the first 20 minutes after administration, followed by Delayed Gastric Emptying
monitoring at least once per hour until 2 hours have
passed. In patients who receive a single neuraxial injec- Labor may delay gastric emptying, and opioids may
tion of a hydrophilic opioid (e.g., morphine), monitoring further exacerbate this delay (see Chapter 29). Parenter-
should be performed at least hourly for the first 12 hours ally administered opioids are known to delay gastric emp-
and then at least every 2 hours for the next 12 hours after tying in laboring women.307 However, clinically useful
opioid administration (and then every 4 hours for another doses of epidural fentanyl have minimal effects on gastric
24 hours in patients who receive epidural EREM). For emptying. Intrathecal administration of fentanyl pro-
patients who receive a continuous infusion of a neuraxial duces greater delays in gastric emptying than epidural
opioid, monitoring should be performed hourly during administration.308 Delays in gastric emptying may increase
the first 12 hours, every 2 hours for the next 12 hours, the risk for nausea and vomiting and also increase the
and then every 4 hours for the duration of the opioid risk for aspiration if general anesthesia is necessary for
infusion. In addition, the guidelines state that greater emergency cesarean delivery.
duration and intensity of monitoring and/or additional
methods of monitoring may be indicated in patients at Recrudescence of Herpes Simplex
increased risk for respiratory depression (e.g., obesity, Virus Infections
obstructive sleep apnea, concomitant administration of
opioid analgesics by other routes). Genital herpes infection (herpes simplex virus [HSV]) is
the most common type of herpes-virus infection during
pregnancy309; however, oral HSV infections (common
Urinary Retention
cold sore or fever blister) resulting from reactivation of
Urinary retention is a bothersome side effect of intraspi- latent HSV infection also occur during pregnancy. Reports
nal opioid administration. The incidence varies widely. It have suggested a relationship between neuraxial opioid
is more common with neuraxial opioid administration administration and reactivation of oral herpes infection.310
than with intramuscular or intravenous administration of Crone et al.311 reported a 10% incidence of reactivation
equivalent doses. Urinary retention is unrelated to sys- after cesarean delivery in patients who had received epi-
temic absorption and is dose independent. The onset of dural morphine, compared with a 1% incidence in similar
urinary retention appears to parallel the onset of analge- patients who did not receive epidural morphine. These
sia. Evidence suggests that the rapid onset of this side observations have been confirmed in two prospective
effect is produced by relaxation of the detrusor muscle studies.312,313 Davies et al.314 reported an increased inci-
(Figure 13-14),306 which most likely results from the dence of postpartum herpes infection in patients with a
sacral spinal action of opioids. Urinary retention can be history of HSV-1 who had received intrathecal morphine.
treated with naloxone; however, because many parturi- Two case reports have reported an association between
ents require catheterization for other reasons, urinary intraspinal administration of fentanyl and meperidine and
retention is often treated with bladder catheterization. reactivation of oral herpes infection.315,316
13 Local Anesthetics and Opioids 287
The mechanism of herpes reaction is unknown.310 administration. Several reports have described the abrupt
Viral reactivation is known to occur with exposure to onset of fetal bradycardia after intrathecal administration
ultraviolet light, immunosuppression, trauma, and fever. of fentanyl or sufentanil.326-328 Clarke et al.327 suggested
Proposed causes include (1) a skin trigger mechanism, that the bradycardia is an indirect effect of decreased
whereby pruritus and scratching trigger reactivation; circulating maternal epinephrine associated with the
(2) an altered immunologic response317; and (3) a gan- rapid onset of analgesia. Epinephrine has a tocolytic
glion trigger mechanism, whereby the intraspinal opioid effect and causes uterine relaxation by stimulating β2-
spreads rostrally and binds to the trigeminal nerve.318 The adrenergic receptors. Consequently, reduced epinephrine
ganglion trigger mechanism involves an alteration of levels may lead to increased uterine tone. Because utero-
sensory modulation that results in reactivation. We are placental perfusion occurs during periods of uterine dias-
unaware of any serious maternal or neonatal complica- tole (i.e., uterine relaxation), uterine tachysystole may
tions that have resulted from neuraxial administration of result in diminished uteroplacental perfusion and fetal
an opioid and reactivation of oral herpes infection. hypoxia. Norepinephrine is known to have a uterine-
stimulating effect329; thus the decrease in epinephrine
Placental Transfer and Fetal concentration alongside an unchanged norepinephrine
concentration may produce uterine hyperactivity and
and Neonatal Effects fetal compromise.
Neuraxial opioid administration may have a direct effect Other mechanisms may also be relevant. Van de Velde
on the infant (i.e., respiratory depression at delivery) that et al.330 questioned the catecholamine imbalance theory,
results from systemic absorption of the opioid followed because intrathecal bupivacaine combined with low-dose
by transplacental transfer. The fetus may also be affected sufentanil (1.5 µg) produced analgesia similar to that
indirectly by opioid-related maternal side effects (i.e., provided by intrathecal sufentanil (7.5 µg), but the inci-
hypoxemia, respiratory depression). dence of fetal bradycardia was higher with sufentanil
7.5 µg. Russell et al.331 demonstrated that intravenous
opioids have central effects, altering the release of oxyto-
Neonatal Depression
cin and vasopressin and inducing uterine hyperactivity.
Systemic opioid absorption can result in neonatal respi Lipid-soluble opioids undergo rapid systemic redistribu-
ratory depression, which is sometimes observed after tion after neuraxial injection; therefore, even neuraxial
systemic opioid administration during labor.319,320 Neur- opioids may have central effects.
axial opioid analgesia techniques may result in better Initial reports indicated that the incidence of FHR
Apgar scores and umbilical cord blood gas and pH mea- abnormalities with intrathecal opioid analgesia was 15%
surements at delivery. Despite the rapid systemic uptake to 20%.264,332 One published report suggests that uterine
of intrathecally administered opioids, the neuraxial anal- tachysystole and fetal bradycardia may follow administra-
gesia requires the administration of smaller doses of tion of either intrathecal or epidural analgesia during
opioid. labor.333 FHR tracings were assessed after administration
Several studies have evaluated neonatal outcome after of either intrathecal sufentanil or epidural bupivacaine.
continuous maternal epidural infusion of opioids and There were no observed differences in the incidence of
local anesthetics.321-323 Collectively, these studies have FHR abnormalities (i.e., recurrent late decelerations and/
demonstrated that maternal epidural opioid administra- or bradycardia) between groups (22% in the intrathecal
tion by continuous infusion rarely results in drug accu- sufentanil group versus 23% in the epidural bupivacaine
mulation and subsequent neonatal depression. Reynolds group).333 In contrast, Mardirosoff et al.334 performed a
et al.324 performed a systematic review of randomized systematic review of all randomized trials comparing
and nonrandomized studies comparing epidural with intrathecal with non-intrathecal administration of opioids
systemic opioid analgesia. They reviewed 12 trials with in laboring women. Twenty-four trials met criteria; the
a total study population of 2102 parturients. Epidural study population included 3513 women. The relative risk
analgesia was associated with better umbilical cord for FHR abnormalities in patients receiving spinal opioids
blood acid-base measurements than systemic opioids, was 1.81 (95% CI, 1.04 to 3.14). The risks of cesarean
suggesting that placental perfusion and gas exchange was delivery for FHR abnormalities were similar in the two
well preserved despite maternal sympathetic blockade groups (6.0% for intrathecal administration versus 7.8%
and effective analgesia. Although not all of the studies for other methods).
used neuraxial opioid infusions, the researchers suggested In a prospective study, Van de Velde et al.330 investi-
that replacement of systemic opioids with modest gated whether intrathecal sufentanil 7.5 µg produced
doses of neuraxial opioids not only produces superior more FHR abnormalities than either conventional
analgesia but also may have a favorable effect on neonatal epidural analgesia or intrathecal bupivacaine combined
outcome.324 with sufentanil 1.5 µg. The high-dose sufentanil group
had more FHR abnormalities (i.e., late decelerations,
fetal bradycardia) but less hypotension than the low-
Fetal Heart Rate Abnormalities
dose sufentanil/bupivacaine group. The incidence
Although epidural or intrathecal opioid administration of FHR abnormalities was similar in the low-dose
has little direct effect on FHR,325 worrisome abnormali- sufentanil/bupivacaine and conventional epidural analge-
ties such as late decelerations and fetal bradycardia sia groups. The rates of cesarean delivery for FHR abnor-
have been observed after intrathecal lipophilic opioid malities were similar in the three groups. Although FHR
288 PART IV Foundations in Obstetric Anesthesia
abnormalities are worrisome, most published trials have 400 µg for the treatment of intrapartum tachysystole and
not reported a higher risk for emergency cesarean deliv- nonreassuring FHR tracings, acute intrauterine resusci-
ery with intrathecal opioid analgesia.330,334,335 However, tation success rates were similar between the two groups
Gambling et al.336 reported more operative deliveries for (72% versus 64% for terbutaline and nitroglycerin,
nonreassuring fetal status after administration of intra- respectively; P = .38), but the incidence of tachysystole
thecal sufentanil 10 µg than with parenteral meperidine 10 minutes after drug administration was lower in the
analgesia. The study’s conclusions, however, were limited terbutaline group.341 Therefore, if there is no response
in that the two study groups differed in frequency of FHR within 2 to 3 minutes of nitroglycerin administration,
assessment. terbutaline 0.25 mg (250 µg) should be administered and
In a randomized trial, Abrao et al.337 evaluated the preparations should be made for emergency cesarean
effects of CSE versus traditional epidural analgesia on delivery if the fetal bradycardia does not resolve.
basal uterine tone and the occurrence of FHR abnor-
malities. Use of the CSE technique was the only inde-
pendent predictor of an increase in basal intrauterine ADJUVANTS
pressure of 10 mm Hg or more (OR, 3.53; 95% CI, 1.21
to 10.36; P = .022). The authors also demonstrated that Epinephrine
the only predictor of FHR abnormalities was an increase
in intrauterine pressure after initiation of analgesia (OR, Epinephrine is often added to epidural and spinal local
18.62; 95% CI, 4.46 to 77.72). A decrease in visual anesthetic solutions to increase the duration of anesthe-
analog scale pain scores immediately after administra- sia, reduce peak plasma drug concentrations, improve
tion of analgesia was also correlated with an increased block reliability, and intensify analgesia/anesthesia.342-344
probability of increased intrauterine pressure and FHR Uptake of epinephrine varies with the choice and con-
abnormalities. Although there were no emergency cesar- centration of local anesthetic as well as the concentration
ean deliveries that resulted from either neuraxial tech- of epinephrine. The effect of epinephrine is greater when
nique, the authors concluded that more studies are it is combined with lidocaine than when it is combined
needed to better understand the effects of the CSE tech- with bupivacaine.159,198 Even concentrations of epineph-
nique on labor progress and fetal physiology.337 However, rine as low as 3.3 µg/mL (1 : 300,000) have been shown
in a letter-to-the-editor, Landau et al.338 suggested that to be effective in reducing the plasma concentrations of
the analgesic techniques were not equipotent. Addition- lidocaine.344
ally, monitoring for FHR abnormalities was only per- The efficacy of epinephrine depends on the specific
formed for 15 minutes. Given that the onset of analgesia local anesthetic as well as the site of injection. Epineph-
is slower with epidural compared with CSE techniques, rine prolongs the duration of epidural lidocaine anesthe-
FHR abnormalities may occur earlier after intrathecal sia by reducing uptake of local anesthetic into the systemic
analgesia. circulation through constriction of the epidural venous
Given the potential risk for fetal bradycardia after plexus. This effect helps maintain the concentration of
neuraxial analgesia in laboring women, the FHR should local anesthetic at the site of injection. During epidural
be monitored before and after the initiation of epidural administration, epinephrine provides optimal results
and intrathecal analgesia. FHR changes are usually tran- when added to lidocaine in a concentration of 5 µg/mL
sient and may be managed successfully with conservative (1 : 200,000); this concentration of epinephrine nearly
measures, including (1) supplemental oxygen administra- doubles the duration of epidural lidocaine anesthesia.345
tion, (2) position changes to relieve aortocaval compres- In contrast to lidocaine, the addition of epinephrine
sion, (3) vasopressor therapy to treat hypotension, (4) 3.3 µg/mL to epidural bupivacaine 0.5% had no effect on
discontinuation of oxytocin infusion, (5) intravenous fluid maternal venous plasma concentrations of drug in labor-
bolus administration, and (6) administration of a tocolytic ing women.346 Similarly, Reynolds et al.347 observed no
agent for persistent uterine tachysystole. effect when epinephrine 5 µg/mL was added to bupiva-
Historically, intravenous or subcutaneous terbutaline caine during administration of epidural anesthesia for
was used to treat persistent uterine tachysystole. More cesarean delivery. Epinephrine did not prolong the epi-
recently, nitroglycerin has been used with some success. dural anesthesia produced by ropivacaine,348 nor did it
Nitroglycerin has several advantages compared with alter absorption of lidocaine after subarachnoid injec-
terbutaline. First, nitroglycerin has a short duration tion.349 In contrast, one group reported that the addition
of action and labor resumes shortly after the period of epinephrine to bupivacaine resulted in a 50% decrease
of tachysystole. In addition, nitroglycerin rarely produces in maternal plasma concentrations of bupivacaine after
significant hypotension, and if hypotension occurs, it paracervical block.350
is easily treated. Several studies have evaluated nitroglyc- Greater reliability and intensity of the block are some-
erin for the treatment of uterine hypertonus. Mercier times observed when epinephrine is added to epidurally
et al.339 described consistent success in treating FHR administered local anesthetics. Epinephrine has intrinsic
abnormalities resulting from uterine tachysystole after analgesic effects that are produced by stimulation of α2-
the administration of one or two doses of nitroglycerin adrenergic receptors. These presynaptic adrenergic
(60 to 90 µg), and Bell340 described the successful use receptors are found at the terminals of primary afferent
of sublingual nitroglycerin (400 µg) in the treatment neurons. They can also be found centrally on neurons in
of uterine tachysystole. In a randomized trial compar- superficial laminae of the spinal cord and in several brain-
ing intravenous terbutaline 250 µg to nitroglycerin stem nuclei.
13 Local Anesthetics and Opioids 289
In addition to the intrinsic analgesic effects of epi- TABLE 13-6 Alkalinization of Local
nephrine, the inherent lipid solubility of each local anes- Anesthetic Solutions
thetic affects the degree of sensory blockade. Each local
anesthetic has a lipid-to-water partition coefficient that Local Anesthetic Sodium Bicarbonate (mL)*
determines the drug uptake between the aqueous and
Lidocaine 1.0
lipid phases within the spinal canal. The outcome of
Bupivacaine 0.1
competition between these lipid and aqueous phases
2-Chloroprocaine 0.3
depends on the lipid solubility of the local anesthetic. If
a local anesthetic is more lipid soluble, the advantage of *Sodium bicarbonate 8.4% (1 mEq/mL) added to 10 mL local
adding epinephrine to the local anesthetic is less signifi- anesthetic solution. Suggested doses are from Warren DT, Neal
cant. For example, the lipid-to-water partition coefficient JM, Bernards CM. Neuraxial anesthesia. In Longnecker DE,
Newman MF, Brown DL, Zapol WM, editors. Anesthesiology.
of lidocaine is 2.7. When epinephrine is added to lido- 2nd edition. New York, McGraw-Hill, 2012. Available at http://
caine, there is marked improvement in the intensity of www.accessanesthesiology.com/content/56638559. Accessed
the block. However, because bupivacaine has a lipid-to- August 2013..
water partition coefficient 10 times greater than that of
lidocaine, the effect of epinephrine on a bupivacaine
block is less pronounced. Because ropivacaine has a lipid- performed carefully because the margin between satisfac-
to-water partition coefficient similar to that of lidocaine, tory alkalinization and complete precipitation is very
epinephrine will intensify a ropivacaine block. However, narrow. All local anesthetics have a tendency to precipi-
the duration of the block remains unchanged. tate, so solutions containing bicarbonate should be
Despite the advantages of epinephrine, concern inspected for precipitation before being administered.
remains about the effects of epinephrine on uterine blood Hypotension occurs more frequently with epidural
flow and the maternal cardiovascular system. In healthy administration of an alkalinized local anesthetic than with
fetuses, epidural administration of epinephrine does not administration of an unbuffered solution.363 This likely
affect umbilical cord blood flow. However, in fetuses results from an accelerated onset of sympathetic block-
with increased vascular resistance, epidural epinephrine ade. Carbonated salts of local anesthetics can also be
administration can increase the umbilical artery S/D administered for a rapid onset of epidural blockade.
ratio.351 Studies of the effects of epinephrine on the pla- However, these drugs have limited availability. Like alka-
cental transfer of local anesthetics have yielded contradic- linized local anesthetics, these preparations are more
tory results. In rabbits, epinephrine did not affect the likely to produce hypotension.
F/M ratio of bupivacaine.352 As a result of the addition of
epinephrine, the F/M ratio for bupivacaine has been
found to be increased353 or unchanged.346,350,354 For lido-
Clonidine
caine, the F/M ratio has variously been reported to be α2-Adrenergic agonists (e.g., clonidine) have been inves-
increased,198,355 decreased,344 or unchanged.356 tigated as adjuvants to local anesthetics and opioids to
improve analgesic efficacy without increasing side effects.
The advantage of clonidine is its ability to provide anal-
Bicarbonate gesia without affecting sensation or producing motor
The addition of sodium bicarbonate to a local anesthetic blockade.364 However, epidural and intrathecal adminis-
solution increases the pH closer to the pKa of the local tration of α2-adrenergic agonists are known to produce
anesthetic. This change increases the proportion of drug hypotension, probably by acting on α2-adrenergic recep-
in un-ionized form that is available to penetrate the nerve tors on preganglionic cholinergic neurons.365 In addition,
sheath and membrane, thereby accelerating the onset of α2-adrenergic agonists produce dose-dependent sedation,
the block and decreasing the minimum concentration which results from α2-adrenergic stimulation in the locus
required for conduction blockade.357 Most studies have ceruleus.366
demonstrated that the addition of sodium bicarbonate Neuraxial clonidine has been administered for labor as
to lidocaine, bupivacaine, or 2-chloroprocaine hastens well as analgesia after cesarean delivery. It exerts its
the onset of epidural blockade by as much as 10 effects by binding to α2-adrenergic receptors located on
minutes.148,358-360 The speed of onset of a ropivacaine primary afferent terminals of the spinal cord, substantia
block does not seem to be affected by alkalinization, but gelatinosa, and brainstem nuclei367 as well as via a cholin-
as with the other local anesthetics, evidence suggests that ergic mechanism.368 Conduction blockade is produced by
alkalinization intensifies epidural ropivacaine anesthesia increases in potassium conductance and in acetylcholine
and improves spread to sacral dermatomes.361 The effects and norepinephrine in the CSF, leading to decreased
of alkalinization are most pronounced in epinephrine- release of substance P and subsequent analgesia.369
containing solutions, particularly commercially prepared Approximately 70% of alpha-adrenergic receptors on
epinephrine-containing formulations. These solutions human myometrium are α2-adrenergic receptors370;
are prepared at a lower pH, ranging from 3.2 to 4.2.362 therefore, the potential effects of clonidine on labor and
The lower pH of these solutions helps preserve the epi- delivery have been evaluated. In an in vitro study, cloni-
nephrine but increases the latency of onset. dine directly enhanced the frequency and amplitude
Sodium bicarbonate 1 mEq/mL (8.4%) may be freshly of human myometrial contraction.371 α2-Adrenergic
added to local anesthetic solutions shortly before use receptor stimulation in the uterus could theoretically
(Table 13-6). Alkalinization of bupivacaine must be enhance uterine contractions and decrease uterine blood
290 PART IV Foundations in Obstetric Anesthesia
flow.365 Indeed, in animal studies, large doses of clonidine responsible for much of labor pain.384 This accounts for
produced a decrease in FHR.372 This effect probably the limited efficacy of neostigmine epidurally adminis-
resulted from direct fetal transfer of drug and from direct tered as the sole agent. However, when combined with
and indirect effects on baroreflexes. However, this effect epidural sufentanil or clonidine for initiation of analgesia,
is unlikely to occur with clinical doses of neuraxial neostigmine produces selective analgesia without side
clonidine. effects.385,386 Large doses of neostigmine can potentially
Multiple studies have evaluated neuraxial clonidine reduce uteroplacental blood flow by CNS activation and
administration in humans as an analgesic adjunct during direct stimulation of uterine contractions.387 When
labor and delivery (see Chapter 23). When combined administered for analgesia after cesarean delivery, epidu-
with local anesthetics and opioids, lower doses may be ral neostigmine (75 to 300 µg) produced modest analge-
used, resulting in less hypotension and sedation. The sia without nausea or vomiting, but the incidence of
FDA has issued a “black box” warning against its use in sedation was increased.388 Neostigmine is not routinely
obstetric patients because of concerns about hemody- used in clinical practice, and its neuraxial administration
namic instability after its use. Therefore, clonidine is is not approved by the FDA.
rarely used for labor analgesia in North America; however,
it is more widely used in some European countries.
Clonidine may be particularly useful in women in whom
other epidural analgesics are contraindicated or in those
who have breakthrough pain with standard local KEY POINTS
anesthetic/opioid solutions despite a functioning epidural
catheter. In this setting, the bolus administration of cloni- • Pregnancy enhances the effect of local
dine 75 µg without a local anesthetic is not usually associ- anesthetic agents.
ated with hypotension. It appears safe to add small doses • Appropriate administration of epidural anesthesia
of intrathecal clonidine (15 to 30 µg) to opioids or local does not adversely affect uterine tone or uterine
anesthetics, but side effects must be treated promptly to or umbilical blood flow.
avoid fetal compromise. • Bupivacaine has greater cardiotoxicity than
Epidural clonidine has been administered for analgesia lidocaine because of its greater electrophysiologic
after cesarean delivery. One study suggested that epidural effects, which predispose to ventricular
clonidine (400 to 800 µg) provided postoperative analge- arrhythmias.
sia, but a continuous infusion was required after 6 hours.373
• Single (levorotary) isomer formulations of amide
Others have demonstrated that epidural clonidine (75 to
local anesthetics, such as ropivacaine and
150 µg) lengthens the duration of postoperative analgesia
levobupivacaine, have a lower potential for
without increasing the incidence of side effects.374,375
cardiotoxicity than racemic bupivacaine.
• The decision to initiate lipid therapy for treatment
Neostigmine of local anesthetic systemic toxicity should be
Both nicotinic and muscarinic cholinergic receptors are based on clinical severity and rate of progression
present in the dorsal horn of the spinal cord. Neostig- of symptoms.
mine prevents breakdown of acetylcholine in the spinal • Fetal acidosis results in a greater accumulation of
cord. The acetylcholine then binds to muscarinic and amide local anesthetic in the fetus.
nicotinic receptors of the spinal cord.376-378 Stimulation of • Local anesthetics, as used clinically, are not
muscarinic receptors facilitates release of gamma- teratogenic.
aminobutyric acid (GABA) in the dorsal horn of the • The elimination half-life of amide local
spinal cord, resulting in analgesia.368,379 Neostigmine and anesthetics is longer in the newborn than in the
clonidine use a common pathway to produce analgesia adult because the former has a greater volume
mediated through acetylcholine release. of distribution.
Several studies have evaluated the addition of neostig- • The fetus and newborn seem to be no more
mine to intrathecal labor analgesics. Although results of vulnerable to the toxic effects of local
these studies were inconsistent in terms of prolonging the anesthetics than the adult.
duration of labor analgesia, all studies found that intra-
thecal administration of neostigmine produced severe • Neonatal neurobehavior depends on many factors
nausea unresponsive to standard antiemetics.380,381 These other than the choice of local anesthetic.
important gastrointestinal side effects limit its clinical use • Alkalinization of a local anesthetic solution
despite its ability to potentiate the analgesic effects of shortens the latency of neural blockade but
intrathecal opioids and clonidine. increases the risk for hypotension during
Epidural neostigmine alone has limited efficacy. Neo- administration of epidural anesthesia.
stigmine appears to be more effective at alleviating • Neuraxial opioid administration produces
somatic pain than visceral pain.382,383 Visceral afferents are analgesia without loss of sensation or
located deep within the spinal cord. Because neostigmine proprioception.
has low lipid solubility, it has a limited ability to traverse • The combination of a neuraxial local anesthetic
biologic membranes. When it is administered without and an opioid increases block density and allows
other agents, it is unable to reach these visceral afferents
13 Local Anesthetics and Opioids 291
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541-6. 367. Gaumann DM, Brunet PC, Jirounek P. Hyperpolarizing afterpo-
344. Abboud TK, David S, Nagappala S, et al. Maternal, fetal, and tentials in C fibers and local anesthetic effects of clonidine and
neonatal effects of lidocaine with and without epinephrine for lidocaine. Pharmacology 1994; 48:21-9.
epidural anesthesia in obstetrics. Anesth Analg 1984; 63:973-9. 368. Chiari A, Eisenach JC. Spinal anesthesia: mechanisms, agents,
345. Liu SS, Lin Y. Local anesthetics. In Barash PG, Cullen BF, Stoelt- methods, and safety. Reg Anesth Pain Med 1998; 23:357-62.
ing RK, et al., editors. Clin Anesthesia. 6th edition. Philadelphia, 369. De Kock M, Eisenach J, Tong C, et al. Analgesic doses of intrathe-
Lippincott Williams & Wilkins, 2009:531-48. cal but not intravenous clonidine increase acetylcholine in cere-
346. Abboud TK, Sheik-ol-Eslam A, Yanagi T, et al. Safety and efficacy brospinal fluid in humans. Anesth Analg 1997; 84:800-3.
of epinephrine added to bupivacaine for lumbar epidural analgesia 370. Jacobs MM, Hayashida D, Roberts JM. Human myometrial
in obstetrics. Anesth Analg 1985; 64:585-91. adrenergic receptors during pregnancy: identification of the
347. Reynolds F, Laishley R, Morgan B, Lee A. Effect of time and alpha-adrenergic receptor by [3H] dihydroergocryptine binding.
adrenaline on the feto-maternal distribution of bupivacaine. Br J Am J Obstet Gynecol 1985; 152:680-4.
Anaesth 1989; 62:509-14. 371. Sia AT, Kwek K, Yeo GS. The in vitro effects of clonidine and
348. Cederholm I, Anskar S, Bengtsson M. Sensory, motor, and sym- dexmedetomidine on human myometrium. Int J Obstet Anesth
pathetic block during epidural analgesia with 0.5% and 0.75% 2005; 14:104-7.
ropivacaine with and without epinephrine. Reg Anesth 1994; 372. Eisenach JC, Castro MI, Dewan DM, Rose JC. Epidural clonidine
19:18-33. analgesia in obstetrics: sheep studies. Anesthesiology 1989; 70:
349. Denson DD, Bridenbaugh PO, Turner PA, et al. Neural blockade 51-6.
and pharmacokinetics following subarachnoid lidocaine in the 373. Mendez R, Eisenach JC, Kashtan K. Epidural clonidine analgesia
rhesus monkey. I. Effects of epinephrine. Anesth Analg 1982; after cesarean section. Anesthesiology 1990; 73:848-52.
61:746-50. 374. Capogna G, Celleno D, Zangrillo A, et al. Addition of clonidine
350. Beazley JM, Taylor G, Reynolds F. Placental transfer of to epidural morphine enhances postoperative analgesia after
bupivacaine after paracervical block. Obstet Gynecol 1972; cesarean delivery. Reg Anesth 1995; 20:57-61.
39:2-6. 375. Massone ML, Lampugnani E, Calevo MG, et al. The effects
351. Alahuhta S, Rasanen J, Jouppila P, et al. Uteroplacental and fetal of a dose of epidural clonidine combined with intrathecal mor-
circulation during extradural bupivacaine-adrenaline and bupiva- phine for postoperative analgesia. Minerva Anestesiol 1998; 64:
caine for caesarean section in hypertensive pregnancies with 289-96.
chronic fetal asphyxia. Br J Anaesth 1993; 71:348-53. 376. Seybold VS. Distribution of histaminergic, muscarinic and sero-
352. Laishley RS, Carson RJ, Reynolds F. Effect of adrenaline on pla- tonergic binding sites in cat spinal cord with emphasis on the
cental transfer of bupivacaine in the perfused in situ rabbit pla- region surrounding the central canal. Brain Res 1985;
centa. Br J Anaesth 1989; 63:439-43. 342:291-6.
353. Reynolds F, Taylor G. Plasma concentrations of bupivacaine 377. Yaksh TL, Dirksen R, Harty GJ. Antinociceptive effects of intra-
during continuous epidural analgesia in labour: the effect of thecally injected cholinomimetic drugs in the rat and cat. Eur J
adrenaline. Br J Anaesth 1971; 43:436-40. Pharmacol 1985; 117:81-8.
13 Local Anesthetics and Opioids 299
378. Bartolini A, Ghelardini C, Fantetti L, et al. Role of muscarinic abdominal hysterectomy pain relief. J Clin Anesth 1998; 10:
receptor subtypes in central antinociception. Br J Pharmacol 291-6.
1992; 105:77-82. 384. Lauretti GR, de Oliveira R, Reis MP, et al. Study of three different
379. Baba H, Kohno T, Okamoto M, et al. Muscarinic facilitation of doses of epidural neostigmine coadministered with lidocaine for
GABA release in substantia gelatinosa of the rat spinal dorsal horn. postoperative analgesia. Anesthesiology 1999; 90:1534-8.
J Physiol 1998; 508 (Pt 1):83-93. 385. Roelants F, Lavand’homme PM. Epidural neostigmine combined
380. Owen MD, Ozsarac O, Sahin S, et al. Low-dose clonidine with sufentanil provides balanced and selective analgesia in early
and neostigmine prolong the duration of intrathecal bupivacaine- labor. Anesthesiology 2004; 101:439-44.
fentanyl for labor analgesia. Anesthesiology 2000; 92: 386. Roelants F, Lavand’homme PM, Mercier-Fuzier V. Epidural
361-6. administration of neostigmine and clonidine to induce labor anal-
381. D’Angelo R, Dean LS, Meister GC, Nelson KE. Neostigmine gesia: evaluation of efficacy and local anesthetic-sparing effect.
combined with bupivacaine, clonidine, and sufentanil for spinal Anesthesiology 2005; 102:1205-10.
labor analgesia. Anesth Analg 2001; 93:1560-4. 387. Nelson KE, D’Angelo R, Foss ML, et al. Intrathecal neostigmine
382. Lauretti GR, Lima IC. The effects of intrathecal neostigmine on and sufentanil for early labor analgesia. Anesthesiology 1999;
somatic and visceral pain: improvement by association with a 91:1293-8.
peripheral anticholinergic. Anesth Analg 1996; 82:617-20. 388. Kaya FN, Sahin S, Owen MD, Eisenach JC. Epidural neostigmine
383. Lauretti GR, Mattos AL, Reis MP, Pereira NL. Combined intra- produces analgesia but also sedation in women after cesarean
thecal fentanyl and neostigmine: therapy for postoperative delivery. Anesthesiology 2004; 100:381-5.
PA RT V
ANESTHESIA BEFORE
AND DURING
PREGNANCY
Donald Caton, MD
During the early years of obstetric anesthesia, physicians experiments that identified chloroform in fetal blood
were primarily concerned with its effect on neonatal res- and urine.1,2
piration. Almost 25 years passed before some investiga- Zweifel later discounted chloroform as a cause of
tors began to suspect that anesthesia might cause other icterus neonatorum, and the issue was dropped. Another
problems. In fact, it was the suspicion that chloroform 75 years passed before physicians began to appreciate that
caused icterus neonatorum that originally stimulated drug exposure during pregnancy might have deleterious
Paul Zweifel to study placental transmission. effects. Events that called attention to the problem
Icterus neonatorum was not Zweifel’s original interest. included (1) sequelae from radiation exposure after the
Under the guidance of Adolf Gusserow, one of the pre- first use of the atomic bomb; (2) the skeletal deformities
eminent obstetricians in Europe, Zweifel had been study- associated with the use of thalidomide, a drug once used
ing glucose metabolism during pregnancy. In the course to treat the nausea of early pregnancy; and (3) the high
of his work, Zweifel unexpectedly found a reducing com- incidence of genital tumors among daughters of women
pound in the urine of infants whose mothers had received who had been given diethylstilbestrol during pregnancy.
chloroform during labor. At first he suspected that the By then the public had also been alerted through the
compound might be glucose, thinking that the metabo- publication of Rachel Carson’s Silent Spring, which con-
lism of this compound had somehow been altered by tained graphic descriptions of the environmental effects
chloroform. After further testing, however, he learned of the indiscriminant use of insecticides. Physicians also
that the reducing substance was not glucose but chloro- knew more about embryology and toxicology, better tech-
form itself. niques for testing drugs were available, procedures for
Zweifel thought that chloroform, transmitted to the collecting information were standardized, and informa-
fetus during labor, might explain some cases of neonatal tion about complications was disseminated. Undoubtedly,
jaundice. By 1876, physicians already knew that chloro- greater public awareness of these developments contrib-
form affected the liver. To cause icterus neonatorum, uted to the resurgence of natural childbirth after 1950.
sufficient quantities of the drug would have to traverse REFERENCES
the placenta during the course of a normal labor; the 1. Zweifel P. Die respiration des fötus. Arch Gynäk 1876; 9:291-305.
rapidity of transfer was a point of contention among 2. Zweifel P. Der uebergang von chloroform und salicylsäure in die
clinicians. To establish the possibility, Zweifel performed placenta. Arch Gynäk 1877; 12:235-7.
C H A P T E R 1 4
CHAPTER OUTLINE
Drug therapy during pregnancy can be complex because may convince mothers to refuse appropriate drug
the physiologic changes of pregnancy may alter drug treatment. New improved drugs are available in many
disposition and effect. Maternal medications may have areas of therapeutics, but many prescribers prefer to
direct effects on the fetus after placental transfer or indi- use older drugs that have a longer empirical history
rect effects through changes in placental and uterine of safety.
function. Even after delivery, drug transfer to breast milk Maternal variations in drug effect are not usually dif-
may be a concern. Nevertheless, pregnant women still ficult to manage, and a change in dosing regimen or the
require medications to treat many acute and chronic con- choice of drug may be all that is required. The greatest
ditions. The challenge is finding the balance between the fears and concerns are for potential fetal effects that may
benefits and risks of therapy. manifest as teratogenicity with fetal loss or congenital
It would seem prudent to use only drugs considered malformations, fetal growth restriction (also known as
safe in pregnancy. Unfortunately, the potential adverse intrauterine growth restriction), preterm labor, and other
effects of many drugs remain unclear. Pregnant women complications. Impaired development and behavioral
are not usually included in early clinical trials, and because problems may manifest after delivery.
of the low incidence of some complications, the first The anesthesia provider should understand the impli-
suggestion of adverse effects may be revealed only cations of pregnancy on drug disposition and effect.
from post-marketing surveillance and registries of com- Although not usually responsible for primary maternal
plications. This uncertainty about safety, and the difficul- drug therapy, he or she will encounter women taking
ties in determining what public information is reliable, many different medications and may sometimes need to
303
304 PART V Anesthesia Before and During Pregnancy
is increased in pregnancy, it is not clear whether blood Drug transfer across the placenta was previously
flow to the liver is significantly increased. Two studies thought to occur mainly by diffusion. This would favor
using clearance of markers concluded that hepatic blood the movement of lipophilic drugs, and placental perfu-
flow was unchanged,12,13 whereas another using Doppler sion would be an important factor affecting transfer. Fetal
ultrasonography reported unchanged hepatic arterial pH is lower than maternal pH, so that weak bases become
flow during pregnancy but increased portal venous flow more ionized in the fetus, thus limiting their transfer back
after 28 weeks’ gestation.14 More importantly, some cyto- across the placenta. Normally, the difference in pH is
chrome P450 isoenzymes (CYP3A4, CYP2D6, and only 0.1 and this “ion trapping” is irrelevant, but fetal
CYP2C9) and uridine diphosphate glucuronosyltransfer- acidosis can significantly increase the fetal concentration
ase (UGT) isoenzymes (UGT1A4 and UGT2B7) have of drugs such as local anesthetics.
increased activity during pregnancy,10,15 which increases It is now known that the placenta contains many drug
the metabolism of drugs such as phenytoin (CYP2C9), transporters that can modify fetal drug exposure, and
midazolam (CYP3A4), and morphine (UGT2B7). Other these are particularly relevant when trying to use trans-
isoenzymes (CYP1A2 and CYP2C19) have decreased placental pharmacotherapy to deliver drugs to the
activity, which reduces the metabolism of drugs such as fetus.18,19 For example, in the treatment of sustained fetal
caffeine and theophylline (CYP1A2). tachyarrhythmia, placental P-glycoprotein, an adenosine
triphosphate–dependent drug efflux pump, will reduce
Elimination. Renal blood flow is increased by 60% to net transfer of substrates such as digoxin and verapamil
80% and glomerular filtration rate is increased by 50% from the mother. With maternal human immunodefi-
in pregnancy; thus, the renal excretion of unchanged ciency virus (HIV) infection, treatment of the fetus is also
drugs such as cephalosporin antibiotics is increased. required, but drug transporters limit the transfer of some
There is also increased activity of transporter proteins antiviral drugs, such as protease inhibitors.
such as renal P-glycoprotein, which may contribute to The placenta also contains many enzymes, especially
the increased clearance of digoxin in pregnancy.16 those such as UGT that catalyze phase II conjugation
Increased minute ventilation enhances elimination of reactions.19,20 Clearance of substrates by UGT in full-
inhalational anesthetic agents. term placentas may be sufficient to contribute to overall
The physiologic changes of pregnancy will affect indi- maternal metabolism.
vidual drugs depending on their physicochemical charac-
teristics and metabolic pathways. Bioavailability is not Fetal and Neonatal Elimination. The fetus and neonate
usually changed significantly. Changes in volume of dis- metabolize drugs, but at a reduced rate compared with
tribution as a result of changes in protein binding may adults.21,22 The fetal circulation guides drug transferred
affect drugs such as phenytoin, but monitoring and modi- across the placenta to undergo first-pass hepatic metabo-
fication of therapy is usually straightforward. Drugs lism, but some drug will bypass the liver. Renal blood
metabolized by the liver may require increases or flow is minimal until near term, and any excreted prod-
decreases in dose, depending on the metabolic pathway ucts would just pass into the amniotic fluid to be swal-
involved. Drugs excreted unchanged by the kidneys often lowed. Elimination of drugs by the fetus is thus mainly
require an increased dose. reliant on placental transfer. It would seem prudent to
minimize the amount of drug transferred to the neonate
and choose drugs that are eliminated rapidly. Relatively
Placental Transfer and Metabolism
large minute ventilation promotes neonatal elimination
Our understanding of placental transfer and metabolism of inhalational anesthetic agents, and this may be further
is rapidly improving (see Chapter 4). Early research was increased by assisted ventilation.
often limited to measuring drug concentrations in the
umbilical vessels and maternal vein at delivery. Results
were variable and difficult to interpret, especially for
Pharmacodynamic Changes
drugs such as anesthetic agents that are administered Changes in the concentrations of various hormones may
shortly before delivery. Umbilical blood samples are alter the response to other substances. In particular, pro-
obtained at variable times after drug exposure, well before gesterone and endorphins may enhance sedation and anti-
steady-state conditions are achieved. The theory of a nociception, respectively. A pharmacodynamic difference
placental barrier was proposed because maternal and fetal specifically refers to a change in response to a given effect-
concentrations were often different. However, differ- site concentration, but it is difficult during pregnancy to
ences in concentrations of binding proteins are mainly carry out the high-fidelity studies necessary for accurate
responsible for the fetal-maternal distribution of drugs at pharmacokinetic-pharmacodynamic modeling. Thus, the
steady state.17 The fetal concentration of albumin is demonstrations of pharmacodynamic changes in preg-
slightly greater than in the mother, but α1-acid glycopro- nancy have been limited to specific experimental designs
tein concentration is only a third of the maternal value where there are large differences in effect.
at term. Umbilical-to-maternal blood ratios of total drug
may be misleading because it is the free drug that equili- General Anesthesia
brates across the placenta. Maternal-to-fetal ratios of
drugs do not provide information on the rate of drug Early animal studies showed that maternal anesthetic
transfer or the amount of drug that has already been requirements were reduced during pregnancy. Minimum
transferred to the fetus. alveolar concentration (MAC) values for inhalational
306 PART V Anesthesia Before and During Pregnancy
0.9
1.2
1.8
0.8
MAC of halothane (vol%)
1.4
0.6
1.2 0.8
0.5
1.0
0.6
0.4 Control Pregnant Control Pregnant Control Pregnant
FIGURE 14-1 ■ Changes in minimum alveolar concentration (MAC), determined by response to transcutaneous electrical stimulation,
for halothane, enflurane, and isoflurane in early pregnancy and for isoflurane in the early postpartum period. (Reproduced with
permission from Gin T. Obstetric pharmacology. In Evers AS, Maze M, Kharasch ED, editors. Anesthetic Pharmacology: Basic Principles and
Clinical Practice, 2nd edition. Cambridge, Cambridge University Press, 2011:948-62. Original data from references 25, 26, and 27.)
agents were reduced by 25% to 40% in pregnant ewes23 required for hypnosis was reduced by 31% and the
and by 16% to 19% in pregnant rats.24 Ethical and practi- bispectral index (BIS) was decreased at isoflurane concen-
cal difficulties with research in pregnant women delayed trations over the range 0.1% to 2.0%.33 During the
confirmation of this finding in humans. Isoflurane MAC second trimester, the sevoflurane concentration required
(determined using transcutaneous electrical stimulation to achieve a targeted BIS of 50 was reduced by 31%.34
instead of the classic skin incision) was decreased by 28% Both in early and term pregnancy, the median concentra-
in women undergoing termination of pregnancy at 8 to tion of nitrous oxide required for loss of consciousness
12 weeks’ gestation.25 Similar reductions in MAC were (MACawake) was reduced by 25% to 27%.35 One study did
found for enflurane (30%) and halothane (27%).26 MAC not show any difference in electroencephalographic
was reduced by 30% in the immediate postpartum period, (EEG) measures between women having cesarean deliv-
with a return to nonpregnant values by 12 to 72 hours ery or gynecologic surgery, but there were many con-
after delivery (Figure 14-1).27,28 founding factors such as the study being conducted partly
Progesterone is probably the cause of the reduced during and partly after surgery, the concurrent use of
anesthetic requirements during pregnancy; chronic pro- significant doses of fentanyl, large variations in EEG
gesterone administration reduced MAC in rabbits, dogs, measures, and small sample size.36
and sheep.29-31 Although human studies have not found a The data for intravenous anesthetic agents are more
good correlation between progesterone concentrations variable, partly because of methodologic challenges. It is
and the reduction in anesthetic requirement, a poor cor- difficult to produce a stable effect-site concentration of
relation may be expected if the effect of progesterone is intravenous drugs to allow accurate measurement of drug
not dose-dependent; it is possible that progesterone con- effect. Increased cardiac output usually results in an
centrations only need to exceed a low threshold to increase in intravenous anesthetic dose requirements to
decrease anesthetic requirements. Lower concentrations produce central effects, and this change would counter
of sevoflurane were required to maintain anesthesia any decrease in requirements with pregnancy. The bolus
in nonpregnant women during the luteal phase of the dose of thiopental for hypnosis (failure to open eyes to
menstrual cycle, when progesterone concentrations are command) was 17% lower, and that for anesthesia (no
elevated, compared with during the follicular phase.32 purposeful movement to a transcutaneous electrical stim-
The progesterone concentrations during pregnancy are ulus) was 18% lower in early pregnancy compared with
much greater than those seen during the luteal phase of nonpregnant women (Figure 14-2).37 A similar reduction
the menstrual cycle. The reduced MAC during preg- was found in the early postpartum period, less than 60
nancy may also be a result of the increased endogenous hours after delivery.38
endorphins that mediate the increase in nociceptive Studies using target-controlled infusions may not be
threshold during pregnancy; it is well known that opioids reliable because the pharmacokinetic models may not be
reduce MAC. accurate in pregnancy, and they are known to predict
Pregnancy also alters other measures of anesthetic concentrations poorly at induction of anesthesia. These
effect. In early pregnancy, the isoflurane concentration methodologic problems may be the reason one study
14 Pharmacology and Nonanesthetic Drugs during Pregnancy and Lactation 307
1.0
increased epidural blood volume, decreasing the capacity
of the epidural space and decreasing the volume of lumbar
Pregnant
cerebrospinal fluid.46,47 These mechanical factors would
Probability of hypnosis 0.8 Nonpregnant
explain the increased spread of local anesthetic. However,
0.6
several studies have also shown that there is increased
sensitivity to local anesthetics during pregnancy. The
onset of conduction block in the vagus nerve with bupi-
0.4
vacaine was faster in pregnant versus nonpregnant
0.2
rabbits.48,49 Sciatic nerve block was of longer duration and
the lidocaine content in the nerves was lower at the time
0.0
of return of deep pain in pregnant versus nonpregnant
1 2 3 4 5 6 7 8 9 10 rats.50 Sensory nerve action potentials were inhibited to
A Dose of thiopental (mg/kg)
a greater extent during median nerve block at the wrist
with lidocaine in pregnant versus nonpregnant women.51
The increased sensitivity may be caused by progesterone
1.0
because exogenously administered progesterone increased
Pregnant
the susceptibility of rabbit vagus nerves to bupivacaine.52
Probability of anesthesia
0.8 Nonpregnant
One study found no changes in conduction block in preg-
nant rats and suggested that enhanced block may be due
0.6
to pregnancy-induced changes that facilitate diffusion of
local anesthetic or an interaction with endogenous anal-
0.4
gesic systems.53
0.2
Analgesia
0.0
1 2 3 4 5 6 7 8 9 10 Pregnancy is associated with increases in nociceptive
response thresholds that are mediated by endogenous
B Dose of thiopental (mg/kg)
opioid systems.54,55 The changes in threshold can be
FIGURE 14-2 ■ Calculated dose-response curves (log[dose] scale)
reproduced using exogenous progesterone and estrogen
for thiopental for hypnosis (A) and anesthesia (B) in pregnant and appear to involve spinal cord kappa (κ) and delta (δ)
and nonpregnant women. The 95% confidence intervals for the opioid receptors and descending spinal α2-noradrenergic
values of ED50 and ED95 are also displayed, slightly offset for pathways.56 Early human studies produced mixed results,
clarity. Raw data are shown for pregnant women (x) and non- probably because of methodologic problems. Recent
•
pregnant women ( ). (Modified with permission from Gin T, Main-
land P, Chan MTV, Short TG. Decreased thiopental requirements in controlled studies showed that heat pain threshold was
early pregnancy. Anesthesiology 1997; 86:73-8.) increased in term pregnant women, and this persisted
during the first 24 to 48 hours after delivery.57,58 Given
the many different factors that influence pain behavior,
found no differences in the concentration of propofol especially those unique to pregnancy and delivery, it is
required for loss of consciousness in early pregnancy.39 difficult to determine how this change in pain threshold
Another study used a slow infusion of propofol for induc- influences perioperative analgesic requirements.
tion of anesthesia and found that the dose and calculated
effect-site concentrations at loss of consciousness were
8% lower than in nonpregnant women.40 The reduction DRUG USE DURING PREGNANCY
in anesthetic requirement for intravenous agents appears
to be less (8% to 18%) than that for inhalational agents General Teratology
(approximately 30%). It is not known whether this reflects
real differences between the drugs or the methodologic Teratology is the study of abnormal development or birth
problems just outlined. defects. Teratogens are substances that act to irreversibly
alter growth, structure, or function of the developing
embryo.59 Ideally, preclinical studies would identify
Local Anesthesia
teratogens, but drug teratogenicity unfortunately can be
The spread of neuraxial block is increased in pregnant markedly species-specific. For example, thalidomide
women (see Chapter 2). This has been shown as early as produces phocomelia in primates but not in rodents.
the first trimester for epidural anesthesia41 and the second In the United States, major malformations affect 2%
trimester for spinal anesthesia.42 One small study sug- to 3% of neonates.60 A major malformation is defined as
gested that although the spread of epidural block was one that is incompatible with survival (e.g., anencephaly),
increased, the latency and density of sensory and motor one that requires major surgery for correction (e.g., cleft
block were not.43 However, two more recent studies palate, congenital heart disease), or one that causes
showed that the median effective dose of intrathecal mental retardation. If all minor malformations (e.g., ear
bupivacaine for motor block was decreased by 13% to tags, extra digits) are included, the incidence of congeni-
35% in pregnant women at term.44,45 Magnetic resonance tal anomalies may be as high as 7% to 10%. Exogenous
imaging has confirmed that pregnant women have causes of birth defects (e.g., radiation, infections,
308 PART V Anesthesia Before and During Pregnancy
U.S. Food and Drug drug, with almost 8% filling a prescription for a Category
BOX 14-1 Administration Drug D or X medication.66
Classification System When counseling patients or responding to queries
from physicians, we prefer to avoid referring to the Physi-
CATEGORY A cians’ Desk Reference. Rather, we use specific descriptions
Controlled studies have shown no risk. Adequate, well- in teratogen databases to provide the best information
controlled studies in pregnant women have failed to demon- available. Many resources are freely available online,
strate a risk to the fetus in the first trimester (and there is in addition to the commercially available databases
no evidence of a risk in later trimesters), and the possibility (Table 14-1).
of fetal harm appears remote. The Teratology Society has suggested abandonment
of the FDA classification scheme.63 In 1997, the FDA
CATEGORY B
held a public meeting to discuss labeling of drugs. There
No evidence of human fetal risk exists. Either animal repro- was consensus that the current classification scheme is
duction studies have not demonstrated fetal risk but no con- probably oversimplified and confusing, does not address
trolled studies in pregnant women have been reported or
animal reproduction studies have shown an adverse effect
the range of clinical situations or the range of possible
(other than a decrease in fertility) that was not confirmed in effects, and should be replaced with narrative labeling.
controlled studies in women in the first trimester (and there Subsequently, a concept paper was presented that out-
is no evidence of risk in later trimesters). lined a new model for labeling and included sections such
as “clinical management statement,” “summary risk
CATEGORY C assessment,” and “discussion of data” for both pregnant
Risk cannot be ruled out. Either studies in animals have and breast-feeding women.67 This proposal has not yet
revealed adverse effects on the fetus (teratogenic, embryo- been implemented. The FDA Office of Women’s Health
cidal, or other) but no controlled studies in women have has created a pregnancy registry website, which lists
been reported, or studies in women and animals are not a variety of registries that women who have used
available. These drugs should be given only if the potential
benefit justifies the potential risk to the fetus.
specific medications during pregnancy can consult (see
Table 14-1). In 2008, the FDA stated they will eliminate
CATEGORY D the A, B, C, D, X classification system.68 As of 2013, the
Positive evidence of human fetal risk exists. However, the new system has yet to be implemented despite comple-
benefits from use in pregnant women may be acceptable tion of the 90-day comment period some time earlier.69
despite the risk (e.g., if the drug is needed for a life-
threatening condition or for a serious disease for which safer
drugs cannot be used or are ineffective). Analgesics
CATEGORY X There is no known teratogenic risk associated with
the use of acetaminophen (paracetamol),70 which
Contraindicated in pregnancy. Studies in animals or human
beings have demonstrated fetal abnormalities, or evidence
is the preferred mild analgesic or antipyretic during
exists of fetal risk based on human experience, or both, and pregnancy.
the risk in pregnant women clearly outweighs any possible Nonsteroidal anti-inflammatory drugs (NSAIDs)
benefit. These drugs are contraindicated in women who are have not been associated with an increased risk for birth
or may become pregnant. defects overall, but the occasional review has suggested
an association with specific defects.71 For example, aspirin
Modified from Friedman JM. Report of the Teratology Society Public is not associated with an overall increase in rates of con-
Affairs Committee symposium on FDA classification of drugs. Teratology genital malformations, but one review suggested a higher
1993; 48:5-6.
risk for gastroschisis.72 Aspirin is not usually the first
choice of NSAID, but low-dose aspirin may still have a
role in some situations, such as preventing fetal loss asso-
the danger of many medications. In addition, the manu- ciated with antiphospholipid antibody syndrome.73
facturer’s prescribing information for many drugs may Studies of the use of NSAIDs and aspirin in the first
state that the drug is not approved for use in pregnancy trimester have reported increased risk for pregnancy loss
despite a long history of uncomplicated unlicensed or (adjusted odds ratio [OR], 1.8 to 8.1).71 In the second
“off-label” use.65 trimester, their use has been associated with fetal crypt-
The FDA categories imply a progressive fetal risk orchidism. In the third trimester, NSAIDs and aspirin are
from Category A to X; however, the drugs in different usually avoided because of significant fetal risks, such as
categories may pose similar risks but may be listed in renal injury, oligohydramnios, and intrauterine constric-
different categories on the basis of risk-to-benefit consid- tion of the ductus arteriosus, an effect that increases with
erations. In addition, the categories create the impression advancing gestational age.74 Renal injury, necrotizing
that drugs within a category present similar risks whereas enterocolitis, and intracranial hemorrhage are other
the category definition permits inclusion (in the same potential complications.
category) of drugs that vary in type, degree, and extent Opioids such as propoxyphene and codeine have no
of risk. known teratogenic risk,75 but they have well-known
Use of potentially teratogenic drugs in pregnancy is potential for addiction. Excessive antepartum use can also
surprisingly commonplace. Over 63% of pregnant lead to neonatal opioid-withdrawal symptoms.76 Surpris-
patients in Canada filled a prescription for at least one ingly, a recent case-control study found that maternal
310 PART V Anesthesia Before and During Pregnancy
TABLE 14-1 Internet Resources for Additional Drug and Teratogen Information
American Academy of Pediatrics: The Transfer of Drugs and http://pediatrics.aappublications.org/content/108/3/776
Other Chemicals into Human Milk .full.html
The American Botanical Council http://www.herbalgram.org
The American College of Obstetricians and Gynecologists http://www.acog.org/About_ACOG/ACOG_Departments/
Resource_Center/WEBTREATS_Teratology_Toxicology
Motherisk http://www.motherisk.org
Organization of Teratology Information Specialists: Fact sheets http://otispregnancy.org/otis_fact_sheets.asp
on exposure during pregnancy to a variety of diseases,
medications, and herbal remedies
The National Library of Medicine PubMed http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed
The National Institutes of Health National Center for http://nccam.nih.gov
Complementary and Alternative Medicine
The National Institutes of Health Office of Dietary Supplements http://dietary-supplements.info.nih.gov
Perinatology.com: Drugs in Pregnancy and Breastfeeding http://www.perinatology.com/exposures/druglist.htm
The Reproductive Toxicology Center* http://www.reprotox.org
RxList: The Internet Drug Index http://www.rxlist.com
SafeFetus.com http://www.safefetus.com
University of Washington Clinical Teratology Web* http://depts.washington.edu/~terisweb
U.S. Food and Drug Administration Office of Women’s Health http://www.fda.gov/AboutFDA/CentersOffices/OC/
OfficeofWomensHealth/
Drugs and Lactation Database (LactMed) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
*Databases, including Reprotox, Reprotext, Teris, and Shepard’s Catalog of Teratogenic Agents, can be purchased from these websites.
opioid treatment (mostly codeine and hydrocodone) 611 infants with cleft lip or cleft palate and 2498 controls
between 1 month before pregnancy and the first trimes- with other birth defects, after adjustment of the data for
ter was associated with an increased OR of 1.8 to 2.7 for potential confounders, no association between diazepam
various cardiac birth defects, spina bifida, and and cleft palate was found (OR, 0.8 for cleft lip with or
gastroschisis.77 without cleft palate, with 95% confidence interval [CI]
Tramadol has analgesic effects from weak opioid of 0.4 to 1.7, and OR, 0.8 for cleft palate alone, with 95%
activity and inhibition of serotonin and norepinephrine CI of 0.2 to 2.5).84 Reanalysis of the Hungarian Case-
uptake. Despite availability in some countries for more Control Surveillance of Congenital Abnormality data
than 30 years, few data are available regarding potential also showed a weak relationship between exposure to
adverse effects in pregnancy. Tramadol exposure in early diazepam in early pregnancy and neural tube defects,
pregnancy was associated with a higher number of spon- limb deficiency defects, and possibly intestinal atresia or
taneous abortions, and it should be avoided in the first stenosis.83 One study found no difference in the incidence
trimester.78 Chronic tramadol use in later pregnancy may of congenital anomalies between 460 women exposed to
result in neonatal withdrawal syndrome. benzodiazepines during pregnancy and 424 control
women without such exposure (i.e., 3.1% versus 2.6%,
respectively).84 Perinatal use of diazepam has been associ-
Sedatives ated with hypotonia, hypothermia, and respiratory
Human epidemiologic studies of the possible teratogenic depression.85 Overall, it appears that the teratogenic risk
effects of various tranquilizers are inconsistent. One of benzodiazepines is small at most,86,87 but there may be
report of nearly 400 patients found a 12% incidence of a small risk for preterm birth and low birth weight.88
birth defects in the offspring of meprobamate users.79 Benzodiazepines should only be used in the first trimester
Another study of similar size did not identify any higher if the perceived benefit offsets the possible teratogenic
risk for malformations.80 These latter two articles found risks and later neonatal effects of continued use. Some
similar results for chlordiazepoxide.79,80 A recent study benzodiazepines such as temazepam are classified as
evaluating meprobamate used in high doses to attempt FDA Category X.
suicide did not show any teratogenic or fetotoxic effects.81
A sample of 35 pregnant women who self-poisoned with
chlordiazepoxide showed no association with congenital
Anticonvulsants
abnormalities but did show dose-related fetal growth Epilepsy is the most common serious neurologic problem
restriction.82 during pregnancy.89 It has been estimated that 3 to 5
Some studies have suggested that first-trimester expo- births per thousand will be to women with epilepsy.90
sure to diazepam increases the risk for cleft lip with or All anticonvulsants cross the placenta. The fetal congeni-
without cleft palate, neural tube defects, intestinal atresia, tal anomaly rate in pregnant women with epilepsy
and limb defects.83 Other reports have not suggested an who ingest anticonvulsant drugs is 4% to 8%, compared
increase in rate of congenital abnormalities after fetal with a background incidence in the general popula
exposure to benzodiazepines. In a case-control study of tion of 2% to 3%.91,92 A twofold higher risk for minor
14 Pharmacology and Nonanesthetic Drugs during Pregnancy and Lactation 311
malformations also exists in this population.92 Cleft lip, phenytoin is approximately 10%.94 Phenytoin may act
with or without cleft palate, and congenital heart disease as a competitive inhibitor of the placental transport of
are especially common. Administration of valproic acid vitamin K. This results in a decrease in fetal coagulation
or carbamazepine entails a 1% risk for neural tube defects factors II, VII, IX, and X. In addition, phenytoin may
and other malformations; thus, alpha-fetoprotein screen- induce fetal hepatic metabolism of the coagulation
ing and targeted ultrasonography are appropriate for factors. The resulting reduction in fetal coagulation
patients taking these agents. In addition, the offspring of factors is associated with a higher risk for hemorrhagic
epileptic women have a 2% to 3% incidence of epilepsy, disease of the newborn.97 To help prevent this coagulopa-
which is five times that of the general population. thy, some physicians advocate oral vitamin K supplemen-
Holmes et al.93 attempted to refute the unproven tation (10 mg daily) for pregnant epileptic patients during
theory that women with epilepsy have a genetic propen- the last month of pregnancy in addition to the parenteral
sity to have children with a higher risk for birth defects administration of vitamin K to the neonate at birth.98
that is separate from the greater risk associated with the Several anticonvulsant medications have metabolites
use of anticonvulsants. These investigators studied chil- that typically are eliminated by the enzyme epoxide
dren of women who had a history of seizures but took no hydrolase. In one study, 19 women taking phenytoin
medications during the pregnancy. There was no differ- underwent amniocentesis. All 4 of the women with low
ence in physical features or cognitive function between enzyme activity in amniocytes had affected fetuses. The
these children and a group of matched controls. In a 15 fetuses with normal amniocyte epoxide hydrolase
second study, Holmes et al.94 screened 128,049 pregnant activity did not have the characteristics of fetal hydantoin
women at delivery to identify the following three groups syndrome.62
of infants: (1) those exposed to anticonvulsant drugs, (2) Carbamazepine is used to treat all types of seizure
those unexposed to anticonvulsant drugs but with a disorders, with the exception of petit mal epilepsy. It is
maternal history of seizures, and (3) those unexposed to most commonly used in the treatment of psychomotor
anticonvulsant drugs with no maternal history of seizures (temporal lobe) epilepsy and grand mal epilepsy. In a
(control group). The frequency of anticonvulsant embry- prospective study involving 72 women with epilepsy who
opathy was higher in the 223 infants exposed to one were taking carbamazepine, the incidence of congenital
anticonvulsant drug than in the 508 control infants anomalies was higher in the 35 fetuses exposed only to
(20.6% versus 8.5%, respectively; OR, 2.8; 95% CI, 1.1 this drug. There was an 11% incidence of craniofacial
to 9.7). The frequency was also higher in 93 infants defects, a 26% incidence of fingernail hypoplasia, and a
exposed to two or more anticonvulsant drugs than in the 20% incidence of developmental delay.99 This constella-
controls (28.0% versus 8.5%; OR, 4.2; 95% CI, 1.1 to tion of fetal effects, named fetal carbamazepine syn-
5.1). The 98 infants whose mothers had a history of epi- drome, closely resembles the malformations seen in cases
lepsy but took no anticonvulsant drugs during pregnancy of fetal hydantoin syndrome. In addition, maternal car-
did not have a higher frequency of abnormalities than the bamazepine exposure has been specifically associated
control infants. The investigators concluded that “a dis- with spina bifida. An analysis of all available data involv-
tinctive pattern of physical abnormalities in infants of ing cohorts of pregnant women ingesting carbamazepine
mothers with epilepsy is associated with the use of anti- supports the conclusion that fetal exposure to this drug
convulsant drugs during pregnancy, rather than with epi- carries a 0.5% to 1% risk for spina bifida.100 Although it
lepsy itself.” A more recent meta-analysis also did not is generally agreed that the use of carbamazepine in preg-
support the view that epilepsy per se represents a terato- nancy is associated with a risk for neural tube defects and
genic risk.95 other anomalies, the exact magnitude of the risk from use
Possible causes of these congenital malformations of carbamazepine alone is unclear.101-104
include genetic differences in drug metabolism, the spe- Phenobarbital is used in the treatment of partial and
cific drugs themselves, and deficiency states (e.g., generalized tonic-clonic seizures and status epilepticus.105
decreased folate levels) induced by the drugs. No con- Fetal exposure to phenobarbital has been associated with
genital malformations appear to be unique to any one major malformations, such as congenital heart defects
anticonvulsant. The characteristics of these syndromes and orofacial clefting. Fetal phenobarbital syndrome is
are so similar that the broad term fetal anticonvulsant characterized by minor dysmorphic features similar to
syndrome, consisting primarily of orofacial, cardiovas- those seen with fetal hydantoin syndrome.91 Fetal expo-
cular, and digital malformations, has been applied to sure to phenobarbital has also been associated with
almost every anticonvulsant drug.96 decreased intellectual and cognitive development in neo-
Among women taking phenytoin, there is a 2% to 5% nates and children. Maternal phenobarbital use during
risk for major congenital anomalies, primarily midline pregnancy can result in hemorrhagic disease of the
heart defects, orofacial clefts, and urogenital defects.91 newborn and neonatal withdrawal symptoms after deliv-
Fetal hydantoin syndrome is a constellation of minor ery. The withdrawal symptoms consist mostly of irritabil-
anomalies, such as craniofacial abnormalities (short nose, ity, begin at about 7 days of life, and usually last for
flat nasal bridge, wide lips, hypertelorism, ptosis, epican- 2 to 6 weeks.105
thal folds, low-set ears, and low hairline) and limb anom- Valproic acid is used to treat absence and generalized
alies (distal digital hypoplasia, absent nails, and altered tonic-clonic seizures. Infants exposed to valproic acid
palmar crease). In addition, neonatal growth and perfor- have a 1% to 2% risk for spina bifida. The neural tube
mance delays have been documented. The risk for fetal defect tends to be lumbosacral. Fetal valproic acid
hydantoin syndrome for the child of a woman taking exposure has also been associated with cardiac defects,
312 PART V Anesthesia Before and During Pregnancy
orofacial clefting, and genitourinary anomalies. Fetal If a patient first presents for care during pregnancy,
valproate syndrome has been described; it is character- most authorities agree that the benefits of anticonvulsant
ized by dysmorphic features, including epicanthal folds, therapy during pregnancy outweigh the risks of discon-
shallow orbits, hypertelorism, low-set ears, flat nasal tinuing the drug. The blood level of the drug should be
bridge, upturned nasal tip, microcephaly, thin vermillion monitored to minimize the dose needed to ensure a ther-
borders, downturned mouth, thin overlapping fingers apeutic level of drug.
and toes, and hyperconvex fingernails.91 Jentink et al.106
found a markedly increased risk for spina bifida (OR,
12.7) craniosynostosis, cleft palate, atrial septal defect,
Antidepressants
and hypospadias. They concluded that valproic acid A summation of 14 studies assessing the effect of fetal
monotherapy should be avoided during pregnancy. A exposure to tricyclic antidepressants evaluated 414
report of the Quality Standards Subcommittee and Ther- cases of first-trimester exposure114; when the study data
apeutics and Technology Subcommittee of the American were pooled or viewed individually, no significant asso-
Academy of Neurology and the American Epilepsy ciation between fetal exposure to tricyclic antidepressants
Society concluded that valproic acid and polytherapy and congenital malformations was found.114 In a surveil-
should be avoided if possible during the first trimester to lance study of Michigan Medicaid recipients,115 467 neo-
decrease the risk for major congenital malformations.107 nates had been exposed to amitriptyline and 75 neonates
They also concluded that, if possible, avoidance of val- had been exposed to imipramine during the first trimes-
proic acid and polytherapy throughout pregnancy should ter; there was no association between tricyclic antidepres-
be considered, and avoidance of phenytoin and pheno- sant use and congenital anomalies. However, a large
barbital throughout pregnancy may be considered, to review of data from the Swedish Medical Birth Register
prevent poor cognitive outcomes.107 Other reviews have reported that use of tricyclic antidepressants was associ-
also confirmed that valproic acid and carbamazepine are ated with a greater risk for congenital malformations
associated with neural tube defects and that valproic acid compared with other antidepressants.116 Results of the
is associated with hypospadias, thus lending further latter study are making their way into reviews that state
support to limiting its use in women of reproductive age. a concern about tricyclic antidepressants.117 Overall, tri-
There are insufficient data to establish risks for birth cyclic antidepressants have been replaced by selective
defects with the newer anticonvulsants.108,109 Felbamate serotonin reuptake inhibitors (SSRIs) as first-line
was approved by the FDA for monotherapy, but later its therapy for depression (see Chapter 51).118
use was severely restricted because of its association with The SSRIs include sertraline, paroxetine, fluox-
aplastic anemia and hepatic failure. Gabapentin was ini- etine, and citalopram. No higher risk for major malfor-
tially released in the United States as an adjunctive treat- mations or developmental (language and behavior)
ment for partial seizures and secondarily generated abnormalities was identified with their use in earlier
tonic-clonic seizures. This agent inhibits dopamine studies.119-121 In a multicenter evaluation of birth defects,
release in the CNS. Lamotrigine appears to have efficacy use of SSRIs was not associated with a higher risk for
comparable to that of carbamazepine in the monotherapy cardiac defects.122 However, in analyses of the individual
for partial epilepsy. An inhibitor of dihydrofolate reduc- medications, sertraline was associated with an increased
tase, lamotrigine decreases embryonic folate levels in risk for septal defects (OR, 2.0; 95% CI, 1.2 to 4.0), and
experimental animals. This finding raises the concern paroxetine was associated with a higher risk for right
that human use of lamotrigine may result in developmen- ventricular outflow tract obstruction (OR, 3.3; 95% CI,
tal toxicity. The manufacturer has established a registry 1.3 to 8.8). Sertraline was also associated with an increased
to evaluate this possibility. A preliminary report from this risk for omphalocele, but this association was based on
registry has described a 6% rate of congenital malforma- only three subjects. Another study found significantly
tions in fetuses exposed to this drug; this rate does not higher risks for craniosynostosis, omphalocele, and anen-
represent a clear increase in the baseline rate of malfor- cephaly in association with exposure to SSRIs as a group;
mations. However, there have not been sufficient numbers this study also found an association between paroxetine
of fetal exposures to support any definitive conclusions.110-112 and right ventricular outflow tract lesions.123 The associa-
Many patients who present to prenatal clinics are tion of septal heart defects with sertraline124,125 and citalo-
already taking these newer anticonvulsants. Patients pram has been seen in other studies.124
should be counseled that even though little information is A cohort study compared postnatal outcome for infants
available, no clear evidence of their teratogenicity exists. exposed to fluoxetine in late gestation (up to the time of
Some investigators have suggested avoiding the newer delivery) with that for infants whose exposure was limited
anticonvulsants until evidence of their safety is accumu- to the first trimester.126 Infants exposed in the third tri-
lated.105 Even in the two decades since newer agents such mester had a greater incidence of perinatal complica-
as lamotrigine were introduced, definitive evaluation of tions, including preterm delivery, admission to the special
their teratogenic potential has not been published. care nursery, poor neonatal adaptation, lower mean birth
Some women may be taking anticonvulsant drugs weight, and shorter body length.126 A subsequent study
without having been reevaluated recently for their need suggested an association between the maternal use of
to continue drug therapy. If a patient with idiopathic SSRIs in late pregnancy and a higher risk for persistent
epilepsy has been seizure-free for 2 years and has normal pulmonary hypertension of the newborn (PPNH).127 The
EEG findings, the neurologist may try to withdraw the association between SSRIs and PPHN has been con-
drug before pregnancy.113 firmed in other studies, which showed an increase from
14 Pharmacology and Nonanesthetic Drugs during Pregnancy and Lactation 313
the background rate of 1.2/1000 neonates to about Pregnancy accelerates the excretion of lithium, so
3/1000, and appears to be a class effect.128 serum lithium levels should be monitored in pregnant
The American College of Obstetricians and Gyne- women.137 Perinatal effects of lithium include hypotonia,
cologists (ACOG) has recommended that use of parox- lethargy, and poor feeding in the infant. In addition,
etine in pregnant women (and in women planning complications (e.g., goiter, hypothyroidism) similar to
pregnancy) be avoided, if possible.129 In addition, it was those seen in adults taking lithium have been noted in
suggested that fetal echocardiography should be consid- neonates.
ered in women who have used paroxetine during early Some authorities recommend discontinuation of
pregnancy. Further, the ACOG has stated that treatment lithium and substitution with another medication during
with all SSRIs should be individualized.129 A report from pregnancy. However, the discontinuation of lithium is
the American Psychiatric Association and the ACOG associated with a 70% chance of relapse of the affective
concluded that although antidepressant use in pregnancy disorder in 1 year, as opposed to a 20% risk for relapse
is well studied, available research has not yet adequately with continuation of lithium therapy.131
controlled for other factors such as maternal illness and
behaviors that can adversely affect pregnancy.130 Cardiovascular Drugs
There are no reports of teratogenicity related to the use
Lithium of inotropic agents such as dopamine, dobutamine,
In the International Registry of Lithium Babies, 25 of or digoxin. Physicians should monitor the maternal
217 (11.5%) infants exposed to lithium during the first digoxin level to ensure a therapeutic level of drug during
trimester of pregnancy were malformed.131 Eighteen pregnancy.
infants had cardiovascular anomalies, and six had the rare Methyldopa and labetalol are often used to treat mild
Ebstein anomaly, which occurs only once in 20,000 non- chronic hypertension during pregnancy. There is no evi-
exposed pregnancies. Subsequent studies have suggested dence of teratogenicity or other adverse fetal effects with
that ascertainment bias may have flawed the findings; the either of these drugs. In one randomized double-blind
reported risk for anomalies after lithium exposure is trial of 152 women with hypertension, there were no
much less than that reported by the registry. malformations in either the labetalol group or the placebo
In a cohort study linking the Swedish Birth Registry group, although the exposure to labetalol occurred in the
with the records of women with bipolar disorder, 59 second and third trimesters.138
infants were identified whose mothers had been treated In a large analysis of published trials involving beta-
with lithium early in pregnancy.132 Four (6.8%) of the 59 adrenergic receptor antagonist therapy, there was little or
infants exposed to lithium had congenital heart disease, no information on teratogenicity for the multiple agents
compared with 2 (0.9%) of 228 infants not exposed studied, including atenolol, labetalol, metoprolol,
to lithium (relative risk [RR], 7.7; 95% CI, 1.5 to 41.2). oxprenolol, pindolol, and propranolol.139 Maternal
None of the infants had Ebstein anomaly. In a prospec- administration of propranolol may result in modest fetal
tive cohort study of 148 women treated with lithium growth restriction.140 It seems prudent to use ultrasonog-
during the first trimester and 148 controls not exposed raphy to assess intrauterine fetal growth in women receiv-
to any known teratogen, there was no significant ing propranolol. Maternal administration of propranolol
difference between groups in the incidence of major con- within 2 hours of delivery may result in neonatal brady-
genital anomalies or cardiac malformations,132 although cardia.75 Atenolol was associated with lower birth weight
one lithium-exposed infant did have Ebstein anomaly. and a trend toward more frequent preterm delivery than
The investigators concluded that lithium is not a major with other antihypertensive drugs and with no therapy.
human teratogen, but they recommended that women These effects were more pronounced when the drug was
exposed to lithium be offered ultrasonography and fetal administered earlier in pregnancy and for a long dura-
echocardiography.133 If the data are pooled, these two tion.141 In one study, treatment of hypertension (mostly
cohort studies do not suggest a statistically significant with atenolol) reduced the risk for severe hypertension
increase in risk for congenital malformations or cardiac and preterm labor.141 In a randomized clinical trial, the
malformations in women exposed to lithium during preg- same group observed that atenolol prevented preeclamp-
nancy. Although the risk for congenital malformations sia but resulted in the birth of infants who weighed 440 g
associated with intrauterine lithium exposure is likely to less than infants in the placebo group.142
be lower than previously reported, an absence of risk The angiotensin-converting enzyme (ACE) inhibi-
cannot be assumed from the available data. Recent tors initially did not appear to be teratogenic when
reviews of available data have come to the same conclu- administered during the first trimester.143 However, a
sion that the risk for anomalies is small, but it is prudent 2007 study suggested an increase in the incidence of con-
to perform fetal echocardiography after first-trimester genital anomalies, particularly cardiac and CNS defects,
exposure.134 after first-trimester exposure to ACE inhibitors.144 Some
Two published cases associated polyhydramnios with authorities contend that this study had major limita-
maternal lithium treatment.135,136 Nephrogenic diabetes tions.145 A very large epidemiologic database study of
insipidus has been reported in adults taking lithium; thus, 465,754 mother-infant pairs showed no difference in
the presumed mechanism of polyhydramnios is fetal dia- abnormality rate between women who used ACE inhibi-
betes insipidus. Polyhydramnios may signal fetal lithium tors during the first trimester, those who used other anti-
toxicity. hypertensive agents, and those who had hypertension but
314 PART V Anesthesia Before and During Pregnancy
used no medications.146 The authors postulated that any between 6 and 12 weeks’ gestation. Because deficiency of
increased risk for birth defects may be due to the hyper- arylsulfatase E is responsible for the chondrodysplasia,
tension. A different set of investigators made the same the embryopathy may result from inhibition of arylsulfa-
conclusion.147 Later in pregnancy, ACE inhibitors can tase E by warfarin. The period between 6 and 9 weeks’
cause fetal renal failure and oligohydramnios, which may gestation is especially critical. Fetal warfarin syndrome
result in fetal limb contractures, craniofacial deformities, consists of nasal hypoplasia, depressed nasal bridge (often
and pulmonary hypoplasia148; therefore, use of ACE with a deep groove between the alae and nasal tip), stip-
inhibitors should be avoided if possible during this period. pled epiphyses, nail hypoplasia, mental retardation, and
Amiodarone is structurally similar to thyroxine and growth restriction. Second- and third-trimester expo-
contains 37% iodine by weight. In a review of 64 reported sures can result in other adverse fetal effects, including
pregnancies in which amiodarone was administered to microcephaly, blindness, deafness, and growth restric-
the mothers, there was no clear increase in the incidence tion. Three prospective studies of women exposed only
of malformations. However, 11 (17%) infants had evi- in the second and third trimesters found that the inci-
dence of hypothyroidism, and two (3%) neonates had dence of malformations must be exceedingly low because
goiter.149,150 The use of amiodarone in pregnancy was there was no evidence of fetal or neonatal CNS or eye
associated with mild abnormalities of neurodevelopment abnormalities.156 Some evidence suggests that a lower
in some of the hypothyroid infants, although this was also dose (< 5 mg/day) has less teratogenic potential.157
observed in some euthyroid infants.150 This agent is most Heparin is a large, water-soluble molecule that does
often used during pregnancy to treat fetal arrhythmias, not cross the placenta. Maternal administration does not
and first-trimester exposure is rare. have an adverse effect on the fetus, and heparin is the
drug of choice for most pregnant women who require
anticoagulation daily. Daily administration of 20,000
Respiratory Drugs units of standard unfractionated heparin for more than
Maternal asthma is relatively common in pregnancy, 20 weeks may be associated with maternal bone demin-
affecting 4% to 8% of pregnant women. It is important eralization.158 Unfractionated heparin should be used for
to maintain appropriate treatment because asthma can prolonged periods only when it is clearly necessary.
increase the risk for adverse fetal and maternal Low-molecular-weight heparin (LMWH) has some
outcomes.151 advantages over standard unfractionated heparin.159
Inhaled β2-adrenergic receptor agonists, cromolyn LMWH does not cross the placenta and has a longer
sodium, and corticosteroids have not been associated half-life than standard unfractionated heparin, which
with congenital malformations. Currently, albuterol is typically allows once-daily dosing in nonpregnant
the preferred short-acting β2-receptor agonist, and sal- patients. In addition, LMWH has a more predictable
meterol is the preferred long-acting β2-receptor agonist. dose-response relationship in nonpregnant patients,
Budesonide is the recommended inhaled corticosteroid which obviates monitoring. However, pregnancy is asso-
because it has a long history of safe usage, but there is no ciated with a higher volume of distribution and acceler-
evidence against the other options, which include beclo- ated clearance of LMWH. Use of LMWH
methasone, ciclesonide, fluticasone, flunisolide, thromboprophylaxis during pregnancy requires adjust-
mometasone, and triamcinolone. ments in the dose of LMWH to accommodate for the
Severe persistent asthma may require systemic oral changes in the pharmacokinetics of this drug that occur
corticosteroid therapy, and this has been associated with during pregnancy. For example, pregnant women may
low birth weight and a three- to five-fold increase in the require twice-daily doses.160
relative risk for cleft lip and palate.152,153 However, other Full anticoagulation is necessary in pregnant women
studies have found no adverse effects and, given the risks with cardiac valve prostheses. In a systematic review of
from severe asthma, oral corticosteroids should be used anticoagulation in pregnant women with mechanical
if required. heart valves, Chan et al.161 evaluated outcomes with the
The 5-lipoxygenase inhibitors and leukotriene following three anticoagulation regimens: (1) oral anti-
receptor antagonists are newer agents with no evidence coagulants (most commonly warfarin) given throughout
of teratogenicity.154 Women using montelukast enrolled pregnancy, (2) heparin administered during the first tri-
in several teratogen information services around the mester and then warfarin for the duration of pregnancy,
world showed no increased risk for birth defects in 160 and (3) heparin administered throughout pregnancy. The
live births.155 data demonstrated progressively higher rates of maternal
Methylxanthines such as theophylline and amino- death with regimens 1, 2, and 3 (1.8%, 4.2%, and 15.0%,
phylline have no adverse fetal effects, but the protein respectively). The use of warfarin throughout pregnancy
binding and metabolism of theophylline are both reduced was associated with warfarin embryopathy in 6.4% of
during pregnancy, making it necessary to monitor drug live-born infants. The substitution of heparin at or before
concentrations and adjust maintenance doses. 6 weeks’ gestation eliminated that risk.161
For women with prosthetic heart valves, the American
College of Chest Physicians (ACCP) has recommended
Anticoagulants use of one of the following three regimens: (1) adjusted-
Warfarin use in early pregnancy can result in an embry- dose LMWH twice-daily throughout pregnancy, with
opathy similar to the X-linked chondrodysplasia punc- doses adjusted to achieve the manufacturer’s peak anti–
tata. The embryopathy can occur with fetal exposure factor Xa LMWH levels 4 hours after subcutaneous
14 Pharmacology and Nonanesthetic Drugs during Pregnancy and Lactation 315
injection; (2) adjusted-dose unfractionated heparin associated with a threefold to fivefold increased risk for
administered subcutaneously every 12 hours throughout cleft lip with or without cleft palate152; and thus, they
pregnancy, with doses adjusted to keep the mid-interval should not be used during this period.
activated partial thromboplastin time at least twice
control or to attain an anti–factor Xa heparin level of 0.35 Antihistamines
to 0.70 units/mL; or (3) unfractionated heparin or
LMWH as just described until the 13th week of preg- Some pregnant patients may be treated with antihista-
nancy, with substitution by vitamin K antagonists until mines for allergies or upper respiratory tract infections.
close to delivery, when unfractionated heparin or LMWH These drugs provide symptomatic therapy with no influ-
is resumed.160 In women at very high risk for thrombo- ence on the course of the disease. If considered necessary,
embolism in whom there is concern about the efficacy combinations of drugs should be avoided if possible.
and safety of unfractionated heparin or LMWH, it is Topical nasal sprays result in less fetal exposure than
suggested to administer vitamin K antagonists through- systemic medication. One study suggested an association
out pregnancy with replacement by unfractionated between pseudoephedrine and defects attributable to vas-
heparin or LMWH close to delivery.160 In high-risk cular disruption, including gastroschisis, small intestinal
women with prosthetic heart valves, it is suggested to add atresia, and hemifacial microsomia.168 Physicians should
low-dose aspirin 75 to 100 mg/day.160 discourage the use of nonprescription drugs for trivial
indications because the long-term fetal effects of the
chronic maternal use of these drugs are unknown.
Antiemetics Sedating or first-generation antihistamines are avail-
Most women in early pregnancy have nausea, with or able in over-the-counter medications and have not
without vomiting (see Chapter 2 and Chapter 16).162 been reported to increase fetal risk.169 Examples include
Complementary therapies such as acupressure and ginger chlorpheniramine, diphenhydramine, methapyrilene,
may be effective, but approximately 10% of women will thonzylamine, pyrilamine, tripelennamine, phenyl
require drug therapy. Although many different drugs can toloxamine, and buclizine. Despite conflicting reports,
be effective, vitamin B6 should be the drug of choice.163 a meta-analysis found no evidence to implicate brom-
A combination of vitamin B6 with the antihistamine dox- pheniramine as a teratogen.170 In the Boston Collabora-
ylamine was previously available as Bendectin, but this tive Program,171 none of the sedating antihistamines
was withdrawn by the manufacturer in 1983 because of was associated with malformations. Two combination
allegations of teratogenicity that were later found to be products—triprolidine with pseudoephedrine (Actifed)
false. Other formulations are now available, and there is and phenylpropanolamine with chlorpheniramine
no evidence of teratogenicity with them or other antihis- (Ornade)—were not associated with malformations. In
tamines. Trimethobenzamide is structurally related to a cohort of 1502 women, antihistamines were not associ-
antihistamines such as diphenhydramine, but it has only ated with congenital malformations.172 Azatadine was
weak antihistamine activity. The mechanism of action is not found to be teratogenic among 127 Michigan Med-
unclear, but it probably acts at the chemoreceptor trigger icaid recipients.115
zone. It has few side effects but also variable efficacy. Limited safety information is available for the nonse-
Nausea and vomiting can also be treated with phenothi- dating antihistamines. In a cohort study, 114 women
azines, but they may cause sedation. exposed to astemizole were matched with 114 women
The prokinetic agent and dopamine antagonist meto- exposed to known nonteratogens.173 There were two
clopramide is not sedating, but it has a “black box” major malformations in the astemizole group and two in
warning because chronic usage has been associated with the control group. In a study of 39 women exposed to
rare cases of tardive dyskinesia. There are no specific cetirizine, the rate of malformations was no higher than
safety concerns during pregnancy. A multicenter study in a control group.174 This finding was replicated in a
did not observe an increased incidence of anomalies,164 study performed through a teratogen information
and a large trial of 3458 women exposed to metoclo- service.175 There are no controlled human studies for
pramide in the first trimester found no association with loratadine or fexofenadine. Desloratadine is the major
increased risk for birth defects, low birth weight, preterm metabolite of loratadine; most data do not point to a risk
delivery, or perinatal death.165 for congenital abnormalities.169
The 5-hydroxytryptamine receptor antagonists are Several antihistamines have primary indications not
widely used and very effective antiemetics with few side directly related to upper respiratory complaints.
effects, so they are also increasingly being used in preg- Hydroxyzine is used for treatment of pruritus, mecli-
nancy. Ondansetron was similar in efficacy to prometha- zine for dizziness, diphenhydramine for sleep and pru-
zine for the treatment of hyperemesis gravidarum but less ritus, and doxylamine (a component of the former
sedating.166 There is no evidence that it has a teratogenic Bendectin) for treatment of nausea and vomiting of preg-
effect.167 nancy. A meta-analysis of antihistamines used mostly for
Corticosteroids such as dexamethasone are now morning sickness in early pregnancy found a protective
commonly used for postoperative and chemotherapy- effect against malformations (OR, 0.76; 95% CI, 0.60
induced nausea and vomiting. Methylprednisolone has to 0.94).176 This apparent benefit may have resulted
been used for refractory nausea and vomiting during from an association between maternal nausea and good
pregnancy. However, a meta-analysis concluded that the fetal outcomes rather than from a direct effect of
use of glucocorticoids before 10 weeks’ gestation was antihistamines.
316 PART V Anesthesia Before and During Pregnancy
drug. Some examples are (1) thalidomide, which is still The amount of a drug in breast milk is a variable frac-
used for erythema nodosum leprosum and multiple tion of the maternal blood concentration, which is pro-
myeloma; (2) the antiviral ribavirin, which is used for portional to the maternal dose. Quoted maternal
hepatitis C and viral hemorrhagic fevers; (3) isotreti- milk-to-plasma ratios can vary because drug transfer is a
noin, which is used for cystic acne; and (4) acitretin, time-dependent process. Even when calculated under
which is used for severe psoriasis. steady-state conditions, there can be large individual
variation. Absolute infant dose (µg/kg/day) can be calcu-
lated as the product of the average concentration in milk
and the estimated daily volume of milk intake, and relative
DRUG USE DURING LACTATION infant dose can be estimated by dividing absolute infant
General Principles dose by the maternal dose.196 It has been suggested that
a relative infant dose less than 10% is generally safe,196
Nursing mothers are understandably concerned about but this will also depend on the oral bioavailability of the
the transfer of drugs and chemicals to breast milk. Correct drug in the infant and the relative toxicity of individual
advice is important to prevent them from unnecessarily agents. However, physicians and patients should be aware
stopping breast-feeding or discontinuing appropriate of the following disclaimers. First, in the case of toxic
drug treatment. Unfortunately, it can be difficult to drugs, any exposure may be inappropriate. Second, the
decide which of the many, sometimes conflicting, sources infant may be allergic to a drug consumed by the mother.
of public information to trust. Pharmaceutical informa- Third, there may be unknown, long-term effects of even
tion leaflets from the manufacturers often discourage the small doses of drugs. Fourth, individual variability in drug
use of drugs during breast-feeding simply as a general disposition may lead to unexpectedly high maternal blood
precaution. The most comprehensive up-to-date infor- and breast milk concentrations. Finally, infants have
mation is found in the Drugs and Lactation database immature enzyme systems and metabolic pathways and
(LactMed) of the National Library of Medicine’s Toxicol- some drugs are eliminated more slowly. The benefits of
ogy Data Network (TOXNET).190 The American breast-feeding are well known, and the risk of drug expo-
Academy of Pediatrics (AAP) has published policy state- sure must be weighed against these benefits.
ments on the benefits of breast-feeding191 and the use of Lactation is not fully established during the first
drugs during lactation.192 The Centers for Disease several days postpartum. The neonate receives only a
Control and Prevention (CDC) provides online informa- small volume of colostrum, and little drug is excreted
tion regarding breast-feeding and various toxins and through milk at this time. Thus, only very small amounts
infectious diseases.193 of drugs administered after vaginal or cesarean delivery
Only a few types of drugs such as cytotoxic and immu- would reach the neonate and significant effects should be
nosuppressive drugs (e.g., cyclophosphamide, metho- unlikely. However, neonatal metabolism and elimination
trexate) and radioactive compounds are strongly are also poorly developed, and several days of maternal
contraindicated during breast-feeding.59 Mothers breast- opioid analgesia with drugs such as meperidine (pethi-
feeding infants with glucose-6-phosphate-dehydrogenase dine) and codeine may result in neonatal accumulation
(G6PD) deficiency should avoid drugs such as sulfon- and side effects.
amides, including the combination of sulfamethoxazole When a mother requires a daily dose of a drug during
and trimethoprim, nitrofurantoin, and primaquine. lactation, the minimum effective dose should be used.
Maternal drugs may also affect lactation, and some Some mothers requiring long-term therapy would already
are used therapeutically for this purpose. Drugs that have been taking drugs during pregnancy, and the fetus
increase the secretion of prolactin can stimulate milk would have been exposed to concentrations much greater
production; these include dopamine antagonists such as than those achieved in the infant through breast-feeding.
phenothiazines, haloperidol, metoclopramide, and Thus, if a drug has been acceptable during pregnancy, it
domperidone, as well as sulpiride, risperidone, and is often reasonable to continue it during breast-feeding
methyldopa. Drugs that decrease the production of unless there are drug-specific factors to the contrary.197
milk include diuretics, estrogen, and dopamine agonists For example, poor neonatal elimination of lamotrigine
such as bromocriptine, cabergoline, lisuride, and may eventually lead to drug accumulation in the infant
quinagolide. Bromocriptine is no longer approved for and adverse effects. In general, medications should be
postpartum lactation suppression because of its associa- taken after breast-feeding, and long-acting preparations
tion with puerperal seizures, stroke, and myocardial should be avoided. If the infant nurses less frequently
infarction. Women who smoke also have lower milk overnight, ingestion of a drug dose at night after nursing
production. will decrease the infant’s exposure.
Drug transfer to breast milk occurs by passive diffu-
sion, but transporter systems are also present.194 The rate
of passive transfer into breast milk depends on the lipid
Anesthetic Drugs
solubility, molecular weight, degree of ionization, and There are generally no concerns regarding anesthetic
protein binding of the drug. Nonionized molecules of drugs and perioperative medicines in the breast milk of
small molecular weight (e.g., ethanol) are readily trans- women who require an anesthetic.198,199 However, the
ferred into breast milk. Drugs that have more than 85% prolonged use of postoperative medications such as anal-
maternal protein binding are often not detectable in the gesics will obviously increase the infant dose, the poten-
infant.195 tial effects of which are discussed next.
318 PART V Anesthesia Before and During Pregnancy
receiving magnesium sulfate 1 g/h intravenously for 24 Respiratory Drugs and Corticosteroids
hours after delivery. The mean breast milk magnesium
concentration was 6.4 ± 0.4 mg/dL, compared with 4.8 Salbutamol, terbutaline, and salmeterol inhalers are
± 0.5 mg/dL in controls. Breast milk calcium concentra- considered compatible with breast-feeding. Maximum
tions were not affected by magnesium sulfate therapy. milk concentrations of theophylline are achieved
between 1 and 3 hours after an oral dose. It has been
calculated that the nursing infant receives less than 1%
Antidepressants and Lithium of the maternal dose. Such exposure appears to have no
Psychotropic agents may be of concern because many of adverse effects.
these medications have long half-lives and the effect of Inhaled and oral corticosteroids are also considered
even small doses on the developing nervous system is not safe. Katz and Duncan227 obtained breast milk 2 hours
known. Nevertheless, the many medications available to after an oral dose of 10 mg of prednisone in one nursing
treat depression or postpartum depression appear to have mother. They detected breast milk concentrations of
little if any immediate effect on the infant.219 Many anti- prednisone and prednisolone that would be unlikely to
depressants have low milk-to-plasma ratios. There are result in any deleterious effect on the infant. McKenzie
few reports of neonatal problems with the use of SSRIs et al.228 administered 5 mg of radioactive prednisolone to
and related drugs.220 Fluoxetine and its metabolite have seven patients and found that 0.14% (a negligible quan-
relatively long elimination half-lives, so other drugs such tity) of the radioactive label was secreted in the milk in
as sertraline and paroxetine are preferred.221 the subsequent 60 hours. Thus, breast-feeding is not con-
Breast milk concentrations of lithium are one third to traindicated in mothers taking corticosteroids. Even at a
one half of maternal serum concentrations,222,223 and maternal dosage of 80 mg/day, the nursing infant would
infant serum concentrations during breast-feeding are ingest a dose equivalent to less than 10% of its endoge-
much lower than fetal serum concentrations that occur nous cortisol production.229
when mothers take lithium during pregnancy. Neonatal
clearance of lithium is reduced, and it may be useful to
monitor neonatal lithium concentrations.
Anticoagulants
Most mothers who require anticoagulation may continue
to nurse their infants with no problems. Warfarin is 98%
Cardiovascular Drugs protein bound. Orme et al.230 reported no warfarin in
Amiodarone concentrations in the infant are unpredict- breast milk or infant plasma in seven women taking war-
able but may be sufficiently high to cause cardiac effects. farin 5 to 12 mg/day. Similarly, de Swiet and Lewis231
Iodine released during its metabolism may cause thyroid found that warfarin appears in breast milk in insignificant
dysfunction. Amiodarone has a very long half-life and is quantities. Heparin does not cross significantly into
still excreted in breast milk weeks after stopping the drug. breast milk and is not active when administered orally.
Beta-adrenergic receptor antagonists with low protein
binding have relatively higher transfer to breast milk, and
those excreted renally are more likely to accumulate in
Antihistamines
neonates. Thus, atenolol with 10% protein binding and No harmful effects have been noted with maternal use of
85% renal excretion would not be the best choice. Breast antihistamines.232 These drugs do not appear to affect
milk concentrations of atenolol are approximately three the milk supply. Little antihistamine is excreted into
times maternal plasma concentrations.224 Even though breast milk, further confirming safety of use during
the total infant dose is only 1% of the maternal thera- lactation.169
peutic dose, and the infant plasma concentration would In theory, histamine type 2 (H2)-receptor antagonists
not normally cause side effects in the infant, atenolol has might suppress gastric acidity or cause CNS stimulation
been associated with neonatal cyanosis and bradycardia. in the infant, but these effects have not been confirmed
Other common drugs such as ACE inhibitors and in published studies. Famotidine, nizatidine, and roxa-
antihypertensives are considered safe. However, diuretics tidine are less concentrated in breast milk and may be
may reduce milk production. Maternal protein binding preferable to cimetidine.233
of digoxin limits infant drug exposure; after a maternal
dose of 0.25 mg, a peak breast milk concentration of 0.6
to 1.0 ng/mL occurs and the milk-to-plasma concentra-
Anti-infective Drugs
tion ratio at the 4-hour peak is between 0.8 and 0.9 ng/ Penicillin and its derivatives are safe in nursing mothers.
mL. In 24 hours an infant might receive approximately With the usual therapeutic doses of ampicillin, the milk-
1% of the maternal digoxin dose,225 and no adverse effects to-plasma concentration ratio is 0.2 or less and no adverse
have been reported in nursing infants of mothers taking effects are noted in nursing infants.234 Theoretically,
this drug. Breast milk clonidine concentrations are infant diarrhea or candidiasis might occur with prolonged
almost twice maternal serum concentrations. However, therapy. Cephalosporins appear in trace amounts in
this exposure does not seem to have any adverse effects breast milk and are also safe.
on the infant.226 Sulfonamides displace bilirubin from binding sites on
There are no safety data for statins, but they are not albumin, so these drugs are best avoided during the first
recommended during breast-feeding because of concerns 5 days of life or in mothers of preterm infants with hyper-
that they may disrupt infant lipid metabolism. bilirubinemia. Sulfonamides appear in breast milk in
320 PART V Anesthesia Before and During Pregnancy
Caffeine
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C H A P T E R 1 5
CHAPTER OUTLINE
In 1978, Steptoe and Edwards1 reported the first live techniques. Advances in the science and international
birth of an infant produced from in vitro fertilization acceptance of ART procedures have resulted in a dra-
(IVF) techniques. Their case highlighted the laparoscopic matic increase in the number of infants born globally
recovery of a single oocyte just before ovulation in a (Figure 15-1).4 A similar increase in the use of these
natural menstrual cycle; after in vitro insemination, the technologies has been witnessed in the United States
resulting embryo was grown in culture media for 2.5 days (Figure 15-2); in 2011, the initiation of 163,038 ART
to the eight-cell stage and was transferred to the uterine cycles resulted in the birth of 61,610 infants.5
cavity (i.e., embryo transfer [ET]). Despite the application of ART procedures to more
IVF techniques were initially developed as a treatment diverse and challenging causes of infertility, the probabil-
for infertility secondary to chronic fallopian tube disease. ity of a live birth after a cycle of hormonal stimulation
Current indications for this emerging spectrum of new has increased from 6% in 1985 to 30% in 2011.5 Atten-
techniques, which as a group are referred to as assisted tion to subtle differences in culture media as well as
reproductive technology (ART), include (1) inadequate improvements in laboratory methods, retrieval routes,
oocyte quality or number (donor oocyte therapy), irrepa- and transfer techniques are primarily responsible for
rability or absence of the uterus (surrogate uterus pro- these improved results.6 Given the importance of small
grams), and significant co-morbidities (embryo and alterations to the overall success of ART, coupled with
ovarian tissue cryopreservation) in women; (2) sperm the associated costs (i.e., approximately $10,000 for each
deficiencies in men; and (3) certain genetic aberrations in cycle that progresses to transfer and limited insurance
couples.2 coverage for these procedures),7 it is prudent for anesthe-
In 1981, Edwards3 estimated that 15 to 20 infants sia providers to be aware of the potential effects that
would be born worldwide through the use of IVF and ET anesthetic agents may have on gametes or embryos.
326
15 In Vitro Fertilization and Other Assisted Reproductive Technology 327
180
120
Thousands
100
FIGURE 15-2 ■ Numbers of assisted reproductive
technology (ART) cycles performed, live-birth
80
deliveries, and infants born in the United States
using ART from 1987 through 2011, as reported 60
to the Centers for Disease Control and Preven-
tion, Division of Reproductive Health, and the 40
Society for Assisted Reproductive Technology
Registry. (Data from U.S. Department of Health 20
and Human Services, Centers for Disease Control
and Prevention, Division of Reproductive Health. 0
2011 Assisted Reproductive Technology [ART] 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Report. Atlanta, CDC/DRH, 2013.)
328 PART V Anesthesia before and during Pregnancy
Fallopian tube
Ovarian ligament
B C
Follicle Ovary
Embryo Transfer
Collection tube
Embryos resulting from IVF may be transferred into
FIGURE 15-3 ■ Transvaginal ultrasound-guided oocyte retrieval. the fallopian tubes (i.e., ZIFT) or the uterine cavity
The ultrasound probe is placed in the vagina and advanced into (IVF-ET). Most ET procedures are performed transcer-
the posterior fornix. The needle, previously inserted through the vically 3 days after retrieval, with the embryos transferred
needle guide, is advanced through the vaginal wall and ovarian via a catheter. The advantages of transcervical ET are
capsule. (Redrawn from Steinbrook R. Egg donation and human
embryonic stem-cell research. N Engl J Med 2006; 354:324-6. Copy-
(1) simplicity—it does not require laparoscopy or anes-
right © 2006 Massachusetts Medical Society. All rights reserved.) thesia; (2) low cost, especially compared with laparo-
scopic intrafallopian transfer procedures; and (3) the
ability to proceed without patent fallopian tube(s). The
primary disadvantage of transcervical ET is that
the probability of successful pregnancy is slightly less
In Vitro Fertilization than that with an ET performed directly into the fallo-
pian tubes (i.e., ZIFT). Embryos in excess of those
Although the term in vitro fertilization is often used syn- required for transfer may be frozen in 1,2-propanediol or
onymously with any aspect of ART, technically it applies glycerol and stored for possible later transfer.
only to the process of oocyte fertilization with spermato-
zoa in culture media. After a microscopic examination,
oocytes are incubated for 4 to 6 hours in culture media
Gamete Intrafallopian Transfer
that resembles human fallopian tube fluid and are then GIFT procedures consist of the transabdominal or
inseminated. The insemination process is sometimes transvaginal collection of oocytes followed by a micro-
delayed with immature oocytes (e.g., metaphase I) in an scopic inspection of the oocytes’ quality and maturation
attempt to increase the probability of normal (i.e., mono- in a laboratory adjacent to the operating room. Mature
spermic) fertilization. oocytes are aspirated into a transfer catheter with washed
At 16 to 20 hours after insemination the oocytes are partner or donor sperm, and the contents (gametes) are
examined for evidence of fertilization (i.e., the presence injected into the distal 3 to 6 cm of one or both fallopian
of two pronuclei and two polar bodies in the perivitelline tubes. The catheter is subsequently inspected microscop-
space) (Figure 15-4).9 The advantages of IVF include the ically to verify that oocytes have not been retained.
ability to document the process of fertilization and to use The GIFT procedure does not involve IVF, because fer-
techniques to improve sperm motility or penetration tilization occurs in vivo in the natural milieu of the
(e.g., intracytoplasmic sperm injection). IVF followed by fallopian tube.
ET represents approximately 99% of the ART proce- Specific advantages of the GIFT procedure include
dures used in the United States5; less than 1% occurs via (1) the convenience of oocyte retrieval and ET occurring
GIFT or ZIFT procedures (see later discussions). Male within a single operative event, (2) the elimination of IVF,
factor infertility is present in approximately 35% of the and (3) the fact that the embryos reach the uterine cavity
couples seeking ART procedures, and intracytoplasmic at a potentially more appropriate (i.e., later) stage of
15 In Vitro Fertilization and Other Assisted Reproductive Technology 329
50
35
Percentage (%)
30
25
20
15
10
0
1995 1997 1999 2001 2003 2005 2007 2009
Age in years
FIGURE 15-5 ■ Percentage of transfers that resulted in live births with assisted reproductive technology (ART) cycles using fresh
nondonor eggs or embryos, according to the women’s age in the years from 1995 to 2009, as reported to the Centers for Disease
Control and Prevention, Division of Reproductive Health, and the Society for Assisted Reproductive Technology Registry. The first
year in which data for women older than 42 were subdivided into ages 43 to 44 and older than 44 was in 2007. (Data from U.S.
Department of Health and Human Services, Centers for Disease Control and Prevention, Division of Reproductive Health. 2009 Assisted
Reproductive Technology (ART) Report. Atlanta, CDC/DRH, 2011.)
18
16
14
Incidence (%)
12
∗
10 ∗
8 ∗
6
4
2
0
Preterm Low Small for NICU Perinatal
delivery birthweight gestational admission mortality
(< 37 wks) (< 2500 g) age
ART pregnancy
Spontaneous pregnancy
FIGURE 15-6 ■ Outcomes associated with singleton births from assisted reproductive technology (ART) and spontaneous pregnancies
in the general population. *P < .05. NICU, Neonatal intensive care unit. (Data from D’Angelo DV, Whitehead N, Helms K, et al. Birth
outcomes of intended pregnancies among women who used assisted reproductive technology, ovulation stimulation, or no treatment. Fertil
Steril 2011; 96:314-20.)
4.0 C
anesthetic agents yield dissimilar pharmacokinetic pro-
files when administered via paracervical, epidural, and a, b a
intrathecal techniques. Anesthetic agents may also affect 3.0
unfertilized oocytes and fertilized embryos differently; a, b
thus, studies of anesthetic agents used for a GIFT (prefer- 2.0 a, b
a, b
tilization) procedure should not be directly compared
with studies of agents used for a ZIFT (postfertilization) 1.0 a, b
a, b
procedure. Finally, significantly greater free concentra-
tions of certain agents (e.g., bupivacaine) exist during 0.0
0.01 0.1 1.0 10.0 100.0
ART stimulation because of a decrease in plasma protein
binding capacity.28 Thus, when selecting anesthetic tech- Anesthetic concentration (µ g/mL)
niques or agents for an ART procedure, the clinician
FIGURE 15-8 ■ Embryo development scores (mean ± SD) at 72
should weigh their known benefits (e.g., greater hemo- hours as a function of anesthetic concentration. Shaded area
dynamic stability, less nausea, less psychomotor impair- represents embryo development score (4.75 ± 0.28) for the
ment) and hypothetical risks (e.g., lower delivery rates). control mouse embryos. a, P < .01 (lidocaine [L], bupivacaine
[B], and 2-chloroprocaine [C] compared with control); b, P < .01
(bupivacaine compared with lidocaine and 2-chloroprocaine).
Local Anesthetic Agents (Modified from Schnell VL, Sacco AG, Savoy-Moore RT, et al.
Effects of oocyte exposure to local anesthetics on in vitro fertiliza-
In animal models, the effect of local anesthetic agents tion and embryo development in the mouse. Reprod Toxicol 1992;
on reproductive physiology appears to be related to 6:323-7.)
the agent, timing, and dose of exposure. Using mouse
oocytes incubated for 30 minutes in culture media with 1.0 and 0.1 µg/mL, respectively (Figures 15-7 and 15-8).
known concentrations of lidocaine, bupivacaine, or In contrast, bupivacaine produced adverse effects only at
2-chloroprocaine, Schnell et al.29 demonstrated that lido- the greatest concentration studied (100 µg/mL). Simi-
caine and 2-chloroprocaine adversely affected both fer- larly, Del Valle et al.30 demonstrated that after 48 hours
tilization and embryo development at concentrations of of culture, 24% of mouse embryos exposed to lidocaine
332 PART V Anesthesia before and during Pregnancy
60
Most animal and human trials suggest minimal to no
40 detrimental effects of propofol on fertilization and early
embryo development,41-45 despite accumulating in a dose-
and duration-dependent manner within the follicular
20
fluid.46-48 General anesthesia provided with propofol and
a 50% oxygen-air mixture was associated with fertiliza-
0 tion, embryo cleavage, and implantation rates similar to
Oocytes fertilized Pregnancy rate
those produced by a paracervical block with mepiva-
FIGURE 15-9 ■ Fertilization and pregnancy rates after transvagi-
caine.44 Hamster oocytes exposed to very high concentra-
nal oocyte retrieval with and without lidocaine paracervical tions of propofol (20 µg/mL) demonstrated no DNA
block. Fertilization and cleavage rates did not differ in the two damage—even through two metaphases—when evalu-
groups. (Modified from Wikland M, Evers H, Jakobsson AH, et al. ated by sister chromatid exchange assays, a sensitive index
The concentration of lidocaine in follicular fluid when used for para- of genotoxic effects.49 These concentrations were 40
cervical block in a human IVF-ET programme. Hum Reprod 1990;
5:920-3.) times greater than those detected clinically in the follicu-
lar fluid of patients undergoing oocyte retrieval.46,47 The
induction and maintenance of general anesthesia with
propofol for GIFT procedures demonstrated negligible
10 µg/mL, in comparison with none in the control group, differences in reproductive outcomes from women receiv-
showed evidence of degeneration. Finally, Ahuja et al.31 ing other forms of anesthesia.42 By contrast, a smaller
noted that hamster oocytes exposed to procaine or tetra- incidence of ongoing pregnancies was observed among
caine demonstrated impaired zona reactions, potentially women given propofol–nitrous oxide anesthesia for ZIFT
allowing additional sperm to enter the oocyte and create procedures when compared with thiopental–nitrous
abnormal chromosomal numbers (polyploidy). oxide–isoflurane anesthesia.50 Further investigation is
These in vitro findings may have limited clinical rel- necessary to further elucidate the full effects of propofol
evance, however, given the lower anesthetic concentra- on various reproductive outcomes.
tions that occur in clinical practice and the washing and Both thiopental and thiamylal (5 mg/kg) can be
screening procedures that oocytes undergo before fertil- detected in follicular fluid as early as 11 minutes after
ization and transfer. Human trial data corroborate the their administration for induction of general anesthesia
minimal effect that local anesthetic agents have on oocytes in patients undergoing GIFT procedures.51 No adverse
or embryos during oocyte retrieval, GIFT, or ZIFT pro- reproductive effects have been observed with these
cedures. Wikland et al.32 reported that the incidence of agents, and when they were specifically compared with
oocyte fertilization and clinical pregnancy was not propofol (2.7 mg/kg) for GIFT procedures, no differ-
reduced among women who received a modified paracer- ences in clinical pregnancy rates were noted.43
vical block with lidocaine for transvaginal oocyte retrieval Ketamine (0.75 mg/kg), administered with midazolam
(Figure 15-9). Favorable pregnancy rates have also been (0.06 mg/kg), has been reported to be an acceptable
reported after GIFT procedures performed during epi- alternative to general anesthesia with isoflurane for
dural lidocaine anesthesia.25 oocyte retrieval.52 No differences in reproductive out-
comes were observed; however, the study was inade-
quately powered to adequately assess this result.
Opioids and Benzodiazepines
Fentanyl, alfentanil, remifentanil, and meperidine do not
appear to interfere with either fertilization or preimplan-
Nitrous Oxide
tation embryo development in animal and human Nitrous oxide reduces methionine synthetase activity,
trials.33,34 When given during oocyte retrieval, fentanyl nonmethylated folate derivatives, and DNA synthesis in
and alfentanil were detected in extremely low (or unde- animals and humans.53,54 Nitrous oxide also impairs the
tectable) follicular fluid concentrations.35 With alfentanil, function of mitotic spindles in cell cultures.55 Although
a 10 : 1 ratio between serum and follicular fluid was Warren et al.56 reported that two-cell mouse embryos
observed 15 minutes after the initial bolus dose.36 Mor- exposed to nitrous oxide within 4 hours of the expected
phine appears unique in terms of adverse effects; when onset of cleavage were less likely to develop to the blas-
sea urchin eggs were incubated in morphine (equivalent tocyst stage (Figure 15-10), this difference had resolved
to a human dose of 50 mg), more than one sperm entered by later stages of embryo development.34
approximately 30% of the oocytes.37 Clinical studies of anesthesia for laparoscopic ART
Midazolam administered systemically in preovulatory procedures support the administration of nitrous oxide
mice did not impair fertilization or embryo development during GIFT and ZIFT procedures.42,50,57 In a multi-
in vivo or in vitro, even when given in doses up to 500 center study, Beilin et al.42 observed a delivery rate of
times those used clinically.38 When used in small bolus or 35% among women given nitrous oxide for GIFT
15 In Vitro Fertilization and Other Assisted Reproductive Technology 333
100
80
60
60
40
∗
40 ∗
20
∗
∗
0 20
6-7 h 3-4 h 0-1 h
Time before expected first cleavage
0
FIGURE 15-10 ■ Developmental outcome of two-cell mouse 5-6 h 3-4 h 0-1 h
embryos exposed to 60% nitrous oxide/40% oxygen for 30
minutes in vitro. Administration of nitrous oxide within 4 hours Time before expected first cleavage
of anticipated cleavage decreased the percentage of embryos
reaching the blastocyst stage. *P < .05 compared with the room FIGURE 15-11 ■ Developmental outcome of two-cell mouse
air (i.e., control) group. (Modified from Warren JR, Shaw B, embryos exposed in vitro to 3% isoflurane for 30 minutes at
Steinkampf MP. Effects of nitrous oxide on preimplantation mouse various times in relation to expected onset of the first cleavage
embryo cleavage and development. Biol Reprod 1990; 43:158-61.) in vitro. *P < .01. (Modified from Warren JR, Shaw B, Steinkampf
MP. Inhibition of preimplantation mouse embryo development by
isoflurane. Am J Obstet Gynecol 1992; 166:693-8.)
anesthesia care (MAC). In a retrospective sequential (34 to 36 hours after hCG administration) is missed,
study design, Wilhelm et al.33 noted lower pregnancy spontaneous ovulation with loss of oocytes can occur,
rates in patients undergoing oocyte retrieval with general invalidating the considerable effort and expense that have
anesthesia (i.e., isoflurane or propofol in combination been incurred to that point. Moreover, if oocyte retrieval
with 60% nitrous oxide in oxygen) than in subsequent is not performed, the patient would be at increased risk
patients who received a remifentanil-based MAC tech- for OHSS, with its potential for significant morbidity. In
nique. The investigators acknowledged that the success contrast, the risk for pulmonary aspiration of gastric con-
rates of ART programs have improved over time and that tents is low, particularly when spinal anesthesia is admin-
it is possible that physician-related factors may have istered (see later discussion).
played a role in the improved success during the second As with other ambulatory surgery cases, the ideal
MAC phase of the study.33 anesthetic technique provides effective pain relief with
These data suggest that volatile halogenated anes- minimal postoperative nausea, sedation, pain, and psy-
thetic agents can affect ART outcomes, with known and chomotor impairment.
potential differences associated with the selected agent.
For example, the metabolic byproduct of sevoflurane, Ultrasonographic-Guided Transvaginal
compound A, has been associated with genotoxic ovarian
cell effects, although reproductive outcomes have not
Oocyte Retrieval
been assessed.64 As a consequence, although volatile Although transvaginal oocyte retrievals can be performed
agents continue to be used for ART procedures, caution under paracervical, spinal, epidural, and general anes-
is advised in the selection of newer agents, such as sevo- thetic techniques, MAC is the most commonly used tech-
flurane, desflurane, and isodesox (a combination of 1% nique.69,70 It is usually adequate for surgical analgesia,
desflurane, 0.25% isoflurane, and 60% oxygen in nitro- but MAC may need to progress to loss of consciousness
gen),65 until further work has been done. (i.e., general anesthesia) to prevent patient movement
at critical times; this problem has been observed in
highly anxious patients.71 The need for additional pain
Antiemetic Agents relief should be anticipated when the needle penetrates
At least one study noted that droperidol and metoclo- the cul-de-sac and, later, each ovary. Of interest, one
pramide rapidly induce hyperprolactinemia with subse- report noted a greater rate of hospital admission after
quent impairment of ovarian follicle maturation and oocyte retrieval, mostly secondary to intra-abdominal
corpus luteum function.66 When these agents are given bleeding, when MAC was used than when general anes-
as a single dose immediately prior to oocyte retrieval, thesia was used.72 Self-administered inhalational analge-
it is unlikely that the mature oocyte will be affected; sia with isodesox (see earlier discussion) by face mask was
however, if they are given on a routine basis after retrieval, associated with less effective analgesia and less patient
the uterine receptivity to the embryo could be affected. satisfaction than physician-administered intravenous
Forman et al.67 demonstrated that low plasma prolactin analgesia.65
concentrations during ART procedures were associated Because paracervical anesthesia incompletely blocks
with a higher incidence of pregnancy. sensation from the vaginal and ovarian pain fibers, addi-
tional analgesia is required, even when greater doses of
local anesthetic are used.73 Epidural and spinal techniques
ANESTHETIC MANAGEMENT provide excellent pain relief with minimal oocyte expo-
sure to anesthetic agents. Compared with sedation with
Because most patients undergoing ART procedures are propofol and mask-assisted ventilation with nitrous oxide,
young and otherwise healthy, many institutions do not epidural bupivacaine anesthesia resulted in fewer compli-
require preoperative laboratory studies, electrocardio- cations, especially nausea and emesis.74 Spinal anesthesia
grams, or chest radiographs before the procedure. may be preferable to epidural anesthesia owing to the
However, the application of ART procedures to patients reduced anesthetic failure rate, reduced systemic and
with a growing spectrum of pathologic processes, such as follicular concentrations of anesthetic agent, and faster
morbid obesity, cancer (with oocyte retrieval performed recovery profile.75 Spinal administration of 1.5% hyper-
prior to chemotherapy or radiation therapy), and severe baric lidocaine (60 mg) is associated with significantly
cardiac, pulmonary, or renal morbidities (with oocyte shorter recovery times than spinal administration of
retrieval performed for ET in surrogate gestational 5% hyperbaric lidocaine (60 mg) in patients undergoing
carriers), has created special concerns that should be ART procedures.76 The addition of intrathecal fentanyl
addressed individually.68 10 µg to lidocaine 45 mg improves postoperative analge-
All patients should follow the fasting guidelines typi- sia for the first 24 hours, with no increase in time
cally used for patients undergoing ambulatory surgery. In to urination, ambulation, and discharge, in comparison
patients with risk factors for pulmonary aspiration of with intrathecal lidocaine alone.77 Low-dose spinal
gastric contents, a nonparticulate antacid should be given bupivacaine has been evaluated for use in these patients,
before the procedure. On occasion, a patient may not given the frequent association of spinal lidocaine with
adhere to strict fasting guidelines; and although delay or postoperative transient neurologic symptoms. However,
cancellation of the procedure is an option, the decision the prolonged time to urination and discharge may
should be made after careful analysis of the potential risks prevent this agent from becoming a commonly used
and benefits. If the window for maximal oocyte retrieval alternative.78
15 In Vitro Fertilization and Other Assisted Reproductive Technology 335
40 cm
H2O 2 sec
40 cm
H2O 2 sec
FIGURE 15-13 ■ Arterial tracings after rapid intravenous injection of 7.5 mL/kg of carbon dioxide (top) and helium (bottom). Recovery
occurs within 1 minute after the carbon dioxide injection, but complete cardiovascular collapse occurs after the helium injection.
(Modified from Wolf JS, Carrier S, Stoller ML. Gas embolism: helium is more lethal than carbon dioxide. J Laparoendosc Surg 1994;
4:173-7.)
General anesthesia can be provided by total intrave- pneumopericardium, mediastinal emphysema, gas embo-
nous anesthesia (TIVA) using propofol (titrated) and lism, and cardiac arrest.82
fentanyl (50 to 100 µg). Midazolam (1 to 2 mg) can be
used as an optional premedication. With TIVA, most Pneumoperitoneum and the
patients can be managed with spontaneous ventilation
via high-flow oxygen mask and the use of carbon dioxide
Trendelenburg Position
analysis.40 (Individuals with significant risk factors for Carbon dioxide is the gas most commonly used to estab-
aspiration should undergo tracheal intubation with a lish pneumoperitoneum. The high blood solubility of
cuffed endotracheal tube.) This anesthetic technique can carbon dioxide facilitates absorption from the peritoneal
produce mean bispectral index scores that range from 47 cavity after laparoscopic surgery and may represent a
to 53 and modified Ramsay sedation scores that are con- life-saving property of the gas in the rare but potentially
sistent with general anesthesia79 and results in greater catastrophic event of gas embolization. For example,
patient satisfaction than MAC, owing to better pain relief rapid intravenous injection of 5 to 10 mL/kg of carbon
and less awareness during the surgical procedure.40 Alter- dioxide produces only transient (<1 minute) hypotension
natively, tracheal intubation and maintenance of anesthe- in anesthetized dogs (Figure 15-13),83 whereas intravas-
sia with a volatile halogenated agent has been used cular administration of a similar volume of a less soluble
successfully; however, greater rates of nausea and emesis gas (e.g., helium, oxygen, nitrogen) is usually fatal.
and more unplanned admissions have been observed with Signs of embolization of large quantities of carbon
this technique than with a propofol, alfentanil, and air- dioxide (or any other gas) in anesthetized patients may
oxygen mixture.80 include hypocapnia, hypotension, hypoxemia, ST-segment
Novel analgesic measures have been investigated and T-wave changes, arrhythmias, and audible changes
during oocyte retrieval. One study evaluated electroacu- in the heart sounds.84 Initial treatment of carbon dioxide
puncture as an alternative to intravenous alfentanil, embolism should include release of the pneumoperito-
although both groups also received a paracervical block, neum and pharmacologic support of the circulation. If
and the acupuncture group experienced greater degrees initial resuscitation efforts are unsuccessful, aspiration of
of preoperative stress and longer periods of discomfort gas from the right atrium (using a multi-orifice central
during oocyte aspiration.81 venous catheter) should be considered. Although the use
of the left lateral recumbent position (Durant’s maneu-
ver), with or without head-down positioning, has been
Embryo Transfer suggested to facilitate removal of the postulated air lock
Described as relatively painless, transcervical ET proce- from the right side of the heart,85 laboratory evidence
dures are most commonly performed without analgesia suggests that this maneuver may have a detrimental effect
or anesthesia; however, on rare occasion, intravenous on cardiac function after venous gas embolism.86
sedation or regional or general anesthesia may be Nearly as soluble in blood as carbon dioxide, nitrous
requested. In contrast, transabdominal gamete or embryo oxide is associated with less peritoneal and diaphragmatic
transfer procedures (i.e., GIFT, ZIFT) are usually per- irritation87 and has been suggested for the establishment
formed via laparoscopy under local, neuraxial, or general of pneumoperitoneum in awake patients undergoing
anesthesia. The anesthetic management for these proce- laparoscopy. A major disadvantage of nitrous oxide is
dures and the associated concerns with regard to the its ability to support combustion, which could increase
laparoscopic technique and the Trendelenburg position the possibility of an explosion if the surgeon uses
are described here. Major intraoperative complications electrocautery.
associated with laparoscopy are rare but include gastric GIFT and ZIFT procedures are often performed with
or intestinal perforation, hemorrhage, pneumothorax, the patient in the Trendelenburg position to facilitate
336 PART V Anesthesia before and during Pregnancy
visualization of the fallopian tubes and other pelvic struc- pneumoperitoneum. Disadvantages of this method
tures. Although their use is controversial, shoulder braces include (1) the need to reposition the patient before lapa-
placed to prevent the patient from moving cephalad on roscopy and (2) a prolonged total operative time if per-
the operating table should be positioned with padding formed on the same day (GIFT) or the need for a second
against the acromioclavicular joints to prevent brachial procedure if performed on consecutive days (ZIFT).
plexus damage. The adduction of the patient’s arms A few patients prefer spinal or epidural anesthesia
against her trunk has been suggested to reduce the risk for GIFT procedures.89,90 Healthy, nonobese patients
for a brachial plexus injury, but the efficacy of this precau- have been reported to successfully undergo laparoscopic
tion is unproven. surgery in the Trendelenburg position with high thoracic
Both pneumoperitoneum and the Trendelenburg (i.e., T2 to T4) spinal or epidural anesthesia.89-92 Limiting
position produce physiologic changes. Hemodynamic intraperitoneal pressure to less than 10 mm Hg may
effects of moderate pneumoperitoneum (< 20 mm Hg) in facilitate the use of neuraxial anesthesia for these proce-
a patient in the Trendelenburg position include increased dures. Obese women are not ideal candidates for neur-
mean arterial and central venous pressures, increased sys- axial anesthesia in laparoscopic surgery.
temic vascular resistance, and decreased stroke volume Adequate analgesia for laparoscopic ART procedures
and cardiac output.88 Heart rate usually does not change, has also been reported with the use of local anesthesia
but in some patients pneumoperitoneum may elicit sinus supplemented with intravenous sedation.93-96 Padilla
bradycardia, heart block, or even cardiac arrest. Finally, et al.93 observed that the quality of intraoperative analge-
pneumoperitoneum aggravates the respiratory effects sia can be improved by limiting maximal intra-abdominal
of the Trendelenburg position (e.g., reduced chest wall pressure to 8 to 10 mm Hg, reducing the rate of carbon
compliance, increased venous admixture). Overall, most dioxide insufflation to 1 L/min, and minimizing ovarian
healthy patients easily tolerate the cardiovascular and manipulation. The difficulty and pain frequently associ-
pulmonary effects of intra-abdominal pressures lower ated with cannulation of the fallopian tubes, however,
than 20 mm Hg. may make local anesthesia an unwise choice for laparo-
scopic ART procedures. Waterstone et al.94 noted that
Laparoscopic-Assisted all 21 patients undergoing local anesthesia for laparos-
copy experienced some discomfort when their fallopian
Reproductive Technology tubes were mobilized. The use of local anesthesia should
The anesthetic plan for GIFT procedures is typically not be interpreted as being devoid of risk for serious
dictated by the method (i.e., transabdominal or transvagi- complications (e.g., bradycardia, cardiac arrest). These
nal) of oocyte retrieval. Many ART programs harvest life-threatening complications are rare, but the manage-
oocytes transabdominally during pelvic laparoscopy, the ment and outcome are greatly assisted by individuals
principal advantage being that the patient is positioned skilled in airway management and cardiopulmonary
and anesthetized once for both the retrieval and transfer resuscitation.97
portions of the procedure. The major disadvantage of this
technique is that oocytes are exposed to both carbon
dioxide pneumoperitoneum and anesthetic agents. The
Postoperative Management
induction of general anesthesia for GIFT procedures can The incidence of anesthetic or surgical complications
be delayed until just before the skin incision in an effort requiring hospital admission after ART procedures is low.
to minimize unnecessary exposure to these agents. Induc- Oskowitz et al.72 reported admission rates after oocyte
tion is usually performed with intravenous propofol, lido- retrieval and GIFT procedures of 0.16% and 0.18%,
caine, fentanyl, and either succinylcholine or rocuronium. respectively. The most common indications for hospital-
After tracheal intubation, the anesthesia provider may ization were hemoperitoneum and syncope after oocyte
decompress the patient’s stomach with a suction catheter retrieval, and nausea, vomiting, and bowel injury after
or Salem sump tube to reduce the risk for gastric perfora- laparoscopic GIFT procedures. Abdominal pain and
tion during instrumentation. Subsequently, a volatile uterine cramping occur commonly after oocyte retrieval.
halogenated agent in oxygen and air, with or without a Incisional pain and referred shoulder pain as a result of
short-acting muscle relaxant, is given to maintain anes- diaphragmatic irritation can also occur after laparoscopic
thesia. The use of a propofol–nitrous oxide technique has ART procedures. Postprocedural discomfort is related
been associated with less postoperative sedation, lower primarily to the number of follicles retrieved (rather than
pain scores, and less emesis than an isoflurane–nitrous the hormonal alterations induced by the stimulation
oxide technique.50 cycle); and when it follows an anesthetic regimen that
Alternatively, oocytes can be retrieved transvaginally includes an opioid, it is graded as minimal to moderate.
and transferred—as oocytes or embryos—laparoscopically. Abdominal discomfort can be managed with the use of a
Of interest, this is the technique most commonly used heating pad and small doses of intravenous fentanyl (25
with ZIFT procedures, whereby oocyte retrieval and IVF to 50 µg) or oral analgesic agents (acetaminophen 500 mg
occur on the day before the ZIFT procedure. Advantages to 1 g).98 The use of nonsteroidal anti-inflammatory
to the combined transvaginal/transabdominal approach drugs should be avoided because changes in the prosta-
include (1) the avoidance of laparoscopy in the 1% to 2% glandin milieu can affect embryo implantation.99
of cases in which oocyte quality or number is inadequate Nausea and emesis can also occur; however, exposure
to justify proceeding with a tubal transfer3 and (2) the to droperidol and metoclopramide should be limited
elimination of oocyte exposure to the carbon dioxide (see earlier discussion); treatment with nondopaminergic
15 In Vitro Fertilization and Other Assisted Reproductive Technology 337
17. Bar-Hava I, Orvieto R, Dicker D, et al. A severe case of ovarian 40. Casati A, Valentini G, Zangrillo A, et al. Anaesthesia for ultra-
hyperstimulation syndrome: 65 liters of ascites aspirated in an sound guided oocyte retrieval: midazolam/remifentanil versus
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from multiple pregnancies associated with assisted reproductive nitrous oxide, or isoflurane does not affect the reproductive
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C H A P T E R 1 6
CHAPTER OUTLINE
Obstetric disease of early pregnancy may result in signifi- little or no change in lung capacities during the first
cant maternal morbidity and even mortality. Safe care of half of pregnancy. Women in early pregnancy who
patients with obstetric disease involves a thorough under- undergo mechanical ventilation require increased minute
standing of the physiologic changes of early pregnancy as ventilation.
well as the specific issues associated with each pathologic
condition. Cardiovascular System
The cardiovascular system also undergoes profound
PHYSIOLOGIC CHANGES OF EARLY changes early in pregnancy. Cardiac output increases
20% to 25% by 8 weeks’ gestation and 35% to 40% by
PREGNANCY 20 weeks’ gestation. Systemic vascular resistance decreases
Respiratory System 30% by 8 weeks’ gestation. Maternal mean arterial pres-
sure decreases approximately 6 mm Hg at 16 to 24 weeks’
The respiratory system undergoes profound physiologic gestation and returns to normal near term.
changes during early pregnancy. Increased progesterone Aortocaval compression typically occurs after 18 to 20
concentration stimulates respiratory efforts by increasing weeks’ gestation, when the uterine fundus reaches the
the sensitivity of the respiratory center to carbon dioxide. umbilicus and is large enough to compress the aorta and
Minute ventilation increases by at least 15% by 12 weeks’ vena cava when the patient is supine. Left uterine dis-
gestation and by 25% by 20 weeks’ gestation. This results placement is rarely needed in early pregnancy, but when
from an increase in tidal volume (respiratory rate is the uterine size is equivalent to an 18- to 20-week gesta-
unchanged) and exceeds the increase in oxygen consump- tion, left uterine displacement should be attained by
tion. The result is a respiratory alkalosis with maternal elevating the right hip 15 degrees off midline with a
arterial partial pressure of carbon dioxide decreasing to wedge or blankets. The need for left uterine displace-
30 to 33 mm Hg by 10 to 12 weeks’ gestation. Moreover, ment occurs earlier in gestation in the presence of mul-
maternal arterial partial pressure of oxygen increases to tiple gestation, polyhydramnios, or gestational
106 to 108 mm Hg in the first trimester. Decreased trophoblastic disease.
bicarbonate concentration partially compensates for the Blood volume increases throughout pregnancy; the
modest respiratory alkalosis that results from the physi- average prepregnancy blood volume of 4350 mL (76 mL/
ologic hyperventilation, leading to a maternal pH that is kg) increases to 4700 mL (81 mL/kg) at 12 weeks’ gesta-
slightly above normal (i.e., approximately 7.44). There is tion, to 5500 mL (89 mL/kg) at 20 weeks’ gestation, and
340
16 Problems of Early Pregnancy 341
to approximately 6600 mL (97 mL/kg) at term. The during general anesthesia with similar end-tidal concen-
increase in blood volume is primarily the result of greater trations of sevoflurane.3 Because it is well-proven that
plasma volume because red blood cell volume increases MAC decreases in pregnancy, this study implies that
to a smaller degree (27 mL/kg). Because pregnant women MAC in pregnant women may not correlate well with
have an expanded blood volume, they typically tolerate depth of anesthesia. Further research is needed in this
a blood loss of 500 to 1500 mL during the first half area.
of pregnancy. A blood loss of 500 to 1500 mL rarely
requires blood transfusion, provided that the blood loss
is replaced with an adequate volume of crystalloid or ECTOPIC PREGNANCY
colloid.
Ectopic pregnancy occurs when the fertilized ovum
implants outside the endometrial lining of the uterus.
Gastrointestinal System Death, infertility, and recurrent ectopic pregnancy are
An increased progesterone level causes relaxation of possible sequelae. The frequency of ectopic pregnancy in
lower esophageal sphincter tone as early as the first tri- the United States increased fourfold to fivefold between
mester. Fasting gastric volume is approximately 30 mL in 1970 and 1992 but appears to have stabilized at a rate of
both nonpregnant women and women in early preg- approximately 16 per 1000 pregnancies.4,5 A higher prev-
nancy. Metoclopramide 10 mg, administered intrave- alence of associated risk factors, especially pelvic inflam-
nously 15 to 30 minutes before anesthesia, can reduce matory disease, as well as earlier diagnosis of previously
this volume by 50%.1 In a study of 100 pregnant women unrecognized ectopic pregnancies may account for the
undergoing general anesthesia by mask at 6 to 22 weeks’ reported increase.
gestation, a pH electrode showed reflux of gastric con- Ruptured ectopic pregnancy is a leading cause of
tents into the esophagus in 17% of patients.2 Most epi- pregnancy-related maternal death during the first trimes-
sodes of reflux occurred in patients who experienced ter and accounts for 6% of all pregnancy-related mater-
hiccups. Only 2% had regurgitation of gastric contents nal deaths in the United States.6,7 Most deaths result from
into the pharynx, and no patient demonstrated clinical hemorrhage (93%); infection (2.5%), embolism (2.1%),
evidence of pulmonary aspiration. and anesthetic complications (1.3%) are less common
General anesthesia may be safely administered by causes.8 More than 30% of women who have had an
means of a mask or a laryngeal mask airway by experi- ectopic pregnancy subsequently suffer from infertility,
enced anesthesia providers in selected obstetric patients and 5% to 23% have a second ectopic pregnancy.9
during early pregnancy. Many anesthesia providers are The number of deaths from ectopic pregnancy
comfortable managing an airway without tracheal intuba- decreased in the United States from 1970 through 2007.
tion until 18 to 20 weeks’ gestation, when the uterus The case-fatality rate decreased from 35.5 deaths per
moves out of the pelvis. The latter movement leads to 10,000 ectopic pregnancies in 1970 to 3.8 per 10,000 in
anatomic and intragastric pressure changes that predis- 1989,10 and the ectopic pregnancy mortality ratio
pose to gastroesophageal reflux. Some anesthesia provid- decreased from 1.15 deaths per 100,000 live births in
ers prefer to intubate the trachea of pregnant women who 1980 through 1984 to 0.5 death per 100,000 live births
require general anesthesia as early as 12 to 14 weeks’ in 2003 through 2007.11 The U.S. Centers for Disease
gestation, given that hormonal changes leading to sphinc- Control and Prevention attributes this decline to
ter relaxation are present early in pregnancy. Patients “improvements in the sensitivity, accuracy, and use of
who receive general anesthesia during the first half of pregnancy testing, ultrasound for diagnosis, and improve-
pregnancy should be intubated if they are at increased ments in therapeutic modalities, including laparoscopic
risk for gastric content aspiration (e.g., history of gastro- surgery and medical management of ectopic pregnancy.”12
esophageal reflux, morbid obesity, food ingestion within However, a recent cluster of 11 maternal deaths from
6 to 8 hours). Pharmacologic prophylaxis (e.g., sodium ectopic pregnancy in Florida between 2009 and 2010
citrate, a histamine-2 (H2) receptor antagonist, and/or increased Florida’s ectopic pregnancy mortality ratio
metoclopramide) is likely to further reduce the risk for from 0.6 death per 100,000 live births in 1999 through
aspiration pneumonia (see Chapter 29). Neuraxial anes- 2008 to 2.5 deaths per 100,000 live births in 2009 through
thesia is associated with a lower risk for aspiration than 2010.12 Because these women collapsed (likely from acute
general anesthesia. rupture and hemorrhage) without ever seeking health
care, it was believed that limited access to early care may
have contributed to the adverse outcomes. Further, of the
Nervous System 11 women who died, 6 tested positive for illicit drugs at
During early pregnancy, the nervous system is more sen- autopsy. Ectopic pregnancy deaths historically have been
sitive to general and local anesthetic agents. The more common in teenagers10 and are 3 to 18 times higher
minimum alveolar concentration (MAC) for volatile in African-American women than in white women.6,8,10
anesthetic agents is decreased by approximately 30%, Factors that alter the normal fallopian tube transport
although the underlying mechanism for this change is system for the fertilized ovum increase the risk for ectopic
unclear. A recent study that compared patients undergo- pregnancy. These factors include (1) previous ectopic
ing cesarean delivery with nonpregnant patients under- pregnancy; (2) previous tubal surgery; (3) pelvic inflam-
going elective gynecologic surgery found no difference mation, especially infection with Chlamydia trachomatis;
between groups in electroencephalographic measures (4) congenital anatomic distortion such as that caused by
342 PART V Anesthesia Before and During Pregnancy
Infundibular
Ovarian
Cervical
Abdominal
FIGURE 16-1 ■ Potential locations of ectopic pregnancies. The majority occur in the ampullary portion of the fallopian tube. (Reprinted
from Chantigian RC, Chantigian PDM. Problems in early pregnancy. In Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s
Obstetric Anesthesia. 4th edition. Philadelphia, Mosby, 2009. Modified from DeCherney AH, Seifer DB. Ectopic pregnancy. In Gabbe SG,
Niebyl JR, Simpson JL, editors. Obstetrics: Normal and Problem Pregnancies. 2nd edition. New York, Churchill Livingstone, 1991:811.)
exposure to diethylstilbestrol in utero; (5) previous pelvic shedding of the decidual lining of the uterine wall, which
or abdominal surgery; (6) use of a contraceptive intra- is probably associated with decreased hormone produc-
uterine device, which may be associated with interstitial tion by the corpus luteum and inadequate human chori-
ectopic pregnancy; (7) delayed ovulation; (8) hormonal onic gonadotropin (hCG) production by the ectopic
changes associated with ovulation induction or progestin- trophoblast. Pain often precedes vaginal bleeding.
only oral contraceptives; (9) lifestyle factors (e.g., Patients with hemorrhage (with or without tubal rupture)
smoking, vaginal douching); (10) history of infertility; may experience dizziness or syncope, may have the urge
and (11) assisted reproductive technology (ART) proce- to defecate because of the effect of blood in the cul-de-
dures (e.g., zygote transfer into the fallopian tube or sac, and may have shoulder pain from diaphragmatic irri-
uterine cavity).13 However, one third of patients with tation by intra-abdominal blood.
ectopic pregnancies have no identifiable risk factors. Physical findings include abdominal tenderness with
The fertilized ovum can implant anywhere along the or without rebound (80% to 95%), a uterus that is smaller
path of migration or in the abdominal cavity (Figure than expected for dates (30%), and a tender adnexal mass
16-1). Most ectopic pregnancies (98%) are tubal (infun- (30% to 50%). A bulging cul-de-sac suggests hemoperi-
dibular or fimbrial, 6%; ampullary, 78%; isthmic, 12%; toneum. With significant hemorrhage there may be signs
interstitial or cornual, 2%). The remaining 2% implant of shock, but some patients may appear hemodynamically
on the cervix, vagina, or ovary or elsewhere in the stable despite a hemoperitoneum volume of 1000 to
abdomen.14 An increasing number of cesarean scar 1500 mL; presumably, these patients have an ectopic
ectopic pregnancies, which may be on a continuum with pregnancy with slow bleeding and are able to compensate
early placenta accreta, are being reported. for the gradual blood loss.
In patients who undergo ART procedures, ectopic
pregnancies have been reported in approximately 2% of
pregnancies.13 Most of these pregnancies are tubal;
Diagnosis
however, approximately 6% are ovarian, abdominal, or Ectopic pregnancy should be excluded in any patient who
cervical, and 12% to 15% are heterotopic (see later has pelvic pain and a positive pregnancy test. In a woman
discussion).14 of reproductive age, the symptoms of ectopic pregnancy
must be differentiated from (1) a threatened, inevitable,
or incomplete abortion; (2) infection after attempted
Clinical Presentation abortion; (3) pelvic inflammatory disease; (4) a degenerat-
The clinical presentation of the patient with an ectopic ing fibroid; (5) appendicitis and other gastrointestinal
pregnancy depends on the gestational age, site of implan- diseases; (6) ovarian torsion; (7) a ruptured or bleeding
tation, and extent of hemorrhage. Prior to rupture, the ovarian cyst; (8) a trapped retroverted uterus in preg-
signs and symptoms are often subtle. Classic clinical signs nancy; and (9) nephrolithiasis.
of impending rupture or a ruptured tubal pregnancy Current tests allow early diagnosis of ectopic preg-
include abdominal or pelvic pain (95%), delayed menses nancy and prompt treatment that decreases morbidity
(75% to 95%), and vaginal bleeding (60% to 80%). and mortality.9 Diagnostic algorithms include the follow-
Vaginal bleeding results from the breakdown and ing guidelines:
16 Problems of Early Pregnancy 343
1. Ultrasonography can reliably confirm only the Systemic, intramuscular, oral, and intragestational forms
presence of an intrauterine pregnancy. The ectopic of chemotherapy have been used successfully in the
pregnancy itself may be difficult to visualize.15 medical management of ectopic pregnancy. Methotrex-
Transvaginal ultrasonography is the current ate, a folate antagonist that interrupts DNA synthesis
modality of choice because it can detect an intra- and thus cell replication, inhibits growth of trophoblastic
uterine gestational sac as soon as 21 days after con- cells of the placenta and is commonly used to treat ectopic
ception (when the beta-hCG concentration is pregnancy. Because methotrexate is toxic to all rapidly-
greater than 1400 mIU/mL with use of the Inter- dividing tissues of the body, there are many contraindica-
national Reference Preparation [IRP] standard). tions to medical treatment of ectopic pregnancy, including
Transabdominal ultrasonography can visualize immunodeficiency and pulmonary, liver, renal, or hema-
an intrauterine pregnancy when the serum beta- tologic disease. Further, the ACOG has recommended
hCG concentration is higher than 6000 to that only early tubal pregnancies (i.e., no cardiac activity,
6500 mIU/mL IRP.16 a gestational sac with a diameter < 3.5 to 4.0 cm, and no
2. A serial beta-hCG concentration that decreases, evidence of tubal rupture or hemoperitoneum) be treated
plateaus, or shows a subnormal increase (< 53% with methotrexate.
over 48 hours) usually indicates a nonviable Methotrexate treatment protocols include a single-
pregnancy—either an ectopic pregnancy or an dose regimen, a two-dose regimen, and a fixed multidose
impending abortion.17 With a spontaneous abor- regimen; the multidose regimen is reserved for patients
tion, a decline in beta-hCG concentration of at with high beta-hCG levels (i.e., > 5000 mIU/mL). From
least 21% to 35% should be seen over 2 days. A day 4 to day 7 after methotrexate treatment, a decrease
slower decline is suggestive of an ectopic preg- in beta-hCG level of 15% must be present to consider
nancy. A beta-hCG concentration greater than the treatment successful. Otherwise, repeat methotrexate
100,000 mIU/mL is usually associated with a viable treatment or surgical intervention is required. Follow up
intrauterine pregnancy.18 and close monitoring until beta-hCG level reaches non-
3. A serum progesterone concentration greater than pregnant values is imperative because of the risk for
25 ng/mL is usually associated with a viable preg- rupture and hemorrhage. Side effects of methotrexate
nancy. A concentration less than or equal to 5 ng/ can be severe and include abdominal pain, vomiting, sto-
mL usually indicates a nonviable pregnancy but matitis, severe neutropenia, and pneumonitis. Compared
cannot distinguish a spontaneous abortion from an with surgical management, medical management of
ectopic pregnancy.19 Most ectopic pregnancies are ectopic pregnancy provides no difference in overall tubal
associated with progesterone levels between 5 and preservation, tubal patency, risk for repeat ectopic preg-
25 ng/mL, a fact that limits the usefulness of this nancy, or success of future pregnancies.
test. Surgical management depends on the location of the
4. Uterine curettage can be performed when nonvia- pregnancy, the hemodynamic stability of the patient, the
bility is established. Identification of trophoblastic available equipment, and the surgeon’s expertise. Most
villi confirms miscarriage of an intrauterine preg- often, diagnostic laparoscopy is performed to confirm the
nancy. Absence of villi signals either a complete diagnosis and locate the ectopic pregnancy. For tubal
spontaneous abortion (confirmed by rapidly ectopic pregnancies, a salpingostomy, salpingotomy, or
decreasing beta-hCG concentration) or an ectopic salpingectomy (usually partial) is performed by means of
pregnancy. laparoscopy or laparotomy. To aid hemostasis during lap-
In the past, culdocentesis was used to aid in the diagnosis aroscopic removal of the ectopic pregnancy, some obste-
of hemoperitoneum and ectopic pregnancy. Although a tricians inject dilute vasopressin into the surface of the
positive result is highly predictive of hemoperitoneum, fallopian tube. This agent causes marked blanching of the
the advent of pelvic ultrasonography and rapid quantita- tube and results in a relatively bloodless surgical field. If
tive beta-hCG tests limits its value in the diagnosis of the vasopressin is accidentally injected intravenously, a
ectopic pregnancy. marked increase in maternal blood pressure may occur.
A laparotomy is indicated if the surgeon is not trained
Obstetric Management in operative laparoscopy, laparoscopic removal is antici-
pated to be difficult (e.g., tube diameter > 6 cm or an
Management options for ectopic pregnancy are expect- interstitial location of the ectopic pregnancy), or there is
ant, medical, and surgical. Management choice depends uncontrollable bleeding. Laparotomy should be per-
on the symptoms and diagnostic findings. formed immediately if there is hemodynamic instability;
Expectant management may be used for selected these cases often require a partial or total salpingectomy.
asymptomatic patients with early tubal ectopic pregnan- If a partial salpingectomy is performed, tubal repair may
cies and stable or decreasing beta-hCG levels. Successful be performed primarily or during a second operation.
resolution has been reported in approximately 50% of Although some experts have noted that outcomes from
these selected patients.4 If expectant management is randomized trials comparing salpingostomy and salpin-
unsuccessful, a medical or surgical approach is required. gectomy are lacking,22 the risk for persistent ectopic
The American College of Obstetricians and Gyne- pregnancy may be higher after salpingostomy than after
cologists (ACOG) as well as the American Society of salpingectomy.23
Reproductive Medicine have published guidelines for Interstitial, cervical, cesarean scar, and abdominal
the medical management of ectopic pregnancy.20,21 ectopic pregnancies as well as early placenta accreta may
344 PART V Anesthesia Before and During Pregnancy
present significant diagnostic and therapeutic challenges, defined as penetration of the placenta into the myome-
resulting in delay of diagnosis and treatment. There is trium, which is discovered in the first or early second
potential for massive hemorrhage because of disruption trimester. Because of similarities in pathogenesis, it is
of organs and adjacent tissues. The desire to preserve thought—although not confirmed—that early placenta
fertility may result in greater blood loss as tissue and accreta may develop from cesarean scar pregnancy. A
organ preservation are attempted. recent review found that 15 of 47 (32%) patients with
Interstitial pregnancy often goes unrecognized and early placenta accreta had spontaneous uterine rupture,
may manifest as uterine wall rupture, massive hemor- in most cases followed by bleeding and shock, which
rhage, and shock. Conservative surgery (e.g., cornual resulted in laparotomy, hysterectomy, or uterine artery
resection) may be attempted, but hysterectomy may be embolization.27 Although the gestational age is early, it is
required if uterine damage is severe. imperative that the anesthesia team is aware of the risk
Cervical pregnancy often results in massive hemor- for hemorrhage during surgical intervention for cesarean
rhage because of the inability of the cervix to contract. scar pregnancy and early placenta accreta.
In the past, most cervical pregnancies necessitated hys- Abdominal pregnancy is defined as implantation in
terectomy to control hemorrhage. More current manage- the peritoneal cavity, not including the fallopian tubes,
ment options that have greater likelihood of maintaining ovaries, or ligaments, and is associated with a high inci-
fertility include (1) methotrexate therapy, (2) local exci- dence of maternal morbidity and fetal demise.28 In a
sion, (3) cerclage and tamponade, (4) ligation of the recently published series of advanced extrauterine preg-
hypogastric arteries or the cervical branches of the uterine nancies, Worley et al.29 identified ten women who pre-
arteries, and (5) angiographic embolization of the uterine sented with extrauterine pregnancies beyond 18 weeks’
arteries followed by a dilation and evacuation (D and E) gestation, of whom three met the diagnostic criteria for
procedure (see later discussion).24 abdominal pregnancy. All patients had difficult surgery,
Cesarean scar pregnancy occurs when a gestational nine patients required blood transfusion, and only five
sac implants in the uterine scar defect (niche) at the site fetuses survived after complicated courses.
of a previous cesarean delivery. Cesarean scar pregnancy Diagnosis of abdominal pregnancy can be difficult,
has a high complication rate. Although relatively rare, its historically being missed in as many as one of nine cases.28
incidence is rising with increasing cesarean delivery rates The diagnosis was missed prior to delivery in four of the
and currently may be as high as 1 in 1800 pregnancies.25,26 ten cases in the series of Worley et al.29 Abdominal pain,
Jurkovic et al.26 described two types of cesarean scar vaginal bleeding, symptoms consistent with partial bowel
pregnancies: (1) implantation on the scar with enlarge- obstruction, shock, or death may be the first indication
ment into the uterine cavity, and (2) implantation into a of this unusual type of pregnancy. Ultrasonography is
scar defect with growth into the myometrium. Depend- useful but may miss the diagnosis in more than 50% of
ing on its progression, the former type may grow nor- cases. Magnetic resonance imaging may prove to be a
mally or may be treated medically. Scar implantation more sensitive diagnostic tool.
results in an increased risk for hemorrhage at delivery. If an extrauterine pregnancy is suspected in early ges-
Growth into the myometrium may lead to eventual tation, laparoscopy can be used to diagnose and remove
rupture and bleeding in the first trimester; prompt surgi- gestational products. If the extrauterine pregnancy is not
cal intervention is preferred over medical management in identified until late gestation, it is associated with
this situation. decreased placental perfusion (which typically results
In a review of 112 cases of cesarean scar pregnancies, in fetal growth restriction) and oligohydramnios (which
Rotas et al.25 found that approximately half occurred in often results in pulmonary hypoplasia and anatomic
women with only one previous cesarean delivery. Many deformities). In 1993, Stevens30 reviewed published
patients have vaginal bleeding, abdominal cramps, and/ cases of abdominal pregnancy since 1809 and found that
or lower abdominal pain. Up to one third of cases may 63% of infants survived when born after 30 weeks’
be asymptomatic and are diagnosed during routine ultra- gestation.
sonography. A review of 751 published cases of cesarean Management of an advanced extrauterine pregnancy
scar pregnancy found that the diagnosis was missed in consists of laparotomy and delivery of the fetus. Once the
107 of 751 cases (13.6%).27 Transvaginal ultrasonography fetus is delivered, management of the placenta is contro-
was the best diagnostic tool. There were a total of 31 versial and fraught with hazard. Removal of the placenta
different primary treatment approaches, which included is associated with massive hemorrhage, prolonged and
hysterectomy, dilation and curettage (D and C), hystero- complicated surgery (e.g., bowel resection), and an
scopic excision, uterine artery embolization, and intra- increased risk for maternal mortality. A decision to leave
gestational aspiration or injection of methotrexate or the placenta in situ results in a higher risk for infectious
potassium. Complications occurred in 331 of the 751 morbidity as well as a potential greater need for addi-
cases (44.1%), of which the most common was hemor- tional surgery.30,31 In the series of Worley et al.,29 the
rhage. The authors noted that local methotrexate and placenta was left in situ in two patients, both of whom
hysteroscopic-directed procedures had the lowest com- developed serious complications. The site of placental
plication rates and that curettage, systemic methotrexate implantation and the ability to adequately ligate the
therapy, or embolization as single treatments should be blood supply often dictates the obstetrician’s decision
avoided. about management of the placenta.
The incidence of early placenta accreta is also rising Heterotopic pregnancy describes the simultaneous
as a result of increasing cesarean delivery rates. It is occurrence of an ectopic and an intrauterine pregnancy.
16 Problems of Early Pregnancy 345
1999 and 2008, the number, rate, and ratio (number per Clinical Presentation and
1000 live births) of elective abortions in the United States Obstetric Management
declined by 3%, 4%, and 10%, respectively.38
In 2008, 62.8% of elective abortions were performed The clinical presentation and management of spontane-
before 8 weeks’ gestation, 91.4% were performed before ous abortion vary. A threatened abortion is defined as
13 weeks’ gestation, and 1.3% were performed after 21 uterine bleeding without cervical dilation before 20
weeks’ gestation.38 Most (75.9%) were performed by D weeks’ gestation. Bleeding may be accompanied by
and C at less than 13 weeks’ gestation, although some cramping or backache. Once the diagnosis is confirmed,
(14.6%) were induced medically, most commonly using the patient’s activities are restricted until symptoms
methotrexate and misoprostol, or mifepristone and miso- resolve. Approximately 25% of pregnancies are compli-
prostol before 8 weeks’ gestation.38 cated by a threatened abortion; approximately half of
Of the 4693 reported pregnancy-related maternal affected women progress to a spontaneous abortion.48
deaths from 1998 to 2005 in the United States, 3% were An inevitable abortion is defined as cervical dilation
the result of induced or spontaneous abortion.39 Deaths or rupture of membranes without expulsion of the fetus
are usually the result of sepsis, hemorrhage, or embo- or placenta. Spontaneous expulsion of the uterine con-
lism.40 Of the 20 abortion-related maternal deaths in the tents usually occurs, but infection can be a complication.
United States in 2003, 10 were related to spontaneous A complete abortion is defined as a total, spontane-
abortion and 10 women died after legal elective abortion ous expulsion of the fetus and placenta. Partial expulsion
(6 after surgical procedures and 4 after medical or non- of the uterine contents (i.e., an incomplete abortion) is
surgical procedures). more common after 8 weeks’ gestation. Persistent bleed-
From a global perspective, abortion is a significant ing and cramping after expulsion of tissue are signs of an
cause of maternal death. A review of causes of maternal incomplete abortion. An incomplete abortion usually
death from 1997 to 2002 by the World Health Organiza- requires a D and E or a D and C procedure to remove
tion (WHO) reported that in some areas of Latin America any remaining fetal or placental tissue. A D and C pro-
and the Caribbean as many as 30% of maternal deaths are cedure refers to dilation of the cervix followed by curet-
caused by abortion.41 In 2006, the WHO estimated that tage, which is typically by suction. A D and E procedure
12, 23, and 37 maternal deaths per 100,000 live births involves greater cervical dilation followed by evacuation
occur as a result of induced abortion in South Asia, Latin of the uterus with surgical instruments. Typically, the
America/Caribbean, and sub-Saharan Africa, respec- latter is required after ossification of the fetal bones,
tively.41 It is likely that many of these abortions are per- which usually occurs around 13 to 15 weeks’ gestation. A
formed by unskilled individuals in a nonsterile environment D and E procedure is associated with more complica-
that does not meet minimal medical standards. The exact tions. Oxytocin and/or an ergot alkaloid (e.g., methyler-
number of maternal deaths that result from induced abor- gonovine) increases uterine tone and may be administered
tion is unknown and likely underreported.41,42 intraoperatively and/or postoperatively to decrease the
Spontaneous abortion occurs in 10% to 15% of clini- amount of uterine bleeding.
cally recognized pregnancies; when subclinical pregnan- Fetal death may go unrecognized for several weeks in
cies are also considered, the incidence of spontaneous a patient with a missed abortion. Occasionally, coagula-
pregnancy loss may be as high as 60%.43 Although most tion defects such as disseminated intravascular coagula-
spontaneous abortions manifest clinically at 8 to 14 tion (DIC) may complicate intrauterine fetal death; this
weeks’ gestation, ultrasonography suggests that fetal possibility is more likely when fetal demise occurs at an
demise usually occurs before 8 weeks’ gestation. If the advanced gestational age. If spontaneous expulsion of the
fetus is viable at 8 weeks’ gestation, the incidence of uterine contents does not occur after a brief period of
subsequent fetal loss is only 3%. observation, evacuation of the uterus is indicated. Man-
The etiology of spontaneous abortion varies among agement options include placement of intracervical lami-
patients. Chromosomal abnormalities are responsible for naria or intravaginal or intracervical placement of a
at least 50% to 80% of all spontaneous abortions.44 Other prostaglandin E2 (PGE2) preparation. This can be fol-
causes include (1) immunologic mechanisms, (2) mater- lowed by induction of labor or a D and C or D and E
nal infections, (3) endocrine abnormalities (e.g., poorly- procedure. Side effects of prostaglandins include nausea,
controlled diabetes mellitus), (4) uterine anomalies, (5) vomiting, diarrhea, and fever. Intra-amniotic instillation
incompetent cervix, (6) debilitating maternal disease, (7) of hypertonic saline is not recommended in cases of intra-
maternal clotting disorders, (8) trauma, and possibly uterine fetal death because coagulation defects may be
(9) environmental exposures (e.g., irradiation, smoking, induced or enhanced.
certain drugs). Recurrent or habitual abortion refers to the occur-
Although some studies (conducted before scavenging rence of three or more consecutive spontaneous abor-
of anesthetic gases was routine) suggested a higher inci- tions in the same patient.
dence of spontaneous abortion among women who were
exposed to trace concentrations of anesthetic agents in
operating rooms,45 reevaluation of these data demon-
Obstetric Complications
strated significant flaws in study design, casting doubt on Complications of D and C and D and E procedures
the original conclusions.46 Later studies have shown no include cervical laceration, uterine perforation, hemor-
increased incidence of spontaneous abortion in women rhage, retained products of conception, and infection.
working in operating rooms.47 The risk for these complications is increased in
16 Problems of Early Pregnancy 347
pregnancies that have progressed beyond the first trimes- test result (indicating transplacental hemorrhage of fetal
ter and is greater for D and E procedures than for D and blood into the maternal circulation) has been demon-
C procedures. Vasovagal events, postabortal syndrome strated in 11% of these patients.50
(i.e., intrauterine blood clots with uterine atony, associ- Women who suffer spontaneous abortion are at
ated with lower abdominal pain, tachycardia, and diapho- increased risk for depressive disorders during the 6
resis), DIC, and unrecognized ectopic pregnancy can also months after miscarriage51 (see Chapter 51).
occur. Management of uterine perforation may involve
simple observation or immediate laparotomy with repair.
Management depends on the suspected severity of injury
Anesthetic Management
to the uterus and adjacent structures. Several anesthetic techniques are appropriate for D and C
Serious infection (e.g., septic abortion) complicates and D and E procedures (Box 16-2). The choice depends
approximately 1 in 200,000 spontaneous abortions. It is on several factors (e.g., whether the cervix is dilated; the
more common after induced abortion, particularly illegal gestational age and ossification of the fetus; the presence
abortion.49 Septic abortion causes significant morbidity of significant blood loss, sepsis, or a full stomach; and the
and is life threatening. Blood cultures should be taken, emotional state and preference of the patient). Dilation of
and broad-spectrum intravenous antibiotics should be the cervix is relatively painful, whereas suction and curet-
administered promptly. Patients with hemodynamic tage are less painful. If the cervix is dilated and the prod-
instability may require invasive hemodynamic monitoring ucts of conception can be curettaged and suctioned,
to guide fluid, blood, and vasoactive drug therapy. Lower sedation with or without a paracervical block may suffice.
genital tract or bowel injury should be excluded, and the If the cervix is not dilated, paracervical block and sedation,
uterus should promptly be re-evacuated. Occasionally, spinal or epidural anesthesia (with sensory blockade from
hysterectomy is necessary and may be lifesaving. T10 to S4), or general anesthesia should be used. General
Rh0(D) immune globulin should be administered to anesthesia may be most appropriate if the patient is emo-
prevent Rh sensitization in Rh-negative woman who tionally upset or if the gestational age is 13 to 15 weeks or
abort. It should also be given to Rh-negative women with greater (which requires a greater degree of cervical dila-
a threatened abortion because a positive Kleihauer-Betke tion for a D and E procedure). Selected patients may
Suggested Anesthetic Techniques for Dilation and Uterine Suction Curettage (D and C)
BOX 16-2
or Evacuation (D and E) for Spontaneous or Induced Abortion
GENERAL CONSIDERATIONS SPINAL ANESTHESIA
• Blood typing and antibody screening or typing and • Single injection with a small-gauge spinal needle: lido-
crossmatching in patients with a large blood loss or caine 40 mg or hyperbaric bupivacaine 7.5 mg, with
those with advanced gestation fentanyl 10 to 20 µg, to achieve sensory blockade from
• Aspiration prophylaxis if patient has a full stomach T10 to S4
• Routine noninvasive monitors
• One peripheral intravenous catheter EPIDURAL ANESTHESIA
• Administration of a short-acting benzodiazepine (e.g., • Placement of midlumbar epidural needle and catheter
midazolam) may be indicated for patients who prefer • Lidocaine 2% with epinephrine 5 µg/mL (12 to 15 mL)
sedation and/or amnesia and fentanyl 100 µg, injected incrementally, to achieve
• Neuraxial (spinal or epidural) anesthesia for hemody- sensory blockade from T10 to S4
namically stable patients without sepsis is an option:
• Intravenous fluids, vasopressors, supplemental oxygen, GENERAL ANESTHESIA
and minimal sedation given as clinically indicated • Rapid-sequence induction with cricoid pressure if the
• Oxytocin and/or an ergot alkaloid available patient has a full stomach
• General anesthesia may be most appropriate for patients • Induction: propofol or thiopental (ketamine or etomi-
with anticipated blood loss or for patients requiring a D date in cases of severe hemorrhage)
and E (e.g., gestation > 15 weeks’ with large fetal size • Mask anesthesia or laryngeal mask airway during early
and fetal ossification) pregnancy if stomach is empty and the patient is hemo-
• In patients with significant blood loss: observation of the dynamically stable; otherwise tracheal intubation with a
patient on the operating table for evidence of hypoten- muscle relaxant
sion for at least 5 minutes after the legs have been • Maintenance: volatile or intravenous anesthetic agents
lowered from the lithotomy to the supine position • High concentration (> 0.5 MAC) of a volatile anes-
thetic agent should be avoided if there is significant
MONITORED ANESTHESIA CARE (WELL TOLERATED bleeding or evidence of uterine atony
WHEN THE CERVIX IS DILATED AND GESTATIONAL AGE IS • Insertion and removal of an oral gastric tube (if trachea
FIRST TRIMESTER) is intubated) to evacuate the stomach
• Intravenous analgesia with fentanyl, alfentanil, or remi- • Tracheal extubation when the patient is awake and
fentanil and sedation with midazolam or propofol responds to verbal commands
• Paracervical block if needed
Modified from Chantigian RC, Chantigian PDM. Problems in early pregnancy. In Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s
Obstetric Anesthesia. 4th edition. Philadelphia, Mosby, 2009.
348 PART V Anesthesia Before and During Pregnancy
benefit from premedication with a short-acting benzodi- and definitive diagnostic tests. The reported incidence
azepine (e.g., midazolam). varies from 1 in 100 to 1 in 2000. The U.S. National Vital
Typically, the cervix is already dilated in patients who Statistics Report for 2004 cited a rate of 4.4 cervical cer-
have had significant preoperative bleeding; rarely does a clages performed per 1000 live births.56 Lidegaard57
patient with a closed cervix have significant bleeding. In reported an incidence of cervical incompetence of 4.6
the presence of significant bleeding, intravascular volume women per 1000 births in Denmark between 1980 and
should be restored first. A paracervical block and sedation 1990.
may then be adequate. Substantial hemorrhage repre- Potential causes of cervical insufficiency include cervi-
sents a relative contraindication to the use of spinal or cal trauma, congenital abnormalities, intrauterine infec-
epidural anesthesia, which probably should also be tion, endocervical inflammation, deficiencies in cervical
avoided in patients with evidence of sepsis. collagen and elastin, and hormonal abnormalities.58 A
General anesthesia may be induced with propofol or common cause of cervical insufficiency is trauma, occur-
thiopental, although ketamine or etomidate may be pre- ring at the time of a previous vaginal delivery or a surgical
ferred in patients with significant bleeding. Large doses procedure (e.g., D and C, conization of the cervix, partial
(1.5 to 2.0 mg/kg) of ketamine increase uterine tone,52 amputation or resection of the cervix, cervical cauteriza-
which may be advantageous in patients who require evac- tion). Congenital abnormalities of the reproductive tract
uation of the uterus. (e.g., unicornuate or bicornuate uterus) may be present
Drugs administered for general anesthesia may influ- in as many as 2% of patients with cervical insufficiency.
ence blood loss during the procedure. Volatile anesthetic Some anomalies may result from maternal exposure to
agents cause dose-dependent relaxation of uterine smooth diethylstilbestrol in utero.
muscle53 and have been associated with increased uterine Warren et al.59 found that more than 25% of women
bleeding.54,55 In two studies that compared blood loss with a diagnosis of cervical insufficiency have a positive
during general anesthesia for elective first-trimester family history of cervical insufficiency as well as a greater
abortion, blood loss was greater when anesthesia was frequency of two genes associated with abnormalities of
maintained with isoflurane compared with propofol.54,55 connective tissue, collagen, and extracellular matrix.
However, the differences were small considering the Other recent studies have found high rates of intra-
blood volume expansion that occurs during pregnancy. amniotic inflammation (measured by elevated amniotic
Some obstetricians contend that relaxation of the uterus fluid matrix metalloproteinase-8 concentration) mostly
(caused by administration of a volatile anesthetic agent) without signs of infection in patients with acute cervical
increases the risk for uterine perforation, and they prefer insufficiency or an asymptomatic shortened cervix.60,61
that administration of a volatile anesthetic agent during The presence of this inflammation was a risk factor for
a D and C or D and E procedure be avoided. impending preterm delivery.60,61 Further research in this
General anesthesia is commonly maintained with area could determine if there is potential for this observa-
oxygen, nitrous oxide, and an opioid. A propofol infusion tion to translate into therapy to prevent preterm labor.
or a low concentration (< 0.5 MAC) of a volatile agent may
be added. The volatile agent should be avoided or discon-
tinued if there is any evidence of uterine atony. In most
Diagnosis
cases, oxytocin diluted in crystalloid is administered intra- Cervical insufficiency remains a clinical diagnosis. A
venously to increase uterine tone and decrease blood loss. definitive diagnosis is made when herniating fetal mem-
The D and C or D and E procedure is performed with branes are visualized or palpated through a partially
the patient in the lithotomy position. After the procedure dilated cervix during the second trimester. A characteris-
is completed and the patient’s legs are lowered, hypoten- tic history from a previous pregnancy allows the pre-
sion may develop in patients who have lost a substantial sumptive diagnosis of cervical insufficiency, once other
amount of blood, especially if neuraxial anesthesia has causes of recurrent pregnancy loss have been excluded.
been used. History suggestive of the diagnosis of cervical insuffi-
ciency consists of two or more second-trimester preg-
nancy losses, loss of each successive pregnancy at an
earlier gestational age, painless cervical dilation to 4 to
CERVICAL INSUFFICIENCY 6 cm, and cervical trauma or anomaly.62 Uterine contrac-
OR INCOMPETENCE tions, vaginal bleeding, or chorioamnionitis during a pre-
vious pregnancy suggests that other mechanisms are
An inherent or traumatic deficiency in the structure responsible for pregnancy loss.
or function of the uterine cervix results in cervical Symptoms of cervical insufficiency include increased
insufficiency or incompetence, which is defined as the vaginal discharge, lower abdominal or back pressure or
inability to sustain a pregnancy to full term. Cervical discomfort, vaginal fullness, and urinary frequency.
insufficiency is characterized by recurrent second- A higher risk for preterm birth has been associated
trimester pregnancy losses with (1) painless cervical dila- with shortened cervical length at early gestational age.63,64
tion; (2) herniation followed by rupture of the fetal Recent trials have indicated that vaginal progesterone
membranes; and (3) a short labor with delivery of a live, treatment in women with a shortened cervix is effective
immature infant. in prevention of preterm birth and neonatal morbid-
The true incidence of cervical insufficiency is difficult ity.65,66 Physical examination may reveal cervical shorten-
to determine owing to a lack of objective clinical findings ing and/or cervical abnormalities. Historically, it has been
16 Problems of Early Pregnancy 349
debated whether serial ultrasonographic evaluations of result in comparable rates of fetal survival in patients with
cervical length and dilation should be considered in the no history of a previous cerclage.75 In one study, better
early second trimester for pregnant women at high risk outcome (i.e., more advanced gestational age) was
for cervical insufficiency.62,67,68 However, a recent decision obtained when a Shirodkar cerclage was performed in
and economic analysis concluded that, of four alterna- patients who had a previous cerclage.76
tives examined, universal transvaginal ultrasonographic Transvaginal cerclage can be performed in most
assessment of cervical length at the time of routine ana- patients with an incompetent cervix. However, if no sub-
tomic ultrasonography and subsequent treatment with stantial cervical tissue is present (e.g., severe cervical lac-
daily vaginal progesterone for women with a short cervix eration, congenital or traumatic cervical shortening) or if
was the most cost-effective strategy and was associated a previous transvaginal cerclage has failed, a transab-
with the greatest reduction in preterm birth less than 34 dominal cerclage may be performed, either before or
weeks’ gestation.69 during pregnancy.77 Although a posterior colpotomy and
division of the transabdominal cerclage occasionally are
performed in an attempt to allow vaginal delivery, most
Obstetric Management patients with transabdominal cerclage undergo cesarean
Management of cervical insufficiency remains controver- delivery. The transabdominal cerclage can remain in situ
sial.58,70,71 A meta-analysis by Berghella et al.72 concluded if further pregnancies are desired, or it can be removed
that cerclage does not prevent preterm birth in all women at the time of cesarean delivery.
and can actually be detrimental in multifetal pregnancies. Although the efficacy of perioperative antibiotics and/
Current evidence, however, shows significant benefit in or tocolytic drugs has not been confirmed, some obstetri-
reducing preterm birth in women with singleton gesta- cians may choose to use them.62
tion who have had a previous preterm birth, have a short- Contraindications to cerclage procedures include
ened cervical length, and are less than 24 weeks’ preterm labor, vaginal bleeding, fetal anomalies, fetal
gestation.73 It was estimated that in these patients, 20 death, rupture of membranes, placental abruption, and
cerclages are needed to prevent one perinatal death and chorioamnionitis. Some obstetricians obtain specimens
more than 6500 infants per year could be saved in the for culture of the amniotic fluid and/or cervix before
United States by this management.74 placement of a cerclage.
The most common cerclage procedures are the modi- Cerclage can be performed (1) prophylactically, before
fied Shirodkar cerclage and the McDonald cerclage, or during pregnancy (interval or primary cerclage); (2)
both of which are performed transvaginally. A ligature therapeutically, when cervical changes are noted in the
(e.g., polyester fiber [Mersilene] tape) is placed around current pregnancy (secondary cerclage); or (3) emer-
the cervix at or near the level of the internal cervical os. gently, in patients with marked cervical changes, includ-
In the more invasive modified Shirodkar procedure, the ing membrane exposure to the vaginal milieu (tertiary
cervical mucosa is incised anteriorly and posteriorly, the cerclage).
bladder may be advanced, the ligature is placed submu- Interval cerclage may increase the risk for infertility
cosally and then tied, and the mucosal incisions are and may prevent easy evacuation of the uterus in the case
closed. The cervical mucosa is left intact with the McDon- of a first-trimester spontaneous abortion. Because pro-
ald cerclage; a purse-string ligature is placed around the phylactic cerclage is more effective than emergency cer-
cervix and then tied (Figure 16-2). These two procedures clage (historical data show fetal survival is 78% to 87%
A B
FIGURE 16-2 ■ Placement of sutures for McDonald cervical cerclage. A, A double-headed polyester fiber (Mersilene) band with four
“bites” is placed in the cervix, avoiding the vessels. B, The suture is placed high up on the cervix, close to the cervical-vaginal junc-
tion, approximately at the level of the internal os. (Reprinted from Chantigian RC, Chantigian PDM. Problems in early pregnancy. In
Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s Obstetric Anesthesia. 4th edition. Philadelphia, Mosby, 2009. Modified
from Iams JD. Preterm birth. In Gabbe SG, Niebyl JR, Simpson JL, editors. Obstetrics: Normal and Problem Pregnancies. 4th edition. New
York, Churchill Livingstone, 2002:803.)
350 PART V Anesthesia Before and During Pregnancy
of the neuraxial blockade may raise intrauterine pressure, GTD caused 0.3% of all pregnancy-related maternal
many prefer the avoidance of general anesthesia during deaths in the United States between 1991 and 1999.8 Risk
pregnancy whenever possible. factors for GTD include advanced or very young mater-
Few clinical studies have compared obstetric outcomes nal age, previous molar pregnancy, and, possibly, nutri-
after administration of neuraxial anesthesia and general tional factors.
anesthesia for cerclage. One retrospective study observed
no difference in fetal outcome after administration of Categorization and Etiology
either general anesthesia (375 cases) or epidural anesthe-
sia (114 cases).83 Another study found no significant dif- The classification and terminology applied to GTD are
ference in plasma oxytocin levels or postoperative uterine varied and can be confusing because GTD encompasses
activity between women who received either spinal or a heterogeneous group of diseases. GTD is also called
general anesthesia for a Shirodkar cerclage.84 gestational trophoblastic tumor or gestational tro-
Fetal heart rate monitoring should be considered phoblastic neoplasia, although in this context neoplasia
during the procedure if the pregnancy is sufficiently simply means “new grown” and does not necessarily dif-
advanced to allow monitoring to be performed easily. In ferentiate benign from malignant forms of GTD.
theory, it is possible that replacement of bulging mem- In 2003, the WHO classified GTD into eight catego-
branes and closure of the cervix may raise intrauterine ries (Box 16-4). The pathologic and clinical features of
pressure with a subsequent reduction in placental blood GTD are summarized in Table 16-1.89 Discussion of pla-
flow. In this case, it would be reasonable to give a toco- cental site trophoblastic tumor, exaggerated placental
lytic agent to help reduce intrauterine pressure. site, placental site nodules and plaques, as well as miscel-
The transvaginal cerclage is removed at 37 to 38 laneous and unclassified trophoblastic lesions, is beyond
weeks’ gestation, or earlier if rupture of membranes or the scope of this chapter. Here the focus is mainly on
onset of labor occurs. Removal of a McDonald cerclage molar pregnancies. Overall, it is helpful to simply remem-
often requires no anesthesia. Anesthesia (e.g., paracervi- ber that GTD always involves trophoblastic cells that
cal block, spinal anesthesia, epidural anesthesia) is usually have abnormally proliferated and/or invaded and/or
necessary for removal of a Shirodkar cerclage. If the Shi- metastasized to distant sites in the body.
rodkar cerclage is epithelialized, some obstetricians elect GTD can be categorized according to pathologic fea-
to leave it intact and perform an elective cesarean tures of the trophoblastic cells, malignant potential of
delivery. the trophoblastic cells, or the genetic makeup of the
Labor often begins within a few hours or days after trophoblastic cells.
suture removal. If an epidural catheter was placed for Pathologically, although all GTD arises from tropho-
cerclage removal, the epidural anesthetic can be allowed blast, hydatidiform moles and gestational choriocarci-
to regress while the patient is observed for evidence of noma arise from villous trophoblast, whereas exaggerated
cervical dilation and the onset of labor. When labor placental site, placental site nodule, placental site tropho-
begins, epidural labor analgesia can be initiated by injec- blastic tumor, and epithelioid trophoblastic tumor arise
tion of drugs through the in situ catheter. from intermediate trophoblast. Further differentiation
of the pathologic features of GTD is outlined in Table
16-1. Gestational choriocarcinoma typically results
GESTATIONAL TROPHOBLASTIC DISEASE from a single trophoblastic cell line that has become
malignant and metastasized to distant sites in the body.
In normal pregnancy, trophoblastic tissue forms the pla- It can occur after a molar pregnancy, a normal pregnancy,
centa. Abnormal trophoblastic proliferation results in or even a pregnancy loss.
gestational trophoblastic disease (GTD). When GTD The spectrum from the most benign to the most malig-
persists after the pregnancy is concluded (diagnosed by nant form of GTD is as follows: (1) partial hydatidiform
persistent elevation of beta-hCG), it is called persistent mole, (2) complete hydatidiform mole, (3) invasive
gestational trophoblastic disease (PGTD). mole, and (4) gestational choriocarcinoma. Benign
Prior to 1970, most cases of PGTD were fatal. Early
diagnosis and effective chemotherapy have reduced the
mortality rate to 0.1% in Great Britain and the Nether- World Health Organization
lands and to 1% in the United States.85,86 This improve- BOX 16-4 Classification of Gestational
ment may be related to the fact that trophoblastic cells Trophoblastic Disease
produce beta-hCG, which provides an easily assayed
biochemical marker to aid in detection and to monitor • Hydatidiform mole:
treatment. Further, it is thought that cytotoxic chemo- • Complete mole
therapeutic drugs are particularly effective against PGTD • Partial mole
because the latter arises from a genotype that is not • Invasive hydatidiform mole
• Choriocarcinoma
entirely that of the patient, thus facilitating rejection of
• Placental site trophoblastic tumor
the trophoblastic cells and leaving them vulnerable to this • Trophoblastic lesions, miscellaneous
therapy.87 • Exaggerated placental site
However, some women still die of GTD, often as a • Placental site nodules and plaques
result of late presentation and drug resistance or con- • Unclassified trophoblastic lesion
comitant human immunodeficiency virus infection.88
352 PART V Anesthesia Before and During Pregnancy
forms of GTD include complete or partial molar preg- by a single sperm or the egg is fertilized by two separate
nancies that have not demonstrated myometrial invasion. sperm. Because both maternal and paternal chromosomes
Malignant forms of GTD include invasive mole (com- are present, it is possible for a fetus to form with a partial
plete or partial molar pregnancies that have demonstrated mole. As a result, patients with partial mole may have a
myometrial invasion), gestational choriocarcinoma, and preoperative diagnosis of incomplete or missed abortion.
placental site trophoblastic tumor. The latter diseases Invasive mole is also called chorioadenoma destruens.
metastasize, most often to the lungs and brain, and are Because this describes any mole (complete or partial) that
fatal if not treated. Complete molar pregnancies have a has invaded into the myometrium, it can have the genetic
higher rate of associated complications and a higher rate makeup of either a complete or partial mole. However,
of subsequent PGTD than partial molar pregnancies. most invasive moles result from complete moles.
Approximately 20% of patients with complete molar
pregnancy have postmolar nonmetastatic PGTD (70% Complete and Partial Hydatidiform Mole
to 90%) or malignant PGTD (10% to 30%) and require
chemotherapy; in contrast, only 5% of patients with The reported incidence of hydatidiform mole varies. In
partial molar pregnancy require chemotherapy.90 the United States, it is detected in 1 in 600 elective abor-
GTD can also be classified according to the genetic tions and 1 in 1500 pregnancies. Rates of 1 in 400 preg-
makeup of the trophoblastic cells. The various means by nancies are reported in Korea and Indonesia and among
which the unusual genetic events occur in GTD are out- Native Americans.85,92,93 Coexistence of an intact fetus
lined here; further details are available elsewhere.87 Typi- with molar components is extremely rare, occurring in 1
cally, the genetic makeup of trophoblastic cells in in 22,000 to 1 in 100,000 pregnancies.92
complete hydatidiform molar pregnancy is androgenic, Patients may have a complete molar pregnancy diag-
meaning nearly all of the genome of the trophoblastic cell nosed during first trimester ultrasonography, or they may
arises from the sperm. It can be either diploid (two sets have vaginal bleeding after delayed menses, suggestive of
of 23 chromosomes [e.g., 46,XY]) or triploid (three sets a threatened, missed, or incomplete abortion. They may
of 23 chromosomes [e.g., 69,XXY]). An ovum lacking spontaneously pass hydropic vesicles. The absence of
chromosomes is fertilized most commonly by one sperm fetal cardiac activity, a uterus large for gestational age,
cell with reduplication (46,XX androgenic) or by two and a marked elevation of beta-hCG strongly suggest the
sperm cells (dispermy, 46,XX or 46,XY androgenic). No diagnosis of hydatidiform mole. Diagnosis may be made
fetus develops. Approximately 90% of hydatidiform after a D and C for an incomplete abortion92; baseline
moles are complete.91 chest radiography and quantitative beta-hCG levels
Typically, the genetic makeup of a partial hydatidiform should be obtained promptly after surgery in such cases.
molar pregnancy is diandric, meaning the chromosomes Molar pregnancies produce hCG in amounts propor-
arise from both the egg and the sperm but is complicated tional to the neoplastic volume. Excessive uterine size
by triploid conception (69,XXX or 69,XXY). One set of is associated with a marked elevation of serum beta-
haploid chromosomes is maternal, and there is either hCG concentration (> 100,000 mIU/mL) secondary to a
reduplication of the paternal donation after fertilization large tumor volume. Large ovarian cysts, hyperemesis
16 Problems of Early Pregnancy 353
gravidarum, and early onset of gestational hypertension TABLE 16-2 Complications of Complete Molar
are also strongly suggestive of GTD. Ultrasonography Pregnancies
may show characteristic multi-echogenic regions that
represent hydropic villi or hemorrhagic foci. Complication Incidence (%)
Excessive uterine size 30-53
Persistent and Malignant Gestational Ovarian theca-lutein cysts (> 6 cm) 4-50
Trophoblastic Disease Hyperemesis gravidarum 14-29
Gestational hypertension 11-27
Persistent or malignant GTD can develop after any
Anemia (hemoglobin < 10 g/dL) 10-54
gestational event, including normal pregnancy, spontane-
Hyperthyroidism 1-7
ous or elective abortion, ectopic pregnancy, and
Trophoblastic emboli 2-7
molar pregnancy. Histologic forms of postmolar PGTD
Acute cardiopulmonary distress 6-27
include noninvasive trophoblastic proliferation, invasive
Malignant sequelae (metastasis) 4-36
mole, gestational choriocarcinoma, and placental site tro-
Other (renal, disseminated intravascular Rare
phoblastic tumor. Diagnosis of postmolar PGTD is made coagulation, infection)
when beta-hCG levels plateau or rise.92,93
Signs and symptoms of malignant GTD after a non- Data from references 88, 90, 94, 96-98, and 100-102. Reprinted
molar gestational event are very subtle and diagnosis may from Chantigian RC, Chantigian PDM. Problems in early
pregnancy. In Chestnut DH, Polley LS, Tsen LC, Wong CA,
be delayed. A quantitative beta-hCG measurement editors. Chestnut’s Obstetric Anesthesia. 4th edition.
should be performed in any patient with continued or Philadelphia, Mosby, 2009.
abnormal vaginal bleeding 6 weeks after the end of gesta-
tion. In any woman of reproductive age with metastatic
disease from an unknown primary tumor, the diagnosis although early presentation does not fit usual definitions
of gestational choriocarcinoma should be considered, (see Chapter 36). Although it is thought that convulsions
given the fact that metastases of gestational choriocarci- rarely occur in these patients,97 prophylactic use of mag-
noma can occur anywhere. The vagina, liver, lung, and nesium sulfate should be considered. An antihypertensive
brain are the most frequently involved sites. Signs and agent (e.g., hydralazine, labetalol) should be given as
symptoms are related to the affected site. Biopsy of required to reduce blood pressure. GTD should be
metastases is rarely needed and can result in profuse strongly suspected in any patient who develops hyperten-
bleeding. The diagnosis of metastatic GTD is suggested sion during early pregnancy.
with a positive beta-hCG result and no pregnancy.85,92,93 Anemia frequently complicates a complete molar
Details on staging and risk-factor scoring of GTD and pregnancy. The visible vaginal bleeding may underrepre-
their implications for therapy and prognosis are available sent the total amount of hemorrhage. Occult bleeding
elsewhere.90,94,95 into and around the tumor results in multiple hemor-
rhagic foci. Because blood loss may occur gradually, the
patient may have a normal intravascular volume despite
Medical Complications the presence of severe anemia. In the 1970s and 1980s,
Routine use of ultrasonography has led to earlier diagnosis blood transfusion was required in as many as 32% to 45%
of molar pregnancy, which has reduced the incidence of of patients.96,99 With earlier diagnosis using ultrasonog-
medical complications. However, excessive uterine size raphy, the incidence of transfusion may be less than in
occurs in up to half of patients with complete molar preg- the past. Nonetheless, blood typing and antibody screen-
nancy and is associated with a higher incidence of medical ing should be performed preoperatively.
complications. Medical complications occur in about 25% Although it occurs infrequently, hyperthyroidism
of patients with uterine size of more than 14 to 16 weeks’ may result from a marked elevation of hCG,100 which can
gestation; they include ovarian theca-lutein cysts, hyper- have a thyrotropin-like effect. Alternatively, hyperthy-
emesis gravidarum, gestational hypertension, anemia, roidism may result from some other thyrotropic sub-
hyperthyroidism, DIC, and sepsis (Table 16-2).90,92-94,96-99 stance produced by the neoplasm.100 Anesthesia or surgery
Ovarian theca-lutein cysts occur primarily in patients can precipitate thyroid storm (i.e., sinus tachycardia,
with extremely high serum beta-hCG concentration atrial fibrillation, hyperthermia, cardiovascular collapse),
(>100,000 mIU/mL).97 They typically regress over 2 to 3 which is treated using a beta-adrenergic antagonist.
months; rarely, torsion, rupture, or infarction may neces- Historically, acute cardiopulmonary distress was
sitate oophorectomy. Patients with theca-lutein cysts and observed after evacuation of molar pregnancy in as many
a uterus more than 4 weeks larger than expected (for as 27% of patients.97,101-103 A higher risk for cardiopulmo-
dates) have a 50% likelihood of development of postmo- nary complications occurs in patients with a uterine
lar GTN.85 size of 16 weeks or greater.101,104 Signs and symptoms
Hyperemesis gravidarum can lead to significant include chest pain, cough, tachycardia, tachypnea, hypox-
electrolyte disturbances and volume depletion, all of emia, diffuse rales, and chest radiographic evidence of
which should be corrected before surgery. bilateral pulmonary infiltrates. It is thought that tropho-
Gestational hypertension occurs in up to 27% of blastic embolization may be the etiology of cardiopul-
women with molar pregnancy, typically in patients monary distress in more than half of cases.103,104 Other
with an excessively large uterus.98 Preeclampsia may be causes include (1) high-output cardiac failure from thy-
diagnosed if proteinuria accompanies hypertension, rotoxicosis, (2) pulmonary congestion from severe
354 PART V Anesthesia Before and During Pregnancy
anemia, (3) gestational hypertension or preeclampsia, (4) risk for cardiopulmonary distress with uterine evacuation.
aspiration pneumonitis, and (5) iatrogenic fluid over- The anesthesia provider should establish adequate intra-
load.103,104 Symptoms usually develop within 12 hours of venous access, and blood products should be immediately
uterine evacuation.103 Some patients require tracheal available. Invasive arterial pressure and/or central venous
intubation, mechanical ventilation, and invasive hemody- pressure monitoring may be indicated in the patient with
namic monitoring. Symptoms usually subside within 72 hypoxemia, severe anemia, hemorrhage, severe gesta-
hours; however, massive embolization or adult respira- tional hypertension or preeclampsia, hyperthyroidism, or
tory distress syndrome may result in death. If the patient a uterus of more than 16 weeks’ size.107
survives trophoblastic embolization, malignant sequelae Although neuraxial anesthesia has been described,
often develop.94,103,105 general anesthesia is often preferred because of the
potential for rapid, substantial blood loss and cardiopul-
monary distress during evacuation of the uterus (Box
Obstetric Management 16-5). For patients with acute hemorrhage and hypovo-
The following preoperative tests are recommended for lemia, induction with thiopental or propofol may cause
patients with suspected hydatidiform mole: (1) complete marked hypotension. In hyperthyroid patients, ketamine
blood count including platelet count, (2) coagulation may result in marked tachycardia.108 Etomidate is an
studies, (3) renal and liver function studies, (3) blood excellent choice for patients with preoperative bleeding
typing and antibody screening, (4) quantitative beta-hCG and preoperative evidence of hyperthyroidism. Anesthe-
level, and (5) chest radiography.92,93 Prompt molar evacu- sia can be maintained using either an inhalational or
ation should be instituted, because a delay in uterine intravenous technique, although it may be necessary to
evacuation may raise the risk for complications. Once the avoid volatile anesthetic agents in some patients to opti-
patient is stabilized, suction curettage is performed to mize uterine contractility,109 and care should be exercised
evacuate the uterus in patients who want to preserve with the use of a propofol infusion in hemodynamically
fertility. Real-time ultrasonography may help the obste- unstable patients.
trician perform a complete evacuation of the uterus in An intravenous oxytocin infusion (20 IU/L of crystal-
patients with excessive uterine size.106 Hysterectomy is loid) is begun either before97,101 or during94 uterine evacu-
performed in patients who have completed childbearing. ation. Oxytocin helps the uterus contract, facilitating safe
Hysterotomy and medical induction of labor are not rec- curettage and reducing blood loss. Some obstetricians
ommended because they are associated with increased have speculated that oxytocin may decrease trophoblastic
blood loss and a higher incidence of postmolar PGTD.93 embolization by constricting the uterine veins.101 Postop-
Rh0(D) immune globulin should be administered to eratively, the patient should be monitored closely for any
Rh-negative patients. evidence of uterine hemorrhage or cardiopulmonary
After uterine evacuation, the beta-hCG level should distress.
be measured weekly until it is undetectable for 3 weeks,
then monthly for 6 months and every 2 months for Suggested Anesthetic Technique
another 6 months. Frequent pelvic examinations are per-
BOX 16-5 for Patients with Gestational
formed while beta-hCG levels remain high. Thorough Trophoblastic Neoplasm
evaluation of the patient with GTD includes screening
for evidence of metastasis (e.g., vagina, liver, lung, brain) PREOPERATIVE EVALUATION
and other potential complications. Prevention of preg- • Evaluation for complications of molar pregnancy
nancy for 12 months is recommended.85 • Measurement of baseline arterial blood gas levels
Malignant GTD should be managed by an experi-
enced team in a trophoblastic center to minimize mortal- GENERAL ANESTHESIA
ity.85,92-94 Chemotherapy is indicated in patients with (1) • Routine noninvasive monitors
histologic evidence of invasive mole or choriocarcinoma, • Consideration of invasive hemodynamic monitoring in
(2) an increase in beta-hCG levels of 10% or greater in patients with hypoxemia, gestational hypertension or
three or more samples taken over at least 2 weeks, (3) a preeclampsia, severe anemia, hyperthyroidism, or a
plateau of beta-hCG levels in four or more samples taken uterine size greater than 16 weeks’ gestation
• Two large-gauge peripheral intravenous catheters
over 3 consecutive weeks, (4) persistence of measurable
• Immediate availability of blood
beta-hCG levels 6 months after molar evacuation, or (5) • Induction: etomidate if evidence of hemorrhage or
evidence of metastasis.95 Some patients may require hemodynamically unstable
delayed hysterectomy, thoracotomy for resection of pul- • Tracheal intubation with a muscle relaxant
monary metastasis, and/or liver or brain irradiation. • Maintenance: inhalation or intravenous technique
Avoid volatile agents if optimization of uterine con-
tractility is required, and exercise caution with the use
Anesthetic Management of a propofol infusion in hemodynamically unstable
Preoperative assessment of the patient with a molar preg- patients
nancy consists of evaluation for specific complications of • Oxytocin infusion (20 IU/L) after cervical dilation or
after partial uterine evacuation
molar pregnancy, including hyperemesis gravidarum,
gestational hypertension and preeclampsia, anemia, and Modified from Chantigian RC, Chantigian PDM. Problems in early
thyrotoxicosis. The main anesthetic considerations are pregnancy. In Chestnut DH, Polley LS, Tsen LC, Wong CA, editors.
the potential for rapid and significant blood loss and the Chestnut’s Obstetric Anesthesia. 4th edition. Philadelphia, Mosby, 2009.
16 Problems of Early Pregnancy 355
HYPEREMESIS GRAVIDARUM
• During pregnancy, the nervous system is more
As many as 50% to 80% of women experience nausea and sensitive to local anesthetics and perhaps general
vomiting during pregnancy; this is the most common anesthetic agents. Lower doses of these drugs
indication for admission to the hospital during the first should be considered, although it is important to
trimester of pregnancy. Symptoms are often worse during be aware of the greater risk for intraoperative
the morning hours, thus the term morning sickness. Symp- awareness during cesarean delivery.
toms typically improve or resolve by the end of the first • Most ectopic pregnancies are located in one of
trimester. the fallopian tubes. Ruptured tubal pregnancies,
On rare occasions, pregnant women experience a per- as well as interstitial, cervical, cesarean scar, and
sistent and severe form of nausea and vomiting called abdominal ectopic pregnancies as well as
hyperemesis gravidarum. This is believed to be an pregnancies with early placenta accreta, may
extreme form of normal nausea and vomiting of preg- result in substantial hemorrhage.
nancy, although there is no single accepted definition. • The most painful part of a dilation and uterine
These women may develop dehydration, ketonuria, evacuation procedure is the dilation of the cervix.
nutritional compromise, weight loss, electrolyte abnor- If the cervix is already dilated and the fetal size is
malities, and/or transient hepatic and renal dysfunction. first trimester, sedation (with or without
Intravenous rehydration, correction of electrolyte abnor- paracervical block) often suffices. If the cervix is
malities, antiemetics, and, rarely, hyperalimentation are closed, either a paracervical block with sedation
indicated. or neuraxial or general anesthesia may be
Hyperemesis gravidarum may be associated with mul- necessary. If the fetal size is advanced (>13 to
tiple gestation, thyrotoxicosis, and/or GTD. Diagnosis is 15 weeks’ gestation), many anesthesia providers
by exclusion, and many other underlying diseases should prefer general anesthesia because of the greater
be ruled out, including gastrointestinal diseases (e.g., surgical stimulation and risk for bleeding
hepatitis, cholecystitis, pancreatitis, partial bowel obstruc- complications.
tion), genitourinary diseases (e.g., pyelonephritis, uremia, • Neuraxial anesthesia is an excellent choice for
ovarian torsion, kidney stones), metabolic disorders, neu- prophylactic cervical cerclage. In a patient who
rologic or psychiatric disorders, acute fatty liver of preg- requires emergency cervical cerclage, it is
nancy, drug toxicity, and preeclampsia. important to prevent a marked increase in
intra-abdominal and intrauterine pressures, which
might cause rupture of bulging fetal membranes.
CORPUS LUTEUM CYSTS • The patient with a molar pregnancy may have
hyperemesis gravidarum, gestational
Symptomatic corpus luteum cysts occasionally occur
hypertension, severe anemia, and/or
during early pregnancy. Typically, they resolve over
hyperthyroidism. These complications are more
several weeks. In some cases, hemorrhage or ovarian
common in patients with excessive uterine size.
torsion necessitates ovarian cystectomy or oophorec-
tomy. After the cyst is removed, the fetus usually is not • Rapid and profound blood loss is possible with
affected, provided that supplemental progesterone is uterine evacuation of a molar pregnancy, and
administered until 10 to 12 weeks’ gestation. acute cardiopulmonary distress can develop after
uterine evacuation.
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et al. Heterotopic pregnancy: two cases and a comparative review. cal intraamniotic inflammation: implications for patient counsel-
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2007; 357:462-9. prognostic factor. Int J Gynecol Cancer 2009; 19:289-93.
66. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal pro- 89. Lurain JR. Gestational trophoblastic disease. I. Epidemiology,
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68. Golan A, Barnan R, Wexler S, et al. Incompetence of the uterine 92. American College of Obstetricians and Gynecologists. Diagnosis
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69. Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical tice Bulletin No. 53, June 2004. (Obstet Gynecol 2004; 103:
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72. Berghella V, Odibo AO, To MS, et al. Cerclage for short cervix 95. Kohorn EI. Negotiating a staging and risk factor scoring system
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2009; 201:375.e1-8. 97. Berkowitz RS, Goldstein DP. Diagnosis and management of the
74. Berghella V, Rafael TJ, Szychowski JM, et al. Cerclage for short primary hydatidiform mole. Obstet Gynecol Clin North Am
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117:663-71. diagnosis, management, and long-term followup of 347 patients.
75. Odibo AO, Berghella V, To MS, et al. Shirodkar versus McDonald Obstet Gynecol 1975; 45:1-8.
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76. Treadwell MC, Bronsteen RA, Bottoms SF. Prognostic factors and 158:1299-306.
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868-72. 1980; 138:6-10.
78. Harger JH. Comparison of success and morbidity in cervical cer- 102. Hammond CB. Diagnosis and management of hydatidiform mole.
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79. Magrina JF, Kempers RD, Williams TJ. Cervical cerclage: 20 103. Twiggs LB, Morrow CP, Schlaerth JB. Acute pulmonary compli-
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66:599-602. 135:189-94.
80. Rust OA, Roberts WE. Does cerclage prevent preterm birth? 104. Kohorn EI. Clinical management and the neoplastic sequelae of
Obstet Gynecol Clin North Am 2005; 32:441-56. trophoblastic embolization associated with hydatidiform mole.
81. Drassinower D, Poggi SH, Landy HJ, et al. Perioperative com- Obstet Gynecol Surv 1987; 42:484-8.
plications of history-indicated and ultrasound-indicated cervical 105. Orr JW Jr, Austin JM, Hatch KD, et al. Acute pulmonary edema
cerclage. Am J Obstet Gynecol 2011; 205:53.e1-5. associated with molar pregnancies: a high-risk factor for develop-
82. McCulloch B, Bergen S, Pielet B, et al. McDonald cerclage ment of persistent trophoblastic disease. Am J Obstet Gynecol
under pudendal nerve block. Am J Obstet Gynecol 1993; 1980; 136:412-15.
168:499-502. 106. Evers JL, Schijf CP, Kenemans P, Martin CB Jr. Real-time ultra-
83. Crawford JS, Lewis M. Nitrous oxide in early human pregnancy. sound as an adjunct in the operative management of hydatidiform
Anaesthesia 1986; 41:900-5. mole. Am J Obstet Gynecol 1981; 140:469-71.
84. Yoon HJ, Hong JY, Kim SM. The effect of anesthetic method for 107. Kim JM, Arakawa K, McCann V. Severe hyperthyroidism associ-
prophylactic cervical cerclage on plasma oxytocin: a randomized ated with hydatidiform mole. Anesthesiology 1976; 44:445-8.
trial. Int J Obstet Anesth 2008; 17:26-30. 108. Kaplan JA, Cooperman LH. Alarming reactions to ketamine in
85. Benedet JL, Bender H, Jones H 3rd, et al. FIGO staging classifica- patients taking thyroid medication—treatment with propranolol.
tions and clinical practice guidelines in the management of gyne- Anesthesiology 1971; 35:229-30.
cologic cancers. FIGO Committee on Gynecologic Oncology. Int 109. Ackerman WE III. Anesthetic considerations for complicated
J Gynaecol Obstet 2000; 70:209-62. hydatidiform molar pregnancies. Anesth Rev 1984; 11:20-4.
C H A P T E R 1 7
Nonobstetric Surgery
during Pregnancy
Marc Van de Velde, MD, PhD
CHAPTER OUTLINE
Estimates of the frequency of nonobstetric surgery per- period was documented or if women stated that it was
formed during pregnancy range from 0.3% to 2.2%.1,2 not possible that they were pregnant.7 This guideline was
Thus, as many as 93,000 and 110,000 pregnant women poorly followed, resulting in 42 serious incidents, 3 preg-
in the United States and the European Union, respec- nancy losses, and several cases of litigation between 2003
tively, may require a surgical or anesthetic intervention and 2009.8 In 2010, the U.K. National Patient Safety
each year. These numbers are likely to be an underesti- Agency stated that women should be offered a pregnancy
mation, because pregnancy may be unrecognized at the test “if there is any possibility that a woman could be
time of operation. The reported incidence of positive pregnant.”8 In certain populations, medical history alone
pregnancy tests in women of childbearing age ranged may be an unreliable means of excluding the possibility
from 0.002% in women presenting for orthopedic of pregnancy.6,7 Thus, some institutions routinely perform
surgery3 to 0.3% in women presenting to an ambulatory pregnancy tests on all women of childbearing age who
surgery center4 to 2.6% in women scheduled to undergo present for elective surgery.3
elective sterilization procedures.5 Surgery may be necessary during any stage of preg-
The practice of routine pregnancy testing for all nancy. Among 5405 Swedish women who had operations
women of childbearing age presenting for elective surgery during pregnancy, 42% occurred during the first trimes-
and anesthesia is controversial. The American Society of ter, 35% during the second trimester, and 23% during
Anesthesiologists Task Force on Preanesthesia Evalua- the third trimester.1 Laparoscopy for gynecologic indica-
tion states “… the literature is inadequate to inform tions was the most common first-trimester procedure
patients or physicians on whether anesthesia causes (34%), whereas appendectomy was the most common
harmful effect in early pregnancy. Pregnancy testing may procedure during the remainder of pregnancy. Indica-
be offered to female patients of childbearing age and for tions for pregnancy-related surgery include cervical
whom the result would change the patient’s manage- incompetence, the presence of ovarian cysts, and condi-
ment.”6 In 2000, the U.K. National Institute for Health tions amenable to fetal surgery (see Chapter 7). Indica-
and Clinical Excellence (NICE) issued preoperative tions for non–pregnancy-related surgery include the
screening guidelines recommending routine pregnancy presence of acute abdominal disease (most commonly
testing for “female patients who say that it is possible they appendicitis and cholecystitis), malignancies, and trauma.
may be pregnant.”7 There was uncertainty among the When caring for pregnant women undergoing nonob-
Guideline Development Group as to whether women stetric surgery, anesthesia providers must consider both
should undergo pregnancy testing if the last menstrual the mother and the fetus. Standard anesthetic procedures
358
17 Nonobstetric Surgery during Pregnancy 359
may have to be modified to accommodate pregnancy- Decreased FRC, increased oxygen consumption, and
induced maternal physiologic changes and the presence diminished buffering capacity result in the rapid develop-
of the fetus. The Confidential Enquiries into Maternal ment of hypoxemia and acidosis during periods of
and Child Health in the United Kingdom demonstrate hypoventilation or apnea. Moreover, induction of inhala-
that, even in early pregnancy, mothers die of hemor- tion anesthesia occurs more rapidly during pregnancy
rhage, sepsis, thromboembolism, and anesthesia; sub- because alveolar hyperventilation and decreased FRC
standard care is often present.9 Erekson et al.10 analyzed allow faster equilibration of inhaled agents. In addition,
2005 to 2009 data from the American College of Sur- induction of anesthesia is accelerated owing to the 30%
geons National Surgical Quality Improvement Program to 40% decrease in the minimum alveolar concentration
database. The rate of major complications (e.g., infec- (MAC) for volatile anesthetic agents that occurs even
tions, reoperation, wound problems, respiratory compli- during early gestation.11 The anesthesia provider must be
cations, venous thromboembolism, blood transfusion, especially vigilant when administering subanesthetic con-
maternal death) for antenatal nonobstetric surgery was centrations of analgesic and anesthetic agents to the preg-
approximately 6%.10 nant patient, in whom unconsciousness can occur quickly
Possible risks to the fetus of antenatal surgery include and unexpectedly.
(1) the effects of the disease process itself, or related
therapy; (2) the teratogenicity of anesthetic agents
or other drugs administered during the perioperative
Cardiovascular System Changes
period; (3) intraoperative perturbations of uteroplacental Cardiac output increases by up to 50% during pregnancy
perfusion and/or fetal oxygenation; and (4) the risk for because of increases in heart rate and stroke volume; both
abortion or preterm delivery. systemic and pulmonary vascular resistances decrease,
but myocardial contractility is unaffected. Early in preg-
nancy (i.e., by 6 weeks’ gestation), significant cardiovas-
MATERNAL SAFETY: ALTERED cular alterations are present.12 By 8 weeks’ gestation, 57%
MATERNAL PHYSIOLOGY of the increase in cardiac output, 78% of the increase in
stroke volume, and 90% of the decrease in systemic vas-
During pregnancy, profound changes in maternal physi- cular resistance that are typically achieved by 24 weeks’
ology result from increased concentrations of various gestation have occurred.13
hormones, mechanical effects of the gravid uterus, During the second half of gestation, the uterus com-
greater metabolic demand, and the hemodynamic conse- presses the inferior vena cava when the mother lies
quences of the low-pressure placental circulation. Hor- supine; the compression reduces venous return and
monal changes are likely responsible for most of the cardiac output by approximately 30%. Although upper
changes that occur during the first trimester. Mechanical extremity blood pressure may be maintained by compen-
effects become apparent when the uterus emerges from satory vasoconstriction and tachycardia, uteroplacental
the pelvis during the second half of gestation (see perfusion is jeopardized whenever the mother lies supine.
Chapter 2). In some women, frank hypotension may occur in the
supine position, especially when neuraxial or general
Respiratory System and Acid-Base anesthesia attenuates or abolishes normal compensatory
mechanisms. For these reasons, it is essential to displace
Balance Changes the uterus laterally during any operation performed after
Alveolar ventilation increases by 30% or more by mid 18 to 20 weeks’ gestation. Vena caval compression also
pregnancy. This increase results in chronic respiratory results in distention of the epidural venous plexus, which
alkalosis with a Paco2 of 28 to 32 mm Hg, a slightly increases the likelihood of intravascular injection of local
alkaline pH (approximately 7.44), and decreased levels of anesthetic during the administration of epidural anesthe-
bicarbonate and buffer base. Although oxygen consump- sia. The reduced capacity of the epidural space most
tion is increased, Pao2 usually increases only slightly or likely contributes to the enhanced spread of epidural local
remains within the normal range. Functional residual anesthetic solution that is observed during pregnancy.
capacity (FRC) diminishes by approximately 20% as the
uterus expands, resulting in decreased oxygen reserve and Changes in Blood Volume
the potential for airway closure. When FRC is decreased
further (e.g., from morbid obesity; perioperative intra-
and Blood Constituents
abdominal distention; placement of the patient in the Blood volume expands in the first trimester and increases
supine, Trendelenburg, or lithotomy position; or induc- 30% to 45% by term. Dilutional anemia occurs as a result
tion of anesthesia), airway closure may be sufficient to of the smaller increase in red blood cell volume than in
cause hypoxemia. plasma volume. Although moderate blood loss is well
Weight gain during pregnancy and capillary engorge- tolerated during pregnancy, preexisting anemia decreases
ment of the respiratory tract mucosa lead to more fre- the patient’s reserve when significant hemorrhage occurs.
quent problems with mask ventilation and tracheal Pregnancy is associated with benign leukocytosis; conse-
intubation (see Chapter 30). Failed intubation (a leading quently, the white blood cell count is an unreliable indi-
cause of anesthesia-related maternal death) is as much a cator of infection. In general, pregnancy induces a
risk during early pregnancy with nonobstetric surgery as hypercoagulable state, with increases in fibrinogen;
it is during cesarean delivery.9 factors VII, VIII, X, and XII; and fibrin degradation
360 PART V Anesthesia before and during Pregnancy
products. Pregnancy is associated with enhancement of limited information may exist on the effects of pregnancy
platelet turnover, clotting, and fibrinolysis; there is a wide on the response to these drugs. Cautious administration
range in the normal platelet count. Thus, pregnancy rep- of such agents is advisable, because their pharmacokinetic
resents a state of accelerated but compensated intravas- and pharmacodynamic profiles may differ from those in
cular coagulation. Although thrombocytopenia may be nonpregnant patients. Pregnancy-associated changes in
present in some pregnant women, these patients may still volume of distribution (due to changes in body composi-
be hypercoagulable. During the postoperative period, tion and/or plasma protein binding capacity), metabolic
pregnant surgical patients are at high risk for thrombo- activity, and hepatic or renal elimination (due to changes
embolic complications; thus, thromboembolism prophy- in glomerular filtration rate and tubular transport pro-
laxis is recommended.14 cesses) may contribute to changes in drug effects and
metabolism.22 For example, in pregnant women, cefazo-
lin clearance is approximately twice as high between 20
Gastrointestinal System Changes and 40 weeks’ gestation and acetaminophen clearance is
Incompetence of the lower esophageal sphincter and dis- increased, compared with nonpregnant women.23,24
tortion of gastric and pyloric anatomy during pregnancy
increase the risk for gastroesophageal reflux, despite
similar gastric emptying rates in pregnant and nonpreg- FETAL CONSIDERATIONS
nant patients15; thus the pregnant woman is at risk for
regurgitation of gastric contents and aspiration pneumo- Risk for Teratogenicity
nitis. It is unclear at what stage during pregnancy this risk
becomes significant. Although lower esophageal sphinc- Although maternal catastrophes that cause severe mater-
ter tone is impaired early in pregnancy (especially in nal hypoxia or hypotension pose the greatest risk to the
patients with heartburn),16 the mechanically induced fetus, considerable attention has focused on the role of
factors do not become relevant until later in pregnancy. anesthetic agents as abortifacients and teratogens. Tera-
It seems prudent to consider any pregnant patient as togenicity has been defined as any significant postnatal
having a higher risk for aspiration after mid gestation; change in function or form in an offspring after prenatal
some anesthesia providers contend that pregnant women treatment. Concern about the potential harmful effects
are at increased risk for aspiration from the beginning of of anesthetic agents stems from their known effects on
the second trimester onward.16 mammalian cells, which include reversible decreases in
cell motility, prolongation of DNA synthesis, and inhibi-
tion of cell division. Despite these concerns, no data
Altered Responses to Anesthesia specifically link any of these cellular events with terato-
In addition to the decrease in MAC for inhaled anesthetic genic changes. Unfortunately, prospective clinical studies
agents, thiopental requirements begin to decrease early of the teratogenic effects of anesthetic agents are imprac-
in pregnancy.17 The effects of pregnancy on propofol tical; such studies would require huge numbers of patients
requirements are conflicting.18,19 Higuchi et al.18 found exposed to the drug under investigation. Therefore,
that the median effective dose for loss of consciousness investigations of anesthetic agents have taken one of the
(ED50) was unchanged in pregnancy, whereas Mongardon following directions: (1) studies of the reproductive
et al.19 reported that lower propofol doses were required effects of anesthetic agents in small animals, (2) epide-
to achieve loss of consciousness in early pregnancy com- miologic surveys of operating room personnel constantly
pared with the nonpregnant state. This effect appeared exposed to subanesthetic concentrations of inhalation
unrelated to increased progesterone levels. More exten- agents, and (3) studies of pregnancy outcome in women
sive neural blockade is attained with epidural and spinal who have undergone surgery while pregnant.
anesthesia in pregnant patients than in nonpregnant
patients (see Chapter 12). Pregnancy also enhances the
Principles of Teratogenicity
response to peripheral neural blockade.
Plasma cholinesterase levels decrease by approximately A number of important factors influence the teratogenic
25% from early in pregnancy until the seventh postpar- potential of a substance, including species susceptibility,
tum day. Fortunately, prolonged neuromuscular blockade dose of the substance, duration and timing of exposure,
with succinylcholine is uncommon, because the larger and genetic predisposition. Like other toxicologic phe-
volume available for drug distribution offsets the impact nomena, the effects of teratogens are dose dependent
of decreased drug hydrolysis.20 Nonetheless, the dose of (Figure 17-1).25 Most teratologists accept the principle
succinylcholine should be controlled carefully in the that any agent can be teratogenic in an animal provided
pregnant patient, and the anesthesia provider should that enough is given at the right time. Thus, the finding
monitor neuromuscular blockade with a nerve stimulator of teratogenesis of an agent after the single administra-
to ensure adequate reversal before extubation. tion of a high dose, or the long-term administration of a
Decreased protein binding associated with lower low dose, does not imply that a single, short exposure
albumin and alpha-glycoprotein concentrations during (e.g., during a typical anesthetic) would incur similar risk.
pregnancy may result in a larger fraction of unbound The interaction between dose and timing is also critical.
drug, with the potential for greater drug toxicity during A small dose of a teratogen may cause malformations or
pregnancy.21 Pregnant surgical patients may require death in the susceptible early embryo, whereas much
drugs that are infrequently used during pregnancy; larger doses may prove harmless to the fetus,25 as was
17 Nonobstetric Surgery during Pregnancy 361
Embryotoxic range
100%
Teratogenic
zone
Embryolethal
zone 50%
Maternal lethal
No-effect range
range
Increasing dosage
FIGURE 17-1 ■ Toxic manifestations with increasing dosage of a teratogen. A no-effect range of dosage occurs below the threshold,
at which embryotoxic effects abruptly appear. Teratogenesis and embryolethality often have similar thresholds and may increase
at roughly parallel rates as dosage increases to a point at which all conceptuses are affected. Increasing dosage causes increased
embryolethality, but teratogenicity appears to decrease, because many defective embryos die before term. A further increase in
dosage reaches the maternal lethal range. (Modified from Wilson JG. Environment and Birth Defects. New York, Academic Press, 1973:31.)
shown with thalidomide. Most studies have used small at the critical time of development; (2) consistent findings
animals (e.g., chick embryos, mice, rats), and their results in two or more high-quality epidemiologic studies;
cannot necessarily be extrapolated to other species, espe- (3) careful delineation of the clinical cases, ideally with
cially humans. Of the more than 2200 agents listed in the identification of a specific defect or syndrome; and
Shepard’s Catalog of Teratogenic Agents,26 approximately (4) an association that “makes biological sense.” Docu-
1200 are teratogenic in animals, but only about 30 of mentation of teratogenicity in experimental animals is
these are known to cause defects in humans. important but not essential. The list of agents or factors
Manifestations of teratogenicity include death, struc- that are proven human teratogens does not include anes-
tural abnormality, growth restriction, and functional thetic agents (which are listed as “unlikely teratogens”)
deficiency.25 Depending on when it occurs, death is or any drug routinely used during the course of anesthe-
referred to as abortion, fetal death, or stillbirth in humans sia (Box 17-1).
and as fetal resorption in animals. Structural abnormali-
ties can lead to death if they are severe, although death
Nondrug Factors Encountered
may occur in the absence of congenital anomalies. Growth
in the Perioperative Period
restriction is considered a manifestation of teratogenesis
and may relate to multiple factors, including placental Derangements of Normal Physiology. Anesthesia
insufficiency and genetic and environmental factors. and surgery can cause derangements of maternal physiol-
Functional deficiencies include a number of behavioral ogy that may result in hypoxia, hypercapnia, stress, and
and learning abnormalities, the study of which is called abnormalities of temperature and carbohydrate metabo-
behavioral teratology. The stage of gestation at which lism. These states may be teratogenic themselves, or
exposure occurs determines the target organs or tissues, they may enhance the teratogenicity of other agents.26
the types of defects, and the severity of damage. Most Severe hypoglycemia and prolonged hypoxia and hyper-
structural abnormalities result from exposure during the carbia have caused congenital anomalies in laboratory
period of organogenesis, which extends from approxi- animals,26,28 but there is no evidence to support teratoge-
mately day 31 to day 71 after the first day of the last nicity after brief episodes in humans. The chronic hypox-
menstrual period. Figure 17-2 shows the critical stages of emia experienced by mothers at high altitudes results
development and the related susceptibility of different in the delivery of infants with lower birth weights but
organs to teratogens. Functional deficiencies are usually with no increase in the rate of congenital defects.26
associated with exposure during late pregnancy or even Maternal stress and anxiety are teratogenic in animals,29
after birth, because the central nervous system (CNS) but their significance as human teratogens remains ques-
continues to mature during this period. tionable; supporting epidemiologic studies are lacking.
Consideration of the possible teratogenicity of anes- Hypothermia is not teratogenic, whereas hyperthermia is
thetic agents must be viewed against the naturally high teratogenic in both animals and humans.26 Congenital
occurrence of adverse pregnancy outcomes. Roberts and anomalies, especially involving the CNS, have repeatedly
Lowe27 estimated that as many as 80% of human concep- been associated with maternal fever during the first half
tions are ultimately lost; many are lost even before preg- of pregnancy. It must be remembered that fetal tempera-
nancy is recognized. The incidence of congenital ture is on average 0.5° C to 1° C higher than maternal
anomalies among humans is approximately 3%, most of temperature. Embryonic oxidative stress from reactive
which are unexplained. Indeed, exposure to drugs and oxygen species has been implicated as one of the mecha-
environmental toxins accounts for only 2% to 3% of such nisms involved in teratogenicity of many agents.30
defects (Table 17-1).25 Shepard26 has listed several criteria
for determining that an agent is a human teratogen, Diagnostic Procedures. Ionizing radiation is a human
including the following: (1) proven exposure to the agent teratogen that can result in an increased, dose-related risk
362 PART V Anesthesia before and during Pregnancy
Age of embryo (in weeks) Fetal period (in weeks) Full term
1 2 3 4 5 6 7 8 9 16 20-36 38
Period of dividing Central Indicates common site of action of teratogen Brain
zygote, implantation nervous
& bilaminar embryo system Eye Eye Teeth Ear Palate Ear Brain
Heart
Heart
Limbs
External genitalia
Central nervous system
Heart
Upper limbs
Eyes
Lower limbs
Teeth
Palate
Not
susceptible to External genitalia
teratogens Ears
Functional defects and
Prenatal death Major morphologic abnormalities
minor morphologic abnormalities
FIGURE 17-2 ■ Critical periods in human development. During the first 2 weeks of development, the embryo typically is not susceptible
to teratogens. During these predifferentiation stages, a substance either damages all or most cells of the embryo, resulting in its
death, or damages only a few cells, allowing the embryo to recover without development of defects. The dark bars denote highly
sensitive periods, whereas the light bars indicate periods of lesser sensitivity. The ages shown refer to the actual ages of the embryo
and fetus. Clinical estimates of gestational age represent intervals beginning with the first day of the last menstrual period. Because
fertilization typically occurs 2 weeks after the first day of the last menstrual period, the reader should add 14 days to the ages shown
here to convert to the estimated gestational ages that are used clinically. (Redrawn from Moore KL. The Developing Human. 4th edition.
Philadelphia, WB Saunders, 1993:156.)
TABLE 17-1 Etiology of Human Developmental BOX 17-1 Teratogenic Agents in Humans
Abnormalities
RADIATION
Causes of Developmental Defects in Atomic weapons, radioiodine, therapeutic uses
Humans Percentage
INFECTIONS
Genetic transmission 20
Chromosomal aberration 3-5 Cytomegalovirus, Herpesvirus hominis, parvovirus B19,
Environmental causes: rubella virus, syphilis, toxoplasmosis, Venezuelan equine
encephalitis virus
Radiation <1
Infection 2-3 MATERNAL METABOLIC IMBALANCE
Maternal metabolic imbalance 1-2 Alcoholism, cretinism, diabetes, folic acid deficiency, hyper-
Drugs and environmental chemicals 2-3 thermia, phenylketonuria, rheumatic disease and congenital
Unknown 65-70 heart block, virilizing tumors
TOTAL 100
DRUGS AND CHEMICALS
Modified from Wilson JG. Environmental and Birth Defects. New Aminopterin and methylaminopterin, androgenic hormones,
York, Academic Press, 1973:49. busulfan, captopril, chlorobiphenyls, cocaine, warfarin anti-
coagulants, cyclophosphamide, diethylstilbestrol, phenytoin,
enalapril, etretinate, iodides (goiter), lithium, mercury
(organic), methimazole (scalp defects), penicillamine, 13-cis-
retinoic acid (Accutane), tetracyclines, thalidomide, tri-
methadione, valproic acid
TABLE 17-2 Fetal Radiation Exposure for TABLE 17-3 Estimated Fetal Radiation
Common Diagnostic Procedures Exposure for Common
Interventional Radiologic
Mean Exposure Maximum Procedures
Procedure (mGy) Exposure (mGy)
Conventional Radiographic Examination Estimate Range
Abdomen 1.4 4.2 Procedure (mGy) (mGy)
Chest < 0.01 < 0.01 Cardiac catheter ablation 0.15-0.6*
Intravenous urogram 1.7 10 ERCP 3.1 0.01-55.9
Lumbar spine 1.7 10 TIPS creation 5.5
Pelvis 1.1 4 Pulmonary angiography 0.02-0.46
Skull < 0.01 < 0.01 Uterine fibroid embolization 42
Thoracic spine < 0.01 < 0.01 Cerebral angiography 0.06
Fluoroscopic Examination ERCP, endoscopic retrograde cholangiopancreatography;
Barium meal 1.1 5.8 TIPS, transjugular intrahepatic portosystemic shunt.
(upper GI) *Depending on procedure duration.
Barium enema 6.8 24 Modified from Dauer LT, Thornton RH, Miller DL, et al. Radiation
management for interventions using fluoroscopic or computed
Computed Tomography tomographic guidance during pregnancy. J Vasc Interv Radiol
Abdomen 8.0 49 2012; 23:19-32.
Head 0.06 0.96
Chest < 0.005 < 0.005 angiography, cerebral embolization, endoscopic retro-
Lumbar spine 2.4 8.6 grade cholangiopancreatography) are frequently complex
Pelvis 25 79 and prolonged, particularly when surgery is not an option.
These procedures, especially the abdominal interven-
GI, gastrointestinal. tions, expose the fetus to a significant radiation dose;
From Valentin J. Pregnancy and medical radiation. ICRP
Publication 84. Ann ICRP 2000; 30:1-43. thus, a number of societies have developed guidance
for the use of these technologies during pregnancy
(Table 17-3).33
for malignant disease, genetic disease, congenital anoma- In contrast to the negligible risk for teratogenicity,
lies, and/or fetal death.26,31 The effects of radiation are observational studies suggest that there is a slightly higher
often classified as being deterministic or stochastic. Deter- risk for childhood cancer at radiation doses greater than
ministic effects are dose related and are observed above or equal to 10 mGy.32 The relative risk for childhood
a certain threshold dose (e.g., pregnancy loss, growth malignancy after maternal abdominal radiation exposure
restriction, mental retardation, organ malformation). In has been estimated to be 2.28 (95% confidence interval,
contrast, stochastic effects are possible at any level of 1.31 to 3.97).31 Nonetheless, if the mother’s condition
exposure with no minimum threshold but with the likeli- necessitates diagnostic testing and radiation exposure,
hood of worsening effects at higher doses. An increased and no other acceptable imaging modality is available,
risk for childhood cancer is a stochastic effect when testing should not be withheld if the benefits to the
fetuses are exposed to ionizing radiation in utero. The mother (and, by extension, the fetus) are judged to out-
type and severity of effects vary with the radiation expo- weigh the risks. Delayed diagnosis of a critical condition
sure to the uterus and fetus and with the gestational age may result in significant harm to the mother and, by
of the fetus. extension, to the fetus. The radiographer should adhere
Radiation is expressed as grays (Gy) or milligrays to the ALARA principle (as low as reasonably achievable)
(mGy) (1 Gy = 100 rad) and is evaluated as cumulative and take measures to minimize the absorbed dose of
dose (i.e., background radiation and medical diagnostic radiation, including abdominal shielding, reduced scan
radiation) throughout the entire pregnancy. Background length, and milliampere modulation.
radiation during gestation is 1.3 to 5.8 mGy.31 There is Intravenous iodinated contrast media crosses the
no evidence that radiation exposure less than 50 mGy placenta to the fetus when administered in the usual clini-
is associated with a teratogenic effect in either humans cal doses and can potentially cause neonatal hypothyroid-
or animals.31 The absorbed fetal dose for all conventional ism; however, the use of radiopaque (iodide containing)
radiographic imaging procedures outside the abdomen contrast media during pregnancy is acceptable.34
and pelvis is negligible and is well below 50 mGy (Table Diagnostic ultrasonography during pregnancy has
17-2). However, direct radiographic examination of long been considered to be devoid of embryotoxic effects.
the abdomen and pelvis (e.g., abdominal computed In animals, ultrasound intensities up to 20 W/cm2 have
tomography) and abdominal imaging studies that include been found to be safe.35,36 However, when higher intensi-
fluoroscopy (e.g., barium enema) may result in more ties (> 30 W/cm2) have been used, or when repeated
significant fetal radiation exposure, with a dose that exposure has occurred during early pregnancy, postnatal
may approach 100 mGy.31,32 Helical computed tomogra- neurobehavioral effects have been described.36,37 Ultra-
phy for suspected pulmonary embolism results in a sound waves also increase the fetal temperature, and
lower fetal radiation dose than ventilation perfusion scan- hyperthermia is a known teratogen. Modern diagnostic
ning. Interventional radiologic procedures (e.g., cerebral ultrasound equipment is capable of inducing significant
364 PART V Anesthesia before and during Pregnancy
increases in temperature, especially when imaging is pro- Studies in rodents and nonhuman primates indicate
longed. Miller et al.38 concluded that these temperature that exposure of the immature brain to anesthetic agents
increments were within the range of temperatures that such as propofol, thiopental, and ketamine (i.e., agents
could be teratogenic. Epidemiologic human data are classified as N-methyl-D-aspartate [NMDA] antagonists
reassuring; no biologic effects have been documented and gamma-aminobutyric acid [GABA] agonists)] are
from diagnostic ultrasonographic examinations in the associated with brain cell apoptosis and functional learn-
pregnant patient, despite widespread use over several ing deficits.50,51 Whether this effect occurs in humans or
decades. Nonetheless, it must be stressed that these epi- other species remains to be determined (see Chapter 10).
demiologic studies were conducted in an era when ultra- These observed changes may represent indirect effects,
sound equipment was less potent and ultrasound-related such as hypoxia or hypoglycemia, as well as direct effects
increases in temperature were lower. Doppler interroga- of the anesthetic agent on the developing brain.
tion emits significantly more acoustic intensity than
pulse-echo imaging equipment; thus, more heat is gener- Human Studies. Teratogenesis has not been associated
ated. Therefore, Doppler technology should be used with the use of any of the commonly used induction
judiciously, keeping the exposure time and acoustic agents—including the barbiturates, ketamine, and the
output to the lowest level possible. benzodiazepines—when they were administered in clini-
No adverse effects on pregnancy and neonatal outcome cal doses during anesthesia.26 Similarly, no evidence sup-
were noted in a small series of pregnant patients (n = 26) ports the teratogenicity of opioids in humans; there is no
exposed to gadolinium (paramagnetic contrast medium).39 increase in the incidence of congenital anomalies among
However, gadolinium-based MRI contrast agents readily offspring of mothers who use morphine or methadone
cross the placenta, enter the fetal circulation, and are during pregnancy.26,49
excreted by the fetal kidneys into the amniotic fluid, Although human data relating to long-term tranquil-
where they may be swallowed by the fetus or resorbed by izer therapy have raised questions about the possible tera-
the mother. Although no toxic effects have been described togenicity of some agents, most studies are retrospective
after gadolinium administration, the long-term conse- and suffer from a variety of methodologic flaws. Benzo-
quences remain unknown. The American College of diazepine therapy became controversial after an associa-
Radiology recommends that intravenous gadolinium be tion between maternal diazepam ingestion during the
avoided during pregnancy and used only if absolutely first trimester and infants with cleft palate, with or
essential.40 without cleft lip, was reported.52 Subsequently, prospec-
tive work in 854 women who ingested diazepam during
the first trimester did not demonstrate a higher risk asso-
Systemic Agents
ciated with benzodiazepine therapy.53 Although the
Animal Studies. Early studies documented teratogenic- present consensus among teratologists is that diazepam
ity in rodents after a variety of neurotropic agents (e.g., is not a proven human teratogen,26 it is appropriate to
opioids, tricyclic antidepressants).41,42 The fetuses exhib- consider the risk-to-benefit ratio before initiating long-
ited a characteristic group of CNS malformations as well term benzodiazepine therapy during the first trimester.
as skeletal abnormalities and growth restriction. Whether No evidence suggests that a single dose of a benzodiaz-
these investigations truly reflect the teratogenic potential epine (e.g., midazolam) during the course of anesthesia
of opioids is questionable, however, because the respira- is harmful to the fetus.
tory depression and impaired feeding that accompany
large bolus injections of opioids also may be teratogenic. Local Anesthetics
In a study designed to avoid such problems, Fujinaga and
Mazze43 maintained clinically relevant concentrations of Procaine, lidocaine, and bupivacaine cause reversible
morphine throughout most of pregnancy in rats by means cytotoxic effects in cultures of hamster fibroblasts.54
of continuously implanted osmotic mini-pumps. Struc- However, no evidence supports morphologic or behav-
tural anomalies were not observed at any morphine dose, ioral teratogenicity associated with lidocaine administra-
although fetal growth restriction was present, and mor- tion in rats,55 and no evidence supports teratogenicity
tality was increased among the offspring. Using the same associated with any local anesthetic used clinically in
methodology, Fujinaga et al.44,45 found fentanyl, sufent- humans.26 Maternal cocaine abuse is associated with
anil, and alfentanil completely devoid of teratogenic adverse reproductive outcomes, including abnormal neo-
effects. Additional animal studies have confirmed the natal behavior and, in some reports, a higher incidence
absence of teratogenicity with other opioids.46 of congenital defects of the genitourinary and gastroin-
Many tranquilizers and anxiolytics taken by pregnant testinal tracts.26 The greatest risk to the fetus most likely
women have been investigated less systematically than results from the high incidence of placental abruption
opioids. Animal studies have demonstrated structural or associated with maternal cocaine use (see Chapter 54).
behavioral teratogenesis after exposure to some of the
barbiturate, phenothiazine, and tricyclic antidepressant Muscle Relaxants
agents.47,48 The reader is referred to standard teratology
reference sources for animal data related to specific Testing muscle relaxants for teratogenicity using standard
drugs.26,49 The package insert provided by a drug’s manu- in vivo animal studies either is complicated by maternal
facturer typically describes unpublished in-house studies respiratory depression and the need for mechanical
related to the drug’s reproductive effects. ventilation (a complex undertaking in rats or mice) or
17 Nonobstetric Surgery during Pregnancy 365
requires the administration of very low doses of the Nitrous Oxide. In contrast to the volatile halogenated
drug. Fujinaga et al.56 used the whole-embryo rat culture agents, nitrous oxide is a weak teratogen in rodents under
system to investigate the reproductive toxicity of high certain conditions, even when normal homeostasis is
doses of d-tubocurarine, pancuronium, atracurium, and maintained. Rats continually exposed to 50% to 70%
vecuronium. Although dose-dependent toxicity was man- nitrous oxide for 2 to 6 days (starting on day 8 of gesta-
ifested, these effects occurred only at concentrations tion) had an increased incidence of congenital abnormali-
30-fold greater than those encountered in clinical prac- ties.63,64 To exclude the possibility that adverse effects
tice. These findings are consistent with earlier studies were a consequence of the anesthetic state, Lane et al.65
demonstrating no toxicity with small doses of muscle exposed rats to 70% nitrous oxide or to a similar concen-
relaxants.57 Given that fetal blood concentrations tration of xenon (a slightly more potent anesthetic devoid
of muscle relaxants are only 10% to 20% of maternal of biochemical effects) for 24 hours on day 9 of gestation;
concentrations, these drugs appear to have a wide margin abnormalities occurred only in the nitrous oxide group.
of safety when administered to the mother during With the exception of one study in which extremely pro-
organogenesis. longed exposure to a low concentration of nitrous oxide
Whether their administration later in gestation has had some minor effects,66 at least 50% nitrous oxide has
adverse effects is unclear. Prolonged disturbance of been required to consistently produce anomalies.64 The
normal muscular activity by muscle relaxants has caused threshold exposure time has not been rigorously deter-
axial and limb deformities in the chick but has seldom mined, although exposure for at least 24 hours typically
been seen in other experimental animals. Although one was necessary.
case report described arthrogryposis (i.e., persistent joint In vivo and embryo culture studies in rats have con-
flexure) in the infant of a woman with tetanus who firmed that nitrous oxide has several adverse reproductive
received d-tubocurarine for 19 days beginning at 55 days’ effects, each of which results from exposure at a specific
gestation, the patient also was hypoxic and received mul- period of susceptibility.67,68 Fetal resorptions occurred
tiple other drugs.58 Many women have received muscle after exposure on days 8 and 11 of gestation, skeletal
relaxants for several days during late gestation without anomalies after exposure on day 8 or 9, and visceral
adverse effect on the neonate. anomalies (including situs inversus) only when exposure
occurred on day 8.69
Initially, teratogenicity associated with nitrous oxide
Inhalation Anesthetics
was thought to result from its oxidation of vitamin B12,
Animal Studies. which interferes with its function as a coenzyme for
Volatile Agents. Many studies have shown that, under methionine synthase.70 Transmethylation from methyl-
certain conditions, the volatile halogenated anesthetic tetrahydrofolate to homocysteine to produce tetrahydro-
agents can produce teratogenic changes in chicks or small folate (THF) and methionine is catalyzed by methionine
rodents. Basford and Fink59 observed skeletal abnormali- synthase (Figure 17-3). Thus, methionine synthase inhi-
ties but no increase in fetal loss when rats were exposed bition could cause a decrease in THF (with a resultant
in utero to 0.8% halothane for 12 hours on days 8 and 9 decrease in DNA synthesis) and lower methionine levels
of pregnancy (i.e., the “critical period” in the 21-day rat (with resultant impairment of methylation reactions).
gestation). Long-term exposure to subanesthetic concen- Nitrous oxide rapidly inactivates methionine synthase
trations of halothane caused fetal growth restriction in in both animals71 and humans.72 Prolonged human
rats but no increase in the incidence of congenital anoma- exposure to nitrous oxide leads to neurologic and hema-
lies,60 whereas isoflurane had no adverse effects.61 tologic symptoms, the latter probably resulting from
More significant reproductive effects have occurred diminished DNA synthesis.70 The hematologic—but
with greater exposures to anesthetic agents. Fetal skeletal not the neurologic—changes are prevented by the
abnormalities or death followed repeated or prolonged co-administration of folinic acid (5-formyl THF) with
maternal exposure of mice to anesthetic concentrations nitrous oxide, with the goal of restoring DNA synthesis.
of volatile anesthetic agents.62 However, teratogenicity in
these studies most likely was caused by the physiologic
changes (e.g., profound hypothermia, hypoventilation)
associated with anesthesia rather than by the anesthetic
Homocysteine 5-Methyl
agent itself. Moreover, some strains of mice are especially THF
likely to demonstrate anomalies such as cleft palate.
Methionine
Mazze et al.63 exposed rats to 0.75 MAC of halothane, N2 O
synthase
isoflurane, or enflurane, or 0.55 MAC of nitrous oxide
for 6 hours daily on 3 consecutive days at various stages Methionine THF
of pregnancy. The animals remained conscious through- Folinic acid
out the study, and normal feeding and sleep patterns
were preserved. Under these conditions, no teratogenic Methylation reactions DNA synthesis
effects were associated with any of the volatile agents.
The only positive finding was a threefold increase in the FIGURE 17-3 ■ Pathway showing the inhibition of methionine
synthase by nitrous oxide (N2O) and its potential metabolic
rate of fetal resorption with nitrous oxide. No evidence consequences (e.g., decreased DNA synthesis and impaired
has suggested reproductive toxicity with either sevoflu- methylation reactions). THF, tetrahydrofolate. (Courtesy M.
rane or desflurane in clinical concentrations. Fujinaga, Palo Alto, CA.)
366 PART V Anesthesia before and during Pregnancy
Considerable evidence indicates that methionine syn- drinks daily.90 Similarly, cigarette smoking carries a rela-
thase inhibition and a consequent lack of THF are not tive risk of 1.8 for spontaneous abortion.91
solely responsible for the teratogenic effects of nitrous Shirangi et al.92 conducted a questionnaire-based
oxide. First, maximal inhibition of methionine synthase survey of 2028 female veterinarians; information on 744
activity occurs at concentrations of nitrous oxide that pregnancies regarding the risk for preterm birth (< 37
are much lower than those required to produce terato- weeks) was collected. The prevalence of preterm birth in
genic effects.73 Second, folinic acid, which bypasses women exposed to unscavenged anesthetic gases was
the effect of methionine synthase inhibition on THF 7.3%, compared with 5.7% in the general population.
formation, partially prevents only one of the structural The identification of the specific gas used was not
abnormalities (i.e., minor skeletal defects) produced by requested; however, halothane, nitrous oxide, enflurane,
nitrous oxide.74 Third, the administration of isoflurane and methoxyflurane were the most commonly used anes-
or halothane with nitrous oxide prevents almost all of thetic gases during the study period. A hazards model
the teratogenic effects but does not prevent the decrease predicted a 2.5-fold increase in preterm delivery risk in
in methionine synthase activity.75,76 Fourth, studies using women exposed to unscavenged gas 1 or more hours per
an in vitro whole-embryo rat culture system have shown week compared with an unexposed group. Of note, a 3.7-
that supplementation of nitrous oxide with methionine fold increased risk was observed in veterinarians working
(but not with folinic acid) almost completely prevents greater than 45 hours a week compared with fewer than
growth restriction and all malformations with the excep- 45 hours.
tion of situs inversus.77 Additional studies have implicated Other studies have not confirmed an association
α1-adrenergic receptor stimulation in the production of between operating room work and higher reproductive
situs inversus by nitrous oxide.68,78,79 Postulated mecha- risk.93,94 Pregnancy outcomes were comparable in exposed
nisms by which sympathetic stimulation might have and nonexposed operating room nurses when question-
adverse reproductive effects include a decrease in uterine naire information was matched with objective data
blood flow and overstimulation of G protein–dependent obtained from medical records and registries of abor-
membrane signal transduction pathways.80 There is also tions, births, and congenital anomalies.93 Similarly, in a
evidence that nitrous oxide may cause neuronal apoptosis 10-year prospective survey of all female physicians in the
in rats.81 United Kingdom, Spence94 found no differences in
In summary, evidence suggests that the etiology of reproductive outcome when anesthesiologists were com-
nitrous oxide teratogenicity in rats is complex and mul- pared with other working female physicians. Although
tifactorial. Determination of the relative roles of methio- these studies may have missed a higher incidence of very
nine deficiency and sympathetic stimulation or other early abortion, their data do not support a statistically
mechanisms awaits performance of further studies. demonstrable reproductive hazard resulting from operat-
Although nitrous oxide is considered a weak teratogen in ing room exposure to anesthetic agents.
rats and mice, reproductive effects occur only after pro- It is possible that the higher waste levels of nitrous
longed exposure to high concentrations that are unlikely oxide encountered in dentists’ offices pose a reproductive
to be encountered in humans during clinical anesthesia. risk.85,95 In 1980, Cohen et al.85 reported a doubling of
Whether nitrous oxide administration is associated with the spontaneous abortion rate among exposed female
neuronal apoptosis and learning impairments in humans chair-side assistants and the wives of exposed male den-
remains to be determined. tists. The incidence of birth defects among the children
of exposed dental assistants was slightly higher than that
Human Studies. for nonexposed assistants. However, the validity of this
Occupational Exposure to Waste Anesthetic Agents. finding is doubtful; the incidence of anomalies among the
Epidemiologic surveys dating from the 1960s and 1970s offspring of nonexposed dentists was similar to that of
suggested that reproductive hazards (e.g., spontaneous the exposed assistants. Moreover, the expected dose-
abortion, congenital anomalies) were associated with response relationship did not exist. In another study,95
operating room and dental surgery work.82-86 These reduced fertility was reported among female dental assis-
hazards were attributed to exposure to trace concentra- tants working with nitrous oxide in an unscavenged envi-
tions of anesthetic agents, principally nitrous oxide. Crit- ronment for more than 5 hours per week. However,
ical reviews of these studies questioned their conclusions. because the affected group consisted of only 19 individu-
The reviewers noted that response bias, inappropriate als, it is difficult to draw firm conclusions from these data.
control groups, lack of verification of medical data, and Overall, the epidemiologic data do not support an
exposure to multiple environmental factors made defini- increased risk for congenital anomalies with long-term
tive conclusions impossible.87-89 exposure to nitrous oxide.
The most consistent risk associated with occupational Studies of Operations Performed during Pregnancy.
exposure was spontaneous abortion, which carried a rela- In 1963, Smith96 reviewed the obstetric records of 18,493
tive risk ratio of 1.3. The ratio for congenital anomalies pregnant women. Sixty-seven (0.36%) had had an opera-
(1.2) had borderline statistical significance.87,89 These tion during pregnancy; only 10 procedures occurred
relative risks are well within the range that might be during the first trimester. Fetal mortality was 11.2%, with
explained by bias or uncontrolled variables.89 For example, the poorest survival occurring after operations for appen-
the relative risk of second-trimester abortion among diceal abscess and cervical incompetence. In 1965,
women who drink one or two alcoholic drinks per day is Shnider and Webster97 examined the records of 9073
1.98; this risk increases to 3.53 with more than three obstetric patients; 147 (1.6%) of this group had had
17 Nonobstetric Surgery during Pregnancy 367
morphologic changes. The CNS may be especially Clearer understanding of the mechanisms by which
sensitive to such influences during the period of major exposures to pain/stress or prolonged anesthesia in the
myelination, which in humans extends from the fourth perinatal period can alter the survival or development
intrauterine month to the second postnatal month (see of immature neurons and glia may prevent some long-
Chapter 10). Several studies have shown that brief intra- term neurobehavioral abnormalities in humans. In the
uterine exposure to halothane adversely affects postnatal meantime, clinicians should administer anesthetic agents
learning behavior and causes CNS degeneration and to newborn infants or pregnant mothers but avoid
decreased brain weight in rats.103-105 The fetal nervous prolonged periods of anesthetic exposure. … Alleviation
system in the rat is most susceptible to the effects of of pain and stress during the perinatal period should
halothane during the second trimester.103 Maternal remain an essential clinical goal until further research
administration of systemic drugs—including barbitu- defines the clinical importance of [experimental] results
rates, meperidine, and promethazine—has also resulted [observed in animals].
in behavioral changes in offspring,106-108 whereas no effect
has been noted with the administration of lidocaine.55 In After a review of the data and a public hearing
humans, investigations of the effects of maternally admin- in March 2007, the Anesthetic and Life Support
istered analgesics at delivery have revealed transient, Drugs Advisory Committee of the U.S. Food and Drug
dose-related depression of neonatal behavior. Administration stated that currently “there are not
Currently used general anesthetic agents act by one of adequate data to extrapolate the animal findings to
two principal mechanisms, (1) the potentiation of GABAA humans.”118
receptors (benzodiazepines, volatile halogenated agents,
and barbiturates) or (2) the antagonism of NMDA recep-
tors (nitrous oxide and ketamine). Drugs that act by Fetal Effects of Anesthesia
either of these mechanisms appear to induce widespread Maintenance of Fetal Well-Being
neuronal apoptosis in the developing rat brain when
administered during the period of synaptogenesis (i.e., The most serious fetal risk associated with maternal
the brain growth-spurt period).81,109-111 Jevtovic-Todorovic surgery during pregnancy is that of intrauterine asphyxia.
et al.81 observed that the administration of a general anes- Because fetal oxygenation depends on maternal oxygen-
thetic “cocktail” (midazolam, isoflurane, and nitrous ation, maintenance of normal maternal arterial oxygen
oxide), in doses sufficient to maintain general anesthesia tension, oxygen-carrying capacity, oxygen affinity, and
for 6 hours in 7-day-old infant rats, resulted in wide- uteroplacental perfusion are critical to fetal well-being.
spread apoptotic neurodegeneration in the developing
brain, deficits in hippocampal synaptic function, and per- Maternal and Fetal Oxygenation. Transient mild
sistent memory/learning impairments. They concluded to moderate decreases in maternal Pao2 are well toler-
that these deficits are “subtle enough to be easily over- ated by the fetus, because fetal hemoglobin has a high
looked” but may persist into adolescence and adulthood.81 affinity for oxygen. Severe maternal hypoxemia results
Ikonomidou et al.110 described neurodegeneration in rat in fetal hypoxia and, if persistent, may cause fetal
pups after NMDA receptor antagonism. These data death. Any complication that causes profound maternal
suggest that prolonged exposure to anesthetic agents at a hypoxemia (e.g., difficult intubation, esophageal intuba-
critical period in brain development may accelerate the tion, pulmonary aspiration, total spinal anesthesia, sys-
normal developmental process of apoptotic neurodegen- temic local anesthetic toxicity) is a potential threat to
eration, potentially resulting in prolonged behavioral the fetus.
deficits.112 Thus, the safety of providing anesthesia during Studies of isolated human placental vessels have
early life has been questioned.113 suggested that hyperoxia might cause uteroplacental
The implications, if any, for the human fetus during vasoconstriction, with potential impairment of fetal
the maternal administration of general anesthesia are oxygen delivery.119 This fear has proved to be unfounded,
unknown because there are methodologic issues with because studies in pregnant women have demonstrated
these animal studies. Surgery may result not only in expo- better fetal oxygenation with increasing maternal Pao2.120
sure to anesthetic agents but also in derangements in Fetal Pao2 never exceeds 60 mm Hg, even when maternal
maternal physiology (e.g., hypoxia, stress, hypoglycemia) Pao2 increases to 600 mm Hg, because of a large
that can lead to apoptosis during the critical period of maternal-fetal oxygen tension gradient (see Chapter 4).
neuronal development.114 Also, it should be noted that in Thus, intrauterine retrolental fibroplasia and premature
experimental studies the rats typically were exposed to closure of the ductus arteriosus cannot result from high
large doses of anesthetic agents for prolonged periods. levels of maternal Pao2. McClain et al.117 observed that
Hayashi et al.115 demonstrated that a single dose of ket- the maternal administration of general anesthesia for 4
amine did not lead to apoptosis but that its repeated hours in gravid ewes produced an initial—but not
administration for several hours caused neuronal degen- sustained—increase in fetal systemic oxygenation, which
eration. It is also important to remember that painful was accompanied by a sustained increase in fetal cerebral
stimuli per se can cause long-term behavioral changes.116 oxygenation. The investigators hypothesized that the
Finally, the species model may be important. For example, increase in fetal cerebral oxygenation resulted from
McClain et al.117 did not observe any histologic or func- greater cerebral perfusion, lower cerebral metabolic rate,
tional effects of exposure to general anesthesia in fetal or both. Histologic examination found no evidence of
lambs. Anand and Soriano113 concluded: neurotoxicity.
17 Nonobstetric Surgery during Pregnancy 369
Maternal Carbon Dioxide and Acid-Base Status. alpha-adrenergic agonist phenylephrine for the treat-
Maternal hypercapnia can cause fetal acidosis, because ment of hypotension during the administration of
fetal Paco2 correlates directly with maternal Paco2. neuraxial anesthesia in obstetric patients (see Chapter
Although mild fetal respiratory acidosis is of little conse- 26).129,130 A meta-analysis of randomized controlled trials
quence, severe acidosis can cause fetal myocardial depres- comparing ephedrine with phenylephrine for the treat-
sion and hypotension. Maternal hyperventilation with ment of hypotension during spinal anesthesia for cesar-
low maternal Paco2 and high pH can adversely affect fetal ean delivery resulted in the following conclusions:
oxygenation by means of several mechanisms.121-123 (1) there was no difference between phenylephrine and
Respiratory or metabolic alkalosis can compromise ephedrine for the prevention and treatment of maternal
maternal-fetal oxygen transfer by causing umbilical artery hypotension, (2) maternal bradycardia was more likely
constriction121 and by shifting the maternal oxyhemoglo- to occur with phenylephrine than with ephedrine,
bin dissociation curve to the left.122 In addition, hyper- (3) women given phenylephrine had neonates with higher
ventilation, independent of changes in Paco2, may reduce umbilical arterial blood pH measurements than those
uterine blood flow and cause fetal acidosis.123 This given ephedrine, and (4) there was no difference between
decrease most likely is a consequence of mechanical the two vasopressors in the incidence of true fetal acidosis
ventilation, whereby increased intrathoracic pressure (i.e., umbilical arterial blood pH < 7.20).129 Cooper
reduces venous return and cardiac output, which in turn et al.130 randomly assigned 147 patients to receive phen-
decreases uteroplacental perfusion. Thus, hyperventila- ylephrine, ephedrine, or both for the maintenance of
tion should be avoided in the pregnant surgical patient. maternal arterial pressure during spinal anesthesia for
Rather, the Paco2 should be kept in the normal range for elective cesarean delivery. Fetal acidosis was more
pregnancy. common in the women who received ephedrine. The
investigators speculated that “increased fetal metabolic
Uteroplacental Perfusion. Maternal hypotension rate, secondary to ephedrine-induced beta-adrenergic
from any cause can jeopardize uteroplacental perfusion stimulation, was the most likely mechanism for the
and cause fetal asphyxia. The most common causes of increased incidence of fetal acidosis in the ephedrine
hypotension in the pregnant patient undergoing surgery group.”130 Ngan Kee et al.131 demonstrated that placental
include (1) deep levels of general anesthesia, (2) sympa- transfer was greater for ephedrine than phenylephrine
thectomy with high levels of spinal or epidural blockade, and fetal metabolism was greater for phenylephrine
(3) aortocaval compression, (4) hemorrhage, and (5) than ephedrine. They also observed increased fetal con-
hypovolemia. In monkeys, prolonged hypotension (i.e., centrations of lactate, glucose, and catecholamines with
systolic blood pressure < 75 mm Hg) caused by deep ephedrine compared with phenylephrine, thus support-
halothane anesthesia resulted in fetal hypoxia, acidosis, ing the hypothesis that the lower fetal pH observed with
and hypotension.124 After experiencing as much as 5 hours ephedrine is related to metabolic effects secondary to
of severe partial asphyxia in utero (pH < 7.00 for at least stimulation of fetal beta-adrenergic receptors. Therefore,
1 hour), neonatal monkeys were depressed and experi- the use of phenylephrine to treat maternal hypotension
enced seizures. Postnatal survival was poor, and patho- is acceptable and may be preferable to ephedrine.
logic brain changes included swelling, necrosis, and However, the potential for phenylephrine to decrease
hemorrhage. The clinical course and neuropathologic maternal cardiac output and alter uteroplacental perfu-
findings in these animals resembled those in infants sion, despite treating hypotension, should be further
known to have suffered severe intrauterine asphyxia and studied.132
who died within a few days of birth. Despite these alarm-
ing data, case reports have described good outcome after Fetal Effects of Inhalation Agents
deliberate induction of moderate degrees of hypotension
during pregnancy, usually to facilitate performance of a The volatile halogenated anesthetic agents can affect the
neurosurgical procedure.125 Fetal and neonatal outcomes fetus directly (by depressing the fetal cardiovascular
were unaffected when maternal systolic blood pressure system or CNS) or indirectly (by causing maternal
was kept between 70 to 80 mm Hg, even when pressures hypoxia or hypotension). Studies in gravid ewes have
as low as 50 mm Hg were briefly permitted. In such cir- shown minimal fetal effects with maternal administration
cumstances, the risk to the fetus must be balanced against of moderate concentrations of a volatile agent.133 Uterine
the risk for uncontrolled maternal bleeding or stroke. perfusion was maintained during the inhalation of 1.0
The multiple factors that influence uteroplacental and 1.5 MAC halothane or isoflurane, because uterine
blood flow are discussed in detail in Chapter 3. Of par- vasodilation compensated for small decreases in maternal
ticular relevance to the pregnant surgical patient are blood pressure. Higher concentrations (e.g., 2.0 MAC)
drugs that cause uterine vasoconstriction. Preoperative given for prolonged periods induced marked maternal
anxiety and light anesthesia increase circulating catechol- hypotension. Consequently, reduced uteroplacental
amines, possibly impairing uterine blood flow.126 Drugs blood flow resulted in fetal hypoxia, diminished fetal
that cause uterine hypertonus (e.g., ketamine in early cardiac output, and fetal acidosis.134
pregnancy in doses higher than 2 mg/kg,127 toxic doses The effects of anesthesia on the stressed fetal lamb
of local anesthetics128) may increase uterine vascular remain unclear. In one study, the administration of 1%
resistance, decreasing uteroplacental perfusion. halothane to the mothers of asphyxiated fetal lambs
New evidence has challenged the historic view that the caused severe fetal hypotension, worsening of fetal aci-
mixed-adrenergic agonist ephedrine is preferred to the dosis, and decreases in cerebral blood flow and oxygen
370 PART V Anesthesia before and during Pregnancy
delivery.134 In other studies, acidosis that was less severe Sodium nitroprusside and esmolol have been used
or of a shorter duration was associated with the mainte- during pregnancy to induce hypotension during surgical
nance of fetal cardiac output and a preservation of the procedures. Standard doses of nitroprusside have proved
balance between oxygen supply and demand.135-137 The to be safe for the fetus146; the risk for fetal cyanide toxicity
protective compensatory mechanisms that exist during appears to be low, provided that tachyphylaxis does not
asphyxia may be abolished by high but not low concen- occur and the total dose is limited. The use of esmolol
trations of volatile agents. during pregnancy remains controversial. Ostman et al.147
The relevance of these data to the human mother observed minimal fetal effects after the administration of
undergoing surgery during pregnancy is not clear. Clini- esmolol in gravid ewes, whereas Eisenach and Castro148
cal experience does not support avoidance of volatile reported significant decreases in FHR and blood pressure
agents, provided that maternal hypotension is prevented. as well as a modest reduction in fetal Pao2. Fetal effects
Indeed, the depressant effect of these agents on myome- dissipated rapidly in the first study but persisted for 30
trial contractility may be beneficial. If intraoperative fetal minutes or more in the second. Two case reports have
heart rate (FHR) monitoring reveals signs of fetal com- described small decreases in FHR but no morbidity when
promise, it may be advisable to discontinue the volatile esmolol was administered with nitroprusside during neu-
agent until the fetal condition improves. rosurgical procedures.149,150 In contrast, severe fetal com-
promise followed the administration of esmolol at 38
weeks’ gestation to correct maternal supraventricular
Fetal Effects of Systemic Drugs
tachycardia.151 Because fetal tachycardia preceded the
Opioids and induction agents decrease FHR variability, onset of severe bradycardia in this case, the authors spec-
possibly to a greater extent than the inhalation agents.138,139 ulated that fetal compromise resulted from reduced
This finding most likely signals the presence of an anes- maternal cardiac output rather than fetal beta-adrenergic
thetized fetus and is not a cause for concern in the absence receptor blockade.
of maternal hypotension or other abnormalities. Fetal
respiratory depression is relevant only if cesarean delivery
is to be performed at the same time as the surgical pro-
Prevention of Preterm Labor
cedure. Even then, high-dose opioid anesthesia need Most epidemiologic studies of nonobstetric surgery
not be avoided when it is indicated for maternal reasons during pregnancy have reported a higher incidence of
(e.g., anesthesia for patients with cardiac disease). The abortion and preterm delivery.1,97,98,152 It is unclear
pediatrician should be informed of maternal drug admin- whether the surgery, manipulation of the uterus, or the
istration so that preparations can be made to support underlying condition is responsible. In a study of 778
neonatal respiration. Some data indicate that remifent- women who underwent appendectomy during pregnancy,
anil may result in less neonatal depression than longer- Mazze and Källén152 found that 22% of women who
acting opioids.140,141 underwent surgery between 24 and 36 weeks’ gestation
Maternal administration of muscle relaxants and delivered in the week after surgery. In the women in
reversal agents typically has not proved to be problematic whom pregnancy continued beyond a week after surgery
for the fetus. It has been suggested that rapid intravenous there was no further increase in the rate of preterm birth.
injection of an anticholinesterase agent might stimulate Although this study’s database was unsuitable for deter-
acetylcholine release, which might cause increased uterine mining the incidence of preterm delivery in women
tone and thus precipitate preterm labor.142 Although this who had surgery before 24 weeks’ gestation, a similar
concern is unproven, slow administration of an anticho- increase appeared likely. Second-trimester procedures
linesterase (after prior injection of an anticholinergic and operations that do not involve uterine manipulation
agent) is recommended. Atropine rapidly crosses the pla- carry the lowest risk for preterm labor.
centa and, when given in large doses, causes fetal tachy- Although the volatile agents depress myometrial
cardia and loss of FHR variability.143 Although neither irritability and thus are theoretically advantageous for
atropine nor glycopyrrolate significantly affects FHR abdominal procedures, evidence does not show that any
when standard clinical doses are administered,144 glyco- one anesthetic agent or technique positively or negatively
pyrrolate is often recommended because it crosses the influences the risk for preterm labor. Published evidence
placenta less readily and may be a more effective antisi- does not support the routine use of prophylactic tocolytic
alagogue. Although limited transplacental passage of agents.153 Monitoring for uterine contractions may be
neostigmine is expected, significant transfer occasionally performed intraoperatively with an external tocodyna-
may occur. One case report described mild fetal brady- mometer (when technically feasible) and for several days
cardia when neostigmine was administered with glyco- postoperatively, allowing tocolytic therapy to be insti-
pyrrolate during emergence from general anesthesia at tuted, if appropriate. Additional surveillance is necessary
31 weeks’ gestation.145 This problem did not occur during in patients who receive potent postoperative analgesics,
the administration of a second general anesthetic to the who may be unaware of mild uterine contractions.
same patient 4 days later, when atropine was administered A relatively new class of tocolytic agents—oxytocin
with neostigmine, presumably because atropine under- receptor antagonists (e.g., atosiban)—has been investi-
goes greater placental transfer than glycopyrrolate. gated.154 Atosiban selectively blunts the calcium influx in
Because the effects of reversal agents are unpredictable, the myometrium and thus inhibits myometrial contractil-
the monitoring of FHR during maternal drug adminis- ity. However, atosiban, in laboratory conditions, blocks
tration is suggested. the protective effects of oxytocin in fetal/neonatal neurons
17 Nonobstetric Surgery during Pregnancy 371
180
Fetal
heart
150
rate
(bpm)
120
A B C D 1 min
FIGURE 17-7 ■ Serial samples of the fetal heart rate tracing and corresponding maternal arterial blood gas measurements in a patient
undergoing eye surgery. A and B, Baseline fetal heart rate of 140 bpm with normal variability. C, Fetal tachycardia and decrease in
variability during inadvertent maternal hypoxemia (maternal PaO2 = 56 mm Hg). D, After correction of maternal ventilation, baseline
fetal heart rate and variability return. (Redrawn from Katz JD, Hook R, Barash PG. Fetal heart rate monitoring in pregnant patients under-
going surgery. Am J Obstet Gynecol 1976; 125:267.)
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comparing rocuronium priming, magnesium pre-treatment and a Gynecol 2005; 12:379-81.
combination of the two methods. Anaesthesia 2012; 67:748-54. 182. Guidelines Committee of the Society of American Gastrointesti-
158. Hans GA, Bosenge B, Bonhomme VL, et al. Intravenous magne- nal Endoscopic Surgeons. Guidelines for diagnosis, treatment,
sium re-establishes neuromuscular block after spontaneous and use of laparoscopy for surgical problems during pregnancy.
recovery from an intubating dose of rocuronium: a randomised Surg Endosc 2008; 22:849-61.
controlled trial. Eur J Anaesthesiol 2012; 29:95-9. 183. Steinbrook RA, Brooks DC, Datta S. Laparoscopic cholecystec-
159. Olgun B, Oguz G, Kaya M, et al. The effects of magnesium tomy during pregnancy: review of anesthetic management, surgi-
sulphate on desflurane requirement, early recovery and postopera- cal considerations. Surg Endosc 1996; 10:511-5.
tive analgesia in laparascopic cholecystectomy. Magnes Res 2012; 184. Adamson DL, Nelson-Piercy C. Managing palpitations and
25:72-8. arrhythmias during pregnancy. Heart 2007; 93:1630-6.
160. Na HS, Chung YH, Hwang JW, Do SH. Effects of magnesium 185. Vanden Hoek TL, Morrison LJ, Shuster M, et al. Part 12: cardiac
sulphate on postoperative coagulation, measured by rotational arrest in special situations: 2010 American Heart Association
thromboelastometry (ROTEM). Anaesthesia 2012; 67:862-9. Guidelines for Cardiopulmonary Resuscitation and Emergency
161. McKellar DP, Anderson CT, Boynton CJ, Peoples JB. Cholecys- Cardiovascular Care. Circulation 2010; 122:S829-61.
tectomy during pregnancy without fetal loss. Surg Gynecol Obstet 186. Einav S, Kaufman N, Sela HY. Maternal cardiac arrest and peri-
1992; 174:465-8. mortem caesarean delivery: evidence or expert-based? Resuscita-
162. Cherry SH. The pregnant patient: need for surgery unrelated to tion 2012; 83:1191-200.
pregnancy. Mt Sinai J Med 1991; 58:81-4. 187. Biehl DR. Foetal monitoring during surgery unrelated to preg-
163. Stånge K, Halldin M. Hypothermia in pregnancy. Anesthesiology nancy. Can Anaesth Soc J 1985; 32:455-9.
1983; 58:460-1. 188. American College of Obstetricians and Gynecologists. Nonob-
164. Strickland RA, Oliver WC Jr, Chantigian RC, et al. Anesthesia, stetric surgery during pregnancy. ACOG Committee Opinion
cardiopulmonary bypass, and the pregnant patient. Mayo Clin No. 474. (Obstet Gynecol 2011; 117:420-1.)
Proc 1991; 66:411-29. 189. Kilpatrick CC, Puig C, Chohan L, et al. Intraoperative fetal heart
165. Merritt WT, Dickstein R, Beattie C, et al. Liver transplantation rate monitoring during nonobstetric surgery in pregnancy: a prac-
during pregnancy: anesthesia for two procedures in the same tice survey. South Med J 2010; 103:212-5.
patient with successful outcome of pregnancy. Transplant Proc 190. Jenkins TM, Mackey SF, Benzoni EM, et al. Non-obstetric
1991; 23:1996-7. surgery during gestation: risk factors for lower birthweight. Aust
166. Buckley TA, Yau GH, Poon WS, Oh T. Caesarean section and N Z J Obstet Gynaecol 2003; 43:27-31.
ablation of a cerebral arterio-venous malformation. Anaesth 191. de Souza DG, Doar LH, Mehta SH, Tiouririne M. Aspiration
Intensive Care 1990; 18:248-51. prophylaxis and rapid sequence induction for elective cesarean
167. Coleman MT, Trianfo VA, Rund DA. Nonobstetric emergencies delivery: time to reassess old dogma? Anesth Analg 2010;
in pregnancy: trauma and surgical conditions. Am J Obstet 110:1503-5.
Gynecol 1997; 177:497-502. 192. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous
168. Augustin G, Majerovic M. Non-obstetrical acute abdomen during oxide: a mechanistic and toxicologic review. Anesthesiology 2008;
pregnancy. Eur J Obstet Gynecol Reprod Biol 2007; 131:4-12. 109:707-22.
PA RT V I
Medical and social connotations of pain have evolved Dick-Read, subsequently republished his book in the
through history. Since 1847, these interpretations often United States with the title Childbirth Without Fear.
influenced obstetric anesthesia. During most of the nine- It marked the beginning of the natural childbirth
teenth century, patients and physicians believed that an movement.
individual’s physical sensitivity to pain varied with educa- Dick-Read combined snippets of ideas from earlier
tion, social standing, and acculturation. Like the princess concepts to formulate his own theory. He agreed with
in Hans Christian Andersen’s fairy tale who could feel a early nineteenth-century physiologists that savages have
pea through 40 mattresses, refined women experienced less pain than “modern women.” Unlike Engelmann,
more pain than “savages.” As American suffragette Eliza- Dick-Read attributed this sensitivity to cultural rather
beth Cady Stanton observed, “[R]efined, genteel, civi- than physical factors. According to Dick-Read, modern
lized women have worse labor pain.” Commenting on women had painful deliveries only because the church
her own nearly painless delivery, Stanton once quipped, and culture had taught them to expect it. He said that
“Am I not almost a savage?” Upper class women often women should be reeducated and taught that childbirth
cited their sensitivity to pain as evidence of cultural supe- is a natural physiologic process. He opined that women
riority, and they used this fact to justify their need for would then cease to fear childbirth and thereby have less
obstetric anesthesia.1 pain. Dick-Read’s method, the basis for childbirth educa-
As the nineteenth century came to a close, the social tion, was a prenatal program that toughened the body
connotations of pain also changed. Many still maintained with exercise and prepared the mind with facts. In yet
that civilized women experienced more pain than savages. another variation, French obstetrician Fernand Lamaze
On the other hand, “sensitivity” to pain now began to substituted Pavlovian conditioning for Dick-Read’s child-
signify physical deterioration rather than cultural superi- birth education.3 With Dick-Read and Lamaze, many of
ority. Thus one medical book published in 1882 ascribed the social concepts of childbirth pain came full circle.4
painful labor to “the abuses of civilization, its dissipa-
tions, and the follies of fashion.” Its author, an American REFERENCES
obstetrician named Engelmann, suggested that the idle 1. Lawrence C. The nervous system and society in the Scottish enlight-
enment. In Barnes B, Shapin S, editors. Natural Order: Historical
life of upper class women led to a “relaxed condition of Studies of Scientific Culture. London: Sage Publications 1979:
the uterus and abdominal walls (and) a greater tendency 19-40.
to malposition.” He suggested that the rigorous physical 2. Engelmann GJ. Labor among Primitive Peoples: Showing the
life of lower class women and “savages” prepared their Development of the Obstetric Science of Today from the Natural
bodies better for childbirth.2 and Instinctive Customs of All Races, Civilized and Savage, Past and
Present. St. Louis: JH Chambers, 1882:130.
Social and cultural interpretations of childbirth pain 3. Dick-Read G. Revelation of Childbirth. London: Heinemann, 1943.
took yet another turn in 1943, with publication of 4. Caton D. Medical science and social values. Int J Obstet Anesth
the book Revelation of Childbirth. Its author, Grantly 2004; 13:167-73.
C H A P T E R 1 8
CHAPTER OUTLINE
THE PROCESS OF LABOR AND DELIVERY increases in prostaglandin production, oxytocin recep-
tors, and myometrial gap junction formation.1,2 As more
Labor, which is also called parturition, is the process by is learned, perhaps a unifying concept of the onset of
which sufficiently frequent and strong uterine contrac- mammalian labor will emerge. Preterm and post-term
tions cause thinning (i.e., effacement) and dilation of the deliveries both constitute important obstetric problems;
cervix, thereby permitting passage of the fetus from the and when more is understood about the mechanism of
uterus through the birth canal. the onset of labor, new approaches to preventing the
preterm and post-term onset of parturition may evolve.
The Passageway
following three components of the process: (1) the
powers (uterine contractions and, in the second stage, The fetus must be of such size and conformation that
the addition of voluntary maternal expulsive efforts); (2) there is no mechanical mismatch with the bony pelvis. At
the passageway (the bony pelvis and the soft tissues times, an ovarian or uterine tumor (e.g., leiomyoma),
contained therein); and (3) the passenger (the fetus). cervical cancer, or a vaginal septum may impede passage
The interaction of these three components determines of the fetus through the birth canal, but these situations
the success or failure of the process. are unusual.
Four pelvic types have been described on the basis of
The Powers the shape of the pelvic inlet (the plane bounded by the
upper inner pubic symphysis, the linea terminalis of the
The uterus, which is a smooth muscle organ, contracts iliac bones, and the sacral promontory) (Table 18-1).3
throughout gestation with variable frequency. The par- The type and size of the pelvis constitute important pre-
turient verifies the onset of labor when she perceives dictors of the success of vaginal delivery.
regular, uncomfortable uterine contractions. In some The most common pelvic type and the one theoreti-
women, the uterus remains relatively quiescent until the cally best suited for childbirth is the gynecoid pelvis. The
abrupt onset of labor. In others, the uterus contracts flexed fetal head presents a circle to the bony pelvis; a
several times per hour for days without causing pain or pelvis with gynecoid features best accommodates this
even a clear perception of uterine contractions. circle. The inlet is round or oval, with the transverse
During labor, the frequency, duration, and intensity diameter only slightly greater than the anteroposterior
of uterine contractions increase. During early labor, diameter. The pelvic sidewalls are straight and do not
the contractions may occur every 5 to 7 minutes, last converge, the ischial spines are not prominent, the sacrum
30 to 40 seconds, and develop intrauterine pressures is hollow, and the subpubic arch is wide. The absence of
(intensity) of 20 to 30 mm Hg above basal tone (10 prominent ischial spines is an important feature, because
to 15 mm Hg). Late in the first stage of labor, contrac- the distance between them—the transverse diameter of
tions typically occur every 2 to 3 minutes, last 50 to 70 the midpelvis—is the narrowest pelvic dimension. The
seconds, and are 40 to 60 mm Hg in intensity. This other pelvic types are less favorable for vaginal delivery.
higher intensity reflects a more widespread propagation Radiographic pelvimetry provides much more infor-
of the contractions, with the recruitment of more myo- mation regarding pelvic dimensions and features than can
metrial cells. be obtained by clinical pelvimetry alone. However, it has
Retraction accompanies contraction as the myometrial only a limited place in clinical management because of its
cells shorten. The walls of the upper, contractile portion poor ability to predict a successful vaginal birth. In the
of the uterus thicken. Cervical dilation and effacement absence of a history of pelvic fracture or musculoskeletal
reflect the traction placed on the cervix by the contract- disease (e.g., a dwarfing condition), there are few circum-
ing uterus. The passive lower uterine segment enlarges stances in which the apparent pelvic anatomy precludes
and becomes thinner as cervical tissue is pulled over the a trial of labor. A pelvis with smaller-than-average dimen-
fetal presenting part by traction from the upper portion sions may be adequate for a particular fetus if the head is
of the uterus. At the end of the first stage of labor, no well-flexed, sufficient molding (i.e., overlapping of the
cervix is palpable on vaginal examination (corresponding unfused skull bones) has occurred, and the labor is strong;
to complete cervical dilation). If there is no mechanical thus, radiographic pelvimetry does not always predict the
obstruction, additional uterine contractions force the presence or absence of cephalopelvic disproportion.4
fetus to descend through the birth canal. At this time, the Further, some risk is associated with radiographic pelvim-
parturient perceives an urge to defecate (reflecting pres- etry. In addition to the potential for point mutations in
sure on the rectum). Her expulsive efforts add to the the maternal oocytes and fetal germ cells, there is a small
force of uterine contractions to hasten descent and but apparently real increase in the incidence of malig-
shorten the second stage of labor. nancy and leukemia in children who were exposed to
18 Obstetric Management of Labor and Vaginal Delivery 385
Positions of the Occiput in Early BOX 18-2 The Cardinal Movements of Labor
BOX 18-1 Labor, Listed in Order of
Decreasing Frequency • Engagement
• Descent
• Left occiput transverse (LOT) • Flexion
• Right occiput transverse (ROT) • Internal rotation
• Left occiput anterior (LOA) • Extension
• Right occiput posterior (ROP) • External rotation
• Right occiput anterior (ROA) • Expulsion
• Left occiput posterior (LOP)
• Occiput anterior (OA)
• Occiput posterior (OP)
The Passenger
– 3
– 2
Fetal size and the relationship of the fetus to the maternal – 1
pelvis affect labor progress. The lie of the fetus (the + 1
relationship of the long axis of the fetus to the long axis + 2
+ 3
of the mother) can be transverse, oblique, or longitudinal. + 4
In the first two, vaginal delivery is impossible unless the
fetus is very immature. FIGURE 18-1 ■ Stations of the fetal head. (Redrawn from Zlatnik
The presentation denotes that portion of the fetus FJ. Normal labor and delivery and its conduct. In Scott JR, DiSaia
overlying the pelvic inlet. The presentation may be PJ, Hammond CB, Spellacy WN, editors. Danforth’s Obstetrics and
cephalic, breech, or shoulder. Cephalic presentations are Gynecology. 7th edition. Philadelphia, JB Lippincott, 1994:116.)
further subdivided into vertex, brow, or face presenta-
tions, according to the degree of flexion of the neck. In
more than 95% of labors at term, the presentation is widest transverse diameter of the fetal head) through the
cephalic and the fetal head is well flexed (i.e., vertex plane of the pelvic inlet. A direct clinical determination
presentation). of engagement cannot be made, but obstetricians assume
The position of the fetus denotes the relationship of that engagement has occurred if the leading bony point
a specific presenting fetal bony point to the maternal of the fetal head is palpable at the level of the ischial
pelvis. In vertex presentations, that bony point is the spines. This is true because the distance between the
occiput. During vaginal examination, palpation of leading bony point and the BPD is typically less than
the sagittal suture and fontanels permits determination the distance between the ischial spines and the plane of
of the fetal position. Positions of the occiput in early the pelvic inlet. If the leading bony point is at the level
labor are listed in Box 18-1. Other markers for position of the spines, the vertex is said to be at zero station. If
are the sacrum for breech presentation, the mentum for the leading bony point is 1 cm above the level of the
face presentation, and the acromion for shoulder presen- spines, the station is designated as −1. Similarly, +1, +2,
tation. (See Chapter 35 for a discussion of nonvertex and +3 indicate that the leading bony point is 1, 2, and
presentations.) 3 cm below the ischial spines, respectively (Figure 18-1).
At +5 station, delivery is imminent. Station refers to pal-
pation of the leading bony point. Often marked edema
The Mechanism of Labor
of the scalp (i.e., caput succedaneum) occurs during labor.
The mechanism of labor refers to the changes in fetal con- In such cases, the bony skull may be 2 to 3 cm higher
formation and position (cardinal movements; Box 18-2) than the scalp.
that occur during descent through the birth canal during The second cardinal movement is descent, although
the late first stage and the second stage of labor. it is artificial to separate descent from the other move-
The first cardinal movement is engagement, which ments because descent occurs throughout the birth
denotes passage of the biparietal diameter (BPD) (i.e., the process. The third cardinal movement is flexion. A very
386 PART VI Labor and Vaginal Delivery
small fetus can negotiate the average maternal pelvis traction, it passes from the birth canal, and expulsion of
without increased flexion. However, under the usual cir- the remainder of the fetus occurs.
cumstances at term, the force from above and resistance This description recounts events in the typical gyne-
from below enhance flexion of the occiput (Figure 18-2). coid pelvis. Abnormalities of the pelvis affect the mecha-
The fourth cardinal movement is internal rotation. nism of labor in specific ways. In an anthropoid pelvis,
At the level of the midpelvis, the fetus meets the narrow- the anteroposterior diameter of the pelvic inlet exceeds
est pelvic dimension, which is the transverse diameter the transverse diameter. Often internal rotation to the
between the ischial spines. Because the BPD of the fetal occiput posterior position rather than the occiput ante-
head is slightly smaller than the suboccipitobregmatic rior position occurs. Because the pelvis is narrow trans-
diameter, in most labors the vertex negotiates the versely, further descent of the vertex occurs with the
midpelvis with the sagittal suture in an anteroposterior occiput in the posterior position. Delivery occurs with
direction. If this did not occur, a larger-than-necessary the occiput in the posterior position, or rotation to the
diameter would be forced to pass through the narrowest occiput anterior position occurs just before delivery. In
portion of the pelvis. Internal rotation describes the cases of persistent occiput posterior position, delivery
change in the position of the vertex from occiput trans- occurs by flexion rather than extension of the fetal head
verse or oblique to anteroposterior. The occiput tends to (see Figure 18-3).
rotate to the roomiest part of the pelvis; thus, in gynecoid In platypelloid pelves, internal rotation may not take
pelves, the fetus is delivered in an occiput anterior place. The widest diameter is the transverse diameter,
position. and descent of the vertex may occur with the occiput in
The next cardinal movement is extension, which the transverse position; rotation to the occiput anterior
occurs as the fetal head delivers (Figure 18-3). Subse- position occurs only at delivery.
quently, the occiput rotates to the side of the back (exter-
nal rotation) as the shoulders pass through the midpelvis
in an oblique diameter. The anterior shoulder moves Clinical Course
under the pubic symphysis. With gentle downward Admission
When a patient enters the labor and delivery unit, the
first question that must be asked is “why?” Did she come
because of regular, painful uterine contractions; decreased
fetal activity; vaginal bleeding; ruptured membranes; or
some other reason? If the tentative diagnosis is labor, is
she at term?
The time of the onset of labor and the presumed status
of the membranes should be determined. Observation of
the patient’s demeanor coupled with the assessment of
cervical effacement and dilation will signal whether the
patient is in early or advanced labor. Examination of
the cervix is deferred in patients with vaginal bleeding in
the second half of pregnancy, unless placenta previa has
A B been ruled out by ultrasonography, to avoid exacerbation
of bleeding. To prevent infection, cervical examination
FIGURE 18-2 ■ A, Relation of the head to the vertebral column may also be deferred in patients with premature rupture
before flexion. B, Relation of the head to the vertebral column of membranes and no labor.
after flexion. (Redrawn from Zlatnik FJ. Normal labor and delivery
and its conduct. In Scott JR, DiSaia PJ, Hammond CB, Spellacy WN,
The obstetrician also directs attention to the second
editors. Danforth’s Obstetrics and Gynecology. 6th edition. Philadel- patient: the fetus. Abdominal examination or ultrasonog-
phia, JB Lippincott, 1990:174.) raphy is used to establish presentation and an estimate of
A B
FIGURE 18-3 ■ Vertex presentations. A, Occiput anterior position. B, Occiput posterior position. (Redrawn from Zlatnik FJ. Normal labor
and delivery and its conduct. In Scott JR, DiSaia PJ, Hammond CB, Spellacy WN, editors. Danforth’s Obstetrics and Gynecology. 6th edition.
Philadelphia, JB Lippincott, 1990:174.)
18 Obstetric Management of Labor and Vaginal Delivery 387
Clock time
FHR Contractions
Examiner
Frequency
Quality
Duration
Rate
Pattern
BP
Position
Station
Effacement
pH
Analgesia (number)
Note #
10
9
Cervical dilation (cm)
8
7
6 us
us
ro aro
5 llip
Pa
4 Nu
3
2
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time (h)
FIGURE 18-4 ■ Flow sheet for charting labor progress. (From Zlatnik FJ. Normal labor and delivery and its conduct. FHR, fetal heart rate.
BP, blood pressure. In Scott JR, DiSaia PJ, Hammond CB, Spellacy WN, editors. Danforth’s Obstetrics and Gynecology. 7th edition. Phila-
delphia, JB Lippincott, 1994:107.)
fetal size. With most obstetric services, external elec- Labor Progress: The Labor Curve
tronic fetal heart rate (FHR) monitoring is used on
admission to assess fetal condition. The baseline rate and One of the central tasks of those providing intrapartum
variability and the presence or absence of accelerations care is to determine whether labor is progressing nor-
and decelerations are of interest. mally and, if not, to determine the significance of the
delay and what the response should be. Parity is an
Subsequent Care important determinant of labor length. (Parity refers to
previous pregnancies of at least 20 weeks’ gestation. A
The maternal vital signs and FHR are recorded periodi- pregnant woman who is gravida 2, para 1 is pregnant for
cally. In some obstetric services, continuous electronic the second time, and her first pregnancy resulted in deliv-
FHR monitoring is used universally; with other services, ery after 20 weeks’ gestation.)
it is monitored via intermittent auscultation. In low-risk A generation of obstetricians is indebted to Emanuel
patients, recording the FHR every 30 minutes in the first Friedman, whose landmark studies of labor provide a
part of the first stage of labor, every 15 minutes in the framework for judging labor progress. Friedman’s
latter part of the first stage, and every 5 minutes in the approach was straightforward: He graphed cervical dila-
second stage is perfectly acceptable. During early labor, tion on the y-axis and elapsed time on the x-axis for
the patient may ambulate or assume any position of thousands of labors. He considered nulliparous and
comfort on the labor bed or in a chair. During advanced parous patients separately, and he determined the statisti-
labor, many women choose to lie down. Choices con- cal limits of normal.5 The curve of cervical dilation over
cerning analgesia or anesthesia are made according to the time is sigmoid shaped (Figure 18-5).
patient’s wishes. Figure 18-4 shows a flow sheet (parto- Most authorities consider Friedman’s most important
gram) that may be useful for charting the course of labor. contribution to be his separation of the latent phase from
During labor, those providing obstetric care must the active phase of the first stage of labor. Many hours of
focus on the following two critical questions: regular, painful uterine contractions may take place with
1. Is the fetus tolerating labor in a satisfactory fashion, little appreciable change in the cervix. During this latent
or is there evidence of fetal compromise (see (or preparatory) phase, the cervix may efface and become
Chapter 8)? softer. Quite abruptly, the active (or dilation) phase
2. Is the labor progress normal? begins, and regular increases in cervical dilation are
388 PART VI Labor and Vaginal Delivery
Dilatation by Parity
Deceleration
phase
Nulliparous Parous
Median Time (h) Median Time (h)
Cervical Dilation (95th Percentile) (95th Percentile)
Acceleration
First Stage
phase
4 to 5 cm 1.3 (6.4) 1.4 (7.1)
maximum slope
5 to 6 cm 0.8 (3.2) 0.8 (3.4)
Phase of
6 to 7 cm 0.6 (2.2) 0.5 (1.8)
7 to 8 cm 0.5 (1.6) 0.4 (1.2)
8 to 9 cm 0.5 (1.4) 0.3 (1.0)
9 to 10 cm 0.5 (1.8) 0.3 (0.9)
Dilation
for cesarean delivery, chorioamnionitis, endometritis, a greater likelihood of variable decelerations of the FHR.
excessive blood loss, depressed Apgar scores, and need If there is a nonvertex presentation or the vertex is high
for neonatal resuscitation have all been associated with a in the pelvis and not well applied to the cervix, amniot-
prolonged latent phase. An ongoing increase in the use omy is deferred to decrease the risk for prolapse of the
of labor induction may be a mediating factor. Primary umbilical cord.
dysfunctional labor and arrest of dilation during the
active phase may also indicate cephalopelvic dispropor-
Second Stage of Labor
tion.5,11,12 Friedman’s original work suggested that an
arrest of dilation during the active phase was associated When the cervix has been completely retracted to form
with the need for cesarean delivery nearly half of the the lower uterine segment and is therefore not palpable
time. Later studies suggest a lower percentage, but it on vaginal examination, full or complete dilation has
is clear that women who experience active-phase been achieved, and the second stage of labor begins.
arrest of dilation are more likely to require abdominal Strong uterine contractions coupled with voluntary
delivery than women with normal labor progress during expulsive efforts by the parturient cause the fetal present-
the active phase. Friedman’s analysis suggested that ing part to descend through the pelvis, resulting in deliv-
active-phase abnormalities pose a threat to the fetus, ery. At complete cervical dilation, there is frequently an
especially if they are combined with operative vaginal increase in bloody show, the parturient may vomit, and,
delivery.13 A later study of women who delivered in the in the absence of anesthesia, she may complain that she
modern era of electronic FHR monitoring and decreased needs to defecate. This sensation of needing to “bear
frequency of mid-forceps deliveries suggested that arrest down” encourages strong Valsalva maneuvers during
disorders by themselves do not have adverse perinatal uterine contractions. The effect of this sensation on the
consequences.12 efficiency of “pushing” efforts during the second stage is
In summary, the contemporary view is that delays in reflected by the suggestion that the duration of the second
the latent phase of the first stage of labor may be associ- stage of labor varies not only according to parity but also
ated with fetopelvic disproportion or the need for cesar- with the presence or absence of epidural analgesia.14 A
ean delivery, but this requires confirmation.10 Delays in second stage longer than 2 hours may be considered
the active phase predict fetopelvic disproportion, although prolonged for a nulliparous woman without epidural
not with precision. Given current obstetric practice and analgesia, but 3 hours are granted if the patient has epi-
fetal monitoring techniques, it is unclear whether first- dural analgesia. For the parous woman the time limits are
stage labor abnormalities are intrinsically associated with 1 and 2 hours, respectively.
neonatal depression at delivery.14 The contemporary obstetrician, although less con-
cerned about the elapsed time during the second stage of
labor than were earlier obstetricians, continues to balance
Amniotomy
the risks of prematurely performing a cesarean delivery
The intact amnion serves as the vessel that contains the with the risks of adverse outcomes associated with a pro-
amniotic fluid and helps protect the uterine contents longed second stage. A generation ago, the teaching was
from the microbial flora of the vagina. The amniotic fluid that a long second stage meant trouble.17 It often did, for
provides mechanical protection for the fetus and umbili- at least two reasons. First, if cephalopelvic disproportion
cal cord and allows growth and movement. existed, the second stage was prolonged; this often
In the absence of intervention, the membranes gener- resulted in a difficult operative vaginal delivery and
ally rupture at the onset of labor or near full cervical serious fetal trauma. Second, umbilical cord compression
dilation. If the membranes are intact, should they be may become severe with descent of the presenting part
artificially ruptured during the course of labor? If so, during the second stage of labor. If FHR monitoring
when? Because there is concern about infection once the was not performed conscientiously, considerable fetal/
membranes are ruptured, the performance of an amni- neonatal compromise could occur in association with
otomy commits the mother to delivery. For this reason, delayed delivery. Cord arterial blood pH varies inversely
it should not be done during the latent phase of labor, with the length of the second stage of labor. In one large
unless (1) there is an indication for effecting delivery and/ population-based cohort study, a second-stage duration
or (2) the patient is close to her EDD, the cervix is favor- longer than recommended was associated with an increase
able, and the physician can confidently predict that labor in maternal obstetric trauma, postpartum hemorrhage,
will progress easily. infection, birth depression, and admission to the neonatal
Advantages of amniotomy during the active phase of intensive care unit in both nulliparous and parous
the first stage of labor are that (1) the ruptured mem- women.18 However, the contemporary view is that the
branes permit the placement of a fetal electrocardio- second stage of labor does not need to be terminated
graphic electrode, which can provide more consistent at any arbitrary time provided that progress in descent
information than external FHR monitoring; (2) the continues and the FHR pattern is reassuring. Clearly it
amniotic fluid can be inspected for the presence or is inappropriate to perform a difficult forceps delivery or
absence of meconium; and (3) amniotomy shortens time vacuum extraction simply because an arbitrary time limit
to delivery.15,16 Disadvantages of amniotomy during the has elapsed.19 Indeed, recent studies suggest that obstetri-
active phase of the first stage of labor are that it may cians should consider allowing a longer second-stage
result in increased scalp edema (i.e., caput succedaneum, duration (than heretofore recommended) to decrease the
which has no clinical significance) and that there may be cesarean delivery rate.7,14
390 PART VI Labor and Vaginal Delivery
If the parturient is allowed to choose her own positions BOX 18-3 Signs of Placental Separation
during labor and delivery, she does not stay in one place.20
Without instruction from birth attendants, the parturient • The uterus rises in the maternal abdomen.
frequently chooses to walk or sit in a chair during early • The shape of the uterus changes from discoid to
labor. Late in the first stage, however, she often returns to globular.
the labor bed. During the second stage of labor, some • The umbilical cord lengthens.
women assume the squatting position, whereas others, • A gush of blood frequently occurs.
with their legs supported by the nurse and the father of the
baby, assume a semi-sitting position. The goal is to achieve
a position in which the parturient’s bearing-down efforts
are most effective. The patient should avoid the supine When the placenta has separated from the uterine
position, which results in aortocaval compression. Aorto- wall, gentle traction on the umbilical cord, coupled with
caval compression seems to be less severe with the patient suprapubic pressure to elevate the uterus, serves to deliver
in the semi-sitting position, and it is avoided altogether the placenta and membranes. In the absence of excessive
with the patient in the lateral position. Indeed, it is per- bleeding, the obstetrician waits for the signs of placental
fectly acceptable for the patient to push and deliver while separation before attempting to deliver it. If traction is
remaining in the left lateral position. A vaginal examina- exerted on the umbilical cord before the placenta has
tion during a contraction may provide information as to separated, problems result. The least serious—but none-
which position is best for a particular individual. theless embarrassing—complication involves separating
Rarely, as the fetal head distends the perineum the umbilical cord from the placenta. This tear in the
shortly before delivery, an episiotomy may be performed. cord leads to bleeding, which is of no concern because
This incision extends either directly posteriorly from the blood is fetoplacental blood that would be discarded;
6 o’clock (midline) or in a 45-degree angle to either side however, the obstetrician’s reputation for gentleness
(mediolateral). The former causes less discomfort, is suffers because the detached segment of umbilical cord
more anatomic, and is easier to repair than the latter. The is held with the placenta remaining in situ. A much more
mediolateral episiotomy’s advantage is that extension serious problem is uterine inversion, which can occur in
through the anal sphincter and rectal mucosa is less likely a case of fundal implantation of the placenta. If the pla-
to occur, but its major disadvantage is that it may cause centa has not separated and the umbilical cord does not
more bleeding or severe postpartum pain. (If the patient break, excessive traction turns the uterus inside out,
has an epidural catheter, the anesthesia provider may give resulting in severe hemorrhage (see Chapter 38).
additional epidural local anesthetic or opioid to provide If the placenta does not separate in a timely fashion
postpartum analgesia.) after delivery (prolonged third stage) or if significant
The place of episiotomy in contemporary obstetrics is bleeding occurs, manual removal of the placenta is indi-
restricted.21 In the past, episiotomy was advocated not cated. Although some obstetricians advocate performing
only to shorten labor but also to protect the woman this procedure with sedation or systemic analgesia, neur-
against the subsequent development of uterine prolapse, axial or general anesthesia is ideal. The obstetrician’s
cystocele, and rectocele. An episiotomy hastens delivery, hand is then passed into the uterine cavity, and the edge
but only by a few minutes. Tears involving the anal of the placenta is identified. The hand is used as a trowel
sphincter (third degree) and rectal mucosa (fourth degree) to separate the placenta from the uterine wall. If the
are more common after midline episiotomy than if epi- obstetrician cannot easily develop a plane between the
siotomy is not performed; in the absence of an episiot- placenta and the uterine wall, the diagnosis of placenta
omy, however, anterior periurethral lacerations are accreta should be considered. Placenta accreta typically
common. Although the latter rarely cause immediate results in severe hemorrhage, which frequently mandates
problems, scientifically valid data on long-term outcome emergency hysterectomy (see Chapter 38). Classically, a
are lacking. Given the recognized association between duration of 30 minutes has been used to define a pro-
midline episiotomies and third- and fourth-degree tears, longed third stage. However, in the absence of significant
the fact that these tears may be associated with long-term bleeding more time may be allowed for placental separa-
morbidity, and the failure to observe any benefits to tion, particularly at earlier gestational ages when it may
routine episiotomy, more restrictive use of this incision be difficult to access the uterus.
is now recommended.21,22 For example, an episiotomy After delivery, and either before or after the placenta
may be indicated in some instances of operative vaginal has been removed, uterotonic agents are administered to
delivery of a large infant, with suspected fetal compro- reduce bleeding. Oxytocin is given intravenously in a
mise, or to manage shoulder dystocia. dilute solution (e.g., starting at an infusion rate of 20 to
80 units/h), or 10 units are given intramuscularly. Bolus
Third Stage of Labor intravenous injection of oxytocin can cause hypotension
and should be avoided (see Chapter 38).23
The third stage of labor begins with the delivery of the If the uterus does not respond to oxytocin, other
infant and ends with the delivery of the placenta. The ecbolic agents can be tried. Methylergonovine
placenta typically separates from the uterine wall within (Methergine, 0.2 mg) has long been available for intra-
a few contractions after delivery of the infant, and expul- muscular administration. It contracts vascular smooth
sion follows a few minutes later. Signs of placental separa- muscle and may cause hypertension. Methylergonovine
tion are listed in Box 18-3. should not be given intravenously except in cases of
18 Obstetric Management of Labor and Vaginal Delivery 391
severe, life-threatening hemorrhage. In such cases, the factors that may alter management of labor from
physician should give the drug slowly and carefully the outset. If a singleton vertex presentation is
monitor the maternal blood pressure. identified in a patient without complications, the
15-Methylprostaglandin F2α (carboprost, Hema- physician proceeds to the following question.
bate) is a newer ecbolic agent. Given intramuscularly, 2. Is the labor progress abnormal? If progress is normal
0.25 mg of 15-methylprostaglandin F2α has been demon- according to the labor curve, no problem exists.
strated to be an effective uterotonic agent when other If progress is abnormal, the physician proceeds to
drugs have failed.24 It can also cause hypertension, but the following question.
the hypertension is typically not as severe as that associ- 3. Is the abnormality in the active phase? An apparent
ated with administration of methylergonovine. More prolongation of the latent phase may represent
important, 15-methylprostaglandin F2α may cause bron- false labor. In the absence of some other indication
chospasm and is relatively contraindicated in patients for effecting delivery, the obstetrician should not
with asthma. administer oxytocin or perform amniotomy, which
Most obstetricians in the United States do not use would involve committing the patient to a long labor
ecbolic agents until the placenta has been delivered, with the risk for failure and the potential need for
whereas European obstetricians typically administer an an unnecessary cesarean delivery. Long latent phases
ecbolic agent immediately after delivery of the infant or do increase patient anxiety and fatigue; reassurance
even with delivery of the anterior shoulder. The timing is essential. At this point, ambulation and sedation
probably does not matter.25 Immediately after the deliv- are alternatives that may be selected on an individual
ery of the placenta, if the obstetrician suspects an abnor- basis, with input from the woman. If false labor has
mality, the hand can be passed into the uterine cavity. occurred, contractions will cease over time, or the
Within several minutes, however, the cervix and birth patient will enter the active phase. Specifically, a
canal contract. Subsequent uterine exploration typically diagnosis of failed induction in the latent phase
requires the administration of anesthesia. should require at least 12 to 24 hours after rupture
of membranes. If primary dysfunctional labor is the
diagnosis or if a secondary arrest of dilation has
Fourth Stage of Labor
occurred during the active phase, the physician is
Many obstetricians consider the first 60 minutes after faced with an abnormality that may indicate cepha-
delivery of the placenta to be the fourth stage of labor. lopelvic disproportion, a mechanical obstruction to
Labor is completed, but this designation emphasizes that delivery. The next question can then be asked.
the patient must be watched carefully for bleeding. More 4. Is the fetus tolerating labor? Although the FHR
than 90% of cases of postpartum hemorrhage result from pattern should be monitored from admission until
uterine atony. If uterine atony is not identified during the delivery, a delay in the active phase of labor calls
first hour after delivery, it is unlikely to occur subse- for a reassessment. If the FHR pattern is nonreas-
quently. The patient should be evaluated frequently to be suring, the physician should effect delivery. If not,
certain that excessive bleeding is not occurring and that the next question is asked.
the uterus remains contracted. Considerable blood loss 5. Does the pelvis appear to be adequate for the infant? An
can occur in the presence of “normal” vital signs; a active-phase delay indicates either insufficient
modest increment in additional blood loss can then be uterine contractile effort to dilate the cervix or a
followed by profound shock. Uterine relaxation and mechanical obstruction to delivery. Obviously this
excessive bleeding after delivery are initially treated with is a critical issue, because the therapeutic alterna-
uterine massage and further ecbolic drug administration tives are very different. If the pelvis is clinically
(see Chapter 38). Management options for persistent small and/or the fetus is large and the labor seems
hemorrhage include uterine tamponade, surgery, and vas- strong (e.g., intense uterine contractions occurring
cular embolization. every 2 minutes), the choice is cesarean delivery. If
the fetopelvic relationship is favorable for vaginal
delivery and the contractions are infrequent, the
LABOR PROGRESS: FIVE choice is intravenous oxytocin, amniotomy, or
MANAGEMENT QUESTIONS both. In the vast majority of cases, however, the
obstetrician is uncertain as to whether oxytocin
The purpose of this section is to provide a step-by-step augmentation will result in successful vaginal deliv-
approach to the management of the laboring woman by ery or whether cesarean delivery will ultimately be
serially posing and answering the following five critical required despite oxytocin augmentation. Given the
questions: uncertainty about whether mechanical obstruction
1. Is the patient in labor? If the answer is “Yes,” certain or insufficient uterine activity is the problem, the
factors must be considered before proceeding. Is proper choice typically is to administer oxytocin to
the patient at term? If she is preterm, is she a can- correct the latter, a decision that recognizes that, if
didate for antenatal corticosteroids and tocolytic the former is present, the attempt will ultimately
therapy? If the patient is at term, are there medical fail. Data support longer periods of oxytocin aug-
or obstetric conditions that affect management? mentation for nonprogressive active-phase labor
Abnormal fetal size or presentation, twin gestation, (at least 4 to 6 hours) provided the FHR pattern is
preeclampsia, and vaginal bleeding are obstetric reassuring.26
392 PART VI Labor and Vaginal Delivery
The benefit of intravenous oxytocin administration for States. Concern for the high cesarean delivery rate has
labor arrest during the active phase of the first stage of created interest in the remarkable results achieved in the
labor is that the majority of the time it succeeds and 1980s with the use of active management of labor at
cesarean delivery is avoided.11 The risks of oxytocin stim- the National Maternity Hospital in Dublin, Ireland.27,34
ulation are both maternal and fetal. If mechanical obstruc- Components of the active management of labor include
tion to delivery exists, greater uterine activity predisposes (1) a rigorous definition of labor, (2) early amniotomy,
the patient to uterine rupture, which is one of the gravest (3) constant nursing attendance, (4) the demand for con-
obstetric complications. Multiparity and a scarred uterus tinued progress in cervical dilation (1 cm or more per
are additional predisposing factors to uterine rupture. hour), (5) vigorous oxytocin stimulation for lack of prog-
Oxytocin has an antidiuretic effect, and in the past there ress, and (6) a “guarantee” that the parturient’s stay in the
were reports of water intoxication with seizures and even labor unit will last no longer than 12 hours. In Dublin,
coma and death as iatrogenic complications of its use. In these practices were associated with a cesarean birth rate
these cases, oxytocin was administered over many hours of less than 5%; however, the rate has been higher in
(often days) in electrolyte-free solutions, with little atten- more recent years.
tion paid to maternal urine output; infusion of electrolyte- The introduction of the active management of labor
containing solutions and close attention to the parturient’s in other obstetric services has been associated with lower
fluid balance should make this a theoretical rather than a cesarean delivery rates than those among historic con-
practical concern. However, uterine tachysystole with FHR trols. One randomized trial indicated that active manage-
decelerations is a real concern when infusing oxytocin. The ment shortened labor, reduced the incidence of cesarean
force generated during uterine contractions interrupts delivery for dystocia, and resulted in fewer maternal
blood flow through the intervillous space because placen- infectious complications without increasing maternal or
tal perfusion occurs during periods of uterine relaxation, neonatal morbidity.35 However, data from other clinical
and uterine contractions can be regarded as episodes trials and a Cochrane review suggest that active labor
of “fetal breath-holding.” If the contractions are occur- management is associated with little or no decrease in the
ring very frequently (e.g., at intervals less than 2 minutes cesarean delivery rate.36,37
apart, defined as uterine tachysystole), there may be
insufficient time between contractions for placental gas
exchange, the fetus may become hypoxemic, and fetal SPECIAL SITUATIONS
compromise may result. Continuous observation permits
a timely diagnosis of uterine tachysystole. Decreasing Premature Rupture of Membranes
the infusion rate, temporarily stopping the infusion, or,
rarely, giving terbutaline promptly corrects the problem. Premature rupture of the membranes (PROM) is defined as
Currently, in the United States, oxytocin for inducing a rupture of the fetal membranes (i.e., the chorioamnion)
or augmenting labor is given intravenously, typically by before the onset of labor. It may occur preterm (before
infusion pump. Continuous electronic FHR monitoring 37 weeks’ gestation) or at term.
is used, and a physician or nurse constantly monitors the
FHR pattern. Although the foregoing procedures are Preterm Premature Rupture of Membranes
quite uniform from service to service, the selected doses
of oxytocin are not. The most significant complication of preterm PROM is
The variability in protocols for oxytocin induction preterm birth.38 Although the length of the latent period
or augmentation of labor reflects confusion in the (the interval between membrane rupture and the onset of
literature.27-31 The goal is to increase uterine activity effi- labor) is inversely related to gestational age, only one in
ciently to dilate the cervix without causing fetal compro- five women with preterm PROM have latent periods
mise as a result of uterine tachysystole. However, the best exceeding 1 week. Indeed, PROM is the precipitating
way to do this is unclear. Recommended starting doses factor in nearly one third of preterm deliveries. Other
of oxytocin vary from 1 to 6 mU/min, and additional risks of preterm PROM include chorioamnionitis and
drug is administered until a satisfactory labor pattern is prolapse of the umbilical cord. If membrane rupture
achieved. Dosage increments typically vary from 1 to occurs during the second trimester and if the fetus experi-
6 mU at intervals of 15 to 40 minutes. High-dose oxyto- ences a long exposure to oligohydramnios, there is risk
cin regimens involve the use of higher starting doses and for pulmonary hypoplasia, perinatal death, neonatal
incremental doses of 4 mU/min or greater. A systematic sepsis, and orthopedic deformities.
review of available trials suggests that the use of a higher Current management of preterm PROM is conserva-
dose regimen for labor augmentation is associated with tive. After the diagnosis is confirmed by inspection and
shortened labor and a decrease in the incidence of cesar- nitrazine and fern testing (or rarely by ultrasound-guided
ean delivery.32,33 instillation of dye into the amniotic fluid and observation
of its passage vaginally),39 electronic FHR monitoring is
used to identify variable FHR decelerations that signal
The Active Management of Labor umbilical cord compression. The mother is also evaluated
Dystocia, which is also called abnormal labor progress, for fever and uterine tenderness, which may indicate
both directly and indirectly (through subsequent repeat chorioamnionitis. If these are absent, the clinician awaits
cesarean deliveries) is the single most important reason the onset of labor or the subsequent development of
for the high rate of abdominal delivery in the United infection. The adjunctive use of maternally administered
18 Obstetric Management of Labor and Vaginal Delivery 393
TABLE 18-3 Natural History of Premature TABLE 18-4 The Bishop Cervix Score
Rupture of the Membranes
at Term Score
Modified from Zlatnik FJ. Management of premature rupture of an indication for abdominal delivery. Antibiotics, oxyto-
membranes at term. Obstet Gynecol Clin North Am 1992;
19:353-64.
cin, and close observation of the mother and fetus are
indicated.
prematurity.53 If candidates are selected with careful BOX 18-4 Classification of Forceps Delivery
attention to the previously listed requirements, elective
induction is both convenient and safe. OUTLET FORCEPS DELIVERY
• Scalp is visible.
Indicated Induction • Skull has reached the pelvic floor, and head is on the
perineum.
Indicated induction of labor is performed when delivery • Sagittal suture is in the anteroposterior diameter or
is indicated for maternal or fetal reasons and both mother within 45 degrees (e.g., occiput anterior, left occiput
and fetus can tolerate labor and vaginal delivery. An indi- anterior, right occiput posterior).
cated induction of labor often arises in the setting of a LOW FORCEPS DELIVERY
medical or obstetric complication such as diabetes mel-
litus, preeclampsia, fetal growth restriction (also known • Station is +2 or greater.
• Hollow of the sacrum is filled.
as intrauterine growth restriction), or the post-term
pregnancy. By definition, the physician is dealing with a MID-FORCEPS DELIVERY
complicated pregnancy when performing an indicated • Vertex is engaged, but the station is 0 or +1.
induction of labor; therefore, close maternal and fetal
monitoring is indicated. When considering the critical
question whether induction should be undertaken, the
obstetrician must weigh the perinatal risks of continued
intrauterine versus extrauterine existence and must also preferable to the continuation of labor in the setting of
consider the potential adverse maternal consequences of genuine fetal compromise or to the performance of a
induction, including a higher risk for infection and/or difficult and traumatic vaginal delivery. Unfortunately,
cesarean delivery. however, more traditional obstetric interventions (e.g.,
If the Bishop score is favorable, amniotomy alone suf- labor, additional labor, operative vaginal delivery) are
fices as a means of inducing labor. Often, however, the often bypassed in favor of cesarean delivery, perhaps
cervix is not favorable, and induction is typically accom- more for medicolegal than for medical concerns. The
plished with oxytocin administration combined with appropriate use of operative vaginal delivery techniques
amniotomy. In some cases, if the cervix is unfavorable, requires an accurate assessment of the situation, technical
oxytocin may be infused for one day, with the membranes skills, and an honest and humble physician.
intact. The infusion is stopped in the evening, and the
patient is permitted to eat. The membranes are ruptured, Vertex Presentation
and the oxytocin infusion is started again the following
morning. Some obstetricians have advocated vaginal or Carefully selected and performed forceps or vacuum-
cervical prostaglandins for the induction of labor; assisted delivery shortens the second stage of labor in
however, it is unclear that these agents offer an advantage cases of nonreassuring fetal status, maternal illness or
over intravenous oxytocin for this purpose.54 exhaustion, and/or undue prolongation of labor with
When induction of labor is indicated in the setting of little or no progress (Box 18-4). The station of the pre-
an unfavorable cervix, the obstetrician may attempt to senting vertex is critical to the safety of the procedure for
raise the Bishop score (“ripen” the cervix) before begin- mother and infant. The current American College of
ning the induction. Both osmotic cervical dilators and Obstetricians and Gynecologists classification permits a
pharmacologic techniques are effective in improving the more rational approach to operative vaginal delivery than
Bishop score.55,56 Typically these adjunctive measures are was available previously.58,59
instituted the evening before the planned induction. A For any operative vaginal delivery, adequate anesthesia
Foley catheter bulb may also be used for mechanical dila- is required. Outlet operative deliveries are perfectly safe
tion. A common pharmacologic method involves the for both mother and fetus. The low station effectively
topical application of prostaglandin E2, either in the vagina rules out cephalopelvic disproportion, and little traction
or in the cervical canal. Prostaglandin E2 has a local effect is required. Outlet operative deliveries shorten the second
in the initiation of softening, effacement, and dilation of stage by only a few minutes. Sustained fetal bradycardia
the cervix, and it also has an oxytocin-like effect on the is a common indication for outlet operative delivery. An
myometrium. Women treated with prostaglandin E2 com- experienced physician may safely perform low-station
monly experience contractions and labor before amniot- operative deliveries in cases of fetal compromise or
omy or oxytocin administration. The same is true for maternal illness or exhaustion. The higher the head, the
misoprostol, a prostaglandin E1 analogue that is now harder the pull. Rotations increase the likelihood of
widely used for cervical ripening and labor induction.57 vaginal tears.59
Prostaglandins should not be administered to induce labor Midpelvic deliveries reflect a more complicated
in women with a prior cesarean delivery, because their use problem.60,61 If the station is overestimated, the vertex
is associated with an increased risk for uterine rupture. may be barely engaged. The hollow of the sacrum is
incompletely filled. Midpelvic deliveries should be
regarded as “trials.” The obstetrician must avoid exces-
Operative Vaginal Delivery sive traction and must be willing to abandon the attempt
Cesarean delivery has become a too frequent solution to in favor of cesarean delivery if vaginal delivery does not
labor room problems. This safe operation is certainly proceed easily.
18 Obstetric Management of Labor and Vaginal Delivery 395
Although operative vaginal delivery was traditionally BOX 18-5 Risk Factors for Shoulder Dystocia
accomplished with obstetric forceps, there has been
interest in the soft plastic cup vacuum extractor.62-65 • Fetal macrosomia
Neither is uniformly better. The vacuum extractor is • Maternal diabetes mellitus
easier to apply, especially if the obstetrician is uncertain • Delayed active phase of labor
of the position of the occiput, and most likely it is associ- • Prolonged second stage of labor
ated with less maternal trauma. Forceps—but not the • Operative vaginal delivery
vacuum extractor—permits the correction of deflection
or slight abnormalities of position that may impede prog-
ress. The vacuum extractor is more likely to slip off;
whether this feature enhances safety is unknown. Neona-
tal results are comparable, but retinal hemorrhages, TABLE 18-5 Management of Shoulder
which are of unclear significance, are more likely with Dystocia
vacuum extraction. The obstetrician should be trained in Maneuver Desired Result
both techniques and should individualize their use.
Persistent occiput-posterior positions often occur in Suprapubic pressure Anterior shoulder
dislodged from above
anthropoid and android pelves. In modern obstetrics, the pubic symphysis
infants in most of these cases are delivered with the Hyperflexion of maternal Cephalad rotation of pubic
occiput posterior. Extension of the episiotomy is a thighs alongside abdomen symphysis
common complication in this circumstance, which argues (McRoberts maneuver)
for the consideration of a mediolateral episiotomy. Intravaginal pressure on Anteroposterior
Deep transverse arrests of the occiput were tradition- posterior shoulder position of shoulders
transformed to oblique
ally managed with rotation and delivery with Kielland’s position
forceps. Current trainees typically have little experience Delivery of posterior arm Once accomplished, added
with this instrument, and they are more likely to select room permits delivery
the vacuum extractor in this circumstance. Cephalic replacement Cesarean delivery
(Zavenelli maneuver)
Nonvertex Presentations
A persistent brow presentation or a transverse lie man-
dates cesarean delivery. Most face presentations and shoulder dystocia. Recognition that shoulder dystocia exists
selected breech presentations can be safely delivered is often followed by equanimity giving way to panic. If
vaginally.66 However, in response to a large international delivery is not accomplished soon, umbilical cord com-
multicenter trial in which planned vaginal delivery was pression may result in asphyxia. Excessive traction on the
associated with worse perinatal outcomes than planned fetal head may result in damage to the brachial plexus
cesarean delivery,67 the American College of Obstetri- (e.g., Erb’s palsy), which may be permanent or temporary.
cians and Gynecologists now recommends cesarean During the manipulations undertaken to effect delivery,
delivery for the persistent singleton breech presentation a fracture of the clavicle or humerus may result.
at term as the preferred mode of delivery for most physi- Risk factors for shoulder dystocia are those that predict
cians, particularly in light of diminishing experience in or reflect mechanical difficulty (Box 18-5).69-72 Women
vaginal breech deliveries.68 with diabetes mellitus are predisposed to shoulder dysto-
cia, not only because fetal macrosomia is more common
but also because the fetus of a mother with diabetes has
Fetal Death
a shoulder circumference that is disproportionately large
If fetal death has occurred, the obstetrician no longer has relative to the head circumference. Desultory labor may
two patients, making maternal safety the only concern. be a harbinger of mechanical mismatch, and operative
Although placenta previa or absolute cephalopelvic dis- vaginal delivery can exacerbate the situation.
proportion may indicate cesarean delivery, the obstetri- Appropriate management of shoulder dystocia begins
cian is often more willing to choose a more complicated with the recognition that there is sufficient time to deliver
operative vaginal delivery than if the fetus were living. the infant safely. Neuraxial anesthesia is ideal but not
essential. Extension of the episiotomy should be consid-
ered. The anterior shoulder is stuck behind the pubic
Shoulder Dystocia symphysis. Although greater posterior room does not
With vertex presentations, most mechanical difficulties directly permit delivery, it does permit vaginal manipula-
are resolved with delivery of the head; once the head is tions that may be necessary to effect delivery. Table 18-5
delivered, the remainder of the fetus follows easily. In as lists a personal plan of management for shoulder dysto-
many as 3% of vaginal deliveries, this is not the case. cia, but other choices are available.69,72,73 Emergency drills
After the (often large) head is delivered, it seems to be and simulation training may improve proficiency in the
“sucked” back into the perineum (the turtle sign). With management of shoulder dystocia.
maternal pushing and gentle traction, nothing happens. If suprapubic pressure (directed toward the floor)
In this case, the anterior shoulder is trapped above the coupled with gentle traction on the head is not effica-
pubic symphysis. This serious complication is called cious, the mother’s thighs are removed from their
396 PART VI Labor and Vaginal Delivery
supports and are hyperflexed alongside her abdomen. 5. Friedman EA. Labor: Clinical Evaluation and Management. 2nd
This maneuver (i.e., the McRoberts maneuver) elevates edition. New York, Appleton-Century-Crofts, 1978.
6. Peisner DB, Rosen MG. Transition from latent to active labor.
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previous assumptions to the contrary, vaginal delivery of 9. Rouse DJ, Weiner SJ, Bloom SL, et al.; for the Eunice Kennedy
the head does not necessarily commit one to vaginal birth Shriver National Institute of Child Health and Human Develop-
of the infant. Cephalic replacement (i.e., the Zavanelli ment (NICHD) Maternal-Fetal Medicine Units Network
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• Assuming that the fetus is tolerating labor 17. Hagelin A, Leyon J. The effect of labor on the acid-base status of
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• Oxytocin is the most valuable obstetric drug, 20. Carlson JM, Diehl JA, Sachtleben-Murray M, et al. Maternal posi-
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68:443-7.
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• Expectant management is the standard choice Clinical management guidelines for obstetrician-gynecologists.
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22. Hartmann K, Viswanathan M, Palmieri R, et al. Outcomes
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condition at term. 2141-8.
• Elective induction of labor is an appropriate 23. Hendricks CH, Brenner WE. Cardiovascular effects of oxytocic
drugs used postpartum. Am J Obstet Gynecol 1970; 108:751-9.
choice for a patient with a favorable cervix. 24. Hayashi RH, Castillo MS, Noah ML. Management of severe
• The declining numbers of operative vaginal postpartum hemorrhage due to uterine atony using an analogue of
deliveries reflect medicolegal concerns rather prostaglandin F2 alpha. Obstet Gynecol 1981; 58:426-9.
than new scientific information. 25. Jackson KW, Allbert JR, Schemmer GK, et al. A randomized con-
trolled trial comparing oxytocin administration before and after
placental delivery in the prevention of postpartum hemorrhage. Am
J Obstet Gynecol 2001; 185:873-7.
26. Rouse DJ, Owen J, Savage KG, Hauth JC. Active phase labor
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Am J Obstet Gynecol 2004; 191:211-6.
C H A P T E R 1 9
CHAPTER OUTLINE
In 1916, Edward Cragin1 stated, “Once a cesarean, always The VBAC rate increased from 2% in 1970 to 28%
a cesarean.” This edict has had a profound effect on in 1995. This change in practice helped reduce the overall
obstetric practice in the United States. The cesarean cesarean delivery rate from 24.7% in 1988 to 20.7% in
delivery rate increased from 5.5% of all deliveries in 1970 1996 (see Figure 19-1). Subsequently the safety of a trial
to 24.7% in 1988 (Figure 19-1). Much of the increase in of labor after cesarean (TOLAC) underwent further
the cesarean delivery rate resulted from performance of scrutiny and criticism, and the VBAC rate sharply
repeat cesarean deliveries. In contemporary practice, declined.5 The VBAC rate in the United States dropped
elective repeat cesarean deliveries account for one third from 28% in 1995 to 9% in 2004. Meanwhile, in 2009,
of all cesarean deliveries. Cesarean delivery is the most the overall cesarean delivery rate rose to 32.9%, the
frequently performed major surgery in the United States. highest rate ever recorded in this country.6
For many years most U.S. physicians ignored Cragin’s
subsequent statement, “Many exceptions occur.”1 In 1981
the National Institute of Child Health and Human PRIMARY CESAREAN DELIVERY:
Development Conference on Childbirth concluded that CHOICE OF UTERINE INCISION
vaginal birth after cesarean (VBAC) is an appropriate
option for many women.2 In 1991, Rosen et al.3 modified Obstetric practice in 1916 hardly resembled obstetric
Cragin’s original dictum as follows: “Once a cesarean, a practice today. In 1916, only 1% to 2% of all infants were
trial of labor should precede a second cesarean except in delivered by cesarean delivery. Most cesarean deliveries
the most unusual circumstances.” In 1988 and again in were performed in patients with a contracted bony pelvis,
1994, the American College of Obstetricians and Gyne- and obstetricians uniformly performed a classic uterine
cologists (ACOG)4 concluded: “The concept of routine incision (i.e., a long vertical incision in the upper portion
repeat cesarean birth should be replaced by a specific of the uterus) (Figure 19-2). A patient with a classic
decision process between the patient and the physician uterine incision is at high risk for catastrophic uterine
for a subsequent mode of delivery.… In the absence of a rupture during a subsequent pregnancy. Such uterine
contraindication, a woman with one previous cesarean rupture may occur before or during labor, and it often
delivery with a lower uterine segment incision should be results in maternal and perinatal morbidity or mortality.
counseled and encouraged to undergo a trial of labor in In 1922, De Lee and Cornell7 advocated the perfor-
her current pregnancy.” mance of a vertical incision in the lower uterine segment.
398
19 Trial of Labor and Vaginal Birth after Cesarean Delivery 399
35
% of all deliveries
30
25
20
15
10
5
0
1970 1975 1980 1985 1990 1995 2000 2005 2010
FIGURE 19-1 ■ Incidence of cesarean delivery in the Year
United States.
Unfortunately, low-vertical incisions rarely are confined prefer to make a low-transverse uterine incision during
to the lower uterine segment. Such incisions often extend most cesarean deliveries.
to the body of the uterus, which does not heal as well as Obstetricians reserve the low-vertical incision for
the lower uterine segment. Kerr8 later advocated the per- patients whose lower uterine segment does not have
formance of a low-transverse uterine incision (see Figure enough width to allow safe delivery. Preterm parturients
19-2). A low-transverse uterine incision results in less may have a narrow lower uterine segment. In these
blood loss and is easier to repair than a classic uterine patients, delivery through a transverse uterine incision
incision.9 Further, a low-transverse uterine incision is may cause an extension of the incision into the vessels
more likely to heal satisfactorily and to maintain its integ- of the broad ligament. For example, a patient with
rity during a subsequent pregnancy. Thus, obstetricians preterm labor at 26 weeks’ gestation may undergo
A B C
D E
FIGURE 19-2 ■ Uterine incisions for cesarean delivery. A, Low-transverse incision. The bladder is retracted downward, and the inci-
sion is made in the lower uterine segment, curving gently upward. If the lower segment is poorly developed, the incision also can
curve sharply upward at each end to avoid extending into the ascending branches of the uterine arteries. B, Low-vertical incision.
The incision is made vertically in the lower uterine segment after reflection of the bladder, with avoidance of extension into the
bladder below. If more room is needed, the incision can be extended upward into the upper uterine segment. C, Classic incision.
The incision is entirely within the upper uterine segment and can be at the level shown or in the fundus. D, J-shaped incision. If
more room is needed when an initial transverse incision has been made, either end of the incision can be extended upward into
the upper uterine segment and parallel to the ascending branch of the uterine artery. E, T-shaped incision. More room can be
obtained in a transverse incision by an upward midline extension into the upper uterine segment. (Modified from Landon MB. Cesarean
delivery. In Gabbe SG, Niebyl JR, Simpson JL, editors. Obstetrics: Normal and Problem Pregnancies. 5th edition. Philadelphia, Churchill
Livingstone Elsevier, 2007:493.)
400 PART VI Labor and Vaginal Delivery
cesarean delivery because of a breech presentation, and Landon et al.11 subsequently conducted a prospective
the obstetrician may perform a low-vertical incision to 4-year observational study of all parturients with a single-
facilitate an atraumatic delivery of the fetal head. ton gestation and a prior cesarean delivery at 19 academic
Obstetricians rarely perform a classic uterine incision medical centers. Among the 17,898 women who attempted
in modern obstetric practice. An obstetrician may perform VBAC, 13,139 (73.4%) delivered vaginally. Symptomatic
a classic uterine incision when the need for extensive uterine rupture occurred in 124 (0.7%) women who
intrauterine manipulation of the fetus (e.g., delivery of a underwent a trial of labor. The rate of endometritis was
fetus with a transverse lie) is anticipated. Some obstetri- higher in women who underwent a trial of labor than in
cians prefer a classic uterine incision in patients with an women who had an elective repeat cesarean delivery
anterior placenta previa. In such cases, the performance (2.9% versus 1.8%), as was the rate of blood transfusion
of a classic incision allows the obstetrician to avoid cutting (1.7% versus 1.0%).15
through the placenta, which might result in significant In a 2004 systematic review of published studies of
hemorrhage. attempted VBAC, Guise et al.16 observed no significant
difference in the incidence of maternal death or hyster-
ectomy between women who attempted a trial of labor
MATERNAL AND NEONATAL and those who underwent repeat cesarean delivery.
OUTCOMES Uterine rupture was more common in the women who
attempted a trial of labor, but the rates of asymptomatic
Multiple studies have demonstrated that TOLAC results uterine dehiscence did not differ.
in a successful VBAC in 60% to 80% of women in whom Wen et al.17 performed a retrospective cohort com-
a low-transverse uterine incision was made for a previous parison of outcomes after TOLAC or elective repeat
cesarean delivery.10-13 A 2010 National Institute of Health cesarean delivery in 308,755 Canadian women with a
(NIH) consensus development panel14 concluded that history of previous cesarean delivery. These investigators
although the TOLAC rate has declined dramatically in observed that the rates of uterine rupture (0.65%), trans-
recent years, the VBAC rate after TOLAC has remained fusion (0.19%), and hysterectomy (0.10%) were signifi-
constant at approximately 74%. However, the panel cantly higher in the TOLAC group. However, the
acknowledged that many published studies were observa- maternal in-hospital death rate was significantly lower in
tional and did not address issues of selection bias. The the TOLAC group (1.6 per 100,000) than in the elective
panel also noted that a history of vaginal delivery, either cesarean delivery group (5.6 per 100,000). Similarly,
before or after a prior cesarean delivery, is consistently Guise et al.18 observed a lower maternal mortality rate in
associated with an increased likelihood of successful women who underwent TOLAC than in women who
VBAC.14 underwent elective repeat cesarean delivery (0.004%
versus 0.013%, respectively).
Cahill et al.19 performed a multicenter cohort study in
Maternal Outcomes which they concluded that among TOLAC candidates
Flamm et al.10 performed a prospective multicenter who had a prior vaginal delivery, those who attempted
study of TOLAC. Of the 7229 patients, 5022 (70%) VBAC had a lower risk for overall major maternal mor-
underwent TOLAC and 2207 underwent elective repeat bidities, as well as maternal fever and transfusion, than
cesarean delivery. Some 3746 (75%) of the women who women who chose repeat cesarean delivery. These inves-
opted for TOLAC delivered vaginally. The incidence of tigators concluded that women who have had a prior
uterine rupture was 0.8%. The incidence of postpartum vaginal delivery have “less composite maternal morbidity
transfusion, the incidence of postpartum fever, and the if they attempt VBAC compared with [those] undergoing
duration of hospitalization were significantly lower in the an elective repeat cesarean delivery.” Further, they con-
TOLAC group than in the elective repeat cesarean cluded that a trial of labor is “a safer overall option for
group. Likewise, in a 1991 meta-analysis of 31 studies, women who have had a prior vaginal birth.”19
Rosen et al.3 noted that maternal febrile morbidity Rossi and D’Addario12 performed a meta-analysis of
was significantly lower among women who attempted studies published in 2000-2007 that compared maternal
VBAC than among those who underwent elective repeat morbidity in women who underwent TOLAC versus
cesarean delivery. women who underwent elective repeat cesarean delivery.
In contrast, McMahon et al.15 performed a population- Successful VBAC occurred in 17,905 (73%) of 24,349
based longitudinal study of 6138 women in Nova Scotia women who underwent TOLAC. Overall maternal mor-
who had previously undergone cesarean delivery and who bidity did not differ between women who underwent
delivered a single live infant between 1986 and 1992. TOLAC and women who underwent elective repeat
Some 3249 women attempted VBAC, and 2889 women cesarean delivery. Likewise, the incidence of blood trans-
chose a repeat cesarean delivery. There was no difference fusion and hysterectomy did not differ between the two
between the two groups in the incidence of “minor com- groups. The incidence of uterine rupture was higher in
plications” (e.g., puerperal fever, transfusion, wound the TOLAC group (1.3% versus 0.4%). Further, mater-
infection). However, “major complications” (e.g., hyster- nal morbidity, uterine rupture, blood transfusion, and
ectomy, uterine rupture, operative injury) were nearly hysterectomy were more common in women who had a
twice as common among women who attempted VBAC failed TOLAC.
than among women who underwent elective repeat The 2010 NIH consensus development panel14 noted
cesarean delivery. that the overall benefits of TOLAC “are directly related
19 Trial of Labor and Vaginal Birth after Cesarean Delivery 401
to having a [successful] VBAC as these women typically admission—and a longer length of hospital stay—than
have the lowest morbidity.” Likewise, the panel noted infants whose mothers attempted VBAC. However, the
that the harms of TOLAC “are associated with an unsuc- 2010 NIH consensus development panel14 concluded that
cessful trial of labor resulting in cesarean delivery because there is insufficient evidence to determine whether sub-
these deliveries have the highest morbidity.” However, stantial differences in respiratory outcomes occur in
the panel concluded that women who undergo TOLAC, infants born via elective repeat cesarean delivery com-
regardless of the ultimate mode of delivery, are at pared with infants born after TOLAC.
decreased risk for maternal mortality compared with
women who undergo elective repeat cesarean delivery.
The panel also cited low-grade evidence of a shorter ELIGIBILITY AND SELECTION CRITERIA
hospitalization overall for women attempting TOLAC
compared with women undergoing elective repeat cesar- Most studies suggest a high likelihood of success with
ean delivery. TOLAC, even in women in whom the indication for
previous cesarean delivery was dystocia or failure to pro
gress in labor. Rosen and Dickinson22 performed a meta-
Neonatal Outcomes analysis of 29 studies of attempted VBAC. Among women
Lydon-Rochelle et al.20 conducted a population-based, whose previous cesarean deliveries were performed for
retrospective cohort analysis of obstetric outcomes for all dystocia or cephalopelvic disproportion, the average
20,095 nulliparous women who gave birth to a live single- rate of successful VBAC was 67%. Later studies have
ton infant by cesarean delivery in civilian hospitals in concluded that a history of previous vaginal delivery
Washington between 1987 and 1996 and who subse- (including previous VBAC) is the greatest predictor for
quently delivered a second singleton child during the successful VBAC.23
same period. These investigators observed that spontane- The highest risk for maternal morbidity and mortality
ous labor was associated with a tripling of the risk for is associated with unsuccessful TOLAC.14 The ACOG13
uterine rupture (i.e., a uterine rupture rate of 5.2 per 1000 concluded that women with at least a 60% to 70% chance
women who had spontaneous onset of labor versus 1.6 of successful VBAC have equal or less maternal morbidity
per 1000 women who underwent elective repeat cesarean when they undergo TOLAC than women who undergo
delivery without labor). Further, the incidence of infant elective repeat cesarean delivery. Conversely, the ACOG13
death was more than 10 times higher among the 91 noted that women who have a lower than 60% probabil-
women who experienced uterine rupture than among the ity of successful VBAC have a greater likelihood of mor-
20,004 who did not (i.e., a 5.5% incidence of infant death bidity than women who undergo elective repeat cesarean
versus a 0.5% incidence, respectively).20 delivery. Thus, the ability to identify women with a high
In the study performed by McMahon et al.15 there likelihood of successful VBAC would improve the safety
was no difference between the two groups in perinatal of TOLAC. Investigators have attempted to develop reli-
mortality or morbidity. However, two perinatal deaths able scoring systems for predicting the success or failure
occurred after uterine rupture in the TOLAC group. of TOLAC, with limited success. Grobman et al.24 devel-
Landon et al.11 observed that hypoxic-ischemic encepha- oped a nomogram specifically for women undergoing
lopathy occurred in no infants whose mothers underwent TOLAC at term gestation with one previous low-
elective repeat cesarean delivery and in 12 infants deliv- transverse cesarean delivery, a singleton gestation, and a
ered at term whose mothers underwent a trial of labor vertex fetal presentation. The nomogram incorporates six
(P < .001). variables that may be ascertained at the first prenatal visit;
The 2010 NIH consensus development panel14 con- those variables include maternal age, body mass index,
cluded that the perinatal mortality rate (death between ethnicity, prior vaginal delivery, prior VBAC, and a recur-
20 weeks’ gestation and 28 days of life) is increased with ring indication for cesarean delivery. This model was
TOLAC when compared with elective repeat cesarean validated in a subsequent study.25
delivery (i.e., 130 deaths per 100,000 infants compared The ACOG13 concluded that the “preponderance of
with 50 deaths per 100,000 infants, respectively). Like- evidence suggests that most women with one previous
wise, the panel concluded that the neonatal mortality rate cesarean delivery with a low-transverse incision are can-
(death in the first 28 days of life) is also increased with didates for and should be counseled about VBAC and
TOLAC when compared with elective repeat cesarean offered TOLAC.” A history of dystocia, a need for induc-
delivery (110 deaths per 100,000 infants versus 50 deaths tion of labor, and maternal obesity are associated with a
per 100,000 infants, respectively).14 lower likelihood of successful VBAC.24,26-28
On the other hand, successful VBAC avoids the neo-
natal risks of elective cesarean delivery. Inappropriate History of More Than One
assessment of gestational age or fetal maturity occasion-
ally leads to the delivery of a preterm infant. Elective
Cesarean Delivery
cesarean delivery results in some cases of iatrogenic neo- Studies that have assessed outcomes of TOLAC in
natal respiratory sequelae, including respiratory distress women with a history of more than one cesarean delivery
syndrome and transient tachypnea of the newborn. have not demonstrated consistent conclusions. One large
Kamath et al.21 observed that newborns born after elec- multicenter study found no increased risk for uterine
tive repeat cesarean delivery had significantly higher rates rupture (0.9% versus 0.7%) in women with more than
of respiratory morbidity and neonatal intensive care unit one previous cesarean delivery, when compared with
402 PART VI Labor and Vaginal Delivery
women with only one previous cesarean delivery.29 A appear to be associated with a higher risk for maternal
second large study observed that the risk for uterine morbidity.36
rupture increased from 0.9% to 1.8% during TOLAC in Ford et al.37 subsequently examined outcomes for
women with two previous cesarean deliveries.30 Both 6555 women with a twin gestation who delivered between
studies observed that TOLAC was associated with some 1993 and 2002. Among 1850 women who underwent a
increase in maternal morbidity in women with more than trial of labor, 836 (45.2%) delivered vaginally. The rate
one previous cesarean delivery, although the absolute of uterine rupture was higher in the trial-of-labor group
magnitude of the difference in morbidity was relatively than in the elective cesarean delivery group (0.9% versus
small.29,30 The ACOG13 concluded that it is reasonable to 0.1%), but the rate of wound complications was lower in
consider TOLAC for women with two previous low- the trial-of-labor group (0.6% versus 1.3%).
transverse cesarean deliveries. Data regarding the risk of The ACOG13 concluded that “women with one previ-
TOLAC in women with more than two previous cesar- ous cesarean delivery with a low-transverse [uterine]
ean deliveries are limited.13 incision, who are otherwise appropriate candidates for
twin vaginal delivery, may be considered candidates for
TOLAC.”
Previous Low-Vertical Incision
Some obstetricians allow a trial of labor after a previous
low-vertical uterine incision, provided that there is docu-
Unknown Uterine Scar
mentation that the uterine incision was confined to the For some patients, there is no documentation of the type
lower uterine segment. (Low-vertical uterine incisions of uterine incision performed during a previous cesarean
often extend above the lower uterine segment, especially delivery. Some obstetricians require documentation of
when performed in preterm patients.) Naef et al.31 retro- the type of previous uterine incision before they allow a
spectively reviewed outcomes for 174 women who patient to attempt VBAC. At least two studies have con-
attempted VBAC after a previous low-vertical cesarean cluded that a trial of labor does not significantly increase
delivery; 144 (83%) women delivered vaginally. Uterine maternal or perinatal mortality in patients with an
rupture occurred in 2 (1.1%) of the patients. These inves- unknown uterine scar.38,39 Perhaps this conclusion is true
tigators concluded that “the likelihood of successful because most patients with an unknown uterine scar had
outcome and the incidence of complications are compa- a low-transverse uterine incision at previous cesarean
rable to those of published experience with a trial of labor delivery. Ultrasonography may help the obstetrician
after a previous low-segment transverse incision.”31 Adair confirm the presence of a low-transverse uterine scar in
et al.32 made similar observations. The ACOG13 con- the pregnant woman with an unknown uterine scar.40 The
cluded that there is no consistent evidence of an increased ACOG13 concluded that “TOLAC is not contraindicated
risk for uterine rupture in women with a previous low- for women with one previous cesarean delivery with an
vertical uterine incision, and that obstetricians and unknown uterine scar type unless there is a high clinical
patients may choose to undergo TOLAC in the presence suspicion of a previous classical uterine incision.”
of a documented prior low-vertical uterine incision.
Suspected Macrosomia
Twin Gestation In 1994 the ACOG4 concluded that an estimated fetal
Some obstetricians believe that uterine overdistention, weight of more than 4000 g does not contraindicate
which occurs with twin gestation, increases the risk for TOLAC. However, in 1999, the ACOG41 included sus-
uterine rupture in patients with a history of previous pected macrosomia on the list of TOLAC eligibility cri-
cesarean delivery. Early reports suggested otherwise, teria that are controversial. In 2004, the ACOG42 noted
but these studies were limited by the small number of that macrosomia is associated with a lower likelihood of
patients.33,34 Cahill et al.35 performed a retrospective successful VBAC but did not include a specific recom-
cohort study of 25,005 obstetric patients with at least one mendation regarding TOLAC in cases of suspected mac-
previous cesarean delivery, which included 535 patients rosomia. However, the ACOG cited one report that
with a twin pregnancy. The investigators observed that observed that the rate of uterine rupture appeared to be
women with a twin gestation were less likely to attempt higher only in women without a previous vaginal deliv-
VBAC but were no more likely to have a failed VBAC or ery.43 A report from the Maternal-Fetal Medicine Unit
to experience major morbidity than women with a single- Cesarean Registry44 concluded that for women with a
ton gestation. history of previous cesarean delivery for dystocia, a higher
Likewise, a report from the Maternal-Fetal Medicine birth weight in a subsequent pregnancy (relative to the
Unit Cesarean Registry36 included outcome measures for first pregnancy birth weight) diminishes the chances of
186 women with a twin gestation who attempted VBAC. successful VBAC. In 2010 the ACOG13 concluded that
Some 120 (64.5%) women delivered vaginally. Women “suspected macrosomia alone should not preclude the
who attempted a trial of labor with twin gestation had no possibility of TOLAC.”
higher risk for transfusion, endometritis, intensive care
unit admission, or uterine rupture than women who
underwent elective repeat cesarean delivery. The investi-
Gestation beyond 40 Weeks
gators concluded that a trial of labor in women with a Studies have consistently demonstrated decreased rates
twin gestation after previous cesarean delivery does not of successful VBAC in women who undergo TOLAC
19 Trial of Labor and Vaginal Birth after Cesarean Delivery 403
after 40 weeks’ gestation.45-47 One study observed an has resulted, in part, from both physician and patient
increased incidence of uterine rupture in women under- preference. VBAC requires more physician effort than
going TOLAC beyond 40 weeks’ gestation,47 but other elective repeat cesarean delivery. In some cases, physician
studies (including the largest study46 that has assessed this reimbursement is greater for elective repeat cesarean
risk factor) have not confirmed an increased risk for delivery than for VBAC, despite the fact that VBAC
uterine rupture in these patients. The ACOG13 con- requires greater physician effort.
cluded that although the likelihood of successful VBAC Stafford49 reviewed the impact of nonclinical factors
may be diminished in more advanced gestations, a “ges- on the performance of repeat cesarean delivery in
tational age of greater than 40 weeks alone should not California. He observed that “proprietary hospitals, with
preclude TOLAC.” the greatest incentive to maximize reimbursement, had
the highest repeat cesarean [delivery] rates.” Nonteach-
Breech Presentation and External ing hospitals and hospitals with low-volume obstetric
services had lower VBAC rates than teaching hospitals
Cephalic Version and hospitals with high-volume obstetric services. Like-
Breech presentation itself does not increase the risk for wise, Hueston and Rudy50 found that women who
uterine rupture. In contemporary practice, most obstetri- undergo elective repeat cesarean delivery are more likely
cians do not allow a trial of labor in any patient with a to have private insurance than women who attempt
breech presentation. Thus, most patients with a breech VBAC. Stafford49 concluded: “Because a cesarean [deliv-
presentation undergo elective cesarean delivery, with or ery] is nearly twice as costly as a vaginal birth,… the
without a history of previous cesarean delivery. The higher repeat cesarean [delivery] rates associated with
ACOG13 concluded that external cephalic version is not proprietary hospitals, non-teaching hospitals, and low-
contraindicated in women with a previous low-transverse volume hospitals contribute to increased health care
uterine incision who are at low risk for adverse maternal expenditures.”
and neonatal outcomes from external cephalic version In contrast, after assessing both the direct and indirect
and TOLAC. costs of VBAC, Clark et al.51 concluded that “any eco-
nomic savings for the healthcare system of a policy of trial
of labor are at best marginal, even in a tertiary care center
Size of Hospital with a success rate for vaginal birth after cesarean of
Most studies of VBAC have been conducted in university 70%.” Further, they stated that “a policy of trial of labor
or tertiary care hospitals with in-house obstetricians, does not result in any cost saving under most birthing
anesthesia providers, and operating room staff. In 1999 circumstances encountered in the United States today.”51
the ACOG41 noted that “the safety of [a] trial of labor is The ACOG41 had earlier acknowledged that “the diffi-
less well documented in smaller community hospitals or culty in assessing the cost-benefit of VBAC is that the
facilities where resources may be more limited.” A 2007 costs are not all incurred by one entity.” In 2004 the
study48 evaluated outcomes for women who attempted ACOG42 made the following conclusion:
VBAC in 17 diverse hospitals, including six university
hospitals, five community hospitals with an obstetrics- A true analysis of the cost-effectiveness of VBAC should
gynecology residency program, and six community include hospital and physician costs, the method of
hospitals without an obstetrics-gynecology residency reimbursement, potential professional liability expenses,
program. The incidence of uterine rupture with attempted and the probability that a woman will continue with
VBAC was significantly higher in community hospitals childbearing after her first attempt at VBAC. Higher
than in university hospitals (1.2% versus 0.6%, respec- costs may be incurred by a hospital if a woman has a
tively). However, the rates of maternal blood transfusion prolonged labor or has significant complications or if the
and composite adverse maternal outcome were identical newborn is admitted to a neonatal intensive care unit.
in community and university hospitals.48
Some women reject TOLAC because they have expe-
rienced prolonged, painful labor during a previous preg-
Contraindications nancy. They fear that they will again experience a
Contraindications to planned TOLAC include13,42: prolonged, painful labor and ultimately need a repeat
• Previous classic or T-shaped incision or extensive cesarean delivery. This fear is more common in women
transfundal uterine surgery who have delivered in smaller hospitals without the avail-
• Previous uterine rupture ability of neuraxial analgesia during labor. Other women
• Medical or obstetric complication that precludes reject TOLAC because they prefer to schedule the date
labor and vaginal delivery of elective repeat cesarean delivery. (A scheduled, elective
• Inability to perform emergency cesarean delivery cesarean delivery allows the patient to arrange for a rela-
because of unavailable surgeon, anesthesia provider, tive or friend to provide child care.) Kirk et al.52 ques-
or operating room staff tioned 160 women regarding factors affecting their
choice between VBAC and elective repeat cesarean
delivery. These investigators concluded that “social exi-
Social and Economic Factors gencies appeared to play a more important role than an
Why do most eligible patients choose to undergo elective assessment of the medical risks in making these deci-
repeat cesarean delivery? The low frequency of TOLAC sions.” Similarly, Joseph et al.53 observed that fear and
404 PART VI Labor and Vaginal Delivery
inconvenience are the most common deterrents to child suffered from developmental delay and cerebral
attempted VBAC. Finally, some women reject a trial of palsy. The court found that the defendants were negli-
labor because of their concern about the adverse effects gent in their failure to deliver the infant in a timely
of labor and vaginal delivery on the maternal pelvic floor, manner and to provide adequate informed consent. The
with the risk for subsequent problems such as urinary and court also concluded that “the ACOG 30-minute rule
fecal incontinence. represented the maximum period of elapse” and did not
Some insurance carriers previously required that eli- represent the minimum standard of care. As a result of
gible women with a history of previous cesarean delivery this verdict, Phelan59 proposed the use of a VBAC consent
attempt VBAC in subsequent pregnancies. These carriers form that includes the following statement: “I understand
denied partial or full reimbursement to women who that if my uterus ruptures during my VBAC, there may
chose elective repeat cesarean delivery unless there was a not be sufficient time to operate and to prevent the death
medical reason to perform repeat cesarean delivery. The of or permanent brain injury to my baby.” Flamm60
ACOG and others have agreed that hospitals and insurers responded that “widespread implementation of this or
should not mandate a trial of labor for pregnant women similar consent forms essentially would mean the end
with a history of previous cesarean delivery.54 In 2004 the of VBAC.”
ACOG42 concluded, “After thorough counseling that Greene61 wrote a sobering editorial on the risks of
weighs the individual benefits and risks of VBAC, the attempted VBAC. Observing that the study performed
ultimate decision to attempt this procedure or undergo a by Lydon-Rochelle et al.20 was an observational study
repeat cesarean delivery should be made by the patient that reflected “broad experience in a wide range of
and her physician.” clinical-practice settings,” he stated that “there is no
reason to believe that improvements in clinical care
can substantially reduce the risks of uterine rupture and
Medicolegal Factors perinatal mortality.” Greene61 concluded his editorial
What is the risk for uterine rupture during VBAC? A as follows:
lower uterine segment scar is relatively avascular, and
massive hemorrhage rarely follows separation of a lower After a thorough discussion of the risks and benefits of
segment scar. In contrast, rupture of a classic uterine scar attempting a vaginal delivery after cesarean section, a
may result in massive intraperitoneal bleeding. Unfortu- patient might ask, “But doctor, what is the safest thing
nately, there is some inconsistency and confusion in for my baby?” Given the findings of Lydon-Rochelle et al.,
reports of the incidence of asymptomatic uterine scar my unequivocal answer: elective repeated cesarean section.
dehiscence as opposed to frank uterine rupture. Uterine
scar dehiscence may be defined as a uterine wall defect In an earlier editorial, Pitkin62 made the following
that does not result in fetal compromise or maternal statement regarding VBAC: “Many women with previous
hemorrhage and that does not require emergency cesar- cesareans can be delivered vaginally, and thereby gain
ean delivery or postpartum laparotomy. In contrast, substantial advantage, but neither the decision for trial
uterine rupture may be accompanied by extrusion of the [of] labor nor management during that labor should be
fetus or placenta and results in fetal compromise, mater- arrived at in a cavalier or superficial manner.”
nal hemorrhage, or both, sufficient to require cesarean
delivery or postpartum laparotomy.55
Some obstetricians have suggested that earlier studies PROFESSIONAL SOCIETY
underestimated the risks of TOLAC. Scott56 reported PRACTICE GUIDELINES
12 women from Salt Lake City, Utah, who experienced
clinically significant uterine rupture during TOLAC. In 1999 the ACOG41 issued guidelines stating that
Some of the women did not experience optimal obstetric because uterine rupture may be catastrophic, VBAC
management. For example, Scott’s series included two should be attempted in institutions equipped to respond
women whose labor occurred at home.56 Of interest, the to emergencies with physicians immediately available to
number of home VBACs in the United States increased provide emergency care. The ACOG63 defended this
from 664 in 2003 to approximately 1000 in 2008, perhaps guideline by noting that “VBAC is a completely elective
as a result of restricted access to TOLAC in some procedure that allows for reasonable precautions in
hospitals.57 assuming this small but significant risk [of uterine
Obstetricians understandably fear that they will be rupture].” In contrast, other obstetric catastrophes (e.g.,
found liable if an adverse event occurs during TOLAC. placental abruption, umbilical cord prolapse) cannot be
In one case, a jury awarded a verdict of $98.5 million predicted. The ACOG63 has also noted that “the opera-
because of a delayed diagnosis of uterine rupture.58 tional definition of ‘immediately available’ personnel
Phelan59 cited another court decision that he predicted and facilities remains the purview of each local institu-
would have a “chilling effect on the future of VBAC.” In tion.” However, this requirement for the immediate
this case, the fetal heart rate (FHR) was normal until it availability of physicians and other personnel clearly
abruptly decreased to 80 beats per minute at a cervical represents a more stringent standard than the “readily
dilation of 9 cm. The interval between the onset of the available” requirement in other published guidelines for
FHR deceleration and emergency cesarean delivery was obstetric care.
27 minutes. At delivery, the fetal head was found in the Earlier, Zlatnik64 made the following comments
left adnexa. The mother required transfusion, and the regarding VBAC in a community hospital: “If a timely
19 Trial of Labor and Vaginal Birth after Cesarean Delivery 405
cesarean [delivery] cannot be performed in a community benefits of TOLAC versus elective repeat cesarean deliv-
hospital, VBAC is out of the question, but the larger ery. The panel also urged professional societies to reas-
question is: Should obstetrics continue to be practiced sess the requirement for immediate availability of surgical
there? Timely cesarean [delivery] is an essential option and anesthesia providers.
for all laboring women.” Subsequently the ACOG13 issued a revised practice
In contrast, the American Academy of Family bulletin, in which they stated that restricting access was
Physicians (AAFP)65 published the following not the intention of their “immediately available” require-
recommendations: ment. The ACOG13 noted that “much of the data con-
cerning the safety of TOLAC was obtained from centers
Women with one previous cesarean delivery with a low capable of performing immediate, emergency cesarean
transverse incision are candidates for and should be offered delivery.” Further, they stated that “although there is
a trial of labor (TOL).…Trial of labor after cesarean reason to think that rapid availability of cesarean delivery
(TOLAC) should not be restricted only to facilities with may provide a small incremental benefit in safety, com-
available surgical teams present throughout labor since parative data examining in detail the effect of alternate
there is no evidence that these additional resources result systems and response times are not available.” A recent
in improved outcomes. At the same time, it is clinically study55 evaluated neonatal outcome after 36 cases of
appropriate that a management plan for uterine rupture uterine rupture that occurred among 11,195 cases of
and other potential emergencies requiring rapid cesarean TOLAC between 2000 and 2009. None of the 17 infants
section should be documented for each woman undergoing who were delivered less than 18 minutes after the iden-
TOLAC. tification of uterine rupture had either an umbilical arte-
rial blood pH less than 7.0 or evidence of neurologic
The AAFP65 has argued that the ACOG guidelines injury. In contrast, three infants who were delivered more
suggest that “one rare obstetrical catastrophe (e.g., than 30 minutes after the diagnosis of uterine rupture had
uterine rupture) merits a level of resource that has not an umbilical arterial blood pH less than 6.8 and suffered
been recommended for other rare obstetrical catastro- neonatal neurologic injury.55
phes that may actually be more common.” The AAFP has The revised ACOG practice bulletin reaffirmed the
acknowledged that these other complications are “largely earlier “immediately available” recommendation, but it
not predictable,” whereas a TOLAC is a “planned event also affirmed thoughtful, informed decision-making.
that may demand a different degree of preparedness.” Specifically, the ACOG13 concluded:
Nonetheless, they stated that their recommendations sig-
nificantly differ from ACOG guidelines because they Because of the risks associated with TOLAC and
could find “no evidence to support a different level of [because] uterine rupture and other complications may
care for TOLAC patients.”65 be unpredictable, the College recommends that TOLAC
In response, Dr. Gary Hankins, Chair of the ACOG be undertaken in facilities with staff immediately
Committee on Obstetric Practice, made the following available to provide emergency care. When resources
statement66: for immediate cesarean delivery are not available, the
College recommends that health care providers and
It’s very troubling when people who may not even be patients considering TOLAC discuss the hospital’s
qualified to perform a cesarean section start issuing resources and availability of obstetric, pediatric,
guidelines about the safety of this kind of thing.… anesthetic, and operating staffs.…The decision to
Their argument is that the available data don’t prove offer and pursue TOLAC in a setting in which the
it’s unsafe—they’re not arguing that it is safe.…Our option of immediate cesarean delivery is more limited
main concern is with having the best possible outcome for should be carefully considered by patients and their
mother and baby. If women are given the true numbers health care providers. In such situations the best
about the bad outcomes that can be associated with VBAC, alternative may be to refer patients to a facility
no woman is going to take the chance [of laboring without with available resources.
immediately available surgical support].
Further, the ACOG13 also encouraged respect for patient
14
The 2010 NIH consensus development panel noted autonomy, as follows:
that approximately one third of hospitals and one half of
obstetric physicians in the United States no longer offer Respect for patient autonomy also argues that even if
TOLAC largely because of fear of liability and litigation. a center does not offer TOLAC, such a policy cannot be
The panel14 expressed concern that practice guidelines used to force women to have cesarean delivery or to deny
have created barriers that prevent women from choosing care to women in labor who decline to have a repeat
TOLAC. The panel concluded that TOLAC remains cesarean delivery.…Respect for patient autonomy
“a reasonable option for many pregnant women with supports that patients should be allowed to accept
one prior low-transverse uterine incision.” The panel increased levels of risk; however, patients should be clearly
acknowledged that decision-making may be difficult, informed of such potential increase in risk and
because the benefit of TOLAC for the woman may come management alternatives.
at the price of increased risk for the infant. The panel
stated that pregnant women should be given the oppor- Birnbach et al.67 reviewed the impact of anesthesia
tunity to make informed decisions about the risks and provider availability on the incidence of VBAC in the
406 PART VI Labor and Vaginal Delivery
United States. They concluded that the “immediately Induction and Augmentation of Labor
available” requirement necessitates having an in-hospital
anesthesia provider who is not performing another simul- Induction of labor is less likely to result in successful
taneous anesthetic. Their economic analysis prompted a VBAC than spontaneous labor.26 Studies of outcomes
conclusion that “the minimum requirement to provide after the use of oxytocin augmentation of labor during
immediate anesthesia care for all deliveries would be to TOLAC have demonstrated conflicting results.3,20,72-74 In
have all deliveries at facilities with greater than 1500 a 1991 meta-analysis of 31 studies of VBAC, Rosen et al.3
deliveries annually.” noted that the use of oxytocin did not increase the risk
for uterine scar dehiscence or rupture during VBAC. In
contrast, in one large retrospective study of more than
OBSTETRIC MANAGEMENT 20,000 women, uterine rupture was nearly five times
more common among women undergoing induction of
Intravenous Access and Availability labor with oxytocin than in those who had an elective
of Blood repeat cesarean delivery.20 Zelop et al.73 observed a higher
rate of uterine rupture in women undergoing oxytocin
It seems prudent to recommend the early establishment induction of labor for attempted VBAC than in similar
of intravenous access in women who undergo TOLAC. women attempting VBAC with spontaneous labor.
Resources for transfusion of blood and blood products Further, the rate of uterine rupture was also higher in
should be readily available. women receiving oxytocin for augmentation of labor, but
the difference was not statistically significant. The
ACOG13 has concluded that “the varying outcomes of
Fetal Heart Rate Monitoring available studies and small absolute magnitude of the risk
Continuous electronic FHR monitoring represents the reported in those studies support that oxytocin augmen-
best means of detecting uterine rupture.68-70 Rodriguez tation may be used in patients undergoing TOLAC.”
et al.69 reviewed 76 cases of uterine rupture at their hos-
pital. A nonreassuring FHR pattern occurred in 59 of the
76 patients and was the most reliable sign of uterine ANESTHETIC MANAGEMENT
rupture.
In the past, some obstetricians contended that epidural
analgesia might mask the pain of uterine scar separation
Intrauterine Pressure Monitoring or rupture and thereby delay the diagnosis of uterine
The intrauterine pressure catheter provides a quantita- scar dehiscence or rupture.75,76 Plauché et al.75 stated,
tive measurement of uterine tone both during and “Regional anesthesia, such as epidural anesthesia, blunts
between contractions. In the past, some obstetricians the patient’s perception of symptoms and the physician’s
contended that an intrauterine pressure catheter should ability to elicit signs of early uterine rupture.” Others
be used in all patients who undergo TOLAC, arguing have argued that the sympathectomy associated with
that a loss of intrauterine pressure and cessation of labor epidural anesthesia might attenuate the maternal com-
will signal the occurrence of uterine rupture. In one pensatory response to the hemorrhage associated with
study,69 39 patients had an intrauterine pressure catheter uterine rupture. For example, sympathectomy might
at the time of uterine rupture. None of these patients prevent the compensatory tachycardia and vasoconstric-
experienced an apparent decrease in resting uterine tone tion that occur during hemorrhage. However, consensus
or cessation of labor, but 4 patients experienced an now exists that these concerns do not preclude adminis-
increase in baseline uterine tone. In these 4 patients, the tration of neuraxial analgesia during TOLAC, for several
increase in baseline uterine tone was associated with reasons.
severe variable FHR decelerations that prompted imme- First, pain, uterine tenderness, and tachycardia have
diate cesarean delivery. The authors concluded that the low sensitivity as diagnostic symptoms and signs of lower
information obtained from the use of the intrauterine uterine segment scar dehiscence or rupture. Some uterine
pressure catheter did not help obstetricians make the scars separate painlessly. Many obstetricians have discov-
diagnosis of uterine rupture.69 ered an asymptomatic lower uterine segment scar dehis-
cence at the time of elective repeat cesarean delivery.
Molloy et al.77 reported 8 cases of uterine rupture
Use of Prostaglandins among 1781 patients who attempted VBAC. None of
Lydon-Rochelle et al.20 observed a uterine rupture rate these 8 patients had abdominal pain, but all had FHR
of 24.5 per 1000 women who attempted VBAC with abnormalities. Johnson and Oriol70 reviewed 14 studies
prostaglandin-induced labor. The ACOG13 cited evi- of VBAC published between 1980 and 1989. Among
dence from small studies that observed an increased risk 10,967 patients who attempted VBAC, 1623 patients
for uterine rupture after the use of misoprostol (prosta- received epidural analgesia. Of those who experienced
glandin E1) in women who attempted VBAC. The uterine rupture, 5 of 14 patients (35%) with epidural
ACOG13,71 has concluded that “misoprostol should not analgesia experienced abdominal pain, compared with 4
be used for third trimester cervical ripening or labor of 23 patients (17%) without epidural analgesia. FHR
induction in patients who have had a cesarean delivery or abnormalities represented the most common sign of
major uterine surgery.” uterine rupture among patients who did and did not
19 Trial of Labor and Vaginal Birth after Cesarean Delivery 407
receive epidural analgesia. None of the investigators in epidural analgesia. Other investigators have reported
these studies observed that epidural analgesia delayed the results of smaller studies suggesting a lower rate of suc-
diagnosis of uterine rupture. cessful VBAC among patients who received epidural
Second, pain, uterine tenderness, and tachycardia have analgesia.88,89 However, this effect was limited to patients
low specificity as diagnostic symptoms and signs of lower who received oxytocin for the induction or augmentation
uterine segment scar dehiscence. Case et al.78 reported 20 of labor. These investigators concluded that epidural
patients with a history of previous cesarean delivery in analgesia does not decrease the likelihood of successful
whom the indication for urgent repeat cesarean delivery VBAC.
was severe hypogastric pain, tenderness, or both. At Fifth, some obstetricians favor the use of epidural
surgery, they confirmed the presence of scar dehiscence analgesia because it facilitates postpartum uterine explo-
in only one of the 20 patients. Eckstein et al.79 suggested ration to assess the integrity of the uterine scar. Meehan
that the unexpected development of pain during previ- et al.91 earlier supported routine postpartum palpation of
ously successful epidural analgesia might be indicative of the uterine scar. However, Meehan et al.92 subsequently
uterine rupture. Crawford80 referred to this phenomenon acknowledged that it is not necessary to repair all such
as the “epidural sieve.” Others have described patients defects. Many obstetricians manage asymptomatic uterine
who received epidural analgesia and subsequently com- scar dehiscence with “expectant observation.” Thus, they
plained of pain and tenderness secondary to uterine scar argue that routine palpation of the uterine scar is unnec-
rupture.81-84 I have provided epidural analgesia for several essary after successful VBAC.9
patients in whom the first suggestion of scar separation Sixth, epidural analgesia provides rapid access to safe,
was the sudden and unexpected development of “break- surgical anesthesia if cesarean delivery or postpartum
through pain” despite the continuous epidural infusion laparotomy should be required.93
of local anesthetic. A recent study85 found evidence of Finally, it is inhumane to deny effective analgesia to
“epidural dose escalation immediately before uterine women who undergo TOLAC. Further, the ACOG13 has
rupture in women who attempted VBAC, when com- concluded that adequate pain relief may encourage more
pared with women who did not have uterine rupture.” women to choose TOLAC. Thus, the availability and use
The authors concluded that “clinical suspicion for uterine of neuraxial analgesia may decrease the incidence of
rupture should be high in women who require frequent unnecessary repeat cesarean delivery.
epidural dosing during a VBAC trial.”85 Thus, epidural The ACOG13 has stated that good and consistent sci-
analgesia may improve the specificity of abdominal pain entific evidence supports a conclusion that epidural anal-
as a symptom of uterine scar separation or rupture. gesia may be used during TOLAC. In my judgment, the
Third, most cases of lower uterine segment scar dehis- availability of neuraxial analgesia is an essential compo-
cence do not lead to severe hemorrhage. In one report of nent of a successful VBAC program. It seems reasonable
six cases of uterine scar dehiscence or rupture, only one to provide analgesia—but not total anesthesia—during
patient had intrapartum vaginal bleeding.68 However, if labor in patients attempting VBAC.
significant bleeding should occur, epidural anesthesia
may attenuate the maternal compensatory response to
hemorrhage. Vincent et al.86 observed that epidural anes-
KEY POINTS
thesia (median sensory level of T9) significantly wors-
ened maternal hypotension, uterine blood flow, and fetal • Cesarean delivery is the most commonly
oxygenation during untreated hemorrhage (20 mL/kg) in performed major operation in the United States,
gravid ewes. Intravascular volume replacement promptly and previous cesarean delivery is the most
eliminated the differences between groups in maternal common indication.
mean arterial pressure, cardiac output, and fetal Pao2.
Maternal heart rate did not change significantly during • A trial of labor is successful in 60% to 80% of
hemorrhage in the control animals. However, there was women in whom a low-transverse uterine
a significant drop in maternal heart rate during hemor- incision was made during previous cesarean
rhage in the animals that received epidural anesthesia.86 delivery.
Fourth, several published series have reported the suc- • A previous vaginal delivery is the greatest
cessful use of epidural analgesia in women undergoing predictor for successful vaginal birth after
TOLAC.39,68,80,87-90 There is little evidence that epidural cesarean delivery (VBAC). A history of dystocia,
analgesia either decreases the likelihood of vaginal deliv- the need for induction of labor, and/or maternal
ery or adversely affects maternal or neonatal outcome in obesity are associated with a lower likelihood of
women who have uterine scar separation or rupture. successful VBAC.
Flamm et al.90 reported a multicenter study of 1776 • Hospitals and insurers should not mandate a trial
patients who attempted VBAC. Approximately 134 (74%) of labor for pregnant women with a history of
of 181 women who received epidural analgesia delivered previous cesarean delivery.
vaginally, compared with 1180 (74%) of 1595 women • The American College of Obstetricians and
who did not receive epidural analgesia. Phelan et al.87 Gynecologists has recommended that resources
reported that among patients who received both oxytocin for performing emergency cesarean delivery
augmentation and epidural analgesia, 69% delivered should be immediately available in women
vaginally. This did not differ from the incidence of vaginal attempting a trial of labor after previous cesarean
delivery among patients who received oxytocin without
408 PART VI Labor and Vaginal Delivery
18. Guise JM, Denman MA, Emeis Cm, et al. Vaginal birth after
delivery (TOLAC). Other groups have argued that cesarean: new insights on maternal and neonatal outcomes. Obstet
this guideline is too restrictive and has created Gynecol 2010; 115:1267-78.
19. Cahill AG, Stamilio DM, Odibo AO, et al. Is vaginal birth after
barriers that prevent women from choosing cesarean (VBAC) or elective repeat cesarean safer in women with
TOLAC. a prior vaginal delivery? Am J Obstet Gynecol 2006; 195:1143-7.
• Continuous electronic fetal heart rate monitoring 20. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of
uterine rupture during labor among women with a prior cesarean
represents the best means of detecting uterine delivery. N Engl J Med 2001; 345:3-8.
rupture. 21. Kamath BD, Todd JK, Glazner JE, et al. Neonatal outcomes after
• Women are more likely to undergo TOLAC if elective cesarean delivery. Obstet Gynecol 2009; 113:1231-8.
they know that they will receive effective 22. Rosen MG, Dickinson JC. Vaginal birth after cesarean: a meta-
analysis of indicators for success. Obstet Gynecol 1990; 76:865-9.
analgesia during labor. 23. Mercer BM, Gilbert S, Landon MB, et al. Labor outcomes with
• Epidural analgesia does not delay the diagnosis increasing number of prior vaginal births after cesarean delivery.
of uterine rupture or decrease the likelihood of Obstet Gynecol 2008; 111:285-91.
24. Grobman WA, Lai Y, Landon MB, et al. Development of a nomo-
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Gynecol 2007; 109:806-12.
25. Costantine MM, Fox K, Byers BD, et al. Validation of the predic-
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Obstet Gynecol 1989; 161:666-9.
C H A P T E R 2 0
CHAPTER OUTLINE
The gate control theory of pain, described more than 40 agents that act on novel receptors or enzymes. By con-
years ago by Melzack and Wall,1 has revolutionized the trast, a laboring woman receives no physical assessment
understanding of the mechanisms responsible for pain of sensory function and is offered only a handful of sys-
and analgesia. Originally explained as the regulation of temic drugs that act primarily through the anatomic
pain signals from the peripheral nerve to the spinal cord blockade of neural traffic.
by the activity of other peripheral nerves, interneurons In this chapter, this paradox in the approach to labor
in the spinal cord, and central supraspinal centers (Figure pain is examined and the basis for current therapy
20-1), the theory has been refined with the concept of (anatomy), the basis for future therapy (neurophysiol-
a neuromatrix, a remarkably dynamic system capable of ogy), and the effects of labor pain on the mother and the
undergoing rapid change.2 Neural circuits and intraneu- infant are reviewed.
ral mechanisms regulate sensitivity at peripheral afferent
terminals; along the conducting axons of peripheral
nerves; in the spinal cord, pons, medulla, and thalamus; MEASUREMENT AND SEVERITY
and at cortical sites of pain transmission and projection. OF LABOR PAIN
For example, the peripheral application of capsaicin to
the skin alters spinal gating mechanisms within 10 The recognition and acceptance of chronic pain, which
minutes, resulting in a light touch signal’s being inter- frequently lacks an obvious outward cause, contrasts to
preted as burning pain.3 the recurrent denial of labor pain, which is accompanied
Despite extensive research (initiated by the gate by visible tissue injury. Dick-Read4 suggested that labor
control theory) into the mechanisms and treatments for is a natural process not considered painful by women in
chronic pain, virtually no research on the neurophysio- primitive cultures that should be handled with education
logic basis or therapies for labor pain has been performed. and preparation rather than through pain medications.
This discrepancy in focus has led to vastly different Lamaze5 popularized psychoprophylaxis as a method of
approaches to the treatment of patients with chronic birth preparation; this method now forms the basis for
versus obstetric pain. A patient with chronic pain typi- prepared childbirth training in the developed world.
cally undergoes a sophisticated physical assessment of Although childbirth training acknowledges the existence
sensory function; is offered therapies, on the basis of the of pain during labor, some scientific-thought leaders still
assessment, from nearly a dozen different classes of anal- consider labor pain to be minor.
gesics; and can benefit from the enormous resources The severity of labor pain has been recognized previ-
expended by the pharmaceutical industry to introduce ously. Melzack,6 using a questionnaire developed to assess
410
20 The Pain of Childbirth and Its Effect on the Mother and the Fetus 411
Action
L Gate control system system Causalgia
40 Digit
Nulliparas amputation
+ –
+ (no prepared childbirth training)
SG T Nulliparas
– – + (prepared childbirth training)
30
S
Multiparas
(trained and untrained)
Chronic back pain
Cancer pain Bruise
20
(nonterminal) Fracture
Phantom limb pain Cut
Postherpetic neuralgia Laceration
Toothache 10 Sprain
Arthritis
Cervical dilation
Hardy7,8 trained subjects to reproduce the intensity of Probability of severe pain
0.8 8
labor pain with the sensation of noxious heat applied to
that the rated intensity of labor pain reflects individual In summary, although significant variability exists in
differences in the perception of all types of pain. In a the rated intensity of pain during labor and delivery, the
study of factors affecting labor pain, 10 of 97 subjects majority of women experience more than minimal pain.
reported that they had never experienced pain before The close correlation between cervical dilation and the
childbirth; these women reported significantly less pain rated severity of pain implies the existence of a causal
during labor and delivery compared with women who relationship and increases the likelihood that a parturient
had previously experienced pain.11 In other studies, the will request analgesia as labor progresses.
variability of pain after cesarean delivery could be pre-
dicted with preoperative quantitative sensory testing
(such as rating the intensity of pain with a standardized PERSONAL SIGNIFICANCE
noxious thermal stimulus), psychologic constructs, and AND MEANING
their combinations.12,13
The mechanism by which people perceive different The International Association for the Study of Pain
levels of pain from the same stimulus remains unclear. (IASP) has defined pain as “an unpleasant sensory and
A study involving brain imaging and a fixed acute noxious emotional experience associated with actual or potential
heat stimulus showed a strong correlation between verbal tissue damage, or described in terms of such damage.”18
pain assessment and the level of activation of various Clearly, this reflects an intensity-discriminatory compo-
cortical brain regions, especially the contralateral somato- nent and an emotional-cognitive component, with pow-
sensory cortex and anterior cingulate cortex.14 The inves- erful interactions between the two. The focus of current
tigators also found that the degree of activation of the interventions is heavily weighted toward the first compo-
thalamus was essentially identical in all subjects, suggest- nent and assumes that labor pain is severe and in need of
ing that differences in perceived pain resulted from mod- pharmacologic treatment. Largely ignored are coping
ulation at suprathalamic levels rather than in the peripheral strategies and the personal meaning of labor pain, which
nerves or spinal cord. The situation in labor may be more varies considerably among women.19
complex. For example, a large genetic polymorphism Although many women rate the pain of labor and
regulates cytokine production and function as well as delivery as severe, the terms used to more fully describe
pregnancy outcome.15 It is possible that interindividual this pain reflect an emotional meaning. In a pioneering
differences in labor pain may partially reflect genetic study of the quantification of pain from experimental
differences in cytokine production or response. dilation of the cervix, Bajaj et al.20 compared pain descrip-
In evaluating and studying labor pain and its treat- tors in women who were in labor, had experimental cervi-
ment, most studies have tended to assess labor pain by cal dilation, were undergoing spontaneous abortion, or
using a set of discrete pain scores. However, labor pain is who had dysmenorrhea (Table 20-1). Women with dys-
a complex, subjective, multidimensional, and dynamically menorrhea used words that indicate suffering, such as
changing experience with both sensory and affective com- “punishing” and “wretched,” whereas those in labor did
ponents that are influenced by many factors. As a result, not. Some researchers have drawn parallels between the
there are substantial individual differences in labor pain. pain derived from mountain climbing, which is associated
Therefore, better identification of the covariates that with a sense of euphoria, and the pain of labor.19 As noted
affect labor progress and its associated pain is needed. by one woman, “You mature and become a stronger per-
Recently, Conell-Price et al.16 developed and validated a sonality when you’ve had a baby and have gone through
dynamic model to account for labor progress in the assess- the pain. I think that is the purpose of it, what the
ment of labor pain. Subsequently, Debiec et al.,17 at the meaning of life is … to protect our children, to be stron-
same institution, combined a biexponential model that ger.”21 However, other women have found no deeper
describes labor progress with a sigmoidal labor pain meaning to the pain of labor or reasons why it should not
model to assess the influence of patient covariates on be treated. Many conditions that involve pain (e.g.,
labor pain.17 Both studies used retrospective patient data trauma, severe dental disease, cancer) are considered a
to develop and test their models. In the former study,16 “normal” part of human life without a spiritual meaning,
the prediction error for the pain scores was large, but the thereby making labor pain unique.
purpose of the model was to identify and remove vari- In summary, there are large interindividual differences
ability associated with labor progress so that other factors in how women experience the personal significance or
(e.g., genetic polymorphisms) can be quantitatively meaning of labor pain. These different perceptions can
studied. In this study,16 cervical dilation accounted for lead to a long-term sense of failure and guilt when phar-
only 16% to 20% of the variability in reported pain. In macologic pain relief is accepted or emotional trauma
the latter study,17 the covariate of ethnicity was found to when it is withheld.
have a statistically significant but clinically trivial effect on
labor progress. The modeling described by these investi-
gators provides a useful quantitative tool for future studies
to identify and assess the effect—or the lack of effect—of
ANATOMIC BASIS
patient and/or environmental covariates on labor prog- First Stage of Labor
ress, labor pain, and therapeutic responses. Better under-
standing of underlying causes of interindividual variability Several lines of evidence suggest that the pain experi-
in labor progress, labor pain, and therapeutic responses is enced during the first stage of labor is transduced by
likely to lead to more tailored therapy. afferents with peripheral terminals in the cervix and
20 The Pain of Childbirth and Its Effect on the Mother and the Fetus 413
TABLE 20-1 Word Descriptors from the McGill Pain Questionnaire Used to Describe Pain from the
Uterus and Cervix
Pain Descriptors Type/Source of Pain
BALLOON DISTENTION
OF THE CERVIX* LABOR† ABORTION‡ DYSMENORRHEA*
Sensory Shooting, boring, Throbbing, shooting, Cutting, cramping, Pulsing, beating, shooting, pricking,
sharp, hot, dull, sharp, cramping, tugging, pulling, boring, drilling, sharp, cutting, pinching,
taut aching, taut aching pressing, cramping, tugging, pulling,
hot, stinging, dull, hurting, heavy, taut
Affective Exhausting, tiring, Tiring Tiring, sickening, punishing, wretched
frightening, grueling
Evaluative Annoying Intense Annoying, intense
Miscellaneous Drawing, Tearing Numb, squeezing Piercing, drawing, squeezing, nagging
squeezing
*Data from Bajaj P, Drewes AM, Gregersen H, et al. Controlled dilatation of the uterine cervix: an experimental visceral pain model. Pain
2002; 99:433-42.
†
Data from Niven C, Gijsbers K. A study of labour pain using the McGill Pain Questionnaire. Soc Sci Med 1984; 19:1347-51.
‡
Data from Wells N. Pain and distress during abortion. Health Care Women Int 1991; 12:293-302.
or inferior hypogastric plexus,34 Cleland reasoned that tract (stimulating thalamic neurons) with further projec-
the sensory afferents and sympathetic efferents were tions to the somatosensory cortex, where pain is per-
likely intermingled; he subsequently demonstrated that ceived. These spinal neurons also send axons through the
the bilateral blockade of the lumbar paravertebral sym- spinoreticular and spinomesencephalic tracts to provide
pathetic chain could produce analgesia during the first signals to the areas of vigilance (locus coeruleus, reticular
stage of labor.33 First-stage labor pain is transmitted by formation), cardiorespiratory regulation (nucleus tractus
afferents that have cell bodies in T10 to L1 DRG and solitarius, caudal medulla), and reflex descending inhibi-
pass through the paracervical region, the hypogastric tion (periaqueductal gray, locus coeruleus and subcoeru-
nerve and plexus, and the lumbar sympathetic chain. leus, nucleus raphe magnus, rostral medial medulla,
Classical teaching states that pain-transmitting C and cerebellum). Thalamic activation from painful stimuli
A-delta nerve fibers enter the spinal cord through the results in the activation not only of the somatosensory
dorsal roots and terminate in a dense network of synapses cortex but also areas of memory (prefrontal cortex), motor
in the ipsilateral superficial laminae (I and II) of the dorsal response (M1 motor cortex), and emotional response
horn, with minimal rostrocaudal extension of fibers. (insular cortex, anterior cingulate cortex). Supraspinal
Whereas this characterization is true for somatic affer- pain pathways activated by pain of the first stage of labor
ents, visceral C fiber afferents enter the cord primarily— can be briefly described sequentially, starting with the
but not exclusively—through the dorsal roots and ascending pathways projecting to the pons and the
terminate in a loose network of synapses in the superficial medulla, thereby activating centers of cardiorespiratory
and deep dorsal horn and the ventral horn. These affer- control and descending pathways as well as the thalamus,
ents also cross to the contralateral dorsal horn, with which in turn sends projections to the anterior cingulate,
extensive rostrocaudal extension of fibers. This anatomic motor, somatosensory, and limbic regions.
distinction underlies the precise localization of somatic The anatomic basis for pain of the first stage of labor
pain and the diffuse localization of visceral pain, which implies that amelioration of pain should occur after
may cross the midline; it may also determine the potency blockade of peripheral afferents (by paracervical, paraver-
or efficacy of drugs that must reach afferent terminals, tebral, lumbar sympathetic, or epidural [T10 to L1
such as intrathecal opioids. dermatome] block) or after blockade of spinal cord trans-
Pain-transmitting neurons in the spinal cord dorsal mission (by intrathecal injection of local anesthetic and/
horn send axons to the contralateral ventral spinothalamic or opioid) (Figure 20-5). In addition, the widespread
Segmental
epidural block Paravertebral
T10-L1 block T10-L1
Lumbar
sympathetic
block
Caudal or true
saddle block Sacral nerve root
block S2-S4
Paracervical
block
Pudendal
block
FIGURE 20-5 ■ Transmission of labor pain. Labor pain has a visceral component and a somatic component. Uterine contractions may
result in myometrial ischemia, which causes the release of potassium, bradykinin, histamine, and serotonin. In addition, stretching
and distention of the lower segments of the uterus and the cervix stimulate mechanoreceptors. These noxious impulses follow the
sensory nerve fibers accompanying sympathetic nerve endings, travel through the paracervical region and the pelvic and hypogastric
plexus, and enter the lumbar sympathetic chain. Through the white rami communicantes of the T10, T11, T12, and L1 spinal nerves,
they enter the dorsal horn of the spinal cord. These pathways could be mapped successfully by demonstration that blockade at
different levels along this path (sacral nerve root block of S2-4, pudendal block, paracervical block, low caudal or true saddle block,
lumbar sympathetic block, segmental epidural block of T10-L1, and paravertebral block T10-L1) can alleviate the visceral component
of labor pain. (From Eltzschig HK, Lieberman ES, Camann WR. Regional anesthesia and analgesia for labor and delivery. N Engl J Med
2003; 348:319-32.)
20 The Pain of Childbirth and Its Effect on the Mother and the Fetus 415
distribution of visceral synapses in the spinal cord implies Mechanical ATP H+ Heat, H+
that intrathecally administered drugs (e.g., opioids) must distortion
have physicochemical properties that facilitate deep pen-
etration into the cord to reach the terminals responsible
for pain transmission.
Pain during the second stage of labor is transmitted by FIGURE 20-6 ■ Afferent nerve endings contain multiple excitatory
the same afferents activated during the first stage of labor ligand-gated ion channels, including those that respond to
but with additional afferents that innervate the cervix mechanical distortion: BNC-1, brain sodium channel-1; ATP,
(vaginal surface), vagina, and perineum. These additional adenosine triphosphate; P2X3, purinergic receptor; H +, hydro-
gen ion; ASIC, acid-sensing ion channel; VR-1, vanilloid receptor
afferents course through the pudendal nerve DRG at S2 type 1.
to S4 and are somatic. Thus, the pain specific to the
second stage of labor is precisely localized to the vagina
and perineum and reflects distention, ischemia, and frank stimulates a type of ligand-gated ion channel—
injury, either by stretching to the point of disruption or P2X3—on sensory afferents in the bladder wall.38
by surgical incision. Studies in nonpregnant women indi- Because P2X3 receptors are widely expressed in C
cate a minor analgesic effect of mechanical self-stimulation fibers,39 this mechanism might be responsible for
of the vaginal surface of the cervix35; this effect may result the pain that results from the acute distention of the
from the stimulation of C fibers, because in women with uterine cervix.
a high oral intake of capsaicin, the activity of such fibers 3. Local ischemia during contractions may result in
is reduced.36 The relevance of this minor effect in reduc- gated or spontaneous activity of other ion channels.
ing the pain of the second stage of labor is questionable Some of these ion channels—the ASIC family—
and has not been examined; however, it does appear to respond directly to the low pH that occurs during
provide evidence that noxious input during labor may ischemia,40 whereas other classes of ion channels
activate endogenous analgesia (see later discussion). may be activated to open spontaneously. For
The anatomic basis for pain of the second stage of example, the vanilloid receptor type 1 (VR-1) can
labor implies that analgesia can be obtained through a be stimulated by capsaicin. It is likely that VR-1
combination of methods used to treat the pain of the first receptors (which also respond to noxious heat) are
stage with a pudendal nerve block or extension of the expressed on visceral afferent terminals, given that
epidural blockade from T10 to S4 (see Figure 20-5). the application of capsaicin or heat to the distal
esophagus in humans results in pain.41 VR-1
receptor–gated ion channels are not normally open
in the absence of high temperature or capsaicin-like
NEUROPHYSIOLOGIC BASIS ligands; however, in the presence of low pH, the
Peripheral Afferent Terminals temperature response of these receptors shifts so
that their channels open at body temperature.42
Visceral nociceptors, such as those that transduce the Uterine cervical afferents (including the C fibers that
pain of the first stage of labor, are activated by stretching innervate the vaginal surface of the cervix) contain sub-
and distention. However, unlike somatic afferents, they stance P, CGRP, and the enzyme nitric oxide synthase.43
are not activated by cutting. With each uterine contrac- C fibers can be divided into two groups: (1) those that
tion, pressure is transmitted to distort and stretch the contain substance P and CGRP and respond to nerve
uterine cervix, thereby leading to the activation of these growth factor through actions on tyrosine kinase A recep-
nerve terminals. How mechanical distention results in tors and (2) those that contain somatostatin, instead of
the depolarization of the nerve terminal and the genera- substance P and CGRP, and respond to glially derived
tion of an action potential is not entirely known, but the growth factor through actions on a c-ret complex.44 Some
following three mechanisms are likely: overlap exists between these rough classifications, and
1. A variety of ion channels respond to the distortion further definition of C fiber subtypes will likely occur as
of the cell membrane, and one of them—brain more markers and neuropeptides are examined. Other
sodium channel-1 (BNC-1) or acid-sensing ion compounds commonly contained in C fiber terminals
channel-2 (ASIC-2)—is exclusively expressed in include glutamate, vasoactive intestinal peptide, and neu-
sensory afferents and might directly depolarize the ropeptide Y. The variable role of C fiber subtypes in the
nerve terminal by opening its channel when the transmission of pain is also unclear. Given that soma-
membrane is distorted (Figure 20-6).37 tostatin typically inhibits substance P release and pain
2. Mechanical distortion may result in the acute release transmission,45,46 the net transmission of nociception at
of a short-acting neurotransmitter that directly but the spinal cord level may reflect a complex interaction
transiently stimulates ion channel receptors on between excitatory and inhibitory C fiber subtypes.
nerve terminals. Although this process has not yet The peripheral afferent neurophysiology of pain
been examined in the uterine cervix, studies have during the first stage of labor suggests that the largely
observed that stretching the bladder urothelium unexplored multiple ion channels that transduce the
releases adenosine triphosphate, which directly mechanical signal of cervical stretching to an electrical
416 PART VI Labor and Vaginal Delivery
agent known to block the NaV1.8 sodium channel, example is the desensitization of VR-1 receptors present
around the peripheral nerves provides a neural blockade on the axons of C fibers. The perineural injection of drugs
twofold to fivefold longer than that provided by injection that desensitize these receptors without first stimulating
of long-acting local anesthetics.85,86 them avoids the induction of receptor-mediated acute
Another subject of current research is the extension of pain and instead produces very long periods of selective
the duration of selective antinociception with no motor sensory analgesia without motor effects.91 The mecha-
or sympathetic block by manipulation of the TRPV-1 nism by which VR-1 receptor desensitization alters the
receptor, which is a nonselective ligand-gated cation transmission of action potentials is under investigation.
channel. TRPV-1 receptors are expressed in peripheral Implications of the neurophysiology of axonal trans-
primary afferent neurons, the nociceptive C and A-delta mission of labor pain are that sodium channel subtype-
fibers, and the dorsal root ganglia, as well as the structures selective agents—or those that affect other ion channels
involving the endogenous antinociceptive descending expressed on axons—may provide safer and more selec-
pathway. TRPV-1 receptors can be activated by capsaicin, tive tools for regional analgesic techniques.
heat, and endovanilloids, leading to release of substance
P, which in turn excites inhibitory neurons in laminae I,
III, and IV. Further, activation of the TRPV-1 receptors
Spinal Cord
causes opening of the small TRPV-1 channels on the When action potentials invade the central terminals of C
neurons and allows entry of co-administered charged and A-delta fiber afferents in the spinal cord, voltage-
molecules of certain sizes. Permanently charged local gated calcium channels open and cause intracellular
anesthetic, when applied alone, would not be able to cross calcium concentration to increase; this increase triggers a
the nerve membrane to exert its effect on sodium chan- multistep process of neurotransmitter docking and fusion
nels in small sensory neurons, but when applied in the with the plasma membrane, which results in neurotrans-
presence of capsaicin or other TRPV-1 agonists, the per- mitter release.92 Inhibition of these calcium channels pro-
manently charged local anesthetic would become perme- duces analgesia. Studies in animals suggest that at least
ant to exert its local anesthetic effect. Binshtok et al.87 one agent that affects the calcium channels, gabapentin,
reported the inhibition of nociceptors by TRPV-1– produces antinociception to visceral stimulation.93
mediated entry of impermeant sodium channel blockers. A nociceptive stimulus can result in the release of
However, stimulation of TRPV-1 receptors, such as with multiple excitatory neurotransmitters, including amino
capsaicin alone, will also result in the induction of acids (glutamate, aspartate) and peptides (especially sub-
receptor-mediated acute pain. Therefore, these investiga- stance P, CGRP, and neurokinin A) that interact with
tors subsequently performed another study in rodents, specific receptors on spinal cord neurons. Although the
and they observed that the co-application of lidocaine and stimulation of neurokinin receptors is necessary for the
its quaternary permanently charged derivative QX-314 perception of moderate to severe pain,94 a complex and
produces a prolonged, predominantly nociceptor- poorly understood interplay exists among these released
selective block by allowing QX314 entry through the neurotransmitters.
TRPV-1 channels without the nocifensive behavior asso- Neurotransmitter release at sensory afferent terminals
ciated with capsaicin when lidocaine is used instead to is controlled by presynaptic receptors that act primarily
activate the TRPV-1 receptors.88 The issues of pain elic- by altering the flux of intracellular calcium when an
ited with administration of TRPV-1 agonists such as action potential arrives. Some of these neurotransmitters
capsaicin and, more importantly, the neurotoxicity of per- are excitatory; for example, the action of acetylcholine
manently charged Na+ channel blockers remain to be on nicotinic acetylcholine receptors amplifies further
overcome and require further research. Additional inves- neurotransmitter release.95 Gamma-aminobutyric acid
tigations of the exploitation of new targets may allow (GABA) is the key endogenous inhibitory neurotransmit-
provision of safer and prolonged selective antinocicep- ter in the nervous system, and stimulation of GABA
tion. Should future research prove the absence of toxicity, receptors significantly reduces the afferent terminal
it is conceivable that amitriptyline or other agents that release of other neurotransmitters.96 Multiple compounds
interact with Na+ channel subtypes and/or TPRV-1 produce analgesia by enhancing the release of GABA at
receptors could be considered for single-injection tech- afferent terminals in the spinal cord. The existence of
niques to produce prolonged and selective analgesia for excitatory and inhibitory systems can make the response
labor pain and postoperative pain relief. to a neurotransmitter or an exogenously-administered
Interactions within the large number of ion channels agent (such as a local anesthetic drug given intrathecally)
expressed on axons can alter neural conduction. An difficult to predict. For example, acetylcholine can
example is the transient refractory period caused by the enhance or reduce the afferent terminal release of neu-
membrane hyperpolarization that follows a short burst of rotransmitters by actions on nicotinic and muscarinic
nerve firing. This phenomenon results from the activa- receptors, respectively.97,98 The net effect of acetylcholine
tion of the Na+/K+ exchange pump and dampens high- appears to be inhibitory, which is indicated by the anal-
frequency nerve activity. The Na+/K+ exchange pump gesic effect of intrathecal administration of the cholines-
activity, in turn, can be reduced by a hyperpolarization- terase inhibitor neostigmine.99
induced current termed Ih. Drugs that block the Ih current The primary mechanism of action of the neurotrans-
enhance the hyperpolarization caused by the Na+/K+ mitter enkephalin, which is released by spinal cord inter-
exchange pump and ultimately serve to reduce nerve neurons, and of norepinephrine, which is released by
traffic89 and provide prolonged analgesia.90 A second axons descending from pontine centers, is the inhibition
20 The Pain of Childbirth and Its Effect on the Mother and the Fetus 419
Labor pain, anxiety, and emotional stress increase cohort study of 1288 parturients delivering either by
gastrin release and inhibit the segmental and supraseg- cesarean or vaginal delivery, Eisenach et al.140 tested
mental reflexes of gastrointestinal and urinary motility. whether the mode of delivery had an independent role in
This in turn results in an increase in gastric acidity and persistent pain and depression at 8 weeks postpartum.
volume and a delay in bladder emptying.132 These changes The impact of mode of delivery on acute postpartum
are further aggravated by the recumbent position, opioids, pain, persistent pain, depressive symptoms, and their
and other depressant medications (e.g., barbiturates), interrelationships was assessed using regression analysis
putting laboring parturients at risk for pulmonary aspira- and propensity adjustment. They reported a 10.9% prev-
tion of gastric contents, especially during emergency alence of severe acute pain within 36 hours postpartum,
induction of general anesthesia for cesarean delivery. whereas the prevalence of persistent pain and depression
In summary, pain-induced activation of the sympa- at 8 weeks postpartum was 9.8% and 11.2%, respectively.
thetic nervous system during labor is associated with car- The severity of acute postpartum pain, but not the mode
diovascular, respiratory, and gastrointestinal effects that of delivery, was independently related to risk for persis-
may alter maternal and fetal well-being. The provision of tent pain and depression at 8 weeks postpartum, both of
effective neuraxial analgesia may mitigate many of these which also resulted in negative effects on activities of
cardiopulmonary effects. daily living and on sleep. Those women with severe acute
postpartum pain had a 2.5- and 3.0-fold increased risk for
persistent pain and depression, respectively, when com-
Psychological Effects pared with those with mild acute postpartum pain. These
The meaning of labor pain is greatly influenced by psy- findings suggest these morbidities may not be related to
chosocial and environmental factors (as previously dis- degrees of physical tissue trauma but rather may be
cussed) and varies considerably among women. Although related to an individual’s pain response to that injury.
the acceptance of labor analgesia has a minor overall Although there is significant interindividual variability
effect on maternal satisfaction with the labor and delivery with regard to acute postpartum pain,141 the severity of
process,133 individual women can be profoundly influ- acute postoperative pain in nonobstetric surgical patients
enced. It has been suggested that women who understand has been correlated with the occurrence of chronic
the origin of their pain and view the labor and delivery pain.142 Whether the presence and severity of labor pain
process as positive and nonthreatening may undergo pain or the presence and severity of acute postpartum pain
without suffering.19 Billewicz-Driemel and Milne134 after either vaginal or cesarean delivery predicts the
reported that a small proportion (< 5%) of women who occurrence of chronic pain is under investigation. Studies
requested and received epidural labor analgesia described in animals suggest that acute intervention at the time of
a sense of deprivation from having missed the natural tissue injury reduces the likelihood of developing chronic
labor experience in its entirety; some of these women pain.143 It is likely that severity of the acute pain is not
may subsequently seek psychiatric counseling.135 just a marker of chronic pain but rather an active partici-
By contrast, unrelieved severe labor pain can have patory component in the pathophysiology of transition-
psychological and physical consequences, including ing from acute to chronic pain.140 Therefore, more careful
depression and negative thoughts about sexual relation- attention to pain treatment and follow-up in days after
ships.6,10 In a 5-year study in Sweden, 43 women requested childbirth may potentially reduce long-term morbidities
elective cesarean delivery owing to a fear of labor and and improve overall outcomes.
vaginal delivery.136 Some countries (e.g., Brazil) have an Reports on the incidence of chronic pain after delivery
extremely high elective cesarean delivery rate (> 80%) vary widely in part because of the difference in the defini-
among upper-class women because of their concerns tion and the inclusion or exclusion of types of chronic
about reduced sexual function after vaginal delivery. pain and not critically separating new pain after delivery
Frank psychotic reactions resembling post-traumatic from preexisting pain. Long-term follow up of postpar-
stress disorder can occur after childbirth, although the tum patients showed that the incidence of chronic pain
incidence is rare (< 1%).137 (defined as new pain that began at the time of labor and
Psychological effects of labor pain can occur in a small delivery) at 6 months and 1 year was remarkably low at
proportion of women. Psychological harm can be expe- 3% and 0.1%, respectively, compared with nonobstetric
rienced through the provision or withholding of labor surgeries with similar tissue injury.144 By using a sciatic
analgesia, underscoring the tremendous variability in the nerve injury–induced neuropathic pain model in rats, it
meaning of labor pain for different women. has been observed that the birthing process plus the
nursing of the pups in combination, but not individually,
may be protective of the development of surgical nerve
Pain after Delivery injury–induced hypersensitivity to pain. This protection
Many women undergo delivery without negative sequelae, is likely mediated by spinal oxytocin because the protec-
but some may experience significant persistent postpar- tive effect is abolished by administration of spinal atosi-
tum pain and even depression. Studies of acute and ban, an oxytocin antagonist.145
chronic postpartum pain have shown a 7% incidence of Further research is needed to better define protective
perineal pain at 8 weeks after vaginal delivery138 and a and/or predictive factors in patients who are at risk for
43% incidence of hyperalgesia at 48 hours and a 23% developing severe acute and/or chronic postpartum pain.
incidence of residual pain at 6 months after cesarean Persistent or chronic pain may be particularly difficult for
delivery.139 In a multicenter, prospective, longitudinal postpartum patients owing to the multiple stresses (e.g.,
20 The Pain of Childbirth and Its Effect on the Mother and the Fetus 423
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longed analgesia. Anesth Analg 1989; 69:122-5. 102. Headley PM, Grillner S. Excitatory amino acids and synaptic
79. Goldin AL, Barchi RL, Caldwell JH, et al. Nomenclature of transmission: the evidence for a physiological function. Trends
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80. Renganathan M, Cummins TR, Waxman SG. Nitric oxide blocks 103. Karpinski N, Dunn J, Hansen L, Masliah E. Subpial vacuolar
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104. Wilder-Smith CH, Knöpfli R, Wilder-Smith OHG. Perioperative 127. Hood DD, Dewan DM, James FM. Maternal and fetal effects of
magnesium infusion and postoperative pain. Acta Anaesthesiol epinephrine in gravid ewes. Anesthesiology 1986; 64:610-13.
Scand 1997; 41:1023-7. 128. Shnider SM, Abboud TK, Artal R, et al. Maternal catecholamines
105. Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase- decrease during labor after lumbar epidural anesthesia. Am J
prostanoid cascade in nociceptive processing. Annu Rev Pharma- Obstet Gynecol 1983; 147:13-15.
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106. Roza C, Laird JM, Cervero F. Spinal mechanisms underlying with intrathecal fentanyl decreases maternal stress. Can J Anaesth
persistent pain and referred hyperalgesia in rats with an experi- 1997; 44:605-19.
mental ureteric stone. J Neurophysiol 1998; 79:1603-12. 130. Jouppila R, Puolakka J, Kauppila A, Vuori J. Maternal and umbili-
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C H A P T E R 2 1
CHAPTER OUTLINE
Pregnant women and their support person(s) obtain Investigators have used sophisticated questionnaires2,3
information about childbirth and analgesia from many and visual analog scales4 to evaluate the maternal percep-
sources. The more traditional sources of information tion of pain during parturition. Melzack et al.5,6 devel-
include obstetricians, childbirth preparation classes, lay oped the McGill Pain Questionnaire to measure the
periodicals, books and pamphlets, and experiences of intensity of labor pain for various conditions. They noted
family and friends. Currently, the Internet has become that labor pain is one of the most intense types of pain
the primary source of information for many patients. among those studied (see Figure 20-2). Parous women
Many health care organizations provide patient access to had lower pain scores than nulliparous women, but
community health libraries on site that include Internet responses varied widely (Figures 21-1 and 21-2). Pre-
access and librarian support to facilitate information pared childbirth training resulted in a modest decrease in
searches. Anesthesia providers should be familiar with the the average pain score among nulliparous women, but it
information that patients in the local area are using for clearly did not eliminate pain in these women.5,6
decision-making, because this information influences
their birth experiences. Knowledge of the information
and biases held by patients helps anesthesia providers in CHILDBIRTH PREPARATION
their interactions with pregnant women.
Prepared childbirth training provides undeniable ben- History
efits to the pregnant woman and her support person.
However, prepared childbirth training should not be The history of modern childbirth preparation began in
equated with nonpharmacologic analgesia.1 Some child- the first half of the 20th century; however, it is important
birth preparation instructors discourage the use of medi- to review earlier changes in obstetric practice to under-
cations during labor and delivery, whereas others make a stand the perceived need for a new approach. Before the
nonbiased presentation of the advantages and disadvan- mid-19th century, childbirth occurred at home in the
tages of various analgesic techniques. The information company of family and friends. The specialty of obstet-
contained in this chapter provides a basis for informed rics developed in an effort to decrease maternal mortality.
discussion of pain relief options among patients, nurses, Interventions initially developed for the management of
obstetricians, and anesthesia providers. complications became accepted and practiced as routine
obstetric care. Physicians first administered anesthesia for
childbirth during this period. The 1848 meeting of the
PAIN PERCEPTION American Medical Association included reports of the use
of ether and chloroform in approximately 2000 obstetric
Anesthesia providers are indebted to John Bonica and cases.7 The combination of morphine and scopolamine
Ronald Melzack for their studies of the pain of childbirth. (i.e., twilight sleep) was introduced in the early 20th
427
428 PART VI Labor and Vaginal Delivery
62 le
31 te
1) l
51 er
2- d
(3 ve
2- ab
2- ra
)
(1 Mil
)
(2 nim
21
2- v
41
)
(4 se
(2 de
Se
(5 ler
o
M
to
ry
M
In
Ve
62 le
31 te
1) l
51 er
2- d
-1 a
(3 ve
)
2- ab
2- ra
)
(1 Mil
41
2- v
)
(4 se
(2 e
Se
)
(5 ler
od
to
ry
M
In
Ve
Pain score group childbirth in his book Birth Without Violence. He advo-
cated childbirth in a dark, quiet room; gentle massage of
FIGURE 21-2 ■ The severity of pain during labor as assessed by the newborn without routine suctioning; and a warm
the McGill Pain Questionnaire for 54 parous women. (Modified bath soon after birth. He opined that these maneuvers
from Melzack R, Taezner P, Feldman P, Kinch RA. Labour is still
painful after prepared childbirth training. Can Med Assoc J 1981;
result in a less shocking first-separation experience and
125:357-63.) a healthier, happier infancy and childhood. Although
there are few controlled studies of this method,
published observations do not support his claim of
century. These techniques were widely used, and influ- superiority.18,19
ential women demanded that they be made available Physicians were the initial advocates of the various
to all parturients.8 Together, these developments moved natural childbirth methods. Obstetricians had become
childbirth from the home and family unit to the increasingly aware that analgesic and anesthetic tech-
hospital environment.9 Despite their desire for analgesia/ niques were not harmless, and they supported the use of
21 Childbirth Preparation and Nonpharmacologic Analgesia 429
natural childbirth methods.10 Subsequently, natural child- primary—source of information for working class and
birth, like the methods of obstetric analgesia introduced indigent women.
earlier in the century, was actively promoted by lay groups
rather than physicians.20 Lay publications, national advo-
cacy groups, and formal instruction of patients accounted
Limitations
for the greater interest in psychoprophylaxis and other Limitations of the widespread application of psychopro-
techniques associated with natural childbirth. phylaxis and other childbirth preparation methods
remain. Proponents assume that these techniques are
easily used during labor and delivery; however, Copstick
Goals and Advantages et al.26 concluded that this assumption is not valid. They
The major goals of childbirth education that were ini- found that patients were able to use the coping tech-
tially promoted by Dick-Read are taught with little modi- niques in the early first stage of labor but that the suc-
fication in formal childbirth preparation classes today. cessful use of the coping skills became less and less
Most current classes credit Lamaze with the major com- common as labor progressed. By the onset of the second
ponents of childbirth preparation, even though Dick- stage, less than one third of mothers were able to use any
Read was the first to promote patient education, relaxation of the breathing or postural techniques taught during
training, breathing exercises, and paternal participation.10 their childbirth classes.26 The method of preparation
Box 21-1 describes the goals of current childbirth prepa- influences the ability of the pregnant woman to use the
ration classes. In addition, some instructors and training breathing and relaxation techniques. Bernardini et al.27
manuals claim other benefits of childbirth preparation observed that self-taught pregnant women are less likely
(Box 21-2). Reviews by Beck and Hall21 and Lindell22 to practice the techniques during the prenatal period or
concluded that much of the research on the efficacy of to use the techniques during labor.
childbirth education does not meet the fundamental Childbirth preparation classes may create false
requirements of the scientific method. Despite these expectations. If a woman does not enjoy the “normal”
shortcomings, childbirth preparation classes are widely delivery discussed during classes, she may experience a
available and attended. sense of failure or inferiority. Both Stewart28 and Guzman
Socioeconomic disparities exist in childbirth education Sanchez et al.29 have discussed the psychological reac-
class attendance.23 In addition, the effect of childbirth tions of women who were unable to use psychoprophy-
education on attitude and childbirth experience depends laxis successfully during labor and delivery. In addition,
in part on the social class to which the mother belongs. several women have written about their disappointment
Most investigators have found that childbirth classes have with the dogmatic approach of their childbirth instruc-
a positive effect on the attitudes of both parents in all tors; these women described instructors who rigidly
social classes, but this effect is more pronounced among defined the “correct” way to have a “proper” birth
“working class”24 and indigent women25; this latter finding experience.30,31
probably reflects the greater availability and use of other
educational materials by middle- and upper-class women. Effects on Labor Pain and Use
Childbirth classes often are the only—or at least the
of Analgesics
Little scientific evidence supports the efficacy of
childbirth preparation in mitigating labor pain. Psy-
BOX 21-1 Goals of Childbirth Preparation
chology, nursing, obstetric, anesthesia, and lay journals
• Patient education about pregnancy, labor, and provide extensive discussions of childbirth preparation,
delivery but most articles describe uncontrolled clinical experi-
• Relaxation training ences. Outcome studies often do not include a group of
• Instruction in breathing techniques women who were randomly assigned to an untreated or
• Participation of father/support person a placebo-control group, and statistical analysis is often
• Early parental bonding incomplete. Despite these shortcomings, supporters of
childbirth preparation assume that it offers benefits for
mother and child. Table 21-1 summarizes a few of the
studies of Lamaze and other childbirth preparation tech-
Purported Benefits of Childbirth niques and their association with labor outcomes. The
BOX 21-2 findings are not consistent. Some researchers have
Preparation
reported a decreased use of analgesics32-35 or regional anes-
• Greater maternal control and cooperation thesia,32-36 shorter labor,37 reduced performance of instru-
• Decreased maternal anxiety mental32,34,36 and cesarean delivery,36 and a lower incidence
• Reduced maternal pain of nonreassuring fetal status,36 whereas others have
• Decreased maternal need for analgesia/anesthesia reported no change in the use of analgesics36-40 or neuraxial
• Shorter labor
• Diminished maternal morbidity
analgesia,38,39 length of labor,34-36,38-41 performance of
• Less fetal stress/distress instrumental38-40 and cesarean delivery,34,38-40 or incidence
• Strengthened family relationships as a result of the of nonreassuring fetal status.33,34,37,39 These diverse find-
shared birth experience ings may reflect different patient populations, poor study
design, or researcher bias.
430 PART VI Labor and Vaginal Delivery
TABLE 21-2 Systematic Review: Continuous Labor Support versus Usual Care
Outcome No. of Trials No. of Subjects Relative Risk* 95% Confidence Interval
Use of neuraxial analgesia 9 11,444 0.93 0.88 to 0.99
Use of any analgesia 13 12,169 0.90 0.84 to 0.97
Spontaneous vaginal delivery 18 14,005 1.08 1.04 to 1.12
Instrumental vaginal delivery 18 14,004 0.84 0.84 to 0.96
Cesarean delivery 21 15,061 0.79 0.67 to 0.92
Patient dissatisfaction with 11 11,133 0.69 0.59 to 0.79
childbirth experience
Duration of labor 11 11,444 −0.58 h† −0.86 to −0.30
Infant with a low 5-minute 12 12,401 0.70 0.50 to 0.96
Apgar score
than women who were randomly assigned to receive preparation classes. These techniques include effleurage,
usual care.41 counterpressure to alleviate back discomfort, light strok-
A meta-analysis evaluated results from 21 studies that ing, and merely a reassuring pat.47 There has been
included more than 15,000 women who were randomly minimal scientific study of the effects of touch and
assigned to receive either continuous childbirth support massage on labor progress and outcome58-60; nonetheless,
or usual care (Table 21-2).56 The pooled data suggested touch and massage provide a comfort that is appreciated
that women who received one-on-one support during by women during labor. These measures may be used by
labor were less likely to use neuraxial analgesia or receive the parturient, her support person, or the professional
any type of analgesia, were more likely to have a sponta- staff members providing intrapartum care. The tech-
neous vaginal delivery, and reported less dissatisfaction niques are easily discontinued if the parturient desires. In
with the childbirth experience.56 In addition, the mean some cases, touch and massage may reduce discomfort.
duration of labor was slightly shorter (approximately More often, touch and massage transmit a sense of caring,
35 minutes) in the women who received continuous which fosters a sense of security and well-being.
support during labor. There were no differences in neo-
natal outcome.
These results are fascinating and have important
Therapeutic Use of Heat and Cold
implications for obstetric care. The patient populations Another simple technique for alleviating labor pain is the
studied represent special situations, and the results may therapeutic use of temperature (hot or cold) applied to
not be reproduced in all populations. For example, a large various regions of the body. Warm compresses may be
randomized, controlled trial in a North American hospi- placed on localized areas, or a warm blanket may cover
tal (in which intrapartum medical intervention is routine) the entire body. Alternatively, ice packs may be placed on
found no differences in the rate of cesarean delivery or the low back or perineum to decrease pain perception.
other labor outcomes between women randomly assigned The therapeutic use of heat and cold during labor has not
to receive continuous labor support from a specially been studied in a rigorously scientific manner. The use
trained nurse and women who received usual care.57 In of superficial heat and cold for comfort is widespread (if
general, results from trials in North America do not not completely understood), and it has no discernible risk
appear as striking as those from Europe or Africa.47 The to the mother or the fetus.47 Cold and heat should not be
aforementioned systematic review of continuous labor applied to anesthetized skin.
support suggested that benefits were greater when the
support person was not a member of the hospital staff.56
Further studies should compare different models of con-
Hydrotherapy
tinuous childbirth support and should include outcomes Hydrotherapy may involve a simple shower or tub bath
such as cost analysis.56 Meanwhile, the preponderance or may include the use of a whirlpool or large tub spe-
of evidence suggests that all parturients should have cially equipped for pregnant women. Purported benefits
access to emotional support, whether it is provided by of hydrotherapy include decreased anxiety and pain and
the husband, a family member, a labor companion (e.g., greater uterine contraction efficiency.47 Results of ran-
doula), or professional hospital staff. domized, controlled trials comparing water baths with
usual care are inconsistent. For example, some studies
have found no difference between groups in the use of
Touch and Massage pharmacologic analgesia,61,62 whereas others have dem-
Various touch and massage techniques are discussed with onstrated a lower use in the water bath group.63,64 A
women and their support persons during childbirth meta-analysis of eight published trials involving almost
432 PART VI Labor and Vaginal Delivery
3000 women concluded that there was a reduction in the A systematic review of studies of maternal position in
use of neuraxial analgesia in women randomly assigned the second stage of labor in women without epidural
to water immersion compared with control subjects (odds analgesia concluded that currently published trials are
ratio [OR], 0.84; 95% confidence interval [CI], 0.71 to generally of poor quality.78 Tentative results suggest that
0.99).65 There were no differences in the rate of operative less severe pain and a lower rate of perineal trauma may
delivery or neonatal outcome, including infection. In be associated with giving birth in the upright position;
summary, bathing, showering, and other hydrotherapy however, blood loss may be greater. Although the inves-
maneuvers are comfort measures with little risk to the tigators concluded that further study is required, many
mother and the infant, provided that appropriate moni- obstetricians and nurses believe that ambulation and the
toring continues during the immersion in water that is upright posture result in a shorter labor that requires less
kept at body temperature. analgesia. An alternative explanation for the observation
that ambulatory parturients appear to have a less painful
and shorter labor is that shorter, less painful labor allows
Vertical Position continued ambulation.
Several investigators have studied the effects of various Other than the possibility of greater blood loss associ-
positions on pain perception and labor outcome. These ated with the upright position during delivery, upright
positions are broadly categorized as vertical (e.g., sitting, positions during most of labor are not associated with any
standing, walking, squatting) or horizontal (e.g., supine, harm to the mother or newborn and may aid maternal
lateral). A systematic review summarized the results from comfort. It is unclear whether birthing cushions or stools
13 controlled trials of maternal posture during the first confer any benefit to the mother or the newborn.
stage of labor.66 In 7 trials in which women served as their
own controls, women reported less pain in the standing
and sitting positions than in the supine position. Six
Biofeedback
other trials randomly assigned women to either an exper- Biofeedback is a relaxation method that is used as an
imental group who were encouraged to remain upright adjunct to the relaxation training taught in Lamaze
or a control group who remained supine or on their classes and other childbirth education programs. Two
side. Women in the upright groups experienced less biofeedback procedures may be applicable to the laboring
pain or no difference in pain when compared with the woman: skin-conductance (autonomic) and electromyo-
recumbent groups. A recent Cochrane review of 21 graphic (voluntary muscle) relaxation. St. James-Roberts
studies also found that walking and the upright position et al.79 demonstrated that electromyographic but not
are associated with shorter labor without the need for skin-conductance biofeedback techniques could be taught
interventions.67 effectively in Lamaze classes. They noted no difference
Ambulation in the presence of neuraxial analgesia does in length of the first stage of labor, use of epidural anal-
not appear to influence the outcome of labor.68-70 In a gesia, incidence of instrumental delivery, or Apgar scores
prospective, randomized study, Bloom et al.68 noted that among electromyographic, skin-conductance, and control
walking did not shorten the duration of the first stage of groups. In a small study, Duchene80 reported reduced
labor or reduce the requirement for oxytocin augmenta- pain perception during labor and delivery and a lower
tion, the use of analgesia, or the requirement for opera- rate of epidural analgesia use (40% versus 70% for a
tive delivery. They concluded that “walking neither control group) with electromyographic biofeedback;
enhanced nor impaired active labor and was not harmful there was no difference between groups in Apgar scores.
to the mothers or their infants.”68 A recent Cochrane review assessing the effectiveness of
A number of studies have assessed maternal position biofeedback found that most studies had a high risk for
during the second stage of labor. There is renewed inter- bias, and although some studies demonstrated reduced
est in the squatting or modified squatting position and its use of analgesics with biofeedback there was insufficient
greater comfort for some women during childbirth. Most evidence to conclude that biofeedback is efficacious.81
authorities have noted that Western women have insuf- Biofeedback training does not appear to confer substan-
ficient muscular strength and stamina to maintain an tial benefit beyond that of traditional relaxation training
unsupported squatting position for any length of time.71-73 taught in childbirth education classes.
Squatting does not appear to alter pelvic dimensions.74
Gardosi et al.71 designed and studied a birth cushion that
allows a modified, supported squat, which resulted in a
Intradermal Water Injections
higher incidence of spontaneous vaginal delivery and a Intradermal or intracutaneous water injections are used
lower incidence of perineal tears. Others have yet to to treat lower back pain, which is a common complaint
substantiate the results of this trial. during labor. The afferent nerve fibers that innervate the
Some studies have evaluated the use of a birth chair to uterus and cervix, as well as the nerve fibers that innervate
facilitate delivery in the sitting position.75-77 These studies the lower back, all enter the spinal cord at the T10
noted no difference in length of the second stage of labor, through L1 spinal segments; therefore, a component of
mode of delivery, occurrence of perineal trauma, or Apgar the pain may be referred pain. The technique consists of
scores in parturients who used a birth chair compared injecting 0.05 to 0.1 mL of sterile water, with an insulin
with those who did not. Of concern, two studies reported or tuberculin syringe, at four sites on the lower back (i.e.,
greater intrapartum blood loss and a higher incidence of over each posterior superior iliac spine, and at 1 cm
postpartum hemorrhage in the birth-chair group.76,77 medial and 3 cm caudad to the posterior superior iliac
21 Childbirth Preparation and Nonpharmacologic Analgesia 433
Acupuncture/Acupressure
Traditional Chinese medicine includes extensive use of
acupuncture. Given that acupuncture can provide anal-
gesia, there is interest in its use for intrapartum analgesia,
although this is not a traditional use of the method. Early
observational reports described conflicting results as to
the efficacy of intrapartum acupuncture. Given the his-
toric lack of use of acupuncture in obstetric patients,
there is a lack of standardization of the acupuncture
points to be stimulated.
FIGURE 21-3 ■ Placement of intradermal water blocks (x).
Approximately 0.05 to 0.1 mL of sterile water is injected intra- Several randomized, controlled trials have compared
dermally to form a small bleb over each posterior superior iliac “real” acupuncture to “false” or “minimal” acupuncture
spine and at 3 cm below and 1 cm medial to each spine on both using shallow insertion of needles in non-acupuncture
sides of the back (i.e., for a total of four injections). The exact points,85,86 whereas other investigators have used a control
locations of the injections do not appear to be critical to the
block success. (From Simkin P. Update on nonpharmacologic
group that did not receive acupuncture.87,88 Four ran-
approaches to relieve labor pain and prevent suffering. J Midwifery domized trials found that pain scores were lower in
Womens Health 2004; 49:489-504.) women randomly assigned to receive acupuncture treat-
ment, as was the rate of use of other modes of analgesia
(e.g., epidural and systemic meperidine).85-88 These results
suggest that acupuncture may hold promise for the treat-
spine on both sides of the back, for a total of four injec- ment of labor pain.85-88 Hantoushzadeh et al.86 also
tions) (Figure 21-3). The injections themselves are observed a shorter duration of the active phase of labor
acutely painful for 20 to 30 seconds, but as the injection and a reduction in use of oxytocin in the acupuncture
pain fades, so does lower back pain. group. No adverse maternal or fetal effects were identi-
Systematic reviews have summarized the four random- fied. Other randomized studies did not find reduced pain
ized controlled trials that compared intradermal water scores with acupuncture.89,90
injections with placebo or standard care.48,66 The results A randomized, controlled trial of acupressure (treat-
of these trials suggested that the intradermal injections ment) compared with touch (control) at the SP6 acupoint
are a simple method of reducing severe low back pain found lower pain scores and a shorter duration of labor
during labor without adverse effects on the mother and in the acupressure group.91 A meta-analysis of 13 acu-
fetus. The analgesic effect appears to last for 45 to 120 puncture trials including 1986 women concluded that
minutes47 but did reduce the rate of use of other analgesic acupuncture may hold promise for labor analgesia;
techniques.48,66 However, a recent Cochrane review however, larger studies are required for definitive conclu-
assessing the effectiveness of water injections during sions.92 All of the randomized, controlled acupuncture
labor did not find evidence that it reduced back pain or studies were performed outside the United States, in
labor pain.82 countries (primarily Scandinavian) in which the use of
neuraxial labor analgesia is less widespread than in the
Transcutaneous Electrical United States. Also, the use of acupuncture requires
trained personnel. (Scandinavian midwives have been
Nerve Stimulation trained to administer acupuncture.) For these reasons it
Transcutaneous electrical nerve stimulation (TENS) is unlikely that either acupuncture or acupressure will
involves the transmission of low-voltage electrical current gain widespread acceptance in the United States for
to the skin via surface electrodes. Advantages of TENS intrapartum analgesia.
are that it is easy to use and discontinue, is noninvasive,
and has no demonstrable harmful effects on the fetus.
The only stated disadvantage is the occasional interfer-
Hypnosis
ence with electronic fetal heart rate monitoring. It is most The use of hypnosis for obstetric analgesia is not new.93
widely used for childbirth in Scandinavia and the United Early proponents touted safety for the mother and the
Kingdom.47 Chao et al.83 evaluated the use of TENS at fetus, lower analgesic requirements, and shorter labor as
specific acupuncture points and observed a reduction in the major advantages of intrapartum hypnosis. Whether
pain perception more commonly in the study group than hypnosis differs substantially from other childbirth prep-
in the control group. However, a systematic review of aration techniques is an unresolved controversy. Fee and
nine trials in more than 1000 women concluded that Reilley94 concluded that the breathing and relaxation
TENS did not reduce labor pain and did not reduce the exercises used in childbirth preparation do not represent
use of additional analgesic agents.84 There also was no a hypnotic trance; support for their conclusion is pro-
effect on the duration of labor or the incidence of vided by the successful teaching of childbirth preparation
434 PART VI Labor and Vaginal Delivery
exercises to women who are not susceptible to hypnosis. more family-centered maternity care. Women currently
However, women susceptible to hypnosis may achieve a view childbirth from the perspective of educated consum-
state much like a hypnotic trance when using the same ers; they expect to have choices and a level of control
exercises. during childbirth. We may not always be comfortable
Instruction in the techniques of self-hypnosis occurs with this situation, but it is a reality for modern obstetric
before the onset of labor and may entail visits to the practice. Our challenge is to provide safe, effective anal-
hypnotist or involvement in a childbirth education gesia in a nonthreatening, “homelike” environment. We
program such as HypnoBirthing. Proponents previously are not solely responsible for a patient’s childbirth experi-
suggested that successful hypnosis training should begin ence, but our interactions with the patient, her family,
early in the third trimester. Rock et al.95 found that hyp- and her obstetrician will influence her perception of
nosis could be introduced to untrained, nonvolunteer childbirth.
patients during labor. On average, this maneuver added Anesthesia providers must become effective educators
approximately 45 minutes of care; however, all but 3 as well as health care providers. Patients should have
of 22 patients in the experimental group required addi- realistic expectations about the pain of labor and the
tional analgesia. Some studies found that hypnosis did variability of individual labor patterns. They should be
not decrease analgesic requirements,96 but a recent review encouraged to define “success” as a positive childbirth
of 13 separate studies noted that hypnosis resulted in experience regardless of the mode of delivery, use of
lower analgesic requirements and a shorter duration of analgesia and anesthesia, or other arbitrary definitions.
the first stage of labor. The authors do not believe their An obstetrician advised prospective mothers100:
findings are conclusive since most studies were not
randomized.97 If you do end up choosing some form of pain relief during
Childbirth preparation and hypnosis seem to have labor, do not feel inadequate if a friend had her baby
similar effects on obstetric outcome. Harmon et al.98 without assistance. Some labors are more intense than
combined hypnosis and skill mastery with childbirth edu- others. Ultimately, holding your baby in your arms is
cation. Experimental patients with a high susceptibility more important than the method you used to bring her
to hypnosis demonstrated less use of opioid, tranquilizer, into the world.
and oxytocic medications; shorter first and second stages
of labor; and a higher incidence of spontaneous vaginal Anesthesia providers may effectively provide similar
delivery. Patients with a low susceptibility to hypnosis did advice. Unfortunately, anesthesia providers usually have
not gain substantial advantage from the addition of hyp- little involvement in prenatal education classes. Our
nosis to the routine childbirth education provided for the active participation in childbirth education classes may
control group. help patients receive more accurate information about
In summary, hypnosis has at least the following three the risks and benefits of analgesia/anesthesia for labor,
limitations: (1) antepartum training sessions are required, vaginal delivery, and cesarean delivery. Anesthesia pro-
(2) trained hypnotherapists must be available during viders can encourage childbirth instructors to prepare
labor, and (3) it offers no clear benefit. Therefore, hyp- patients for the unexpected and to acknowledge that the
nosis is unlikely to attain widespread use during commonly described “typical” labor may, in fact, be atyp-
childbirth. ical. Well-informed patients are more likely to accept the
interventions that may become necessary during labor.
Women with medical or obstetric diseases that may
IMPLICATIONS FOR ANESTHESIA increase anesthetic risk should be encouraged to discuss
PROVIDERS these problems with an anesthesia provider before the
onset of labor; thus, we must develop procedures to facili-
Childbirth preparation classes and nonpharmacologic tate antepartum consultation. Beilin et al.101 found in a
analgesic techniques are not comparable to neuraxial survey study that most women would prefer a pre-labor
analgesia/anesthesia for the relief of labor pain. Thus, visit with their anesthesiologist. In summary, the active
some might wonder whether it is important or useful for participation of the anesthesia provider in childbirth edu-
anesthesia providers to have knowledge of these tech- cation will lead women to perceive the anesthesia pro-
niques. If our only obligation to the obstetric patient is a vider as an integral part of the obstetric care team.
technical one (i.e., to eliminate pain safely with the use Some nonpharmacologic analgesic techniques may
of neuraxial analgesia), knowledge of these techniques is have benefits other than decreased pain perception. For
perhaps superfluous. However, the practice of obstetric example, some obstetricians and nurses believe that
anesthesia should not be limited to the performance of ambulation and subsequent squatting (or use of a birth
pain-relieving procedures; our contributions to the care cushion) shortens labor and increases the rate of sponta-
of the obstetric patient and her family should extend neous vaginal delivery. Even if this belief proves not to
beyond the administration of neuraxial analgesia. be true, many women prefer to be mobile during labor
Much has been written in professional and lay journals and, at a minimum, to retain the ability to walk to the
concerning the “proper” childbirth experience. Each bathroom. We should attempt to develop and use anal-
patient’s expectations of labor influence her childbirth gesic techniques that take advantage of these relatively
experience. Yarrow99 described the results of a nonscien- simple maneuvers. For example, the use of intrathecal
tific poll of 72,000 readers of Parents Magazine, which opioids during early labor allows for continued ambula-
revealed that there is an undeniable movement toward tion and the use of showers and/or tubs. Some techniques
21 Childbirth Preparation and Nonpharmacologic Analgesia 435
of epidural analgesia allow sitting with support. Finally, 9. Devitt N. The transition from home to hospital birth in the
epidural analgesia/anesthesia does not eliminate the ben- United States, 1930-1960. Birth Fam J 1977; 4:47-58.
10. Beck NC, Geden EA, Brouder GT. Preparation for labor: a his-
eficial effects of other comfort measures, such as massage, torical perspective. Psychosom Med 1979; 41:243-58.
and continued emotional support from family and friends. 11. Dick-Read G. Childbirth Without Fear: The Principles and Prac-
Whenever possible, anesthesia providers should tice of Natural Childbirth. New York, Harper & Brothers, 1944.
provide safe anesthetic care that is compatible with rea- 12. Dick-Reed G. Natural Childbirth. London, Heinemann, 1933.
13. Lamaze F. Painless Childbirth: Psychoprophylactic Method.
sonable patient expectations. Future studies on the effi- London, Burke, 1958.
cacy of childbirth education, nonpharmacologic analgesic 14. Velvovsky I, Platonov K, Ploticher V, Shugom E. Painless Child-
techniques, and neuraxial analgesic techniques should birth Through Psychoprophylaxis: Lectures for Obstetricians.
evaluate the patient’s overall experience and satisfaction London, Foreign Languages Publishing House, 1960.
rather than limit assessment to the usual measures of 15. Karmel M. Thank You, Dr. Lamaze: A Mother’s Experiences in
Painless Childbirth. New York, Lippincott, 1959.
obstetric outcome.102 In an editorial that accompanied 16. Karmel M. Thank You, Dr. Lamaze: A Mother’s Experiences in
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on the behavioral state of newborn infants during the first hour
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of consumerism in pain control during the birth process. Am J
• Childbirth preparation does not eliminate the Obstet Gynecol 1992; 167:581-7.
pain of labor or substantially reduce the use of 21. Beck NC, Hall D. Natural childbirth: a review and analysis.
Obstet Gynecol 1978; 52:371-9.
analgesia/anesthesia, but it does decrease the 22. Lindell SG. Education for childbirth: a time for change. J Obstet
anxiety associated with labor. Gynecol Neonatal Nurs 1988; 17:108-12.
• Emotional support provided by doulas reduces 23. Lu MC, Prentice J, Yu SM, et al. Childbirth education classes:
the use of analgesics, the length of labor, and sociodemographic disparities in attendance and the association of
attendance with breastfeeding initiation. Matern Child Health J
the incidence of operative deliveries in selected 2003; 7:87-93.
patient populations. 24. Nelson MK. The effect of childbirth preparation on women of
• Biofeedback, transcutaneous electrical nerve different social classes. J Health Soc Behav 1982; 23:339-52.
25. Zacharias JF. Childbirth education classes: effects on attitudes
stimulation, acupuncture, and hypnosis may toward childbirth in high-risk indigent women. JOGN Nurs
provide mild to moderate analgesic benefits for 1981; 10:265-7.
some patients. 26. Copstick S, Hayes RW, Taylor KE, Morris NF. A test of a common
• Intradermal water injections may provide assumption regarding the use of antenatal training during labour.
J Psychosom Res 1985; 29:215-8.
effective treatment of low back pain during labor. 27. Bernardini JY, Maloni JA, Stegman CE. Neuromuscular control
• Anesthesia providers should become active of childbirth-prepared women during the first stage of labor.
participants in childbirth education. We should JOGN Nurs 1983; 12:105-11.
28. Stewart DE. Psychiatric symptoms following attempted natural
encourage and facilitate the honest discussion of childbirth. Can Med Assoc J 1982; 127:713-6.
the risks and benefits of the analgesic/anesthetic 29. Guzman Sanchez A, Segura Ortega L, Panduro Baron JG.
techniques available at our hospitals. Psychological reaction due to failure using the Lamaze method.
• No nonpharmacologic technique consistently Int J Gynaecol Obstet 1985; 23:343-6.
30. Behan M. Childbirth machismo. Parenting April 1988: 53-57.
provides the quality of intrapartum pain relief that 31. Crittendon D. Knock me out with a truck. Wall Street Journal
is provided by neuraxial analgesia. November 6, 1992; A14.
32. Hetherington SE. A controlled study of the effect of prepared
childbirth classes on obstetric outcomes. Birth 1990; 17:86-90.
33. Rogers CH. Type of medications used in labor by Lamaze and
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C H A P T E R 2 2
CHAPTER OUTLINE
PATIENT-CONTROLLED ANALGESIA
Meperidine
Morphine and Diamorphine
Systemic drugs have been used to decrease the pain of (e.g., coagulopathy) or presents technical challenges
childbirth since 1847, when James Young Simpson used (e.g., severe scoliosis, the presence of spinal hardware).
diethyl ether to anesthetize a parturient with a deformed
pelvis. Since that time, the provision of labor analgesia has
advanced significantly owing to a heightened awareness of PARENTERAL OPIOID ANALGESIA
the neonatal effects of heavy sedation or general anesthe-
sia administered during vaginal delivery and a greater Opioids are the most widely used systemic medications
desire of women to actively participate in childbirth. for labor analgesia. These compounds are agonists at
Neuraxial (i.e., epidural, spinal, combined spinal- opioid receptors (Table 22-2). Their popularity lies in
epidural [CSE]) analgesic techniques have replaced sys- their low cost, ease of use, and the lack of need for spe-
temic drug administration as the preferred method cialized equipment and personnel. Although these drugs
for intrapartum analgesia in both the United States provide moderate pain relief, parturients commonly
and Canada (Table 22-1).1,2 By contrast, in the United report dissociation from the reality of pain rather than
Kingdom, fewer than one third of parturients received a complete analgesia. Since neuraxial labor analgesia has
neuraxial analgesic technique during labor and vaginal become more accessible, systemic opioids have become
delivery in 2011.3 less popular, owing to the frequency of maternal side
Despite the increased use of neuraxial analgesia for effects (e.g., nausea, vomiting, delayed gastric emptying,
labor, the use of systemic analgesia remains a common dysphoria, drowsiness, hypoventilation) and the potential
practice in many institutions worldwide for several for adverse neonatal effects. However, a renewed interest
reasons. Many women labor and deliver in an environ- in opioid administration during labor has occurred owing
ment where the provision of safe neuraxial analgesia to the growing use of patient-controlled delivery systems.
is not available. Some parturients decline neuraxial Although systemic opioids have long been used for
analgesia or choose to receive systemic analgesia during labor analgesia, there is little scientific evidence to suggest
early labor. Finally, some women may have a medical that one drug is superior to another; most often, drug
condition that contraindicates a neuraxial procedure selection is based on local policy or personal preference
438
22 Systemic Analgesia: Parenteral and Inhalational Agents 439
TABLE 22-1 Types of Labor Analgesia at Hospitals Providing Obstetric Care by Number of Births
Stratum 1 Stratum 2 Stratum 3
(≥1500 births) (500-1500 births) (100-500 births)
Labor Analgesia 1981 1992 2001 1981 1992 2001 1981 1992 2001
None 27 11 6 33 14 10 45 33 12
Parenteral 52 48 34 53 60 42 37 48 37
Epidural 22 51 61 13 33 42 9 17 35
(Table 22-3). The efficacy of systemic opioid analgesia changes. Opioids may also affect the fetus in utero. The
and the incidence of side effects are largely dose depen- fetus and neonate are particularly susceptible to opioid-
dent rather than drug dependent. induced side effects for several reasons. The metabolism
As a result of their high lipid solubility and low molec- and elimination of these drugs are prolonged compared
ular weight (< 500 Da), all opioids readily cross the pla- with adults, and the blood-brain barrier is less well devel-
centa by diffusion and are associated with the risks of oped, allowing for greater central effects. Opioids may
neonatal respiratory depression and neurobehavioral result in decreased variability of the fetal heart rate
440 PART VI Labor and Vaginal Delivery
(FHR), although this change usually does not reflect a respiratory depressant. Normeperidine also crosses the
worsening of fetal oxygenation or acid-base status. The placenta and is largely responsible for the neonatal side
likelihood of neonatal respiratory depression depends on effects encountered with meperidine use.7
the dose and timing of opioid administration. Even in the Maternal administration of meperidine may reduce
absence of obvious neonatal depression at birth, there fetal aortic blood flow, fetal muscle activity, and FHR
may be subtle changes in neonatal behavior for several variability.7 Sosa et al.8 demonstrated that intravenous
days. Reynolds et al.4 performed a meta-analysis of meperidine 100 mg, given during the first stage of
studies that compared epidural analgesia with systemic labor, resulted in an increased incidence of umbilical
opioid analgesia using meperidine, butorphanol, or fen- cord arterial blood acidemia at delivery when compared
tanyl. The authors concluded that lumbar epidural anal- with a placebo. Normeperidine may result in neonatal
gesia was associated with improved neonatal acid-base respiratory depression. After maternal intramuscular
status at delivery. Similarly, in a multicenter randomized administration of meperidine, the greatest risk for
trial, Halpern et al.5 compared patient-controlled epidu- neonatal respiratory depression occurs if meperidine is
ral analgesia using a local anesthetic combined with an given to the mother 3 to 5 hours before delivery, whereas
opioid to patient-controlled analgesia (PCA) using a par- the risk is least if it is given within 1 hour before delivery.7
enteral opioid; the investigators demonstrated an Normeperidine accumulation is associated with altered
increased need for active neonatal resuscitation in the neonatal behavior, manifesting as reduced duration
parenteral opioid group (52% versus 31%). of wakefulness and attentiveness and impaired breast-
Opioids may be administered as intermittent bolus feeding.9 Meperidine administration is associated with
doses or by PCA. Bolus doses are used more commonly, lower Apgar scores and muscle tone in the neonate.
but the newer synthetic opioids are increasingly used Maternal side effects are of less clinical concern, although
with patient-controlled devices. Because the mode of there is a high incidence of nausea, vomiting, and
delivery influences a drug’s pharmacologic profile, the dysphoria.
opioids will be discussed by route of administration. The maternal half-life of meperidine is 2.5 to 3 hours,
whereas that of normeperidine is 14 to 21 hours.10 The
half-life of both compounds is increased by up to three
times in the neonate as a result of reduced clearance.10
INTERMITTENT BOLUS PARENTERAL Consequently, the adverse effects may be seen in the
OPIOID ANALGESIA neonate up to 72 hours after delivery. The action of
meperidine is reversed by naloxone; however, the action
Opioids may be given intermittently by subcutaneous, of normeperidine is not. This is important because antag-
intramuscular, or intravenous injection. The route and onism with naloxone may exacerbate normeperidine-
timing of administration influence maternal uptake and induced seizures owing to suppression of the anticonvulsant
placental transfer to the fetus. Subcutaneous and intra- effect of meperidine.
muscular routes have the advantage of ease of administra- The quality of labor analgesia with meperidine has
tion but are painful. Absorption varies with the site of been questioned, with some reports indicating that less
injection and depends on local and regional blood flow; than 20% of laboring women obtain satisfactory pain
consequently, the onset, quality, and duration of analgesia relief with its use. The analgesic benefit of intravenous
are highly variable. meperidine 50 mg has been observed to be comparable
Intravenous administration offers several advantages. with that of intravenous acetaminophen 1000 mg, but
The onset of analgesia is faster, and the timing and mag- with a greater incidence of adverse effects (64% versus
nitude of the peak plasma concentration of drug are more none).11
predictable. It is also possible to titrate dose to effect. For A randomized, double blind, placebo-controlled trial
these reasons the intravenous route is generally preferred of intramuscular meperidine 100 mg versus 0.9% normal
when available. saline for labor analgesia was terminated after an interim
analysis of 50 patients, which revealed a significantly
greater reduction in pain scores with meperidine.12
Meperidine However, the analgesic effect of meperidine was modest,
In 1947, meperidine (pethidine) became the first syn- with a median change in visual analog pain scores (VAPS)
thetic opioid to be used for intrapartum analgesia. More of 11 mm at 30 minutes; 68% of women required addi-
extensively studied than newer drugs, meperidine is the tional analgesia during labor.
most common opioid given for labor analgesia in the The effect of meperidine on the progress of labor is
United Kingdom.6 The usual dose is 50 to 100 mg intra- unclear. Historically, meperidine has been given to
muscularly, which can be repeated every 4 hours. The decrease the length of the first stage of labor in cases of
onset of analgesia occurs in 10 to 15 minutes, but 45 dystocia; however, recent studies have not demonstrated
minutes may be required to reach peak effect. The dura- such an effect, and investigators have concluded that
tion of action is typically 2 to 3 hours. meperidine should not be given for this purpose.8
Meperidine is highly lipid soluble, readily crosses the Despite the concerns just highlighted, meperidine
placenta, and equilibrates between the maternal and continues to be the most common opioid given for
fetal compartments within 6 minutes. Meperidine is labor analgesia worldwide; this is most likely the result of
metabolized in the liver to produce normeperidine, a its familiarity, ease of administration, availability, and
pharmacologically active metabolite that is a potent low cost.
22 Systemic Analgesia: Parenteral and Inhalational Agents 441
represents only 20% of that occurring by redistribution, associated with less nausea and vomiting but more mater-
resulting in a rapid increase in context sensitive half-life nal sedation. Analgesia was comparable between the
with an increased duration of infusion.10 Fentanyl has a groups. Neonatal neurobehavioral scores were lower in
longer elimination half-life than morphine, but it is the nalbuphine group at 2 to 4 hours, but there was no
metabolized to inactive metabolites in the liver that are difference between groups at 24 hours. The umbilical
excreted in the urine. vein-to-maternal vein concentration ratio was higher
Fentanyl readily crosses the placenta; however, the with nalbuphine (mean ± SEM, 0.78 ± 0.03) than with
average umbilical vein/maternal vein ratio remains low, meperidine (0.61 ± 0.02). A subsequent study failed to
most likely owing to a significant degree of maternal demonstrate an analgesic advantage with either drug but
protein binding and drug redistribution. In a chronically again reported transient neonatal neurologic depression
instrumented sheep model, Craft et al.20 detected fen- with nalbuphine.24
tanyl in fetal plasma as early as 1 minute after maternal Amin et al.25 compared the neonatal outcome for
administration; however, maternal plasma levels were women who received either nalbuphine or saline-control
approximately 2.5 times greater than fetal plasma levels. before elective cesarean delivery. They found lower
Rayburn et al.21 compared responses in women who 1-minute Apgar scores and a significantly longer time to
received intravenous fentanyl (50 to 100 µg as often as sustained respiration in the nalbuphine group. However,
once per hour at maternal request) with the experience 5-minute Apgar scores and umbilical cord blood gas mea-
of women who did not receive analgesia. The mean dose surements were similar between groups.
of fentanyl administered was 140 µg (range, 50 to 600 µg). Nicolle et al.26 evaluated the transplacental transfer
All patients who received fentanyl experienced brief anal- and neonatal pharmacokinetics of nalbuphine in 28
gesia (mean duration, 45 minutes), sedation, and a tran- women who received the drug either intramuscularly or
sient reduction in FHR variability (30 minutes). There intravenously during labor. The investigators found a
was no difference between groups in neonatal Apgar high umbilical vein-to-maternal vein concentration ratio
scores, respiratory status, or Neurologic and Adaptive of 0.74, which did not correlate with the administered
Capacity Scores (NACS). Rayburn et al.22 also compared dose. The estimated neonatal half-life was 4.1 hours,
intravenous fentanyl (50 to 100 µg every hour) with an which is greater than the adult half-life and, more impor-
equi-analgesic dose of meperidine (25 to 50 mg every 2 tantly, longer than the half-life of naloxone. There was a
to 3 hours). The researchers observed less sedation, vom- transient reduction in FHR variability in 54% of the
iting, and neonatal naloxone administration with fen- fetuses, which was not associated with the plasma con-
tanyl, but they observed no difference between groups in centration of nalbuphine. Analgesia was rated as effective
NACS. The two groups had similarly high pain scores, by 54% of parturients.
suggesting that both drugs have poor analgesic efficacy. Giannina et al.27 compared the effects of intravenous
nalbuphine and meperidine on intrapartum FHR trac-
ings. Nalbuphine significantly reduced both the number
Nalbuphine of FHR accelerations and FHR variability, whereas
Nalbuphine is a mixed agonist-antagonist opioid analge- meperidine had little effect.
sic with agonist activity at κ-opioid receptors, thereby A recent prospective pilot study of 302 nulliparous
producing analgesia, and partial agonist activity at parturients (57 women who received nalbuphine, and a
µ-opioid receptors, thus resulting in less respiratory control group of 245 women who received neither nal-
depression.13 A partial agonist is a drug that has receptor buphine nor epidural analgesia) reported a marked reduc-
affinity but produces a submaximal effect compared with tion in duration of the active phase of the first stage of
a full agonist, even when given at very high doses.10 labor in the nalbuphine group (75 minutes versus 160
Nalbuphine can be administered by intramuscular, minutes in the control group); this effect appeared to be
intravenous, or subcutaneous injection, with a usual dose independent of oxytocin use.28 Additional investigations
of 10 to 20 mg every 4 to 6 hours. The onset of analgesia are needed to verify this finding.
occurs within 2 to 3 minutes of intravenous administra-
tion and within 15 minutes of intramuscular or subcuta-
neous administration. The drug is metabolized in the
Butorphanol
liver to inactive compounds that are then secreted into Butorphanol is an opioid with agonist-antagonist proper-
bile and excreted in feces.13 ties that resemble those of nalbuphine. It is 5 times as
Nalbuphine and morphine are of equal analgesic potent as morphine and 40 times more potent than
potency and result in sedation and respiratory depression meperidine.29 The typical dose during labor is 1 to 2 mg
at similar doses. However, because of its mixed receptor intravenously or intramuscularly. Butorphanol is 95%
affinity, nalbuphine demonstrates a ceiling effect for metabolized in the liver to inactive metabolites. Excre-
respiratory depression at a dose of 0.5 mg/kg.13 Nalbu- tion is primarily renal. A plateau effect for respiratory
phine causes less nausea, vomiting, and dysphoria than depression is noted, where butorphanol 2 mg produces
morphine. Concerns that it may have an antianalgesic respiratory depression similar to that of morphine 10 mg
effect, particularly in men, led to the withdrawal of nal- or meperidine 70 mg. However, butorphanol 4 mg
buphine in the United Kingdom in 2003.13 results in less respiratory depression than morphine
Wilson et al.23 performed a randomized, double-blind 20 mg or meperidine 140 mg.29
comparison of intramuscular nalbuphine 20 mg and Maduska and Hajghassemali30 compared intramuscu-
meperidine 100 mg for labor analgesia. Nalbuphine was lar butorphanol (1 to 2 mg) with meperidine (40 to
22 Systemic Analgesia: Parenteral and Inhalational Agents 443
80 mg) and found similar efficacy of labor analgesia. Robson36 compared intramuscular meptazinol with
Butorphanol and meperidine exhibited rapid placental meperidine at the same doses (100 mg if maternal weight
transfer with similar umbilical vein-to-maternal vein con- was ≤ 60 kg, 125 mg if 61 to 70 kg, and 150 mg if
centration ratios (0.84 and 0.89, respectively) and no dif- ≥ 70 kg). Meptazinol provided significantly better anal-
ferences in FHR tracings, Apgar scores, time to sustained gesia than meperidine but resulted in a similar frequency
respiration, or umbilical cord blood gas measurements at of maternal side effects.
delivery. Nicholas and Robson37 subsequently compared intra-
Hodgkinson et al.31 performed a similar study com- muscular meptazinol 100 mg with meperidine 100 mg in
paring the intravenous administration of butorphanol (1 a randomized, double-blind trial in 358 parturients. Mep-
or 2 mg) and meperidine (40 or 80 mg) for labor analge- tazinol provided significantly better pain relief at 45 and
sia. Maternal pain relief was found to be adequate and 60 minutes, but the two drugs provided a similar duration
comparable, but there were fewer maternal side effects of analgesia, and there was no significant difference
(e.g., nausea, vomiting, dizziness) in the women who between groups in maternal side effects. Neonatal out-
received butorphanol. There was no difference between comes were similar between groups, except significantly
groups in neonatal Apgar or neurobehavioral scores. more infants whose mothers had received meptazinol had
Conversely, in a double-blind comparison of intrave- an Apgar score of 8 or higher at 1 minute.
nous butorphanol (1 or 2 mg) and meperidine (40 or Other investigators have reported little difference in
80 mg) during labor, Quilligan et al.32 noted lower pain analgesic efficacy, maternal side effects, or neonatal out-
scores at 30 minutes and 1 hour after the administration comes between meptazinol and meperidine. In a study
of butorphanol. There was no significant difference in of 1100 patients, Morrison et al.38 found that neither
Apgar scores between the two groups of infants; however, drug given at equal doses (150 mg in patients weighing
the mean FHR was noted to be higher among those > 70 kg, 100 mg in those weighing ≤ 70 kg) was effective
fetuses whose mothers received butorphanol. at relieving pain. Maternal drowsiness was significantly
Nelson and Eisenach33 investigated the possible syn- less pronounced with meptazinol, but the incidence of
ergistic effect of giving both intravenous butorphanol and vomiting was higher. FHR changes and neonatal out-
meperidine; they compared the administration of both comes, including Apgar scores, need for resuscitation,
drugs with the administration of either drug alone. and suckling ability, were comparable. The overall use of
Women received intravenous butorphanol 1 mg, meperi- naloxone was similar in the two groups, but if the dose-
dine 50 mg, or butorphanol 0.5 mg with meperidine delivery interval exceeded 180 minutes, significantly
25 mg. All three groups reported a similar reduction in more neonates in the meperidine group required
pain intensity; however, only 29% of the women achieved naloxone.
clinically significant pain relief. There was no difference De Boer et al.39 assessed neonatal blood gas and acid-
among groups in maternal side effects or neonatal Apgar base measurements after maternal intramuscular admin-
scores. The investigators concluded that there was no istration of meptazinol (1.5 mg/kg) or meperidine
therapeutic benefit to combining the two drugs. (1.5 mg/kg) during labor. Capillary blood gas measure-
Atkinson et al.34 performed a double-blind trial of ments at 10 minutes of life showed a significantly lower
intravenous butorphanol (1 to 2 mg) and fentanyl (50 to pH and a higher Paco2 in the meperidine group, although
100 µg) administered hourly on maternal request. The this difference resolved by 60 minutes. These findings
investigators found that butorphanol provided better suggest that meptazinol causes less neonatal respiratory
analgesia initially, with fewer requests for additional drug depression.
doses or progression to epidural analgesia. There was no Meptazinol may confer some benefits over meperidine
difference in adverse maternal or neonatal effects between in early neonatal outcome, but it is not widely used. A
the two groups. recent survey indicated that it is the intramuscular labor
analgesic of choice in only 14% of obstetric units in the
United Kingdom.6 The cost of meptazinol is consider-
Meptazinol ably higher than that of meperidine. Meptazinol is not
Meptazinol is a partial opioid agonist specific to µ-opioid available in the United States.
receptors with a rapid onset of action (i.e., 15 minutes
after intramuscular administration). The intramuscular
dose (50 to 100 mg) and duration of action for labor
Pentazocine
analgesia are similar to those for meperidine. Its partial Pentazocine is a selective κ-opioid receptor agonist with
agonist activity is thought to result in less sedation, respi- some weak antagonist activity at µ-opioid receptors.13 It
ratory depression, and risk for dependence than occurs may be given orally or systemically by intramuscular or
with other opioid agonists. intravenous injection. The typical parenteral adult dose
Meptazinol is metabolized by glucuronidation in the is 30 to 60 mg, which is equivalent to morphine 10 mg.
liver and then excreted in the urine. This process is more Onset of action occurs within 2 minutes when given
mature in the neonate than is the metabolic pathway of intravenously and within 20 minutes if given by the intra-
meperidine. The adult half-life is 2.2 hours, and the neo- muscular route. Metabolism occurs in the liver by oxida-
natal half-life is 3.4 hours.35 tion and glucuronidation; metabolites are then excreted
Theoretically, this rapid elimination should confer a in the urine.
lower incidence of adverse neonatal effects than occurs Pentazocine causes similar respiratory depression to
with meperidine. In a single-blind study, Jackson and that seen with equipotent doses of morphine and
444 PART VI Labor and Vaginal Delivery
meperidine, but it exhibits a ceiling effect with doses in Claahsen-van der Grinten et al.42 reported that intrapar-
excess of 60 mg. Psychomimetic effects (e.g., dysphoria, tum tramadol (initial dose of 100 mg, then subsequent
hallucinations) may complicate its use, particularly with doses of 50 to 100 mg, up to a maximum dose of 250 mg)
increasing doses. resulted in normal Apgar scores and NACS, with no cor-
In a double-blind study of 94 laboring women who relation to tramadol or M1 concentrations. However, the
received intramuscular administration of pentazocine (up single neonate who required naloxone had the highest
to 60 mg) and meperidine (up to 150 mg), Mowat and plasma concentration of tramadol.
Garrey40 observed equivalent and adequate analgesia for The analgesic efficacy of tramadol in labor has been
approximately 40% of women in each group. The inci- questioned. Keskin et al.43 compared intramuscular tra-
dence of sedation was comparable between groups, and madol 100 mg and meperidine 100 mg for labor analge-
fewer women in the pentazocine group complained of sia; they observed greater pain relief and a lower incidence
nausea and vomiting. of nausea and fatigue with meperidine. There was no
In a randomized study comparing intramuscular significant difference between groups in neonatal
administration of pentazocine 30 mg with tramadol outcome, but more infants in the tramadol group required
100 mg in 100 laboring women, Kuti et al.41 observed supplemental oxygen for respiratory distress and hypox-
greater analgesia in the pentazocine group at 1 hour, with emia. The investigators concluded that meperidine pro-
a longer time to subsequent request for additional anal- vided superior analgesia and was associated with a better
gesia (181 minutes versus 113 minutes, P < .05). The side-effect profile.
overall analgesic effect of both drugs was modest, with By contrast, Viegas et al.44 conducted a randomized,
only 30% to 50% of women reporting satisfactory pain double-blind trial to compare intramuscular administra-
relief. More women in the pentazocine group were tion of tramadol 50 mg, tramadol 100 mg, and meperi-
drowsy, but the result did not achieve statistical signifi- dine 75 mg during labor. Tramadol 100 mg and
cance. There were no cases of maternal respiratory meperidine 75 mg provided similar labor analgesia;
depression, and there was no difference between groups however, a higher incidence of maternal and neonatal
in neonatal outcomes. The investigators concluded that adverse effects was observed with meperidine.
pentazocine provides better labor analgesia than Kooshideh and Shahriari45 evaluated the intramuscu-
tramadol. lar administration of tramadol 100 mg or meperidine
50 mg on labor duration and analgesic efficacy in 160
parturients. The investigators observed that tramadol was
Tramadol associated with a reduced duration of both the first stage
Tramadol is an atypical, weak, synthetic opioid that has (140 versus 190 minutes, P < .001) and the second stage
affinity for all opioid receptors, but particularly the of labor (25 versus 33 minutes, P = .001). There was no
µ-opioid subtype. Tramadol also inhibits neuronal reup- difference in median and maximum pain scores between
take of norepinephrine and serotonin, and it directly groups 1 hour after drug administration; however, lower
stimulates presynaptic serotonin release, which may pain scores were observed during the second stage of
account for some of its analgesic effects.13 Tramadol can labor in the meperidine group. Nausea, vomiting, and
be administered orally or by intramuscular or intravenous drowsiness occurred less frequently in the tramadol
injection at a dose of 50 to 100 mg every 4 to 6 hours in group.
adults. Although the initial bioavailability after oral
administration is only 70% owing to a significant first-
pass effect, this increases to almost 100% with repeated PATIENT-CONTROLLED ANALGESIA
doses.10,13
The analgesic potency of tramadol is equal to that of Patient-controlled analgesia has been used to control
meperidine and one fifth to one tenth that of morphine. postoperative pain for several decades and for the provi-
In equi-analgesic doses, tramadol causes less respiratory sion of labor analgesia in more recent years. First
depression than morphine; at usual doses, no clinically described in women with thrombocytopenia who were
significant respiratory depression occurs. The onset of unable to undergo a neuraxial analgesia procedure, its use
analgesia is within 10 minutes of intramuscular adminis- has grown in availability and popularity. A 2007 survey
tration, with an effective duration of 2 to 4 hours. Trama- demonstrated that 49% of obstetric units in the United
dol is metabolized by demethylation and glucuronidation Kingdom offered PCA for labor analgesia.46 Purported
in the liver to several metabolites, one of which has inde- advantages of PCA include (1) superior pain relief with
pendent analgesic activity (M1). The metabolites are lower doses of drug, (2) less risk for maternal respiratory
almost entirely excreted in the urine. The elimination depression compared with bolus intravenous administra-
half-life is 5 to 6 hours, whereas that of the active metab- tion, (3) less placental transfer of drug, (4) less need for
olite is 9 hours. antiemetic agents, and (5) greater patient satisfaction.47
Tramadol readily crosses the placenta, and an umbili- The smaller, more frequent dosing used with this mode
cal vein-to-maternal vein ratio of 0.94 has been observed of analgesia may result in a more stable plasma drug
at delivery.42 Neonates possess complete hepatic capacity concentration and a more consistent analgesic effect
for metabolism of tramadol to its active metabolite M1. when compared with that of intermittent bolus adminis-
The elimination profile of M1 suggests a terminal half- tration regimens.47
life of 85 hours because of its requirement for renal elimi- PCA represents an alternative method of labor anal-
nation, which is an immature process in neonates. gesia when neuraxial analgesia is not requested or is
22 Systemic Analgesia: Parenteral and Inhalational Agents 445
Fentanyl
unavailable, contraindicated, or unsuccessful. The partu- The pharmacokinetic profile for fentanyl (i.e., rapid
rient can tailor the administration of analgesia according onset, high potency, short duration of action, absence of
to her individual needs, and with some regimens the active metabolites) has resulted in its selection as one of
bolus dose can be altered to allow further titration of the most commonly used opioids for PCA during labor
analgesia as labor progresses. and delivery. In the United Kingdom, it is used in 26%
However, PCA for labor is not without limitations. of the units that offer PCA during labor.46
Despite the frequency of dose administration, the coor- Nikkola et al.51 observed that fentanyl PCA (50 µg
dination of peak opioid concentrations with uterine con- loading dose, 20 µg bolus, 5 minute lockout) provided a
tractions can be difficult and result in suboptimal moderate reduction in labor pain in 50% of the parturi-
analgesia. In addition, the relatively small doses of opioid ents receiving this mode of analgesia; however, less
may be less effective at controlling pain as labor pro- overall pain relief was experienced when compared with
gresses. Finally, a number of maternal and fetal side a group that received epidural analgesia. The use of fen-
effects have been described (see later discussion). A tanyl was also associated with a higher incidence of
variety of drugs, doses, and regimens have been studied, maternal dizziness and sedation.
including comparisons of PCA with and without a con- Rayburn et al.52 compared fentanyl PCA (bolus 10 µg,
tinuous intravenous infusion (Table 22-4). lockout interval 12 minutes) to intermittent intravenous
nurse-administered fentanyl boluses (50 to 100 µg every
hour, on demand). The degree of analgesia, adverse
Meperidine maternal effects, and neonatal outcomes (e.g., neonatal
Meperidine was the first opioid to be used for PCA Apgar scores, naloxone requirements, neurobehavioral
during labor. Isenor and Penny-McGillivray48 compared scores) were similar between the two groups. The two
PCA meperidine (background infusion 60 mg/h with groups used a similar total amount of fentanyl, had com-
bolus doses of 25 mg, up to a maximum dose of 200 mg) parable umbilical serum concentrations of fentanyl, and
with intermittent intramuscular meperidine (50 to had incomplete analgesia during late labor.
100 mg every 2 hours). Women in the PCA group Morley-Forster and Weberpals53 observed a 44% inci-
reported lower pain scores than women in the intramus- dence of moderate neonatal depression (1 minute Apgar
cular group, even when adjustment was made for the < 6) in a retrospective review of 32 neonates whose
increased total amount of meperidine used.48 There was mothers had received fentanyl PCA (at various initial
no difference in maternal side effects, FHR abnormali- doses, basal infusion rates, and lockout intervals) during
ties, or neonatal Apgar scores between groups. labor. A total of 9.4% of the neonates required naloxone;
More recent studies have indicated that when admin- the total dose of fentanyl was significantly higher in the
istered by PCA, meperidine appears to be less effective mothers of neonates who required naloxone than in those
than the shorter-acting opioids. Douma et al.49 random- who did not (mean ± SD, 770 ± 233 µg versus 298 ±
ized parturients in labor to receive either meperidine 287 µg, respectively). By contrast, in a retrospective eval-
(49.5 mg loading dose, 5 mg bolus dose with 10 min uation of fentanyl PCA (loading 50 µg, bolus 20 µg,
lockout, maximum total dose 200 mg), fentanyl (50 µg lockout interval 5 minutes) compared with no analgesia
loading dose, 20 µg bolus dose with 5 min lockout, during labor, Hosokawa et al.54 observed lower mean
maximum dose 240 µg/h), or remifentanil (40 µg loading umbilical arterial blood pH measurements, but compa-
dose, 40 µg bolus dose with 2 min lockout, maximum rable Apgar scores and no requirement for naloxone or
dose 1200 µg/h). Meperidine provided the least effective bag-and-mask ventilation in the 129 neonates whose
analgesia, with no change in pain scores from baseline at mothers received fentanyl.
446 PART VI Labor and Vaginal Delivery
VAPS, Visual analog pain score (0-100 mm); M, meperidine; R, remifentanil; F, fentanyl; b, bolus; l/o, lockout; NS, nonsignificant.
448 PART VI Labor and Vaginal Delivery
Maternal satisfaction was similar, although the incidence minutes). During the study period of 90 minutes, pain
of sedation, oxyhemoglobin desaturation (Sao2 < 92%), scores were significantly lower in the group receiving the
and the need for supplemental oxygen were higher with higher infusion dose, but there was no difference between
remifentanil. groups in patient satisfaction, FHR abnormalities, or
neonatal Apgar scores.
Altogether, these studies suggest that fixed-dose remi-
Efficacy and Optimal Regimen
fentanil PCA protocols are less effective than titratable
Remifentanil can be given as a PCA bolus, as a continu- regimens, with the potential for low and high doses
ous infusion, or as a combination of the two. Although a resulting in poor analgesia or adverse effects, respectively.
number of studies have compared remifentanil to other Evidence is conflicting as to whether the use of a back-
opioids using fixed, nontitratable PCA doses, Volmanen ground infusion confers additional benefits, particularly
et al.75 attempted to determine the minimum effective given the greater risk for maternal sedation and respira-
dose of remifentanil for labor analgesia by titration to tory depression; one parturient became apneic within 3
effect. Using a starting bolus dose of 0.2 µg/kg, and dose minutes of increasing a background infusion from 0.05
increases of 0.2 µg/kg (lockout interval 1 minute) over a to 0.1 µg/kg/min.80 Furthermore, a continuous remifen-
1-hour study period, the median effective bolus dose was tanil infusion regimen may not take advantage of the
observed to be 0.4 µg/kg (range, 0.2 to 0.8 µg/kg). drug’s intrinsic onset and offset characteristics in target-
However, frequent episodes of Sao2 below 94% (in 10 of ing the episodic nature of uterine contraction pain.73
17 subjects), maternal sedation, and reduced FHR vari- The analgesic benefit of remifentanil may be opti-
ability were observed. mized by training parturients to press the PCA button
Starting with a remifentanil PCA bolus dose of with the first perception of a contraction, given that the
0.25 µg/kg (lockout interval 2 minutes) without a back- peak analgesic effect occurs within 1 to 3 minutes.13 A
ground infusion, Blair et al.76 titrated the bolus and infu- novel delivery system (preemptive remifentanil analgesia
sion doses to a maximum of 1 µg/kg and 0.05 µg/kg/min, modality [PRAM]) is in development; this system uses a
respectively. In 17 of 21 participants, satisfactory analge- mathematical analysis of the previous three contractions
sia was achieved with a PCA bolus dose of 0.25 µg/kg or to deliver a bolus dose 45 seconds before the next pre-
0.5 µg/kg with no background infusion; adding a back- dicted contraction to coordinate the peak action of remi-
ground infusion resulted in no further improvement of fentanil with uterine contractions.81
analgesia but an increased incidence of adverse effects.
D’Onofrio et al.77 conducted an observational study of Side Effects
205 parturients in whom a continuous infusion of remi-
fentanil was titrated (initial to maximum dose range, Remifentanil can cause significant respiratory depression
0.025 to 0.15 µg/kg/min) with a goal of achieving pain through reductions in the ventilatory rate and tidal
scores less than or equal to 4 during contractions. Ade- volume.13 Although the safety profile of remifentanil
quate analgesia was achieved within 30 minutes but PCA in labor has been specifically evaluated, the data are
required a median remifentanil infusion dose of 0.075 µg/ conflicting.77,82 Volikas et al.82 investigated the maternal
kg/min. The Sao2 remained above 95% in all patients and neonatal effects of remifentanil PCA (bolus dose
without supplemental oxygen, and there were no reported 0.5 µg/kg, lockout interval 2 minutes) in 50 women.
neonatal side effects. Effective analgesia was reported in 86% of study partici-
Balki et al.78 compared the effect of a fixed remifen pants, and 44% experienced slight drowsiness (but were
tanil bolus dose with a titratable background infusion arousable to voice and maintained Sao2 > 93%). Mild
versus a fixed background infusion with a titratable bolus itching and FHR changes occurred in the first 20 minutes
dose. Both groups started with a remifentanil bolus dose of remifentanil PCA but did not require treatment.
of 0.25 µg/kg (lockout interval 2 minutes) and a back- Umbilical cord blood gas measurements and neonatal
ground infusion rate of 0.025 µg/kg/min. If analgesia was Apgar scores and neurologic examinations were all within
inadequate, either the background infusion or bolus dose normal limits.
was increased in a stepwise manner to a maximum of Several theories have attempted to explain the rela-
0.1 µg/kg/min or 1 µg/kg, respectively. The mean pain tively high incidence of sedation and respiratory depres-
scores, satisfaction scores, and cumulative remifentanil sion with the use of remifentanil PCA in laboring women.
doses were similar in the two groups; only one patient Despite the rapid onset of remifentanil, administration of
eventually requested epidural analgesia. The incidence of a bolus dose of remifentanil may result in an onset of
maternal side effects was higher in the escalating bolus analgesia after the cessation of uterine contractions
dose group, including drowsiness (100% versus 30%) and (which have an average duration of 60 to 70 seconds).
frequency of Sao2 less than 95% (60% versus 40%). Thurlow et al.64 have encouraged parturients to request
There was no difference in the incidence of adverse neo- a bolus dose at the very first detection of a contraction.
natal effects. The investigators advocated the use of a Some investigators have suggested that administration of
titrated background infusion (range, 0.025 to 0.1 µg/kg/ a PCA bolus between contractions might reduce the risk
min) with a constant PCA bolus dose (0.25 µg/kg, lockout for sedation and improve the efficacy of analgesia;
interval 2 minutes). however, a report by Volmanen et al.83 does not support
Balcioglu et al.79 compared two remifentanil back- this hypothesis. After administration of a remifentanil
ground infusion rates (0.1 and 0.15 µg/kg/min) with a bolus, the onset of electroencephalographic depression
constant PCA bolus dose (15 µg, lockout interval 5 occurs before the onset of respiratory depression and the
450 PART VI Labor and Vaginal Delivery
peak respiratory depression occurs approximately 2.5 until they are deemed competent. Women must not have
minutes after bolus injection.84 received other opioids in the previous 4 hours and should
Studies of remifentanil PCA during labor have be fully informed of the potential side effects, including
reported a wide range in the incidence of nausea (0% to the possibility of requiring supplemental oxygen and
60%).77,78 Pruritus occurs in approximately 16% of par- needing increased levels of monitoring. Continuous pulse
turients.49 Nausea and emesis can occur through an oximetry is advocated, and supplemental oxygen should
opioid-induced increase in vagal activity, which may be readily available and administered if Sao2 consistently
result in a decrease in mean arterial pressure and heart falls below 95% (see Box 22-1). The PCA infusion should
rate; however, this has not been reported in laboring be given via a dedicated intravenous catheter and infusion
women receiving remifentanil PCA, perhaps reflecting set with anti-syphon valves. Sedation scores and respira-
the doses administered and/or the high maternal sympa- tory rate should be recorded every 30 minutes, and orders
thetic activity during labor. should specify clear triggers for contacting the anesthesia
Maternal administration of remifentanil PCA during service. Continuous FHR monitoring is essential.
labor appears to have minimal effect on FHR abnormali- In summary, the analgesic efficacy of remifentanil,
ties, umbilical cord blood gas measurements, and Apgar particularly in early labor, has been demonstrated.
scores.73 Comparison studies have reported a lower inci- Optimal labor analgesia may require titration of remifen-
dence of FHR abnormalities with remifentanil than with tanil PCA with labor progression; however, clinicians
meperidine.68 Neonatal depression has been observed should remain vigilant for the common side effects (i.e.,
after general anesthesia that includes remifentanil; maternal sedation, respiratory depression) and comply
however, any contribution from remifentanil is likely with local protocols to ensure safe drug use. To date, the
minor given its rapid neonatal metabolism.73 This last studies of remifentanil administration for labor analgesia
characteristic has led to the use of remifentanil for seda- have included only healthy parturients with low-risk
tion in neonatal intensive care units. singleton pregnancies. Therefore, the information may
Remifentanil is the most commonly used opioid for not be applicable to all laboring women, and analgesia
PCA during labor in the United Kingdom.46 However, it must be administered on an individual patient basis.
is not specifically approved for this use in the United
Kingdom or the United States, and strict adherence to
local guidelines is required for safe practice (Box 22-1). OPIOID ANTAGONISTS
Labor nurses and midwives should undergo a period of
training and supervised practice with remifentanil PCA Naloxone is a pure opioid antagonist at the µ-, κ-, and
δ-opioid receptors, although it has the greatest affinity
for the µ-opioid receptor.10,13 It is the drug of choice to
treat adverse opioid effects in both the mother and the
Guidelines for Patient-Controlled newborn, and it may be given intravenously, subcutane-
BOX 22-1
Anesthesia with Remifentanil* ously, or intramuscularly. The onset of action after an
intravenous dose (1 to 4 µg/kg) is 2 minutes, with a dura-
ELIGIBILITY
tion of action of 30 to 40 minutes; this duration may be
• Informed consent less than that of the opioid whose action it antagonizes,
• No opioids in the previous 4 hours and repeated doses or an infusion may be necessary.
• Dedicated intravenous cannula for remifentanil
administration
The administration of naloxone during labor or before
delivery may reverse the quality of analgesia and confer
PROTOCOL only a limited reduction in maternal side effects; however,
• Bolus: 40 µg some neonatal benefit may be obtained. Hodgkinson
• Lockout interval: 2 min et al.85 reported significantly higher neurobehavioral
scores in neonates born to mothers who had received an
CONTINUOUS OBSERVATIONS intrapartum combination of meperidine and naloxone
• SaO2 (pulse oximetry) compared with meperidine alone. However, this differ-
• Nursing supervision: one-on-one ence did not persist beyond 2 hours after birth. Clark
30-MINUTE OBSERVATIONS et al.86 reported minimal differences in the neurologic
• Respiratory rate
and acid-base status of neonates born to mothers who had
• Sedation score received both meperidine and naloxone compared with
• Pain score no-analgesia controls, although there was some evidence
that high-dose naloxone may have resulted in beneficial
INDICATIONS FOR CONTACTING THE neonatal effects.86 When neonatal depression is antici-
ANESTHESIA PROVIDER pated due to maternal opioid administration, it is best to
• Excessive sedation score (not arousable to voice) administer naloxone directly to the infant. Naloxone
• Respiratory rate < 8 breaths/min reverses neonatal respiratory depression by increasing
• SaO2 < 90% while breathing room air both minute ventilation and the gradient of the CO2
response curve.
*Sample guidelines adapted from those used by the Ulster
Community and Hospitals Trust, Ulster, United Kingdom. Studies have evaluated prophylactic neonatal naloxone
Labor nurses must establish competency in the use of administration immediately after delivery of infants
remifentanil patient-controlled analgesia before providing care. whose mothers received opioids during labor. When
22 Systemic Analgesia: Parenteral and Inhalational Agents 451
compared with saline administration, Weiner et al.87 received promethazine or placebo; this may reflect either
observed that intravenous naloxone resulted in a short- an antianalgesic effect of promethazine or a possible anal-
lived (30 minutes) improvement in neurobehavioral gesic effect of metoclopramide.
scores, whereas intramuscular naloxone resulted in similar Benzodiazepines (e.g., diazepam, lorazepam, mid-
improvements for the duration of the study period azolam) have been used for sedation in labor but are
(48 hours). associated with significant side effects. Diazepam rapidly
The recommended neonatal dose of naloxone is crosses the placenta and accumulates in the fetus at con-
0.1 μg/kg (1 μg/mL solution). Administration of nalox- centrations that may exceed maternal concentrations.
one is not recommended during the primary steps of The elimination half-life of the parent drug is 24 to 48
neonatal resuscitation; however, it may be given after hours, but active metabolites may persist for up to 120
positive-pressure ventilation has restored normal heart hours. Diazepam may cause maternal and neonatal respi-
rate and Sao2, if maternal opioid administration occurred ratory depression, as well as neonatal hypotonicity,
during the 4 hours before delivery.88 The preferred route impaired thermoregulation, and an abnormal stress
of naloxone administration is intravenous; intramuscular response. These effects may be dose related. Lorazepam
administration is acceptable, although absorption may be has a half-life of 12 hours and is metabolized to an inac-
delayed with this route. Endotracheal administration of tive glucuronide. McAuley et al.90 gave lorazepam 2 mg
naloxone is not recommended. Naloxone should not be or placebo prior to the intramuscular administration of
given to the neonate of a mother who is opioid dependent meperidine 100 mg for labor analgesia. Analgesia was
or on methadone maintenance therapy; this action may better in the lorazepam group, but lorazepam administra-
result in withdrawal activity and seizures.88 tion was associated with a nonsignificant increase in neo-
natal respiratory depression. Neonatal neurobehavioral
scores were similar in the two groups. Amnesia was
OPIOID ADJUNCTS AND SEDATIVES common with lorazepam.
Midazolam has a rapid onset of action and an elimina-
Historically, many drugs have been used as adjuncts to tion half-life of 1 to 4 hours.13 It is metabolized in the
parenteral opioid analgesia. Most of them cause maternal liver to one major and several minor pharmacologically
sedation and neonatal depression and are now used infre- active compounds, which may persist in patients with
quently, particularly because neuraxial and opioid PCA critical illnesses accompanied by hepatic and/or renal
techniques achieve satisfactory analgesia more safely. impairment. Midazolam readily crosses the placenta and
Barbiturates are sedative agents with no analgesic when used at high doses (e.g., induction of general anes-
effect. They are lipid soluble, rapidly cross the placenta, thesia) can result in neonatal hypotonia. Midazolam
are detectable in fetal blood, and can result in neonatal causes potent anterograde amnesia, a characteristic that
depression, especially if combined with systemic opioid may be undesirable for the childbirth experience.
administration. Ketamine is a phencyclidine derivative that acts as a
Phenothiazines (e.g., chlorpromazine, promethazine, noncompetitive antagonist at the NMDA receptor and,
propiomazine) are dopamine antagonists that have seda- at high doses, as an agonist at µ-opioid receptors. Most
tive, antiemetic, and antipsychotic properties. They commonly given by intravenous or intramuscular injec-
rapidly cross the placenta and reduce FHR variability. tion, ketamine in small doses (0.2 to 0.5 mg/kg intrave-
Neurobehavioral outcomes after the maternal adminis- nously) can provide dissociative analgesia whereas larger
tration of these agents have not been studied carefully, doses (1 to 2 mg/kg intravenously, 5 to 10 mg/kg intra-
but there is no evidence that they cause neonatal respira- muscularly) can be used to induce general anesthesia.
tory depression. Phenothiazines (particularly chlorprom- When given intravenously, ketamine has an onset
azine) may cause hypotension from alpha-adrenergic within 30 seconds and a duration of action of 5 to 10
receptor blockade, and they may produce unwanted minutes; intramuscular administration has an onset of 2
extrapyramidal movements.13 Parenterally administered to 8 minutes with a duration of 10 to 20 minutes.13 Ket-
promethazine (25 to 50 mg) has an onset of 15 minutes amine is hepatically metabolized to active metabolites,
and a duration of action of up to 20 hours; it rapidly which are excreted in the urine.
crosses the placenta, resulting in detectable fetal levels Ketamine’s sympathomimetic properties cause an
within 1 to 2 minutes of maternal intravenous adminis- increase in heart rate, systolic pressure, and cardiac
tration.13 Propiomazine is a mild respiratory depressant output, which should be avoided in preeclamptic and
that may further depress maternal ventilation when hypertensive patients; however, these effects may be valu-
co-administered with opioids. It has a faster onset and able during the induction of anesthesia in hypovolemic
shorter duration of action than promethazine. patients. In addition, given its bronchodilatory effects,
Metoclopramide is a procainamide derivative that ketamine has long been considered the intravenous
can increase gastric motility and reduce nausea and vom- induction agent of choice for asthmatic subjects.
iting. As an antagonist at central dopamine receptors, it Ketamine may be used for labor analgesia. Joselyn
can also cause drowsiness.13 After meperidine administra- et al.91 reported acceptable labor analgesia with an intra-
tion for labor analgesia, Vella et al.89 found metoclo- venous infusion of ketamine (bolus 0.1 mg/kg with an
pramide as effective as promethazine for reducing the infusion of 0.2 mg/kg/h, titrated to effect). The average
incidence of nausea and vomiting. Reduced pain scores ketamine infusion rate was 0.17 mg/kg/h, yielding an
and nitrous oxide use were observed in women who average total dose of 57 mg (range, 18 to 160 mg). No
received metoclopramide compared with those who unpleasant hallucinations were experienced; however,
452 PART VI Labor and Vaginal Delivery
with the initial dose, emesis and transient light-headedness measurements have been reported.94 Even when used
and nystagmus occurred. All neonates had a 5-minute immediately prior to delivery, there is no evidence that
Apgar score of 9 or 10. nitrous oxide causes neonatal respiratory depression or
Ketamine may also provide effective analgesia just altered neurobehavioral scores. The neonate rapidly
before vaginal delivery in parturients without neuraxial eliminates nitrous oxide by respiration, resulting in a
anesthesia, or it may be used as an adjunctive agent in half-life of less than 3 minutes.94
parturients with unsatisfactory neuraxial analgesia/ A systematic review of 16 studies concluded that
anesthesia. Using incremental doses of intravenous ket- nitrous oxide is not a potent labor analgesic, but it appears
amine (0.2 to 0.4 mg/kg, up to a maximum dose of to confer benefit and high levels of satisfaction for some
100 mg) immediately before delivery, Akamatsu et al.92 women.94 In one observational study in laboring women,
reported that 78 of 80 women experienced complete nitrous oxide was rated as being more effective than sys-
analgesia with no adverse maternal or neonatal effects. temic meperidine, although it was less effective than epi-
The occurrence of amnesia and a dreamlike state was dural analgesia.95
high, but only one woman found this unpleasant. To achieve optimal analgesia from nitrous oxide, inha-
Administration of small doses of ketamine (10- to lation should ideally begin in anticipation of the next
20-mg doses, repeated at intervals of 2 to 5 minutes, contraction; however, the timing of uterine contractions
while not exceeding a total dose of 1 mg/kg during a is not always predictable. Therefore the patient is encour-
30-minute period) is associated with a low incidence of aged to breathe the mixture of nitrous oxide in oxygen
maternal hallucinations; however, amnesia is common. In from the very beginning of the contraction until the end
these settings, the anesthesia provider must maintain of the contraction.
continual verbal contact with the patient and must ensure Although a low incidence of serious adverse events
that the patient remains sufficiently awake to maintain (3 per 10,000 administrations of 50% nitrous oxide in
adequate ventilation and protect her airway. oxygen) has been reported, suitable equipment must be
available to ensure the safe administration of nitrous
oxide. An apparatus that limits the concentration of
INHALATIONAL ANALGESIA nitrous oxide (e.g., a nitrous oxide/oxygen blender or a
premixed 1 : 1 cylinder) is required and should be checked
The use of inhalational analgesia for labor varies by periodically for correct delivery concentrations. The
country. Although many of the anesthetic agents used constituent gases separate at approximately 7° C (19.4 F),
in surgery have been administered for pain relief which is not usually of practical concern.13 Inhalation
during childbirth, only nitrous oxide has achieved wide may occur through a mask or mouthpiece containing a
clinical use. one-way demand valve, which opens only when negative
inspiratory pressure is applied. This is a safety feature
that limits gas delivery in a drowsy patient, and it also
Nitrous Oxide helps limit pollution of the environment with unscav-
Globally, nitrous oxide is the most common inhalational enged gases.
agent used for labor analgesia.93 Typically it is adminis- Environmental pollution from unscavenged gases may
tered as 50% nitrous oxide in oxygen using a blender be significant, and it remains unclear whether regular
device (e.g., Nitronox in the United States) or premixed occupational exposure to subanesthetic concentrations of
in a single cylinder (e.g., Entonox in the United Kingdom). nitrous oxide results in significant health risks for health
The availability and use of nitrous oxide for labor anal- care workers. Overall, epidemiologic data do not suggest
gesia varies greatly between countries; when provided the presence of higher reproductive risks in health care
alone or in combination with other forms of analgesia, workers exposed to nitrous oxide in the work environ-
the incidence of its use during labor is 1% (or less) in the ment (see Chapter 17).
United States, 43% in Canada, and 62% in the United The most common side effects of nitrous oxide are
Kingdom.93 nausea and vomiting (occurring in up to 33% of parturi-
The mechanism of action of nitrous oxide is not fully ents), drowsiness, dizziness, and the presence of paresthe-
understood, although it is believed to enhance the release sias, which may be related to maternal hyperventilation
of endogenous opioid peptides in the midbrain and during contractions.94 There is a potential risk for oxy-
modulate descending spinal pain pathways.94 Because of hemoglobin desaturation due to diffusion hypoxia,
its low solubility, it has a very rapid onset and offset, and although this appears to occur very rarely. It is unclear
it undergoes minimal metabolism. Although nitrous whether the incidence of intrapartum maternal hypox-
oxide has limited cardiovascular effects, it can cause emia differs among women who use nitrous oxide
depression of ventilation through a reduction in tidal when compared with women who receive no analgesia
volume; partial compensation of this ventilatory effect is during labor. However, the risk for maternal hypoxemia
achieved by an increase in respiratory rate. Nitrous oxide with nitrous oxide may be more common with the con-
is nonirritating to the airway and does not interfere with comitant administration of opioids or other sedatives96;
uterine activity. the entire obstetric care team should be aware of this
Nitrous oxide readily crosses the placenta, and a possibility.
fetal-to-maternal concentration ratio of 0.8 occurs within Although the intrapartum use of nitrous oxide has pla-
15 minutes; however, no apparent detrimental effects teaued or slightly declined in the United Kingdom, some
on FHR, Apgar scores, or umbilical cord blood gas anesthesiologists, obstetricians, and midwives in the
22 Systemic Analgesia: Parenteral and Inhalational Agents 453
United States have expressed a renewed interest in the use maternal blood loss, Apgar scores, or umbilical cord
of nitrous oxide for intrapartum analgesia.93,97 Nitrous blood gas measurements. The mean umbilical cord con-
oxide clearly does not provide analgesia comparable with centrations of fluoride ions in the enflurane group were
that provided by neuraxial techniques, but it has other below that associated with nephrotoxicity. A subsequent
benefits, including its lower cost and “less invasive study that compared administration of 1% enflurane in
nature.”97 In 2012, the United States Agency for Health- air to 50% nitrous oxide in oxygen during the first stage
care Research and Quality (AHRQ)97 published a review of labor observed lower pain scores, but higher levels of
of the effectiveness of nitrous oxide for analgesia during drowsiness, with enflurane.102
labor. The report included a systematic review of 58 pub-
lications. The authors concluded that inhalation of nitrous Isoflurane
oxide provides less effective intrapartum pain relief than
epidural analgesia, but the quality of the published studies McLeod et al.103 observed improved labor analgesia with
was predominantly poor. Apgar scores in newborn infants the self-administration of 0.75% isoflurane in oxygen
whose mothers used nitrous oxide were similar to those of compared with Entonox. Subsequent studies observed
newborns whose mothers used other methods of analgesia satisfactory pain relief with minimal levels of drowsiness
or received no analgesia. The report concluded that addi- with various concentrations of an isoflurane-Entonox
tional research is needed to address all of the following mixture.104,105 Ross et al.106 evaluated the use of a 0.25%
key questions: efficacy, patient satisfaction, effect on the isoflurane-Entonox mixture in 221 parturients in whom
route of delivery, adverse effects, and health system factors Entonox alone provided inadequate analgesia. No
affecting the use of nitrous oxide.97 mothers became unduly sedated or lost consciousness,
and there was no adverse effect on Apgar scores, neonatal
respiratory status, or maternal blood loss. The require-
Volatile Halogenated Agents ment for neonatal resuscitation was greater in mothers
All volatile halogenated agents cause dose-dependent who had received systemic opioids within 5 hours of birth
relaxation of uterine smooth muscle. Yoo et al.98 observed in addition to the inhaled mixture. The same investiga-
that the minimum alveolar concentration (MAC) of vola- tors verified clinically acceptable performance and safety
tile agents required to decrease the spontaneous myome- of premixed isoflurane-Entonox cylinders.107
trial contractility of isolated uterine muscle from pregnant
women by 50% (ED50) was similar for halothane, sevo- Desflurane
flurane, and desflurane (1.72, 1.44, and 1.66 MAC,
respectively). Other in vitro studies demonstrated that the Because of its low blood-gas partition coefficient, desflu-
ED50 for sevoflurane varied from 0.8 to 1.0 MAC and rane has a rapid onset and offset; however, it is also highly
that the ED50 for desflurane varied from 0.9 to 1.4 irritating to the airway, making it a less attractive option
MAC.99,100 In contrast, Yoo et al.98 observed that the ED50 for inhalation analgesia. Abboud et al.108 compared inha-
of isoflurane was significantly higher (2.35 MAC) than lation of 1% to 4.5% desflurane versus 30% to 60%
that for sevoflurane, desflurane, and halothane; an addi- nitrous oxide, both in oxygen, and found similar analgesia
tional unique feature observed with isoflurane was its scores and neonatal outcomes between groups. The inci-
ability to modulate KATP channels.98 Whether these find- dence of amnesia was significantly greater with desflurane
ings suggest that isoflurane is less likely to be associated than with nitrous oxide (23% versus 0%).
with uterine atony in clinical practice requires further
study. In general, when uterine tone is desirable (e.g., Sevoflurane
after delivery), volatile anesthetic concentrations higher
than 0.5 MAC are not recommended and intravenous Sevoflurane is the volatile halogenated agent most com-
oxytocin should be administered concurrently. monly used for inhalation induction of general anesthe-
A number of studies have examined the use of volatile sia. It has a short onset and offset of action, but it is less
agents for labor analgesia; most of these investigations irritating and has a less unpleasant odor than the other
used special breathing equipment and did not fully volatile agents.
address the issue of unscavenged gases, which may limit Toscano et al.109 conducted a safety and feasibility pilot
their clinical application. study of 50 parturients breathing 2% to 3% sevoflurane
in an oxygen/air mixture via a compact anesthesia deliv-
ery system. They aimed for an end-tidal sevoflurane con-
Enflurane
centration of 1.2% to 1.4% (0.8 to 0.9 MAC during
Abboud et al.101 compared the analgesic effects of 0.25% pregnancy) at the peak of uterine contractions. The mean
to 1.25% enflurane with the administration of 30% to (± SD) pain score was significantly lower during the times
60% nitrous oxide, both given in oxygen during the when parturients inhaled sevoflurane compared with
second stage of labor in 105 women. Satisfactory pain times when they did not inhale sevoflurane (3.3 ± 1.5
relief was reported in approximately 89% of women in versus 8.7 ± 1.0, respectively, on a scale of 0 to 10). Four
the enflurane group and 76% of women in the nitrous women became drowsy, but there were no episodes of
oxide group; this outcome was achieved most frequently oxyhemoglobin desaturation or loss of consciousness, and
with the use of 0.5% enflurane and 40% nitrous oxide, there were no unexpected increases in blood loss. In addi-
respectively. Amnesia rates were less than 10% in both tion, there were no reported adverse effects on FHR or
groups, and there were no differences observed in neonatal Apgar scores.
454 PART VI Labor and Vaginal Delivery
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chloride on the active phase during first stage of labour: a pilot venous fentanyl during labor. Anesthesiol Rev 1991; 18:31-6.
study. J Obstet Gynaecol 2011; 31:724-7. 53. Morley-Forster PK, Weberpals J. Neonatal effects of patient-
29. Nagashima H, Karamanian A, Malovany R, et al. Respiratory and controlled analgesia using fentanyl in labor. Int J Obstet Anesth
circulatory effects of intravenous butorphanol and morphine. Clin 1998; 7:103-7.
Pharmacol Ther 1976; 19:738-45. 54. Hosokawa Y, Morisaki H, Nakatsuka I, et al. Retrospective evalu-
30. Maduska AL, Hajghassemali M. A double-blind comparison ation of intravenous fentanyl patient-controlled analgesia during
of butorphanol and meperidine in labour: maternal pain relief labor. J Anesth 2012; 26:219-24.
and effect on the newborn. Can Anaesth Soc J 1978; 25: 55. Morley-Forster PK, Reid DW, Vandeberghe H. A comparison of
398-404. patient-controlled analgesia fentanyl and alfentanil for labour
31. Hodgkinson R, Huff RW, Hayashi RH, Husain FJ. Double-blind analgesia. Can J Anaesth 2000; 47:113-9.
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following intravenous butorphanol and meperidine. J Int Med Res venous analgesia during labour: a comparison between pentazo-
1979; 7:224-30. cine and pethidine. S Afr Med J 1985; 67:764-7.
32. Quilligan EJ, Keegan KA, Donahue MJ. Double-blind compari- 57. Long J, Yue Y. Patient controlled intravenous analgesia with
son of intravenously injected butorphanol and meperidine in par- tramadol for labor pain relief. Chinese Med J 2003; 116:1752-5.
turients. Int J Gynaecol Obstet 1980; 18:363-7. 58. Podlas J, Breland BD. Patient-controlled analgesia with nalbu-
33. Nelson KE, Eisenach JC. Intravenous butorphanol, meperidine, phine during labor. Obstet Gynecol 1987; 70:202-4.
and their combination relieve pain and distress in women in labor. 59. Frank M, McAteer EJ, Cattermole R, et al. Nalbuphine for obstet-
Anesthesiology 2005; 102:1008-13. ric analgesia: a comparison of nalbuphine with pethidine for pain
34. Atkinson BD, Truitt LJ, Rayburn WF, et al. Double-blind com- relief in labour when administered by patient-controlled analgesia
parison of intravenous butorphanol (Stadol) and fentanyl (Subli- (PCA). Anaesthesia 1987; 42:697-703.
maze) for analgesia during labor. Am J Obstet Gynecol 1994; 171: 60. Leppa M, Korvenoja A, Carlson S, et al. Acute opioid effects on
993-8. human brain as revealed by functional magnetic resonance
35. Franklin RA, Frost T, Robson PJ, Jackson MB. Preliminary imaging. Neuroimage 2006; 31:661-9.
studies on the disposition of meptazinol in the neonate. Br J Clin 61. Glass SA, Hardman D, Kamiyama Y, et al. Preliminary pharma-
Pharmacol 1981; 12:88-90. cokinetics and pharmacodynamics of an ultra-short-acting opioid:
36. Jackson MB, Robson PJ. Preliminary experience of the use of remifentanil (GI87084B). Anesth Analg 1993; 77:1031-40.
meptazinol as an obstetric analgesic. Br J Obstet Gynaecol 1980; 62. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil:
87:296-301. placental transfer, maternal and neonatal effects. Anesthesiology
37. Nicholas AD, Robson PJ. Double-blind comparison of mep- 1998; 88:1467-74.
tazinol and pethidine in labour. Br J Obstet Gynaecol 1982; 89: 63. Hinova A, Fernando R. Systemic remifentanil for labor analgesia.
318-22. Anesth Analg. 2009; 109:1925-9.
456 PART VI Labor and Vaginal Delivery
64. Thurlow JA, Laxton CH, Dick A, et al. Remifentanil by patient- 87. Wiener PC, Hogg MI, Rosen M. Effects of naloxone on pethidine-
controlled analgesia compared with intramuscular meperidine for induced neonatal depression. I. Intravenous naloxone. Br Med J
pain relief in labour. Br J Anaesth 2002; 88:374-8. 1977; 23:228-9.
65. Ng TK, Cheng BC, Chan WS, et al. A double-blind randomised 88. American Academy of Pediatrics and American Heart Association.
comparison of intravenous patient-controlled remifentanil with Neonatal Resuscitation. 6th edition. Elk Grove Village, IL,
intramuscular pethidine for labour analgesia. Anaesthesia 2011; American Academy of Pediatrics, 2011:247-8.
66:796-801. 89. Vella L, Francis D, Houlton P, Reynolds F. Comparison of the
66. Evron S, Glezerman M, Sadan O, et al. Remifentanil: a novel antiemetics metoclopramide and promethazine in labour. Br Med
systemic analgesic for labor pain. Anesth Analg 2005; 100: J (Clin Res Ed) 1985; 290:1173-5.
233-8. 90. McAuley DM, O’Neill MP, Moore J, Dundee JW. Lorazepam
67. Volikas I, Male D. A comparison of pethidine and remifentanil premedication for labour. Br J Obstet Gynaecol 1982; 89:
patient-controlled analgesia in labour. Int J Obstet Anesth 2001; 149-54.
10:86-90. 91. Joselyn AS, Cherian VT, Joel S. Ketamine for labour analgesia.
68. Blair JM, Dobson GT, Hill DA, et al. Patient controlled analgesia Int J Obstet Anesth 2010; 19:122-3.
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thesia 2005; 60:22-7. use of ketamine for parturition. I. Primary anesthetic for vaginal
69. Leong WL, Sng BL, Sia AT. A comparison between remifentanil delivery. Anesth Analg 1974; 53:284-7.
and meperidine for labor analgesia: a systematic review. Anesth 93. Rooks J. Nitrous oxide for pain in labor—why not in the United
Analg 2011; 113:818-25. States? Birth 2007; 34:1.
70. Schnabel A, Hahn N, Jens Broscheit J, et al. Remifentanil for 94. Rosen MA. Nitrous oxide for relief of labor pain: a systematic
labour analgesia: a meta-analysis of randomised controlled trials. review. Am J Obstet Gynecol. 2002; 186:S110-26.
Eur J Anaesthesiol 2012; 29:177-85. 95. Harrison RF, Shore M, Woods T, et al. A comparative study of
71. Volmanen P, Akural E, Raudaskoski T, et al. Comparison of remi- transcutaneous electrical nerve stimulation (TENS), Entonox,
fentanil and nitrous oxide in labour analgesia. Acta Anaesthesiol pethidine + promazine and lumbar epidural for pain relief in labor.
Scand 2005; 49:453-8. Acta Obstet Gynecol Scand 1987; 66:9-14.
72. Volmanen P, Sarvela J, Akural EI, et al. Intravenous remifentanil 96. Zelcer J, Owers H, Paull JD. A controlled oximetric evaluation of
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Acta Anaesthesiol Scand 2008; 52:249-55. 97. Agency for Healthcare Research and Quality. Nitrous oxide for
73. Hill D. Remifentanil in obstetrics. Curr Opin Anaesthesiol 2008; the management of labor pain. AHRQ Comparative Effectiveness
21:270-4. Review No. 67. AHRQ Publication No. 12-EHC071-EF, August,
74. Tveit TO, Seiler S, Halvorsen A, Rosland JH. Labour analgesia: 2012. Available at http://www.effectivehealthcare.ahrq.gov/
a randomised, controlled trial comparing intravenous remifentanil ehc/products/260/1175/CER67_NitrousOxideLaborPain
and epidural analgesia with ropivacaine and fentanyl. Eur J Anaes- _FinalReport_20120817.pdf. Accessed March 12, 2013.
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75. Volmanen P, Akural EI, Raudaskoski T, Alahuhta S. Remifentanil ics on spontaneous contractility of isolated human pregnant
in obstetric analgesia: a dose-finding study. Anesth Analg 2002; uterine muscle: a comparison among sevoflurane, desflurane, iso-
94:913-7. flurane, and halothane. Anesth Analg 2006; 103:443-7.
76. Blair JM, Hill DA, Fee JP. Patient-controlled analgesia for labour 99. Yildiz K, Dogru K, Dalgic H, et al. Inhibitory effects of desflurane
using remifentanil: a feasibility study. Br J Anaesth 2001; 87: and sevoflurane on oxytocin-induced contractions of isolated
415-20. pregnant human myometrium. Acta Anaesthesiol Scand 2005; 49:
77. D’Onofrio P, Novelli AM, Mecacci F, Scarselli G. The efficacy 1355-9.
and safety of continuous intravenous administration of remifent- 100. Turner RJ, Lambros M, Kenway L, Gatt SP: The in-vitro effects
anil for birth pain relief: an open study of 205 parturients. Anesth of sevoflurane and desflurane on the contractility of pregnant
Analg 2009; 109:1922-4. human uterine muscle. Int J Obstet Anesth 2002; 11:246-51.
78. Balki M, Kasodekar S, Dhumne S, et al. Remifentanil patient- 101. Abboud TK, Shnider SM, Wright RG, et al. Enflurane analgesia
controlled analgesia for labour: optimizing drug delivery regi- in obstetrics. Anesth Analg 1981; 60:133-7.
mens. Can J Anaesth 2007; 54:626-33. 102. McGuinness C, Rosen M. Enflurane as an analgesic in labour.
79. Balcioglu O, Akin S, Demir S, Aribogan A. Patient-controlled Anaesthesia 1984; 39:24-6.
intravenous analgesia with remifentanil in nulliparous subjects in 103. McLeod DD, Ramayya GP, Tunstall ME. Self-administered iso-
labor. Expert Opin Pharmacother 2007; 8:3089-96. flurane in labour: a comparative study with Entonox. Anaesthesia
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for labor analgesia: the good and the bad. Anesth Analg 2007; 104. Arora S, Tunstall M, Ross J. Self-administered mixture of Entonox
104:1616-7. and isoflurane in labour. Int J Obstet Anesth 1992; 1:199-202.
81. Birnbach DJ, et al. Preemptive remifentanil analgesia modality 105. Wee MY, Hasan MA, Thomas TA. Isoflurane in labour. Anaes-
(PRAM): a new paradigm for intravenous labor analgesia. ASA thesia 1993; 48:369-72.
abstract, October 2009. 106. Ross JA, Tunstall ME, Campbell DM, Lemon JS. The use of
82. Volikas I, Butwick A, Wilkinson C, et al. Maternal and neonatal 0.25% isoflurane premixed in 50% nitrous oxide and oxygen for
side-effects of remifentanil patient-controlled analgesia in labour. pain relief in labour. Anaesthesia 1999; 54:1166-72.
Br J Anaesth 2005; 95:504-9. 107. Ross JA, Tunstall ME: Simulated use of premixed 0.25% isoflu-
83. Volmanen PV, Akural EI, Raudaskoski T, et al. Timing of intra- rane in 50% nitrous oxide and 50% oxygen. Br J Anaesth 2002;
venous patient-controlled remifentanil bolus during early labour. 89:820-4.
Acta Anaesthesiol Scand 2011; 55:486-94. 108. Abboud TK, Swart F, Zhu J, et al. Desflurane analgesia for vaginal
84. Babenco HD, Conard PF, Gross JB. The pharmacodynamic effect delivery. Acta Anaesthesiol Scand 1995; 39:259-61.
of a remifentanil bolus on ventilatory control. Anesthesiology 109. Toscano A, Pancaro C, Giovannoni S, et al. Sevoflurane analgesia
2000; 92:393-8. in obstetrics: a pilot study. Int J Obstet Anesth 2003; 12:79-82.
85. Hodgkinson R, Bhatt M, Grewal G, Marx GF. Neonatal neurobe- 110. Yeo ST, Holdcroft A, Yentis SM, Stewart A. Analgesia with sevo-
havior in the first 48 hours of life: effect of the administration of flurane during labour. I. Determination of the optimum concen-
meperidine with and without naloxone in the mother. Pediatrics tration. Br J Anaesth 2007; 98:105-9.
1978; 62:294-8. 111. Yeo ST, Holdcroft A, Yentis SM, et al. Analgesia with sevoflurane
86. Clark RB, Beard AG, Greifenstein FE, Barclay DL. Naloxone in during labour. II. Sevoflurane compared with Entonox for labour
the parturient and her infant. South Med J 1976; 69:570-5. analgesia. Br J Anaesth 2007; 98:110-5.
C H A P T E R 2 3
CHAPTER OUTLINE
Epidural analgesia and spinal analgesia are the most effec- via the pudendal nerve to the 2nd, 3rd, and 4th sacral
tive methods of intrapartum pain relief in contemporary spinal segments. Neuraxial analgesia is the only form of
clinical practice.1,2 During the first stage of labor, pain analgesia that provides complete analgesia for both stages
results primarily from distention of the lower uterine of labor. During the first stage of labor, visceral pain
segment and cervix (see Chapter 20). Painful impulses are impulses entering the spinal cord at T10 to L1 must
transmitted by means of visceral afferent nerve fibers, be blocked. During the late first stage of labor and the
which accompany sympathetic nerve fibers and enter the second stage of labor, somatic impulses entering the
spinal cord at the 10th, 11th, and 12th thoracic and 1st spinal cord from S2 to S4 must also be blocked (see
lumbar spinal segments. As labor progresses and the fetus Chapter 20).
descends in the birth canal, distention of the vagina and In a survey of 1000 consecutive women who chose a
perineum results in painful impulses that are transmitted variety of analgesic techniques for labor and vaginal
457
458 PART VI Labor and Vaginal Delivery
delivery (including nonpharmacologic methods, transcu- Neuraxial analgesia is not used by all laboring women,
taneous electrical nerve stimulation, intramuscular although surveys of obstetric anesthesia practice in the
meperidine, inhalation of nitrous oxide, epidural analge- United States have shown that the use of neuraxial anal-
sia, and a combination of these techniques), pain relief gesia has grown over the past three decades.11 Data col-
and overall satisfaction with the birth experience were lected from the U.S. Standard Certificate of Live Birth
greater in patients who received epidural analgesia.2 Simi- in 27 states in 2008 indicated that 61% of women who
larly, randomized studies that have compared epidural had a singleton vaginal delivery received neuraxial anal-
analgesia with systemic opioids and/or inhalation analge- gesia.12 The rate was higher among white women than in
sia (i.e., nitrous oxide) have shown that pain scores are women of other races/ethnicities, and it was also higher
lower and patients are more satisfied with neuraxial in larger maternal units than in smaller units.11,12 In the
analgesia.3 United Kingdom, the National Health Service Maternity
The provision of analgesia for labor may result in other Statistics for 2010-2011 indicated that approximately one
benefits. Effective epidural analgesia reduces maternal third of parturients chose to receive neuraxial analgesia
plasma concentrations of catecholamines (Figure 23-1).4 during childbirth.13
Decreased alpha- and beta-adrenergic receptor stimula- The availability of skilled anesthesia providers influ-
tion may result in better uteroplacental perfusion and ences the neuraxial analgesia rate.11 Other factors include
more effective uterine activity.5,6 Painful uterine contrac- the information and advice provided to pregnant women
tions result in maternal hyperventilation. The hyperven- by obstetricians, nurses, and childbirth education instruc-
tilation, in turn, leads to maternal respiratory alkalosis, a tors. The personal and cultural expectations of a laboring
leftward shift of the oxyhemoglobin dissociation curve, woman, as well as obstetric complications,2 also affect the
increased maternal hemoglobin affinity for oxygen, and childbirth experience and the use of neuraxial analgesia
reduced oxygen delivery to the fetus.7 Hypocarbia also (see Chapters 20 and 21).
leads to hypoventilation between contractions, which In contemporary clinical practice, health care costs
may cause a decrease in maternal Pao2. Effective epidural have assumed significant importance. Studies using 1998
analgesia blunts this “hyperventilation-hypoventilation” data estimated that the incremental cost to society
cycle.8 Additionally, one study showed that paternal for providing epidural labor analgesia was $260 to $340
anxiety levels were lower, and both paternal involvement per parturient (approximately $367 to $481 in 2012
in the childbirth process and paternal satisfaction were dollars).14,15 A major problem with such analyses is the
greater, in men whose partners received epidural analge- difficulty of determining the total value of neuraxial anal-
sia than in those whose partners did not.9 Finally, the gesia. For example, the ability to rapidly convert epidural
presence of an epidural catheter and effective epidural analgesia to surgical anesthesia may also have value.
analgesia facilitate the rapid initiation of epidural anesthe- Ideally, the anesthesia provider should tailor the anal-
sia for emergency cesarean delivery. Neuraxial anesthesia gesic technique to meet the individual parturient’s needs.
for cesarean delivery is associated with greater overall Factors that should be considered in formulating an anal-
maternal safety than emergency administration of general gesic plan for individual parturients include coexisting
anesthesia (see Chapter 26).10 maternal disease, the airway examination, fetal status,
spontaneous versus induced labor, stage of labor, and
anticipated risk for operative delivery. The risks and ben-
efits of the various epidural and spinal analgesic tech-
1000 niques should be assessed for each parturient. Good
technique requires thoughtful preparation and meticu-
Plasma concentration (pg/mL)
800
lous attention to detail to ensure maternal and fetal safety.
The ideal labor analgesic technique is safe for both
the mother and the infant, does not interfere with the
600 progress of labor and delivery, and provides flexibility in
response to changing conditions. In addition, the ideal
400 technique provides consistent pain relief, has a long
duration of action, minimizes undesirable side effects
200 (e.g., motor block), and minimizes ongoing demands on
* the anesthesia provider’s time. No single technique or
anesthetic agent is ideal for all parturients during labor.
0
Before epidural After epidural The American Society of Anesthesiologists (ASA) has
* P < .05 published practice guidelines for obstetric anesthesia
(see Appendix B),16 as well as guidelines for neuraxial
Plasma epinephrine anesthesia in obstetric patients (see Appendix A). Guide-
Plasma norepinephrine lines promulgated by professional organizations in other
countries also address obstetric anesthesia care. All
FIGURE 23-1 ■ Influence of epidural analgesia on maternal obstetric anesthesia providers should review their coun-
plasma concentrations of catecholamines during labor. *P < .05 try’s respective guidelines. Specific neuraxial techniques
compared with before initiation of epidural analgesia. (Modified
from Shnider SM, Abboud TK, Artal R, et al. Maternal catechol- for labor analgesia, including their advantages, disadvan-
amines decrease during labor after lumbar epidural anesthesia. Am tages, side effects, and complications, are considered in
J Obstet Gynecol 1983; 147:13-5.) this chapter.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 459
PREPARATION FOR Chapters 37, 42, and 49). It is also controversial whether
NEURAXIAL ANALGESIA mild or isolated abnormalities in tests of blood coagula-
tion preclude the use of neuraxial analgesia. The dose and
Indications and Contraindications timing of administration of drugs administered for
thromboprophylaxis must also be considered (see Chapter
Epidural analgesia is indicated to treat the pain experi- 44).26 The anesthesia provider should consider the risks
enced by a woman in labor. In 2008 and 2010, respec- and benefits of neuraxial analgesia for each patient
tively, the American College of Obstetricians and individually.
Gynecologists (ACOG)17 and the ASA18 reaffirmed an Thorough preparation for neuraxial labor analgesia
earlier, jointly published opinion that stated that “in the involves several steps (Box 23-2). These include (1) a
absence of a medical contraindication, maternal request review of the parturient’s obstetric history; (2) a focused
is a sufficient medical indication for pain relief during preanesthetic evaluation that includes maternal obstetric,
labor.” Furthermore, the ACOG19 has stated that “deci- anesthetic, and health history; and (3) a brief physical
sions regarding analgesia should be closely coordinated examination (i.e., vital signs, airway, heart, lungs, and
among the obstetrician, the anesthesiologist, the patient, back).16 Routine measurement of the platelet count is not
and skilled support personnel.” Neuraxial analgesia is an necessary; however, assessment of the platelet count and
appropriate treatment for the pain of labor, including other laboratory measurements may be indicated in
early labor (defined as regular uterine contractions that selected patients.16 Similarly, routine intrapartum blood
cause progressive effacement and dilation of the uterine typing and screening or crossmatching is not necessary
cervix). Randomized controlled trials20-24 and a meta- in healthy parturients, although consideration should be
analysis25 have confirmed that initiation of neuraxial anal- given to sending a blood sample to the blood bank (to
gesia in early labor does not increase the risk for cesarean facilitate the rapid availability of blood products in case
delivery (see later discussion). of emergency need).16 For parturients at increased risk
Epidural analgesia may facilitate an atraumatic vaginal for hemorrhage, intrapartum typing, and screening or
breech delivery, the vaginal delivery of twin infants, and crossmatching should be performed. Fetal well-being
vaginal delivery of a preterm infant (see Chapters 34 and should be assessed by a skilled provider, and equipment
35). By providing effective pain relief, epidural analgesia (including resuscitation equipment) should be checked by
facilitates blood pressure control in preeclamptic women the anesthesia provider (see Box 12-1). Informed consent
(see Chapter 36). Epidural analgesia also blunts the should be obtained (see Chapters 12 and 33). Early and
hemodynamic effects of uterine contractions (e.g., sudden ongoing communication among the obstetric and anes-
increase in cardiac preload) and the associated pain thesia providers, nursing staff, and other members of the
response (tachycardia, increased systemic vascular resis- multidisciplinary team is encouraged.
tance, hypertension, hyperventilation) in patients with
other medical complications (e.g., mitral stenosis, spinal
cord injury, intracranial neurovascular disease, asthma;
Types of Neuraxial Analgesia
see Chapters 42, 49, and 53). The technical aspects of neuraxial analgesic/anesthetic
Box 23-1 lists the contraindications to administration techniques are discussed in detail in Chapter 12. These
of epidural or spinal analgesia. Some anesthesiologists
have suggested that systemic maternal infection, preexist-
ing neurologic disease, or severe stenotic heart lesions are Checklist: Preparation for
relative contraindications to neuraxial analgesia. However, BOX 23-2
Neuraxial Labor Analgesia
most cases of systemic infection (especially if properly
treated), or neurologic or cardiac disease, do not contra- 1. Communicate (early) with the obstetric provider:
indicate the administration of neuraxial analgesia (see • Review parturient’s obstetric history.
2. Perform focused preanesthetic evaluation:
• Review maternal obstetric, anesthetic, and health
history.
Contraindications to Epidural and • Perform targeted physical examination (vital signs,
BOX 23-1 airway, heart, lungs, back).
Spinal Analgesia
3. Review relevant laboratory measurements and
• Patient refusal or inability to cooperate imaging studies.
• Increased intracranial pressure secondary to a mass 4. Consider need for blood typing and screening or
lesion crossmatching.
• Skin or soft tissue infection at the site of needle 5. Formulate analgesia plan.
placement 6. Obtain informed consent.
• Frank coagulopathy 7. Perform equipment check:
• Recent pharmacologic anticoagulation* • Check routine equipment.
• Uncorrected maternal hypovolemia (e.g., hemorrhage) • Check emergency resuscitation equipment.
• Inadequate training in or experience with the technique 8. Obtain peripheral intravenous access.
• Inadequate resources (e.g., staff, equipment) for moni- 9. Apply maternal monitors (blood pressure, heart rate,
toring and resuscitation pulse oximetry).
10. Monitor fetal heart rate.
*Safety depends on specific drug and timing and dose of the most 11. Perform a team time-out.
recent drug administration (see Chapters 39 and 44).
460 PART VI Labor and Vaginal Delivery
techniques include continuous epidural, combined spinal- complete analgesia is significantly faster than with epidu-
epidural, and caudal analgesia and continuous and single- ral techniques (2 to 5 minutes versus 10 to 15 minutes,
shot spinal analgesia. Continuous epidural and combined respectively).27 In a meta-analysis of the onset time of CSE
spinal-epidural analgesia are the most common techniques compared with low-dose epidural analgesia,27 the mean
used for neuraxial labor analgesia. There are advantages difference in onset was −5.4 minutes (95% confidence
and disadvantages to each technique (Table 23-1). interval [CI], −7.3 to −3.6). More women with spinal
analgesia than with epidural analgesia had effective anal-
gesia at 10 minutes (relative risk [RR], 1.9; 95% CI, 1.5 to
Epidural Analgesia
2.5). In particular, the onset of sacral analgesia is signifi-
Continuous lumbar epidural analgesia has been the main- cantly slower after the initiation of lumbar epidural anal-
stay of neuraxial labor analgesia for several decades. gesia than with spinal analgesia. It may take several hours
Placement of an epidural catheter allows analgesia to be of lumbar epidural infusion, or several bolus injections of
maintained until after delivery. No dural puncture is local anesthetic into the lumbar epidural space, to achieve
required. The presence of a catheter and effective anal- sacral analgesia. Rapid onset of sacral analgesia is advanta-
gesia allow the conversion to epidural anesthesia should geous in the parturient in whom analgesia is initiated late
cesarean delivery be necessary. Injection of a local anes- in the first stage of labor or in a parous parturient with
thetic in the lumbar epidural space allows both cephalad rapid progress of labor. Spinal analgesia requires signifi-
and caudad spread of the anesthetic solution. cantly lower drug doses to attain effective analgesia than
Analgesia is initiated by bolus injection of drug(s) does epidural analgesia; therefore, the risk for local anes-
through the epidural needle, catheter, or both. Analgesia thetic systemic toxicity is decreased. In addition, there is
is maintained with anesthesia provider- or patient- less systemic absorption of spinal anesthetic agents into
administered intermittent bolus injections or a continu- the maternal circulation, so maternal and fetal plasma
ous epidural infusion, or both. The catheter is removed drug concentrations are lower with spinal than with epi-
after delivery when there is no further need for analgesia dural analgesia.
or anesthesia. An additional advantage of spinal analgesia is that com-
plete analgesia for early labor can be accomplished with
the intrathecal injection of a lipid-soluble opioid without
Combined Spinal-Epidural Analgesia
the addition of a local anesthetic. Thus, motor blockade
Combined spinal-epidural (CSE) analgesia has become is avoided and the risk for hypotension is lower.28 This
increasingly popular in the past 15 years. Onset of method is ideal for patients who wish to ambulate or for
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 461
those with preload-dependent cardiac conditions such as misplacement and direct injection into the fetus. However,
stenotic heart lesions. Finally, use of the CSE technique this technique is useful for parturients in whom access to
may lower the incidence of failure of epidural analgesia the lumbar spinal canal is not possible (e.g., because of a
(e.g., a nonfunctioning epidural catheter).29,30 The likeli- fused lumbar spine).
hood of an epidural catheter placed for labor analgesia
failing to provide satisfactory anesthesia for a subsequent Single-Shot Techniques
cesarean delivery was more than five times higher for
catheters placed as part of an epidural technique than for In general, single-shot techniques (spinal, lumbar epidu-
catheters placed as part of a CSE technique.31 ral, or caudal) are not useful for most laboring women
Cappiello et al.32 have described a technique in which because of their limited duration of action. These tech-
a dural puncture is made with a small-gauge spinal needle niques may be indicated for parturients who require anal-
but no drug is injected into the subarachnoid space. After gesia or anesthesia shortly before anticipated vaginal
injection of epidural local anesthetic and opioid, blockade delivery or in settings in which continuous epidural anal-
of sacral dermatomes occurred more frequently in partu- gesia is not possible.33
rients with a dural puncture than in those without, pre-
sumably because of enhanced anesthetic solution
migration across the dural puncture site.
Informed Consent
CSE analgesia has several possible undesirable side Informed consent is an important aspect of preparation
effects. Dural puncture is required to initiate CSE anal- for neuraxial labor analgesia (see Chapters 12 and 33).
gesia, although puncture with a small-gauge pencil-point The preanesthetic evaluation and informed consent
needle does not appear to increase the risk for post–dural process allow the physician to allay the patient’s concerns
puncture headache.27 A more serious concern, however, and to demonstrate a commitment to her care. Most
is that dural puncture during labor may be a risk factor laboring women understand the need for informed
for postpartum neuraxial infection, a rare but potentially consent and appreciate the opportunity to participate in
life-threatening complication (see Chapter 32). decisions about their care.
The incidence of pruritus is higher with intrathecal
opioid administration than with epidural opioid admin-
istration.27 Another potential drawback of CSE analgesia
Equipment and Monitors
is that it is not clear for 1 to 2 hours after initiation of Resuscitation equipment, drugs, and supplies must be
analgesia whether the epidural catheter is properly sited immediately available for the management of serious
in the epidural space. Thus, CSE analgesia may not be complications of neuraxial analgesia (e.g., hypotension,
the technique of choice if a functioning epidural catheter total spinal anesthesia, systemic local anesthetic toxicity)
is critical to the safe care of the patient (e.g., a mother (see Box 12-1).16 Emergency airway equipment should
with an anticipated difficult airway or a worrisome fetal be checked before the administration of neuraxial
heart rate [FHR] tracing). analgesia.
The most common CSE technique for labor analgesia During the initiation of neuraxial analgesia, the partu-
is the needle-through-needle technique in a midlumbar rient’s oxygen saturation is measured continuously and
interspinous space (see Chapter 12). Analgesia is main- the blood pressure is assessed every 2 to 3 minutes for 15
tained via the epidural catheter, as with traditional epi- to 20 minutes after the neuraxial anesthetic administra-
dural analgesia. tion, or until the mother is hemodynamically stable (see
Chapter 12). The FHR should be monitored before and
after the initiation of neuraxial analgesia; it may be dif-
Continuous Spinal Analgesia
ficult to monitor the FHR during the actual procedure.16
Continuous spinal analgesia is used occasionally for labor During maintenance of neuraxial analgesia, maternal
analgesia but is not practical for most parturients. Because blood pressure is measured every 15 to 30 minutes, or
the available catheters require dural puncture with a more frequently if hypotension ensues. The sensory level
large-gauge introducer needle, the technique is associ- of analgesia and the intensity of motor block (Box 23-3)
ated with an unacceptably high incidence of post–dural are assessed after the administration of the test and thera-
puncture headache. However, continuous spinal analge- peutic doses of local anesthetics. Subsequently, sensory
sia is a management option in patients with unintentional level, motor block, and pain control are assessed at regular
dural puncture. Continuous spinal analgesia can readily intervals.
be converted to surgical anesthesia if necessary.
Caudal Analgesia
BOX 23-3 Assessment of Motor Block
Continuous caudal epidural analgesia is used infrequently
in modern obstetric anesthesia practice. It is technically • Complete: patient unable to move feet or knees
• Almost complete: patient able to move feet only
more difficult to place a caudal catheter than a lumbar • Partial: patient just able to move knees
epidural catheter. Large volumes of anesthetic solution • None: patient capable of full flexion of knees and feet
are required to extend neuroblockade to the low thoracic
spinal segments, resulting in higher maternal plasma con- Adapted from Bromage PR. Epidural Analgesia. Philadelphia, WB
centrations of drug. There is a risk for needle/catheter Saunders, 1978:144.
462 PART VI Labor and Vaginal Delivery
Prior to the initiation of neuraxial analgesia, ultraso- Suggested Procedure for Initiation
nographic imaging of the back may be helpful, especially BOX 23-4
of Epidural Labor Analgesia
in parturients whose landmarks are difficult to palpate.
1. Complete preparation for neuraxial analgesia check-
Intravenous Hydration list (see Box 23-2).
2. Position patient with the help of an assistant (lateral
Placement of an intravenous catheter (preferably 18-gauge decubitus or sitting).
or larger) and correction of hypovolemia with intravenous 3. Initiate maternal blood pressure and pulse oximetry
hydration are necessary before the initiation of neuraxial monitoring and fetal heart rate monitoring.
analgesia to mitigate hypotension that can result from 4. Initiate an intravenous fluid bolus (500 mL of lac-
tated Ringer’s solution).
sympathetic blockade. Data from small studies are con- 5. Site epidural catheter in epidural space using sterile
flicting as to whether a fluid bolus administered immedi- technique.
ately before the initiation of analgesia decreases the risk 6. Administer an epidural test dose (see Table 12-2).
for nonreassuring FHR patterns.34-36 Most anesthesia pro- 7. If the test dose is negative, secure epidural catheter
viders administer approximately 500 mL of lactated and position patient in the lateral position.
Ringer’s solution (without dextrose), although the ASA 8. Administer 5 to 15 mL of epidural local anesthetic,
Task Force on Obstetric Anesthesia has stated that a fixed in 5-mL increments (usually low concentration of
volume of intravenous fluid is not required before neur- local anesthetic combined with a lipid-soluble opioid
axial analgesia is initiated.16 Severe hypotension is less [see Table 23-2]).
likely with the contemporary practice of administering a 9. Monitor maternal blood pressure every 2 to 3
minutes for 15 to 20 minutes, or until parturient is
dilute solution of local anesthetic for epidural analgesia hemodynamically stable.
or an intrathecal opioid for spinal analgesia. 10. Assess pain score and extent of sensory blockade
Studies of intravenous hydration and spinal anesthesia (cephalad and caudad).
for cesarean delivery suggest that there is no advantage 11. Initiate maintenance epidural analgesia (see Table
to administering the fluid before the initiation of anes- 23-5).
thesia (preload) compared with administering the fluid at
the time of initiation of anesthesia (co-load).37 Rarely,
hydration should be guided by serial assessment of intra-
vascular fluid volume (e.g., central venous pressure, INITIATION OF EPIDURAL ANALGESIA
transthoracic echocardiography). Fluid administration
should be judicious in parturients at risk for pulmonary A procedure for initiating epidural labor analgesia is out-
edema (e.g., women with severe preeclampsia). lined in Box 23-4. Commonly, after siting the epidural
A balanced electrolyte solution (e.g., lactated Ringer’s catheter in the epidural space, a test dose is administered
solution) without dextrose is the most commonly used to rule out intrathecal or intravascular placement of the
intravenous fluid for bolus administration. Data are con- epidural catheter. After a negative test, epidural analgesia
flicting as to whether the maintenance intravenous infu- is established with the incremental injection of a local
sion of dextrose-containing fluid during labor is associated anesthetic, usually in combination with a lipid-soluble
with a lower incidence of umbilical cord blood acide- opioid. Maternal vital signs are monitored and clinical
mia.38,39 One randomized controlled trial demonstrated analgesia is verified.
shorter labor in women who received an intravenous
solution of normal saline with dextrose compared with
saline without dextrose.40 However, anesthesia and
Epidural Test Dose
obstetric providers should avoid the bolus administration The purpose of the test dose is to help identify uninten-
of dextrose-containing solutions in laboring women. tional cannulation of a vein or the subarachnoid space.
The test dose should contain a dose of local anesthetic
and/or another marker sufficient to allow the recognition
Maternal Positioning of intravenous or subarachnoid injection but not so large
Either the lateral decubitus or the sitting position can be as to cause systemic toxicity or total spinal anesthesia.
used during initiation of neuraxial analgesia (see Chapter The most common intravascular test dose contains epi-
12). Factors to consider when positioning the parturient nephrine (see Chapter 12).
for the procedure include patient comfort, avoidance of The use of the epinephrine test dose in obstetrics is
aortocaval compression, ability to monitor the FHR, pro- not without detractors. Some anesthesia providers fear
vider comfort and experience, and optimal positioning of that intravenous injection of epinephrine may decrease
the spine and palpation of landmarks. Patient position uteroplacental perfusion and precipitate fetal compro-
relative to the baricity of the anesthetic solution should mise. However, there has been no report of adverse
be considered during initiation of spinal analgesia/ neonatal outcome after intravenous injection of an
anesthesia. There is little evidence that patient position epinephrine-containing test dose. Another argument
influences the extent of neuroblockade during initiation against routine use of a test dose is that aspiration of
of epidural analgesia/anesthesia. After completion of the multi-orifice catheters is 98% sensitive in identifying
procedure, parturients should be assisted to the lateral their intravascular location.41 (The sensitivity of aspira-
position for the first 15 to 30 minutes after the neuraxial tion is significantly lower for single-orifice catheters.)
injection to alleviate aortocaval compression. The epidural test dose contributes to undesirable motor
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 463
blockade.42,43 Finally, because modern epidural labor allows for the use of lower doses of each agent, thus
analgesia involves the infusion of a low concentration of minimizing undesirable side effects. For example, when
local anesthetic solution, unintentional intravascular or used alone without an opioid, the local anesthetic dose
intrathecal administration is not likely to result in cardio- required for effective epidural analgesia is associated with
vascular collapse or total spinal anesthesia. an unacceptably high incidence of motor blockade. Simi-
Others argue that the test dose still has a role in obstet- larly, used alone, high doses of epidural opioid are
ric anesthesia practice.44 Large volumes of a concentrated required for satisfactory analgesia during early labor, and
local anesthetic solution are still routinely administered such doses are associated with significant systemic absorp-
for emergency cesarean delivery. Although not a safety tion and systemic side effects. The addition of an opioid
issue, it is easier for the parturient and anesthesia provider to the local anesthetic also shortens latency,48 an impor-
to identify a misplaced catheter at the time of initial tant aspect of labor analgesia, especially with the use of
placement and to replace the catheter at that time rather long-acting (and therefore, long-latency) local anesthet-
than identify the misplaced catheter after the sterile field ics. Thus, contemporary epidural labor analgesia practice
has been breached and the parturient repositioned. most often incorporates low doses of a long-acting local
The epinephrine test dose is less specific in laboring anesthetic combined with a lipid-soluble opioid.
women because cyclic changes in maternal heart rate
complicate interpretation of its effects.45 For this reason, Local Anesthetics
if used, the test dose should be given immediately after a
uterine contraction so there is less confusion as to whether Bupivacaine. Traditionally, the amide local anesthetic
tachycardia is caused by pain or intravenous epinephrine. bupivacaine has been the most commonly used agent for
Other methods of detecting intravascular injection are epidural labor analgesia. Bupivacaine is highly protein-
discussed in Chapter 12. bound, a feature that limits transplacental transfer. The
No matter whether a formal test dose is used or not, umbilical vein–to–maternal vein concentration ratio is
it is imperative that the anesthesia provider take the time approximately 0.3.49 After epidural administration of
to look for evidence of unintentional intrathecal injection bupivacaine (without opioid) during labor, the patient
of local anesthetic. Finally, every anesthesia provider first perceives pain relief within 8 to 10 minutes,50 but
should remember that no single test dose regimen can approximately 20 minutes is required to achieve the peak
exclude every case of unintentional intravenous or sub- effect. Duration of analgesia is approximately 90 minutes.
arachnoid injection. Box 12-3 summarizes steps that may Bupivacaine 6.25 to 12.5 mg (e.g., 10 to 20 mL of a
be taken to decrease the risk for unintentional intrave- 0.0625% solution, or 5 to 10 mL of a 0.125% solution)
nous or subarachnoid injection of local anesthetic. combined with fentanyl or sufentanil is adequate to initi-
ate labor analgesia in most parturients (Table 23-2).
The potency of local anesthetics for neuraxial labor
Choice of Drugs analgesia is often assessed by determining the median
The ideal analgesic drug for labor would provide rapid effective concentration of local anesthetic solution when
onset of effective analgesia with minimal motor blockade, administered as a 20-mL epidural bolus (this concentra-
minimal risk for maternal toxicity, and negligible effect on tion is often referred to as the minimum local anesthetic
uterine activity and uteroplacental perfusion. It would concentration [MLAC]). It is lower for women in early
undergo limited transplacental transfer and thus have labor than in late labor,51 and it is also lower when the
minimal direct effect on the fetus. Finally, this ideal agent local anesthetic is combined with a lipid-soluble opioid.52
would have a long duration of action. Although this perfect It is important to consider both the local anesthetic
analgesic drug does not exist, the combination of a local dose and concentration for initiation and maintenance of
anesthetic with an opioid allows us to approach this goal. epidural analgesia. Christiaens et al.53 randomly assigned
Traditionally, local anesthetics were administered to parturients to receive epidural bupivacaine 20 mg diluted
block both the visceral pain of labor (lower uterine in 4 mL, 10 mL, or 20 mL (0.5%, 0.2%, and 0.1%
segment distention and cervical dilation) and the somatic solutions, respectively). Analgesia in the 10-mL and
pain (descent of the fetus in the birth canal). Almost 40 20-mL groups was superior to that in the 4-mL group,
years ago, investigators identified dense concentrations and duration of analgesia was longest in the 20-mL
of opioid receptors in the dorsal horn of the spinal cord.46 group. Lyons et al.54 compared the minimum local anes-
The application of small doses of an opioid to these thetic volume (MLAV) and minimum local anesthetic
receptor sites generates a specific and profound opioid dose (MLAD) for 0.125% and 0.25% bupivacaine for
response.46 The introduction of neuraxial opioids to the epidural labor analgesia. Bupivacaine 0.125% produced
armamentarium of the obstetric anesthesia provider analgesia equivalent to that provided by bupivacaine
moved us closer to the prediction made by Benjamin 0.25%, with a 50% increase in required volume and a
Rush in 1805: “A medicine would be discovered which 25% reduction in dose (Table 23-3). Stated differently,
should suspend sensibility altogether and leave irritability a dose-sparing effect is achieved by administering a
or powers of motion unimpaired.”47 Intrathecal opioids 0.125% solution of bupivacaine rather than a 0.25%
effectively relieve the visceral pain of the early first stage solution. Ginosar et al.55 randomized parturients to
of labor, although they must be combined with a local receive maintenance of analgesia with an epidural infu-
anesthetic to effectively relieve the somatic pain of the sion of either bupivacaine 0.25% at 5 mL/h or bupiva-
late first stage and the second stage of labor. The com- caine 0.0625% at 20 mL/h (10 mg/h in both groups).
bination of a local anesthetic with a lipid-soluble opioid The median bupivacaine dose was lower and patient
464 PART VI Labor and Vaginal Delivery
advantage for ropivacaine in terms of outcome of labor studies have demonstrated that the epidural administra-
(see later discussion), although the incidence of motor tion of lidocaine, bupivacaine, and 2-chloroprocaine have
blockade was less in the ropivacaine groups.66,74,75 similar neonatal outcomes.86,87 Although some investiga-
There is no clear evidence of greater patient safety, tors have observed subtle differences in neurobehavior
lower risk for instrumental vaginal delivery, or other between infants exposed to lidocaine and those exposed
improved outcomes when ropivacaine is used to provide to other local anesthetics, these differences are within the
epidural labor analgesia.74,76 A 2010 review concluded inherent variability of the examinations and are not clini-
that there is no advantage to the routine use of ropiva- cally significant. Other factors (e.g., mode of delivery)
caine compared with bupivacaine for labor analgesia.76 In appear to be much more important determinants of neo-
contrast, ropivacaine offers greater patient safety in set- natal condition.
tings in which high concentrations and greater volumes
of drugs are administered (e.g., brachial plexus blockade 2-Chloroprocaine. An ester local anesthetic, 2-
or epidural anesthesia for cesarean delivery).77 chloroprocaine has a rapid onset of action. Epidural
Like bupivacaine, ropivacaine is often combined with administration of 10 mL of 2% 2-chloroprocaine provides
fentanyl or sufentanil for labor analgesia. Ropivacaine effective analgesia for approximately 40 minutes. The
concentrations used to initiate epidural analgesia range short duration of action limits its usefulness during
from 0.08% to 0.2% (see Table 23-2). Higher concentra- labor. In addition, the epidural administration of 2-
tions are used if the drug is administered without an chloroprocaine may adversely affect the efficacy of subse-
opioid. quently administered epidural bupivacaine and opioids,88,89
although it is unclear whether the mechanism is related to
Levobupivacaine. Levobupivacaine is the levorotary pharmacokinetic or pharmacodynamic properties of the
enantiomer of bupivacaine (which is a racemic mixture). drug.90,91 In obstetric practice, 2-chloroprocaine is most
It is not available in the United States. Both preclinical commonly used for extension of epidural labor analgesia
and clinical studies have suggested that, like ropivacaine, for instrumental vaginal delivery (see later discussion) or
levobupivacaine has less potential for cardiotoxicity than emergency cesarean delivery (see Chapter 26).
bupivacaine when equal doses of the two drugs are com-
pared.78,79 One study found that levobupivacaine was Opioids
essentially equipotent to bupivacaine with a potency ratio
of 0.98; however, the 95% CI was wide (0.67 to 1.41).80 Lipid-Soluble Opioids: Fentanyl and Sufentanil. Mor-
Other studies have suggested that levobupivacaine and phine was one of the first opioids to be studied for labor
ropivacaine have similar potency.81,82 In an MLAC study analgesia. However, because of its long latency, side
that compared the motor blocking potency of bupiva- effects, and inconsistent analgesia, morphine has largely
caine and levobupivacaine,83 levobupivacaine was less been replaced by the lipid-soluble opioids fentanyl and
potent than bupivacaine (potency ratio, 0.87; 95% CI, sufentanil (see Chapter 13). The lipid-soluble agents
0.77 to 0.98).83 Beilin et al.66 compared epidural bupiva- have a rapid onset of action. Permeability (of the dura-
caine, ropivacaine, and levobupivacaine (0.0625% with arachnoid) is not a rate-limiting factor, and increasing the
fentanyl 2 µg/mL) for labor analgesia. There were no concentration gradient (by administration of a larger
differences among groups in obstetric outcomes, although dose) facilitates faster entry into the spinal cord. The high
the incidence of motor blockade was lower in the ropi- lipid solubility of these agents also results in a shorter
vacaine and levobupivacaine groups. Therefore, although duration of action and greater systemic absorption than
epidural bupivacaine is more potent than ropivacaine for occurs with water-soluble drugs.
both sensory and motor blockade during labor, and may Some investigators have suggested that the improved
be more potent than levobupivacaine, there do not appear analgesia results from a supraspinal action rather than a
to be any clinical advantages of one drug over the other primary spinal action. However, several studies have
two drugs for epidural labor analgesia. refuted this theory, including studies of epidural opioid
administration by bolus92 and continuous infusion.93 Vella
Lidocaine. Lidocaine is an amide local anesthetic with et al.92 observed that the initiation of epidural analgesia
a duration of action intermediate between those of bupi- with 0.25% bupivacaine with epidural fentanyl 80 µg*
vacaine and 2-chloroprocaine. During labor, the admin-
istration of a 0.75% to 1.0% solution of lidocaine typically
*The Institute of Safe Medicine Practices (ISMP) has recommended
provides satisfactory analgesia. Lidocaine is not com- that health care providers never use µg as an abbreviation for micro-
monly used for initiation or maintenance of epidural grams, but rather they should use mcg (http://www.ismp.org/tools/
labor analgesia, in part because of its shorter duration of errorproneabbreviations.pdf, accessed February 2013). The use of
action in comparison with bupivacaine, ropivacaine, and the symbol µg is frequently misinterpreted and involved in harmful
medication errors. The abbreviation may be mistaken for mg (mil-
levobupivacaine. Lidocaine is less protein-bound than ligrams), which would result in a 1000-fold overdose. The symbol µg
these other amide local anesthetics, and at delivery, the should never be used when communicating medical information,
umbilical vein–to–maternal vein lidocaine concentration including pharmacy and prescriber computer order entry screens,
ratio is approximately twice that of bupivacaine.84 Early computer-generated labels, labels for drug storage bins, and medica-
studies discouraged the epidural administration of lido- tion administration records. However, most scholarly publications
have continued to use the abbreviation µg. The editors have chosen
caine in pregnant women because epidural lidocaine was to retain the use of the abbreviation µg throughout this text. However,
associated with abnormal neonatal neurobehavioral find- the editors recommend the use of the abbreviation mcg in clinical
ings.85 Subsequently, larger, more carefully controlled practice.
466 PART VI Labor and Vaginal Delivery
in the fetus and neonate, and (4) decreased intensity of dose, another study found no differences in latency and
motor blockade. quality of analgesia among epidural sufentanil doses of 5,
Several studies have directly compared the administra- 10, 20, 30, 40, and 50 µg.114 However, the duration of
tion of epidural fentanyl or sufentanil combined with a analgesia was longer after the higher doses of sufentanil.
local anesthetic for the initiation of labor analgesia. There The range of fentanyl and sufentanil doses used for
were no differences in analgesia in women in early labor the initiation of epidural labor analgesia is shown in
randomly assigned to receive either fentanyl 100 µg or Table 23-2. Pain and analgesic requirements vary depend-
sufentanil 20 µg immediately after a lidocaine 45-mg/ ing on several factors, including parity, stage of labor,
epinephrine 15-µg test dose.108 In contrast, a second presence of ruptured membranes, oxytocin augmenta-
study demonstrated slightly better analgesia 20 minutes tion, and whether the opioid is administered in combina-
after injection of 0.125% bupivacaine (15 mg) with suf- tion with a local anesthetic. One study reported that
entanil 15 µg than after the same dose of bupivacaine the ED50 of epidural sufentanil was higher in women
with fentanyl 75 µg.109 undergoing prostaglandin induction of labor than in
In the United States, fentanyl is more commonly women with spontaneous labor.115 Conell-Price et al.116
used because historically it has had a lower acquisition developed a model of labor pain in nulliparous women
cost than sufentanil. Additionally, the concentration and found that the use of oxytocin was associated with
of the commercially available sufentanil preparation 48% more pain at the start of labor. Preliminary evidence
(50 µg/mL) may make drug errors more likely with suf- suggests that pharmacogenetics may also play a role in
entanil than with fentanyl because sufentanil doses sig- dose requirements. Camorcia et al.117 reported that nul-
nificantly lower than 50 µg are used for initiation of liparous women who were heterozygous or homozygous
epidural analgesia. for the single nucleotide polymorphism (SNP) A118G
There are few rigorous dose-response studies of epidural (substitution of adenine for guanine at position 118) of
fentanyl or sufentanil combined with bupivacaine for ini- the gene encoding the µ-opioid receptor (OPRM1) had
tiation of epidural labor analgesia. Herman et al.110 ran- a lower ED50 for epidural sufentanil administered for
domly assigned 100 laboring women with a cervical labor analgesia.
dilation of 5 cm or less to receive 0.125% bupivacaine Several early studies suggested that the duration of
10 mL, combined with fentanyl 0 to 100 µg (in 25-µg epidural and spinal analgesia may exhibit circadian
increments) or sufentanil 0 to 25 µg (in 5-µg increments), rhythm (chronobiology), possibly secondary to human
injected after a negative epidural test dose (bupivacaine biologic rhythms.118 More recently, however, in a second-
7.5 mg with epinephrine 15 µg). Using a probit dose- ary analysis of data from a large study, Scavone et al.119
response analysis, these researchers calculated the effec- found no evidence of a circadian response to intrathecal
tive dose in 95% of subjects (ED95) to be 50 µg for fentanyl or intravenous opioid labor analgesia. In a
fentanyl and 8 µg for sufentanil; these figures equate to detailed analysis of data from a study designed to test
a sufentanil-to-fentanyl potency ratio of 6.3 : 1. Capogna whether parturient response to intrathecal bupivacaine
et al.111 sought to determine the median effective analge- exhibited a circadian rhythm, Shafer et al.120 demon-
sic dose (ED50) of epidural fentanyl and sufentanil alone strated that external daily rhythms, such as nursing shifts,
(no local anesthetic) for the initiation of epidural may contribute to the appearance of biologic rhythm.
analgesia in nulliparous women with a cervical dilation Thus, whether a circadian response to neuraxial local
between 2 and 4 cm. The ED50 of fentanyl was 124 µg anesthetic or opioid exists, or is clinically significant,
(95% CI, 118 to 131) and the ED50 of sufentanil was requires further study.
21 µg (95% CI, 20 to 22), with a potency ratio of 5.9 : 1. Current evidence supports the administration of epi-
The potency ratio in volunteers subjected to an electrical dural opioid doses at the lower end of the dose range for
stimulus was approximately 5 : 1.112 Taken together, these nulliparous women, for women in early labor, or when
data suggest that the potency ratio of sufentanil to fen- the opioid is co-administered with a local anesthetic.
tanyl administered into the epidural space is approxi- Higher doses are associated with a higher incidence of
mately 6 : 1. maternal side effects and the potential for neonatal
Several studies have compared bupivacaine combined depression (see later discussion). The major maternal side
with fentanyl 50 µg and 100 µg. No differences in the effect of epidural fentanyl and sufentanil for labor anal-
onset, duration, and quality of analgesia were noted in gesia is pruritus. Neonatal outcomes do not appear to be
Asian women randomly assigned to receive 0.125% bupi- adversely affected by the addition of fentanyl or sufent-
vacaine (10 mg) combined with either 50 or 100 µg of anil to a local anesthetic for epidural analgesia (see later
fentanyl.113 In contrast, when 0.125% bupivacaine discussion). In fact, the combination of drugs allows
(15 mg) with epinephrine 15 µg was administered to lower doses of both drugs to be administered, resulting
laboring Italian women with either 50 or 100 µg of fen- in lower concentrations of both drugs in the neonate.
tanyl, there was no difference in the onset or duration of Two studies found that the diluent volume (2 to
analgesia, but more women in the 100-µg group had 20 mL) did not affect the onset and duration of epidural
excellent analgesia.106 labor analgesia when fentanyl was injected into the epi-
There were no differences in latency, duration of anal- dural space after the injection of a local anesthetic
gesia, and quality of analgesia when analgesia was induced solution.121,122
with 0.125% bupivacaine (12.5 mg)/epinephrine 12.5 µg
and either 7.5 or 15 µg of sufentanil.105 Similarly, after Other Opioids. Morphine was one of the first opioids
injection of a lidocaine 60-mg/epinephrine 15-µg test used for labor analgesia. Hughes et al.123 compared
468 PART VI Labor and Vaginal Delivery
analgesia using epidural administration of morphine alone or in combination with bupivacaine has any advan-
(2.0, 5.0, and 7.5 mg) with that using epidural bupiva- tages over a combination of a long-acting amide local
caine 0.5%. Morphine was effective in 7 of 11 parturi- anesthetic and a lipid-soluble opioid.
ents until the end of the first stage of labor, but all Butorphanol is a lipid-soluble opioid agonist-
parturients required bupivacaine for adequate analgesia antagonist, with weak µ-receptor and strong κ-receptor
during the second stage of labor. Subsequently, investi- activity. Because κ-opioid receptors appear to be involved
gators combined morphine with bupivacaine and in the modulation of visceral pain, κ-receptor agonists
observed a longer duration of analgesia compared with should be useful agents for the relief of labor pain, which
that for bupivacaine alone.124 However, the inconsistent has a significant visceral component (see Chapter
analgesia, long latency (30 to 60 minutes), and high inci- 20).124,135,136 Somnolence is the most prominent side
dence of side effects of morphine (which continued after effect of epidural butorphanol. The addition of butor-
delivery), along with the introduction of lipid-soluble phanol 1, 2, or 3 mg to 0.25% bupivacaine (25 mg)
opioids and epidural infusion pumps into clinical prac- shortened latency and prolonged the duration of analge-
tice, have made the use of epidural morphine for labor sia in comparison with epidural bupivacaine alone in one
analgesia largely obsolete. study.135 The investigators concluded that the optimal
Several studies described the use of alfentanil with dose of butorphanol was 2 mg. Of concern was the
bupivacaine for labor analgesia.125,126 Alfentanil has lower observation of a transient sinusoidal FHR pattern in the
lipid solubility than both fentanyl and sufentanil. Only a 3-mg group that was not unlike that seen after the intra-
few small studies have compared alfentanil with other venous administration of butorphanol.136 However, there
opioids for labor analgesia. was no difference among groups in Apgar scores, umbili-
Several groups of investigators have reported the use cal cord blood gas and pH measurements, or neurobe-
of epidural hydromorphone for labor analgesia.127-129 havioral scores. Similarly, Abboud et al.124 observed that
The lipid solubility of hydromorphone lies between those the addition of butorphanol 1 or 2 mg to 0.25% bupi-
of morphine and fentanyl, but is closer to that of mor- vacaine resulted in better quality and longer duration of
phine.130 In a large prospective observational study, effec- analgesia than the epidural administration of bupivacaine
tive labor analgesia was obtained by initiating analgesia alone, without maternal or neonatal side effects.
with 0.25% bupivacaine (20 to 25 mg) with epinephrine However, some anesthesia providers have noted that the
(40 to 50 µg), followed by hydromorphone 100 µg.127 epidural administration of butorphanol results in som-
However, Mhyre129 observed that effective labor analge- nolence and occasional dysphoria, which are side effects
sia could not be provided by 0.035% bupivacaine (7 mg) of κ-receptor stimulation.
with hydromorphone 100 to 110 µg. In another trial, Diamorphine (heroin) is available for epidural anal-
parturients were randomly assigned to receive either epi- gesia in the United Kingdom. Using isobolographic
dural hydromorphone 300 µg or saline-control immedi- analysis, McLeod et al.137 concluded that the combina-
ately after the initiation of analgesia with lidocaine 45 mg, tion of diamorphine and levobupivacaine is additive
epinephrine 15 µg, and fentanyl 100 µg.128 Duration of when used for first-stage labor analgesia. Several studies
analgesia and side effects were similar in the two groups. from the United Kingdom have reported diamorphine
At the current time, further investigation is required doses between 250 and 500 µg/h (i.e., diamorphine 25 to
before hydromorphone can be recommended for epidu- 50 µg/mL combined with a low concentration of bupi-
ral labor analgesia. vacaine).125,138 Whether diamorphine offers any advan-
Meperidine may be used effectively alone (without a tages over fentanyl or sufentanil has not been studied.
local anesthetic), in part because it possesses local anes- It is not available for clinical administration in the
thetic properties.131 When given during labor, epidural United States.
meperidine 100 mg provides analgesia similar to that
provided by 0.25% bupivacaine, with less motor block- Adjuvants
ade. However, this dose of epidural meperidine produces
more sedation, nausea, and pruritus than epidural bupi- Although the contemporary mainstay of epidural labor
vacaine. Handley and Perkins132 observed that the addi- analgesia includes administration of a long-acting amide
tion of meperidine 25 mg to 0.125%, 0.187%, or 0.25% local anesthetic combined with a lipid-soluble opioid,
bupivacaine (10 mL) provided adequate analgesia for the other drugs may be added as adjuvants. Adjuvants may
first stage of labor. The use of the more concentrated prolong the duration of analgesia or decrease the required
solutions (i.e., 0.187% and 0.25% bupivacaine) did not anesthetic dose, thus reducing the risk for specific side
enhance the quality or duration of analgesia but did effects.
shorten latency (10 to 20 minutes versus 20 to 30 minutes
for the less concentrated solution). Epidural administra- Epinephrine. Some anesthesia providers add a low
tion of meperidine effectively prevents or treats the shiv- dose of epinephrine (1.25 to 5 µg/mL [1 : 800,000 to
ering that often occurs during labor.133 Investigators from 1 : 200,000]) to the local anesthetic solution (Table 23-4).
Saudi Arabia randomly allocated women to receive 0.1% The addition of epinephrine shortens the latency and
bupivacaine with either meperidine 1 mg/mL or fentanyl prolongs the duration of epidural bupivacaine analge-
2 µg/mL.134 No differences were noted between groups sia.50,139 The MLAC of bupivacaine with epinephrine
in analgesic characteristics, except that women in the (66 µg) is 29% lower than that of bupivacaine without
meperidine group had a higher incidence of nausea and epinephrine,140 perhaps as a result of the stimulation of
vomiting. Currently there is no evidence that meperidine alpha-adrenergic receptors in the spinal cord.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 469
80
Other Opioids. Early studies demonstrated that the
60 intrathecal administration of 0.5 to 2 mg of morphine
40
reliably produced analgesia during the first stage of
labor, but the analgesia was less reliable during the second
20 stage of labor and during instrumental vaginal deliv-
ery.187,188 However, intrathecal administration of these
0
5 µg 10 µg 15 µg 20 µg 25 µg 35 µg 45 µg relatively large doses of morphine resulted in a high inci-
dence of side effects, including somnolence, nausea and
Group (fentanyl dose)
vomiting, pruritus, and respiratory depression. In addi-
FIGURE 23-4 ■ Duration of intrathecal fentanyl analgesia (mean
tion, the onset of analgesia is slower with intrathecal
± SD) among nulliparous women in active labor who received morphine than with lipid-soluble opioids, and the long
5, 10, 15, 20, 25, 35, or 45 µg. Duration of analgesia (time from duration of action may be a disadvantage (i.e., the parturi-
intrathecal dose to first request for additional analgesia) differed ent may deliver before the regression of side effects).
significantly among the groups (analysis of variance [ANOVA], Abouleish189 reported a case of life-threatening respira-
P < .005). *P < .05 versus groups 15 through 45 µg; **P < .05
versus groups 25 through 45 µg. (From Palmer CM, Cork RC, Hays tory depression 1 hour after delivery and 7 hours after
R, et al. The dose-response relationship of intrathecal fentanyl for the administration of 1 mg of hyperbaric intrathecal
labor analgesia. Anesthesiology 1998; 88:355-61.) morphine.
472 PART VI Labor and Vaginal Delivery
Responders (%)
study from Sweden193 found no advantage to adding mor- 60
phine 0.05 or 0.1 mg to bupivacaine 1.25 mg and sufen- 50 Levobupivacaine
tanil 5 µg. The addition of low-dose morphine to 40 Bupivacaine
intrathecal bupivacaine and a lipid-soluble opioid may be 30
Ropivacaine
Levobupivacaine
useful in low-resource settings in which continuous epi- 20 Bupivacaine
dural infusion techniques are impractical.33 When used Ropivacaine
10
as part of a CSE technique, the addition of intrathecal
0
morphine to bupivacaine and fentanyl has been shown to 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
result in less breakthrough pain during labor190-192 as well Dose of local anesthetic (mg)
as decreased analgesic use in the first 24 hours postpar-
tum, compared with intrathecal bupivacaine and fentanyl FIGURE 23-5 ■ Predicted (lines) and observed (symbols) dose-
without morphine.190,191 The incidence of intrapartum response of intrathecal bupivacaine, levobupivacaine, and ropi-
side effects was similar190,192; however, the morphine vacaine combined with sufentanil 1.5 µg in 450 laboring women.
The dose-response curves were constructed with the use of a
group had a higher incidence of postpartum nausea (17% probit regression model. The curves were compared with use
versus 0% for no morphine).190 of likelihood ratio tests. No difference was observed between
An alternative drug is meperidine. Meperidine is ropivacaine and levobupivacaine. Significant differences were
unique among the opioids in that it possesses weak local observed between bupivacaine and ropivacaine (P = .003) and
bupivacaine and levobupivacaine (P < .001). (From Van de Velde
anesthetic properties,131 and it has been used in large M, Dreelinck R, Dubois J, et al. Determination of the full dose-
doses (e.g., 1 mg/kg) as the sole agent to provide spinal response relation of intrathecal bupivacaine, levobupivacaine, and
anesthesia for surgical procedures.194 Intrathecal admin- ropivacaine, combined with sufentanil, for labor analgesia. Anesthe-
istration of meperidine (10 to 20 mg) results in effective siology 2007; 106:149-56.)
labor analgesia within 2 to 12 minutes, with a duration
of 1 to 3 hours. Honet et al.195 compared the efficacy of Local Anesthetics
intrathecal meperidine 10 mg, fentanyl 10 µg, and sufen-
tanil 5 µg in 65 laboring women. The three drugs were In the late first stage and the second stage of labor, a
similar in onset of analgesia (< 5 minutes) and duration local anesthetic must be added to the spinal opioid to
of effective analgesia (80 to 100 minutes). However, the block somatic stimuli from the vagina and perineum
meperidine group had significantly lower pain scores caused by descent of the fetus. The local anesthetic
after cervical dilation had progressed beyond 6 cm. works synergistically with the opioid, so lower doses of
As labor advances, the nature of pain becomes increas- both drugs can be used.168,169,173,199 Bupivacaine is most
ingly somatic; only meperidine also functions as a local commonly combined with fentanyl or sufentanil. The
anesthetic. This fact helps explain why meperidine pro- ED95 of bupivacaine was 3.3 mg when combined with
vided more effective analgesia during advanced labor, sufentanil 1.5 µg186 and 1.7 mg when combined with fen-
including the second stage. Booth et al.196 observed that tanyl 15 µg.200 Intrathecal bupivacaine doses between
intrathecal meperidine was associated with a significantly 1.25 and 2.5 mg are commonly used (see Table 23-2).
higher incidence of nausea and vomiting than a combina- Levobupivacaine and ropivacaine are not usually used for
tion of fentanyl and bupivacaine for labor analgesia. intrathecal injection in the United States. They are less
Therefore, intrathecal meperidine does not seem to offer potent than bupivacaine for intrathecal labor analgesia
any advantages over bupivacaine-fentanyl for routine (Figure 23-5).186,201 Spinal lidocaine has not been studied
intrathecal analgesia, although it may be useful for the for use in labor analgesia, but it is unlikely to have any
rare patient with a contraindication to bupivacaine- advantages compared with other, longer-acting amide
fentanyl administration. local anesthetics. Common doses of spinal local anes-
In the United Kingdom, some anesthesia providers thetics are shown in Table 23-2.
have advocated the intrathecal administration of diamor- Controversy exists as to whether the lower incidence
phine (heroin) for labor analgesia, although it is not and degree of motor blockade associated with ropivacaine
commonly used for this purpose. This drug is not avail- and levobupivacaine66,201 are a result of their inherent
able for clinical use in the United States. Kestin et al.197 difference in potency or of greater sensory-motor separa-
observed that the intrathecal administration of diamor- tion with the S(−)-enantiomer drugs.186 Camorcia et al.201
phine (0.2 to 0.5 mg) provided good to excellent analge- have suggested that, especially during intrathecal use,
sia in 90% of laboring women. The mean duration of ropivacaine may be associated with less motor blockade
analgesia was approximately 100 minutes. However, 75% than bupivacaine, even when equipotent doses (e.g.,
of patients had pruritus, nausea, and vomiting. In con- 3.6 mg ropivacaine and 2.4 mg bupivacaine) are admin-
trast, Vaughan et al.198 randomly assigned parturients to istered. However, this difference, even if it exists, is
receive intrathecal bupivacaine 2.5 mg with either fen- unlikely to have any clinical significance during spinal
tanyl 25 µg or diamorphine 0.25 mg. Duration of anal- labor analgesia because all local anesthetics administered
gesia was longer in the diamorphine group, but the for this purpose are administered in low doses that lead
incidence of side effects was low in both groups. to minimal motor blockade.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 473
Baricity of the Intrathecal Solution. The local routinely add adjuvant drugs, because they are associated
anesthetic/opioid solutions commonly injected for intra- with higher cost, higher rate or severity of side effects,
thecal labor analgesia have lower specific gravity relative and probably an increased risk for drug error.
to that of CSF and hence are hypobaric.202 The extent of
cephalad sensory blockade is higher for spinal analgesia
initiated with the parturient in the sitting position than MAINTENANCE OF ANALGESIA
in the lateral position.203 Adding dextrose to the solution
(opioid alone or opioid with local anesthetic) to make the Epidural Analgesia
solution hyperbaric results in less extensive sensory
blockade but also in inadequate analgesia.204-206 It is prob- Painful labor lasts several hours in most parturients;
ably necessary for the opioid to penetrate the spinal cord therefore, a single intrathecal or epidural injection of
rather than just the nerve roots; therefore, injection of a local anesthetic and/or opioid typically does not provide
hyperbaric solution of opioid and local anesthetic below adequate analgesia for the duration of labor. Supplemen-
the level of the spinal cord may lead to inadequate anal- tal doses are needed to maintain analgesia in most women.
gesia, even though the local anesthetic provides sensory Neuraxial analgesia is maintained with the intermittent
blockade to the T10 dermatome. or continuous administration of analgesics, usually a
combination of a long-acting amide local anesthetic and
a lipid-soluble opioid. By far the most common technique
Intrathecal Adjuvants
is administration of drugs via a catheter into the epidural
Several drugs have been investigated as adjuvants to space. It is occasionally advantageous to administer drugs
local anesthetics, opioids, or combinations of local anes- via a catheter into the subarachnoid space.
thetics and opioids for intrathecal labor analgesia (see
Table 23-4). In one study, the addition of clonidine Drugs for the Maintenance of Epidural Analgesia
30 µg to sufentanil (2.5 to 5 µg) prolonged the duration
of analgesia from 104 to 145 minutes without motor In the past, epidural labor analgesia was maintained with
block.207 Other investigators have had similar results the intermittent injection or continuous infusion of a
when clonidine was combined with sufentanil,208 neuraxial local anesthetic alone. Currently, most anesthe-
bupivacaine/ropivacaine and sufentanil,209,210 and neostig- sia providers maintain analgesia with a combination of a
mine.211 Intrathecal clonidine alone also provides analge- low-dose, long-acting amide local anesthetic and a lipid-
sia.212 Unfortunately, a disadvantage of clonidine is the soluble opioid (Table 23-5). In practice, neither lidocaine
high incidence of maternal hypotension and sedation as nor 2-chloroprocaine is used for maintenance of analge-
well as FHR abnormalities. The slightly longer duration sia. Both have a short duration of action, and tachyphy-
of analgesia provided by the addition of clonidine to laxis may develop more quickly with either of these local
bupivacaine and sufentanil is not an advantage when anesthetics than occurs with the longer-acting local
maintenance analgesia is provided by a continuous epi- anesthetics. Lidocaine crosses the placenta to a greater
dural infusion. Therefore, at present, intrathecal cloni- extent than bupivacaine, and there is less differentiation
dine cannot be recommended for routine spinal labor between the dose required for sensory and motor block-
analgesia, although it might be considered in parturients ade.217 There is no evidence that any one of the three
with contraindications to the use of other drugs.167 long-acting local anesthetics (bupivacaine, ropivacaine,
Adding intrathecal neostigmine to sufentanil,
bupivacaine/sufentanil, or clonidine has been found to
potentiate the analgesia and prolong its duration.211,213 TABLE 23-5 Anesthetic Solutions for
However, intrathecal neostigmine was associated with a Maintenance of Epidural Analgesia:
markedly higher incidence of severe nausea that was Continuous Infusion or Patient-
unresponsive to standard antiemetics.211,213 Therefore, Controlled Epidural Analgesia*
neostigmine cannot be recommended as an adjuvant for
Drug† Concentration
intrathecal labor analgesia.
Analgesia is prolonged by 15 to 40 minutes when epi- Local Anesthetics
nephrine is added to intrathecal bupivacaine-opioid.214-216 Bupivacaine 0.05-0.125%
Even an epinephrine dose as low as 2.25 µg prolonged Ropivacaine 0.08-0.2%
analgesia by 15 minutes.215 However, epinephrine 200 µg Levobupivacaine 0.05-0.125%
combined with bupivacaine 2.5 mg and sufentanil 10 µg Lidocaine‡ 0.5%-1.0%
resulted in a significant incidence of motor blockade214; Opioids
epinephrine doses between 12.5 and 100 µg prolonged Fentanyl 1.5-3 µg/mL
analgesia without any difference in the quality of Sufentanil 0.2-0.4 µg/mL
analgesia.216
In summary, no adjuvant studied to date prolongs the *Local anesthetic is most often combined with an opioid.
duration of fentanyl or sufentanil/bupivacaine analgesia †
Continuous infusions are usually administered at a rate of
long enough to avoid the use of maintenance epidural 8-15 mL/h into the lumbar epidural space.
‡
Lidocaine is not usually used for maintenance of epidural
analgesia for most parturients, and no adjuvant reduces analgesia because it crosses the placenta to a greater extent
or eliminates the side effects associated with the analgesic than the other amide local anesthetics and may be associated
drugs used clinically. Therefore, it makes little sense to with greater tachyphylaxis.
474 PART VI Labor and Vaginal Delivery
levobupivacaine) has any advantages in terms of clinical in women randomly assigned to receive epidural bupiva-
outcomes over the other two.66,75,76 Fentanyl is more caine with fentanyl 2.5 µg/mL or bupivacaine alone to
often detected in umbilical artery blood samples than maintain analgesia. There were no differences between
sufentanil (as discussed earlier)109; however, neonatal out- groups in measures of neonatal well-being at birth or 24
comes are good after maintenance epidural analgesia with hours after delivery.
either drug. Bernard et al.222 combined sufentanil 0, 0.078, 0.156,
As with the induction dose, the combination of a local 0.312, or 0.468 µg/mL with bupivacaine 0.125% and epi-
anesthetic with a lipid-soluble opioid allows administra- nephrine 1.25 µg/mL. Each solution was administered as
tion of a lower concentration and a smaller total dose of a 12-mL bolus via PCEA. Sufentanil concentrations
local anesthetic for maintenance of analgesia. This lower than 0.156 µg/mL did not provide adequate anal-
approach improves safety and leads to less motor block- gesia for the second stage of labor, and higher doses were
ade and greater patient satisfaction. Chestnut et al.98 associated with an increased incidence of pruritus. Loftus
demonstrated that maintenance of epidural analgesia by et al.109 compared bupivacaine with sufentanil 0.25 µg/
a continuous infusion of 0.0625% bupivacaine with fen- mL or fentanyl 1.5 µg/mL as a continuous epidural infu-
tanyl 2 µg/mL resulted in comparable maternal and neo- sion at 10 mL/h. Neonates in the fentanyl group had
natal outcomes, with a lower incidence of motor blockade, slightly lower 24-hour neuroadaptive capacity scores
compared with maintenance of analgesia by a continuous (NACS) than the sufentanil group.
epidural infusion of 0.125% bupivacaine alone. When
administered as intermittent epidural boluses for the Administration Techniques
maintenance of analgesia, the addition of sufentanil to
bupivacaine resulted in better quality analgesia and Intermittent Bolus. Before the introduction of infusion
decreased motor blockade at delivery.105 pumps, epidural analgesia was routinely maintained by
In contemporary clinical practice, the bupivacaine the intermittent administration of an additional thera-
concentration of maintenance bupivacaine/opioid solu- peutic bolus dose of local anesthetic when analgesia
tions ranges from 0.05% to 0.125%. Hess et al.218 retro- began to wane. When the patient began to experience
spectively analyzed the use of three solutions at their recurrent pain, the anesthesia provider assessed the pain
institution: bupivacaine 0.125% and bupivacaine relative to the stage of labor and the extent of sensory
0.0625%, both with fentanyl 2 µg/mL, administered at blockade and then administered another epidural bolus
8 to 12 mL/h, and bupivacaine 0.04% with fentanyl of local anesthetic. Analgesia was usually reestablished
1.7 µg/mL and epinephrine 1.7 µg/mL, administered at with the bolus injection of 8 to 12 mL of a local anesthetic/
15 mL/h. There were more interventions for break- opioid solution.
through pain in the two low-concentration groups and The spread and quality of analgesia may change with
more interventions for hypotension and motor blockade repeated lumbar epidural injections of local anesthetic.
in the high-concentration group. Beilin et al.219 initiated After several injections, blockade of the sacral segments,
analgesia with intrathecal bupivacaine/fentanyl and an intense motor blockade, or both may develop.146 The
epidural test dose, and then randomly assigned women sensory level and the intensity of motor blockade should
to receive maintenance epidural analgesia with one of be assessed and recorded before and after each bolus
four solutions: bupivacaine 0.125%, bupivacaine injection of local anesthetic.
0.0625%, or bupivacaine 0.04% with epinephrine 1.7 µg/ This intermittent bolus technique has several disad-
mL (all with fentanyl 2 µg/mL) or placebo (saline) at vantages, the most salient of which is that pain relief is
10 mL/h. The time to request for supplemental analgesia constantly interrupted by the regression of analgesia.
was longest in the bupivacaine 0.125% group; however, The patient must notify the labor nurse or midwife that
this group also had a higher incidence of motor blockade she is again uncomfortable and request additional anal-
than the other groups. Therefore, to avoid motor block- gesia. In the United States, labor nurses are not allowed
ade, it would seem reasonable to use a bupivacaine con- to administer additional epidural analgesic drugs223;
centration less than 0.125%, especially if it is administered therefore, the nurse must call the anesthesia provider,
via continuous epidural infusion (see later discussion). resulting in unavoidable delays in administration of addi-
The dose-response relationships for fentanyl and suf- tional analgesic drugs and additional pain for the patient.
entanil combined with a local anesthetic for the mainte-
nance of epidural analgesia have not been well studied. Continuous Infusion. Administration of a continuous
The concentration range of fentanyl used in clinical prac- epidural infusion of a dilute solution of local anesthetic
tice is 1.5 to 3 µg/mL, and that of sufentanil, 0.2 to combined with an opioid is a popular technique for
0.33 µg/mL. The optimal opioid concentration probably the maintenance of epidural analgesia during labor.
varies according to the local anesthetic concentration, the The potential benefits of a continuous epidural infusion
mode of drug delivery (i.e., bolus versus infusion), pres- include the maintenance of a stable level of analgesia and
ence of epinephrine, and the stage of labor, among other a less-frequent need for bolus doses of local anesthetic,
factors. Bader et al.220 infused epidural bupivacaine which may reduce the risk for systemic local anesthetic
0.125% with fentanyl 2 µg/mL at 10 mL/h for 1 to 15 toxicity. An additional advantage is a decreased workload
hours. Maternal and neonatal fentanyl concentrations, for the anesthesia provider.
and their ratio, remained constant over the infusion Published studies, however, have suggested that the
period, and no adverse maternal or neonatal outcomes continuous epidural infusion and intermittent bolus
were noted. Porter et al.221 compared neonatal outcomes injection techniques have a comparable safety record.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 475
Studies comparing intermittent bolus injections with more rapid rate of infusion most likely narrows the
continuous infusion were performed before the era of margin of safety.
neuraxial opioid administration; thus, the studies used
concentrations of bupivacaine (0.125% to 0.25%) higher Patient-Controlled Epidural Analgesia. The method
than those typically used in contemporary practice. In of delivering the anesthetic solution into the epidural
theory, maintenance of a constant level of anesthesia space influences the density of neuroblockade. Given the
should promote maternal hemodynamic stability and same concentration of local anesthetic, analgesia main-
improve fetal and neonatal outcome. Only one published tained by infusion results in greater drug use, a higher
study has suggested a trend toward less frequent hypoten- degree of motor blockade,225,229 and a higher incidence of
sion and a lower incidence of abnormal FHR patterns instrumental vaginal delivery than intermittent boluses.228
during the continuous epidural infusion of bupivacaine However, intermittent manual bolus administration by
than with intermittent bolus injections of bupivacaine; the anesthesia provider results in more breakthrough
however, neonatal outcomes were similar with the two pain, less patient satisfaction, and more work for the
techniques.224 anesthesia provider. PCEA is a method of delivering
Randomized trials of intrapartum epidural analgesia anesthetic solution to the epidural space that overcomes
maintained by either intermittent bolus injection or con- these disadvantages. Since its first description in 1988 by
tinuous infusion of bupivacaine have consistently demon- Gambling et al.,230 many studies have consistently found
strated that women require fewer bolus injections that the analgesia with PCEA is comparable to that with
administered by the anesthesia provider (i.e., fewer epi- continuous infusion techniques.229,231-237
sodes of breakthrough pain) with the continuous infusion Van der Vyver et al.238 reported a meta-analysis of nine
technique.224-226 The continuous infusion technique randomized controlled trials (n = 640) comparing PCEA
lengthens the time between bolus injections and leads to (without a background infusion) with continuous epidu-
greater patient satisfaction.226,227 This is advantageous in ral infusion analgesia. There were fewer anesthetic inter-
a busy obstetric anesthesia practice, in which an anesthe- ventions in the PCEA group, and the total bupivacaine
sia provider may not always be available to give an addi- dose was lower, as was the incidence of motor blockade
tional bolus dose of local anesthetic immediately after the (Figure 23-6). There were no differences in pain scores,
onset of recurrent pain. patient satisfaction, and maternal and neonatal outcomes
Most studies suggest that the continuous epidural between groups.
infusion technique leads to the administration of a larger Data are conflicting as to whether PCEA should
total dose of bupivacaine,225-228 but such a dose does not include a background infusion.237,239-247 Most studies
seem to result in higher maternal venous or umbilical have reported background infusions of 3 to 4 mL/h.
venous bupivacaine concentrations at delivery.226,228 The Bupivacaine consumption is higher in PCEA with a
continuous epidural infusion of bupivacaine often achieves background infusion than in a pure PCEA technique
satisfactory perineal analgesia, obviating the need for without a background infusion.238 A meta-analysis of five
a bolus dose of local anesthetic at delivery. Unfortunately, studies237,240,241,243,244 reported in the ASA Practice
a prolonged epidural infusion of 0.125% bupivacaine Guidelines for Obstetric Anesthesia16 concluded that a
at 10 to 14 mL/h may cause significant motor block- background infusion provides better analgesia than pure
ade.86,224,225,227,228 Titrating the dose of bupivacaine to meet PCEA without a background infusion. In a 2009 review,
the individual needs of each patient (rather than adminis- Halpern and Carvalho248 concluded that a background
tering the same dose to all patients), as well as reducing infusion improves analgesia and results in fewer unsched-
the total mass of bupivacaine by lowering the local anes- uled interventions by the anesthesia provider. There is
thetic concentration and adding an opioid, helps mini- no evidence that the higher local anesthetic dose associ-
mize motor blockade while providing effective analgesia. ated with a background infusion increases motor block-
Migration of the epidural catheter into the subarach- ade or has adverse effects on obstetric outcome when
noid, subdural, or intravenous space may occur with low-concentration infusion solutions are used. A typical
either the intermittent bolus injection or continuous infu- background infusion provides one third to one half of
sion technique. If the epidural catheter should migrate the total hourly dose.248 Sng et al.249 described a novel
into a vein during the continuous epidural infusion of a PCEA system in which they used a computer-integrated
dilute solution of local anesthetic, it is unlikely that the infusion pump to modify the background infusion rate
patient will have symptoms of local anesthetic toxicity; based on the previous hour’s requirement for patient-
rather, the level of anesthesia will regress. For this reason, administered bolus doses.
the anesthesia provider should suspect the intravenous A wide variety of PCEA regimens have been described
migration of an epidural catheter when a patient unex- (Table 23-6). The anesthesia provider can manipulate the
pectedly complains of pain during maintenance of anal- infusion solution (local anesthesia/opioid concentration),
gesia during a continuous epidural infusion. patient-controlled bolus volume, lockout interval, back-
Migration of the epidural catheter into the subdural ground infusion rate, and maximum allowable dose per
or subarachnoid space during an infusion should result in hour. Patient-controlled bolus doses from 2 to 20 mL
the slow ascent of the level of anesthesia and a greater and lockout intervals from 5 to 30 minutes have been
density of motor blockade. These observations apply to reported235,245-247,250-253; most studies have evaluated
the epidural infusion of a 0.125% solution of bupivacaine patient-controlled bolus doses of 5 to 12 mL. No
at a modest rate (e.g., 5 to 8 mL/h). The continuous study has found any differences in unscheduled pro-
infusion of a more concentrated solution or the use of a vider interventions when investigators manipulated the
476 PART VI Labor and Vaginal Delivery
Study (first PCEA Mean (SD) Infusion Mean (SD) Weighted mean difference
author [yr]) (n) (n) (95% confidence interval)
–10 –5 0 5 10
Favors Favors
B infusion PCEA
Likewise, larger volumes of a less concentrated anesthetic epidural space, or administration of an inadequate dose
solution provide better analgesia than smaller volumes of of local anesthetic.
a more concentrated solution. Presumably, distribution
of anesthetic solution in the epidural space is better when Equipment
larger volumes are administered under high injection
pressure.258 Several studies have demonstrated that timed Anesthesia providers should consider the safety of their
(automated) intermittent boluses (5 to 10 mL every 30 to equipment when choosing a maintenance technique.
60 minutes) administered via a programmable pump result The use of an infusion pump identical to that used for the
in improved patient satisfaction, less drug use, longer intravenous administration of other drugs increases the
duration of analgesia, and less breakthrough pain than a chance that a nurse or physician will inject oxytocin, mag-
continuous infusion of the same mass of drug per unit of nesium sulfate, or another drug into the epidural space
time.259-263 For example, Wong et al.259 randomly assigned unintentionally. Thus, the use of an infusion pump that is
patients to receive either a continuous epidural infusion used exclusively for epidural analgesia and that differs
of a dilute bupivacaine/fentanyl solution at 12 mL/h or from the pumps used for intravenous drug and fluid
6 mL of the same solution delivered as an automated administration is recommended. The pump should be
bolus every 30 minutes. Similarly, Sia et al.263 randomly easy to use, reliable, adjustable, and sturdy. PCEA pumps
assigned patients to receive either a continuous epidural should differ from patient-controlled intravenous analge-
infusion of a ropivacaine/fentanyl solution at 5 mL/h or sia (PCIA) pumps. The PCEA “buttons” should be labeled
5 mL of the same solution delivered as an automated with instructions that only the patient (not medical pro-
bolus every hour. All patients in both studies were allowed viders or family members) should push the button. If pos-
PCEA for the treatment of breakthrough pain. The total sible, pumps should be preprogrammed with maximum
dose of local anesthetic was smaller in the automated bolus safe limits to prevent errors in pump programming.
groups than in the continuous infusion groups. The anesthesia provider should use infusion tubing
Capogna et al.264 compared motor block and mode of (which connects the pump to the epidural catheter) that
delivery in women randomized to receive an automated is unique for the epidural administration of drugs. Some
timed bolus of levobupivacaine 0.0625% with sufentanil tubing is color coded (yellow). The presence of an injec-
0.5 µg/mL (10 mL every 60 minutes) or the same solu- tion side-port increases the likelihood of unintentional
tion as a continuous infusion (10 mL/h). Women were epidural administration of the wrong drug; thus, use of
able to treat breakthrough pain with PCEA using levobu- tubing that does not have an injection side-port is recom-
pivacaine 0.125% (5-mL bolus). The incidence of motor mended. The epidural catheter and tubing should be
block was greater in the continuous infusion group. Of clearly labeled with the word “epidural.” Patient safety
interest, the rate of instrumental vaginal delivery was also experts266 and the U.K. National Patient Safety Agency
higher in the continuous infusion group (7% versus 20%; (NPSA)267 have recommended that syringes, needles, and
risk ratio, 2.9; 95% CI, 1.1 to 7.9). catheters used for neuraxial injections be modified so that
In a systematic review and meta-analysis of nine studies it is not possible to use this equipment for intravenous
(n = 344), George et al.265 concluded that the intermittent injections, thus making the possibility of drug adminis-
programmed bolus technique was associated with a small tration error less likely.
decrease in total anesthetic consumption and improved Each labor unit must have a clear policy as to who may
patient satisfaction. Although no difference was found administer and adjust epidural infusion parameters. Anes-
in the need for anesthesia provider intervention and thesia personnel should be responsible for changes in the
other outcomes, the confidence intervals were wide. The content or rate of the infusion and the volume of bolus
authors concluded that further study is needed to ascer- doses or develop protocols that allow nurses to make
tain whether this technique impacts clinically significant changes within the guidelines of the protocol or by order
anesthetic and obstetric outcomes. Infusion pumps with of the anesthesia provider. In the presence of maternal
the ability to deliver this mode of analgesia are now distress or fetal bradycardia, the nurse or obstetrician
coming on the market. may discontinue the epidural infusion, but the anesthesia
provider should be notified immediately.
Solutions for maintenance of neuraxial analgesia, con-
Patient Monitoring during Maintenance
sisting of dilute local anesthetic and opioid, require
Epidural Analgesia
careful preparation, because these solutions are not com-
The use of a continuous epidural infusion technique or mercially available. A hospital pharmacist or compound-
PCEA does not abolish the need for frequent assessment ing pharmacy should prepare the solution in a clean or
of the patient by the anesthesia provider at regular inter- sterile environment. Preservative-free drugs and saline
vals. Assessment should involve determining the quality should be used to prepare the solutions. Solution con-
of analgesia and progress of labor, recording the sensory tents should always be double-checked for content and
level and intensity of motor block, and reviewing mater- expiration date by the anesthesia provider before analge-
nal vital signs and FHR tracings for the previous hour. sia is initiated.
An inappropriately high level of anesthesia signals the
administration of an excessive dose of local anesthetic or Spinal Analgesia
subdural or subarachnoid migration of the catheter. A
low level of anesthesia may signal intravenous migration Placement of a catheter in the subarachnoid space allows
of the catheter, movement of the catheter outside the the anesthesia provider to administer continuous spinal
478 PART VI Labor and Vaginal Delivery
analgesia by intermittent bolus injection or continuous from the infusion tubing. Opening the infusion system
infusion of a local anesthetic combined with an opioid. to air may increase the risk for contamination and drug
Continuous spinal analgesia is an option when uninten- error. The catheter and pump should be clearly labeled
tional dural puncture has occurred (see later discussion). so that all care providers know that the catheter is a
The technique has also been described for use in patients spinal, not an epidural, catheter.
in whom placement of an epidural catheter is difficult Patient-controlled spinal analgesia for labor has been
(e.g., in patients with morbid obesity or abnormal verte- described.272 Continuous spinal analgesia with opioids
bral anatomy, such as kyphoscoliosis, or in patients with has also been described for patients with obstructive
severe cardiac disease who require careful titration of cardiac lesions.273,274 If intrathecal local anesthetics are
analgesia.)268 used for intrapartum analgesia, the sensory level and the
Reports of this technique usually describe the use of a intensity of motor blockade should be monitored. More-
standard epidural catheter placed through an 18- or over, the anesthesia provider must be prepared to treat
19-gauge epidural needle. To reduce the risk for post– hypotension and other complications associated with
dural puncture headache, very small (e.g., 28- to 32-gauge) high spinal anesthesia.
catheters were developed for insertion through small
(e.g., 22- to 26-gauge) spinal needles. Unfortunately,
several cases of cauda equina syndrome (associated with Ambulatory “Walking”
the use of spinal microcatheters during surgery in non-
pregnant patients) prompted the U.S. Food and Drug
Neuraxial Analgesia
Administration to remove these microcatheters from the The term “walking” or “mobile” epidural analgesia was
market in 1992.269 The etiology of these neurologic defi- first coined to describe low-dose CSE opioid analgesia
cits is unclear. Some anesthesiologists have suggested that because motor function was maintained and the ability to
neurologic injury may result from the maldistribution of walk was not impaired.275 However, the term is more
local anesthetic within the subarachnoid space.270 The accurately applied to any neuraxial analgesic technique
very slow rate of injection through a caudally directed that allows safe ambulation. Initial studies using clinical
microcatheter may lead to pooling of local anesthetic testing to assess sensory and motor impairment and
solution in the terminal part of the dural sac. If the local dorsal column function produced conflicting results.
anesthetic solution is hyperbaric, the neighboring ele- After initiation of epidural analgesia with 15 mL of 0.1%
ments of the cauda equina experience prolonged exposure bupivacaine/fentanyl 2 µg/mL, Buggy et al.276 demon-
to a high concentration of local anesthetic and a hypergly- strated that 66% of women had altered proprioception
cemic, hyperosmotic marinade (e.g., 550 to 800 mOsm/L). and 38% had impaired vibration sense. In contrast, Parry
Permanent neural damage may occur from the combina- et al.277 found that dorsal column function was impaired
tion of tissue dehydration and a toxic concentration of in only 7% of laboring women who received low-dose
local anesthetic. It is unclear whether this complication is epidural or CSE analgesia. The same group of investiga-
unique to the use of microcatheters. tors then used computerized dynamic posturography to
Arkoosh et al.271 reported a randomized multicenter assess balance in nonpregnant women, term pregnant
study comparing continuous spinal labor analgesia (via a women not in labor, and laboring women after initiation
28-gauge catheter) with continuous epidural analgesia. of CSE analgesia with bupivacaine 2.5 mg and fentanyl
The incidence of neurologic complications was not dif- 5 µg.278 Pregnancy significantly affected balance func-
ferent between the two groups, and patients in the spinal tion, but initiation of CSE analgesia did not further
group had better early analgesia, less motor blockade, and impair function. However, further supplementation of
better patient satisfaction. The incidence of post–dural analgesia with the epidural injection of 10 mL of 0.1%
puncture headache also was not different between the bupivacaine/fentanyl 2 µg/mL in a subgroup of patients
two groups (spinal 9%, epidural 4%; P = .10), although resulted in impaired balance function. The investigators
a type II statistical error is possible given the size of the concluded that the results support the safety of allowing
study and the low incidence of this outcome. The spinal ambulation after low-dose CSE analgesia, but further
catheter was associated with a higher incidence of techni- studies are required to understand the relative contribu-
cal difficulties and catheter failures. The researchers con- tions of dorsal column function, proprioception, and
cluded that larger studies are needed to determine the lower limb motor strength to overall balance and ability
safety of the spinal catheter, which is not marketed in the to ambulate.278
United States. Several studies have shown that an epidural test dose
Continuous spinal analgesia can be initiated with the containing lidocaine 45 mg and epinephrine 15 µg
same drug combination and dose used to initiate CSE adversely affects the ability to ambulate after initiation of
analgesia (see Table 23-2).268 For maintenance of analge- CSE or low-dose epidural analgesia.42,43
sia, my colleagues and I administer our standard epidural The concept of the “walking epidural” is popular in
solution (0.06% bupivacaine with fentanyl 2 µg/mL) at the lay press; however, many women, once comfortable,
an initial rate of 2 mL/h. The infusion is then titrated to prefer to rest rather than ambulate. The ability to walk
patient needs. We prefer to use our standard PCEA to the toilet or sit in a chair at the bedside, however,
pumps for the continuous infusion, with the PCEA func- remains desirable to many laboring women. In a small
tion disabled. This approach allows the anesthesia pro- study, the ability to walk to the toilet to void resulted in
vider to administer a small (1 to 3 mL) bolus from the lower postvoid residual volume than voiding on a
infusion bag without disconnecting the spinal catheter bedpan.279 Although ambulation per se has not been
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 479
Criteria for Ambulation during BOX 23-6 Anesthesia for Vaginal Delivery
BOX 23-5
Labor with Neuraxial Analgesia
LUMBAR EPIDURAL CATHETER
• Reassuring fetal status • Supplement existing analgesia with 5 to 10 mL of 1%
• Engagement of fetal presenting part or 2% lidocaine or with 5 to 10 mL of 2% or 3%
• Stable orthostatic vital signs (asymptomatic and within 2-chloroprocaine.
10% of baseline)
• Ability to perform bilateral straight-leg raises in bed SPINAL ANESTHESIA
against resistance • Intrathecal injection of hyperbaric bupivacaine 6 to
• Ability to step up on a step stool with either leg taking 8 mg or hyperbaric lidocaine 25 to 50 mg.
the first step, without assistance • Administer a larger dose for a “trial of forceps” in case
• Satisfactory trial of walking accompanied by a nurse or cesarean delivery is necessary.
midwife
• Patient must be accompanied by a companion at all COMBINED SPINAL-EPIDURAL ANESTHESIA
times • Intrathecal injection of bupivacaine 2.5 to 5 mg with
• Intermittent fetal heart rate monitoring (every 15 fentanyl 15 to 25 µg.
minutes) • Follow with administration of additional drug(s) via
epidural catheter if anesthesia is inadequate.
used during labor. However, caudal analgesia is used position of the blood pressure cuff markedly influence the
rarely in modern obstetric anesthesia practice. Sacral measured blood pressure. With laboring patients in the
analgesia adequate for labor and delivery can be achieved full lateral position, the mean difference in systolic blood
with an injection of 12 to 15 mL of 0.25% bupivacaine, pressure between the dependent and upper arm was
1.0% to 1.5% lidocaine, or 2% 2-chloroprocaine. 10 mm Hg; the mean difference in diastolic pressure was
Single-shot spinal anesthesia for vaginal delivery may 14 mm Hg. Therefore, the incidence of hypotension may
be indicated in a parturient who does not have epidural vary with the position of both the patient and the blood
anesthesia and who requires perineal anesthesia. A pressure cuff.
so-called saddle block can be administered to achieve A meta-analysis of studies comparing low-dose epidu-
blockade of the sacral spinal segments; a small dose of a ral analgesia with CSE analgesia found no difference in the
hyperbaric local anesthetic solution is adequate for this incidence of hypotension between the two techniques.27
purpose. A saddle block may be advantageous in the The prevention of hypotension includes avoidance of
patient with a preterm fetus or a vaginal breech presenta- aortocaval compression. Preston et al.285 noted a higher
tion. In these cases, dense perineal relaxation may facilitate incidence of severe FHR decelerations in women placed
an atraumatic vaginal delivery. A saddle block performed in the supine-lateral tilt position than in those in the full
with the patient in the sitting position with hyperbaric lateral position after initiation of epidural analgesia. In
local anesthetic solution provides excellent anesthesia for contrast, Beilin et al.286 found no difference in maternal
an outlet/low forceps delivery. A higher level (T10) of blood pressure and FHR decelerations between the two
anesthesia often is required for a midforceps delivery. positions.
Clear communication between the obstetrician and Traditionally, intravenous “preload” (also known as
anesthesia provider is essential. If the obstetrician is “prehydration”) with 0.5 to 1.5 L of crystalloid solution
certain that the application of forceps (or vacuum extrac- has been used to reduce the incidence and severity of
tion) will result in a successful delivery, a saddle block will hypotension after the initiation of neuraxial labor anal-
likely provide satisfactory anesthesia. However, in some gesia. However, several randomized controlled trials have
cases, the obstetrician will perform a trial of forceps. We shown that the incidence of hypotension after preload
alter our technique when giving spinal anesthesia for a with 0.5 to 1.0 L of fluid is no lower than that after no
trial of forceps. If the trial fails, cesarean delivery must preload.34,287 In women undergoing spinal anesthesia for
follow. In some cases, we give a dose of local anesthetic cesarean delivery there is no difference in the incidence
appropriate for cesarean delivery. Alternatively, a saddle of hypotension when crystalloid is administered as a rapid
block can be administered via the CSE technique. If bolus prior to the initiation of neuroblockade (preload)
spinal anesthesia is inadequate for the planned procedure, compared with administration concurrently with the ini-
additional local anesthetic can be given through the epi- tiation of anesthesia (co-load).37 Data are inconsistent as
dural catheter. to whether a fluid bolus decreases the risk for nonreas-
suring FHR changes associated with the initiation of
neuraxial analgesia (see earlier discussion). Many anes-
SIDE EFFECTS OF thesia providers omit a fluid bolus. In our practice, my
colleagues and I usually administer approximately 500 mL
NEURAXIAL ANALGESIA of intravenous crystalloid (co-load) at the time of initia-
Hypotension tion of neuraxial labor analgesia.
The hypotension associated with neuraxial analgesia is
Neuraxial anesthesia–induced sympathetic blockade leads usually easily treated. Treatment includes the administra-
to peripheral vasodilation and increased venous capaci- tion of additional intravenous crystalloid, placement of
tance. Recent data from women undergoing spinal the mother in the full lateral and Trendelenburg position,
anesthesia for cesarean delivery suggests that the hypo- and administration of an intravenous vasopressor. Tradi-
tension that occurs after extensive neuroblockade primar- tionally, ephedrine 5 to 10 mg has been administered;
ily reflects decreased systemic vascular resistance.283 however, studies in women undergoing spinal anesthesia
Hypotension is often defined as a 20% to 30% decrease for elective cesarean delivery have shown that phenyleph-
in systolic blood pressure (compared with baseline) or a rine is equally efficacious in restoring blood pressure and
systolic blood pressure less than 100 mm Hg. Modest is associated with higher umbilical arterial blood pH
hypotension rarely has adverse consequences in young, measurements at birth.288 No differences in neonatal
nonpregnant patients. However, placental circulation has outcome have been noted. Because there is no evidence
limited autoregulation; thus, maintenance of uteroplacen- that the choice of vasopressor influences maternal or neo-
tal perfusion largely depends on maintenance of maternal natal outcome, the use of either drug is acceptable. The
blood pressure (see Chapter 3). Uncorrected hypotension FHR should be monitored continuously, and treatment
results in decreased uteroplacental perfusion. If hypoten- should be more aggressive if nonreassuring FHR patterns
sion is severe and prolonged, hypoxia and acidosis will are noted or if the mother is symptomatic (e.g., presence
develop in the fetus. Blood pressure should be monitored of presyncope or nausea). Ephedrine crosses the placenta
frequently (every 2 to 3 minutes) after initiation of anal- and may increase both FHR and FHR variability (e.g.,
gesia, until stable blood pressure is ascertained. saltatory FHR pattern).289,290
The incidence of hypotension after initiation of neur- Data are conflicting as to whether there is a dose-
axial analgesia during labor is approximately 14%.27 Kin- response relationship between hypotension and intrathe-
sella and Black284 reported that maternal position and the cal local anesthetics when these drugs are administered
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 481
in low doses for labor analgesia. Palmer et al.291 found no to its sedating effects. Although propofol 10 to 20 mg was
difference in blood pressure in women randomly assigned found effective for the treatment of pruritus in several
to receive intrathecal fentanyl combined with either 1.25 studies in nonobstetric patients, its efficacy was no differ-
or 2.5 mg of bupivacaine. In contrast, Lee et al.292 noted ent than placebo in an obstetric study.300 Charuluxananan
a greater decrease in blood pressure at 10 minutes in et al.301 found that the 5-HT3 receptor antagonist ondan-
women who received bupivacaine 2.5 mg than in women setron was more efficacious than placebo for the treat-
who received 1.25 mg. Because 1.25 mg is less than the ment of established pruritus; however, a second study that
ED95 for bupivacaine (when combined with fentanyl)200 compared ondansetron 4 mg to pentazocine (a κ-opioid
and there is no apparent advantage to combining bupi- and partial µ-opioid receptor agonist) 15 mg found that
vacaine 1.25 mg with fentanyl over using fentanyl alone,293 pentazocine was superior to ondansetron.302 Another
there is little reason to manipulate the dose of intrathecal group of investigators found that ondansetron was no
bupivacaine with the goal of decreasing the incidence and more effective than diphenhydramine.303
severity of hypotension when low doses are used for labor A number of drugs have been investigated for prophy-
analgesia. laxis against neuraxial opioid–induced pruritus, primarily
coincident with neuraxial morphine administration. In a
meta-analysis of nine studies, the incidence of pruritus
Pruritus was not reduced with prophylactic 5-HT3 receptor
Pruritus is the most common side effect of epidural or antagonists compared with placebo, although the inci-
intrathecal opioid administration.294 Intrathecal opioid dence of severe pruritus requiring treatment was lower.304
administration is associated with a higher incidence and Similarly, prophylactic dexamethasone was also not asso-
severity of pruritus than epidural opioid administration ciated with a lower incidence of pruritus after intrathecal
(41.4% versus 1.3% in one study295).27 The incidence of morphine administration.305
pruritus after intrathecal opioid administration is close to We do not routinely administer prophylaxis for the
100% in some studies, although the need for treatment is pruritus associated with neuraxial administration of
much lower.168 The incidence and severity of pruritus are opioids for labor analgesia. The pruritus is typically self-
dose dependent for both epidural99 and spinal168,177 opioid limiting; the severity of pruritus usually diminishes mark-
administration. The co-administration of local anesthetic edly in the first hour after opioid administration, and
decreases the incidence of pruritus,199 whereas the co- most women do not require treatment. For moderate to
administration of epinephrine may worsen pruritus.296 severe pruritus that requires treatment, we usually admin-
The cause of the neuraxial opioid-induced pruritus is ister nalbuphine 2.5 mg and repeat the dose in 10 to 15
poorly understood, but it appears to be unrelated to his- minutes if no improvement is noted. The advantage of
tamine release. The pruritus appears to be mediated nalbuphine is that it is less likely to reverse the intrathecal
through central µ-opioid receptors, given that µ-opioid or epidural opioid analgesia.306
receptor antagonists relieve itching.297,298 The pruritus
may be caused by a perturbation of sensory input that
results from rostral spread of the opioid within the CSF
Nausea and Vomiting
to the level of the trigeminal nucleus in the medullary Nausea and vomiting occur frequently during labor. It is
dorsal horn.297 A disruption of sensory modulation is con- difficult to determine the incidence of nausea and vomit-
sistent with the observation that a similar pattern of pru- ing directly related to epidural and intrathecal opioid
ritus is seen in medical conditions in which sensory administration. Nausea and vomiting may also be second-
modulation is disturbed (e.g., diabetic neuropathy, mul- ary to neuraxial analgesia–induced hypotension. Maternal
tiple sclerosis).299 blood pressure should be measured when the patient
Few studies have addressed the treatment of established complains of nausea in the presence of neuroblockade.
pruritus (see Chapter 28). The most effective treatment Other causes of nausea and vomiting during labor are
is a centrally acting µ-opioid antagonist (e.g., naloxone pregnancy itself, pain, opioid-induced delay of gastric
or naltrexone) or a partial agonist-antagonist such as nal- emptying (see later discussion), and systemic opioids,
buphine (Table 23-7). However, the use of these agents which are sometimes administered before intrathecal or
in a bolus or continuous infusion may reverse the anal- epidural opioids. In one study, the incidences of nausea
gesia. Antihistamines (e.g., diphenhydramine) are often (7% versus 44%) and vomiting (2% versus 17%) were
prescribed but are usually ineffective because the mecha- significantly lower in women randomly assigned to receive
nism of pruritus is not related to histamine release. Any intrathecal fentanyl than in those assigned to receive sys-
observed effect of diphenhydramine is probably related temic hydromorphone analgesia in early labor.21
The etiology of neuraxial opioid-associated nausea is
TABLE 23-7 Treatment of Neuraxial Opioid- unclear, but it may be caused by the modulation of affer-
Induced Pruritus ent input at the area postrema (i.e., the chemoreceptor
trigger zone) or at the nucleus of the tractus solitarius,
Drug Dose which is a key relay station in the visceral sensory
Naloxone 40-80 µg intravenous bolus
network.307 Of interest, nausea is less common after epi-
1-2 µg/kg/h continuous intravenous infusion dural or intrathecal opioid administration during labor
Nalbuphine 2.5-5 mg intravenous bolus than after the administration of the same drugs for post–
Naltrexone 6 mg orally cesarean delivery analgesia. Norris et al.295 noted that
women who received epidural or intrathecal opioid
482 PART VI Labor and Vaginal Delivery
100.0 * 37.75
99.5 ‡ 37.50
‡
99.0 † 37.25 FIGURE 23-7 ■ Maternal tympanic temperature in the 4
hours immediately after initiation of epidural analge-
37.00 sia, stratified by ultimate intrapartum fever status
98.5
** (febrile ≥ 38.0° C or afebrile < 38° C). *P < .001;
†P < .05; ‡P < .01 (repeated measures analysis, febrile
36.75 versus afebrile); **P = .26 (repeated measures analy-
98.0 sis, afebrile group temperature change over time).
0 1 2 3 4 (Modified from Goetzl L, Rivers J, Zighelboim I, et al.
Duration of exposure to epidural analgesia (hours) Intrapartum epidural analgesia and maternal temperature
regulation. Obstet Gynecol 2007; 109:687-90.)
analgesia during labor had an incidence of nausea of only incidence of clinical fever ranges from 20% to 30% in
1.0% or 2.4%, respectively. women randomized to receive epidural analgesia com-
Although the incidence of nausea is low, treatment pared with 5% to 7% in women in the control groups.309
should be available. No studies, however, have specifically Newer evidence suggests that the slow increase in
addressed the treatment of neuraxial analgesia-associated mean temperature observed in women with epidural
nausea and vomiting during labor. Metoclopramide, analgesia may be an averaging artifact.311 In a prospective
ondansetron, and droperidol have been used prophylacti- observational study of women with epidural analgesia,
cally in women who received neuraxial morphine for anal- Goetzl et al.311 observed the incidence of fever was 22.2%.
gesia after cesarean delivery or nonobstetric surgery (see The mean temperature increase over 8 hours was 0.72°
Chapter 28). Used in low doses, these agents have few C, similar to that observed in earlier studies. However,
significant side effects. When administered intravenously, the investigators noted that temperature increased in
metoclopramide should be administered slowly over 1 to only a subset of women; the remaining cohort had no
2 minutes to minimize feelings of restlessness and anxiety temperature increase (Figure 23-7). In the small subset
that may accompany rapid intravenous administration.308 of women who eventually developed clinical fever, core
A partial explanation for metoclopramide’s efficacy may temperature began to rise within an hour of initiation of
be its action in promoting gastric emptying. The package epidural analgesia. The researchers concluded that most
insert for droperidol contains a “black box” warning women do not become febrile after epidural analgesia,
because of concern that the administration of this agent and therefore it is unlikely that a perturbation in thermo-
may increase the risk for severe cardiac dysrhythmias regulation induced by epidural analgesia is the cause of
(secondary to prolongation of the QT interval and tors- epidural analgesia–associated fever.
ades de pointes). The warning suggests that patients be The mechanism of temperature elevation in some
monitored for dysrhythmias for several hours after dro- women who receive epidural labor analgesia is incom-
peridol administration. Because maternal electrocardio- pletely understood but likely reflects an inflammatory
graphic monitoring is rarely undertaken in healthy process. Several lines of evidence support this mecha-
parturients, the drug is now rarely used in the United nism.309 Risk factors for intrapartum fever are similar to
States by obstetric anesthesia providers. factors that are associated with the request for epidural
analgesia, including nulliparity, prolonged rupture of
membranes, and prolonged labor. In an observational
Fever study in women who self-selected the type of analgesia,
Both observational and randomized controlled trials have the histologic diagnosis of placental inflammation was
consistently noted a gradual rise in core temperature over more common in women with epidural analgesia.312
several hours in laboring women receiving epidural anal- However, the incidence of maternal fever was not differ-
gesia that was not observed in women receiving no anal- ent between women with and without epidural analgesia
gesia, inhaled nitrous oxide, or parenteral opioids.309 The in the absence of placental inflammation. Additionally,
mean increase in core temperature is typically small Goetz et al.313 noted higher baseline maternal serum
(< 1.0° C); however, women with epidural analgesia are levels of interleukin-6 (IL-6), a marker of inflammation,
more likely to have clinical fever (usually defined as core in laboring women who eventually developed fever; final
temperature ≥ 38° C) than those without epidural anal- IL-6 levels were directly related to the duration of epi-
gesia (risk ratio, 3.34; 95% CI, 2.63 to 4.23).3 In a retro- dural analgesia.313 In a subsequent study, women with
spective study, Herbst et al.310 identified the use of epidural analgesia randomized to receive maternal meth-
epidural analgesia as a risk factor for intrapartum fever, ylprednisolone (100 mg) had a lower rate of fever than
along with prolonged labor and a prolonged interval those who received placebo, again suggesting that an
between rupture of membranes and delivery. The inflammatory mechanism is involved.314
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 483
HSV type 1 (HSV-1) is typically found in the trigeminal with epidural fentanyl administered as a bolus (50 to
ganglia and causes orofacial lesions, whereas HSV-2 is 100 µg)341,342 or with a prolonged infusion.339 In another
more commonly found in the lumbosacral ganglia. study, intrathecal fentanyl 25 µg resulted in delayed
However, either of these viruses can infect any region of gastric emptying compared with epidural fentanyl 50 µg
the body. plus bupivacaine or bupivacaine alone.343 Delayed gastric
The common cold sore or fever blister is a mani emptying may predispose a patient to nausea and vomit-
festation of the reactivation of latent infection. Reactiva- ing. In addition, it may result in a greater volume of
tion can occur after exposure to ultraviolet light, fever, gastric contents, which—in theory—might be problem-
immunosuppression, or trauma. Prospective randomized atic in patients who require induction of general anesthe-
studies have demonstrated a higher incidence of postpar- sia for emergency cesarean delivery.
tum oral HSV reactivation in women randomly assigned
to receive neuraxial (epidural,331,332 intrathecal333) mor-
phine than among women assigned to receive systemic COMPLICATIONS OF
morphine for post–cesarean delivery analgesia. Case
reports have associated intraspinal administration of
NEURAXIAL ANALGESIA
meperidine and fentanyl with the subsequent recurrence Inadequate Analgesia
of HSV infection.334,335
To our knowledge, postcesarean reactivation of HSV The reported failure rate for neuraxial analgesia varies
infection after neuraxial opioid administration has not according to the definition of “failure.”30,344,345 In survey
resulted in clinically significant maternal or neonatal studies the rate of epidural catheter replacement has
complications.336 In addition, we are unaware of any ranged from 5% to 13%.30,344,345 Successful location of the
study that has investigated whether epidural or intrathe- epidural space is not always possible, and satisfactory
cal opioid administration during labor increases the inci- analgesia does not always occur, even when the epidural
dence of recurrent oral HSV infection after vaginal space has been identified correctly. Factors such as patient
delivery. Therefore, we do not withhold neuraxial age and weight, the specific technique, the type of epidu-
opioids during labor in women with a history of oral ral catheter, and the skill of the anesthesia provider are
herpes. associated with the rate of failure of neuraxial analge-
sia.30,345 Failure to provide adequate analgesia not only
results in a dissatisfying experience for the patient but
Delayed Gastric Emptying also may lead to litigation.346 The risk for failed anesthe-
Labor may result in delayed gastric emptying, which may sia and the potential need to place a second epidural
be exacerbated by opioid administration (see Chapter catheter should be discussed with the patient during the
29).337,338 Intravenous or intramuscular opioid adminis- preanesthetic evaluation, before placement of the first
tration results in delayed gastric emptying in laboring epidural catheter.
women. Studies suggest that epidural fentanyl combined Pan et al.30 used quality assurance data to retrospec-
with bupivacaine and administered as part of a con- tively assess the failure rate among more than 12,000
tinuous epidural infusion does not result in delayed neuraxial procedures performed for labor analgesia
gastric emptying compared with infusion of bupivacaine over a 3-year period (Table 23-8). The overall failure
alone339,340; however, delayed gastric emptying may occur rate of 12% included procedures that resulted in no or
inadequate analgesia, unintentional dural puncture with The extent of neuroblockade should be assessed with
an epidural needle or catheter, intravenous cannulation a cold or sharp stimulus that starts over the lateral thighs
with the epidural catheter, or replacement of the cathe- (the dermatomal level at which the tip of the epidural
ter for any reason. After initial adequate analgesia, 6.8% catheter is sited) and moves both cephalad and caudad on
of the catheters were replaced, although eventually both sides. Inexperienced anesthesia providers often fail
98.8% of women received adequate pain relief. The rate to check for the presence of sacral blockade. In the case
of failed analgesia was significantly lower after CSE than of no sensory blockade, the epidural catheter should be
after epidural analgesia (10% versus 14%, respectively; replaced. If the extent of neuroblockade is inadequate (in
P < .001). either the cephalad or caudad direction), or if there is
Typically, failed analgesia after injection of intrathecal unilateral blockade or missed segments, the injection of
or epidural anesthetics results in no neuroblockade, uni- a large volume (10 to 15 mL) of a dilute local anesthetic
lateral blockade or missed segments, or inadequate density solution (e.g., 0.0625% to 0.125% bupivacaine) may
of neuroblockade. Patient complaints of pain should result in satisfactory analgesia. An advantage of using
prompt timely evaluation and treatment (Box 23-7). The a more dilute solution of local anesthetic is the ability
progress of labor should be assessed, and the patient to increase the administered volume to ensure adequate
should be queried as to the nature of the pain. Typically, spread of analgesia.
pain becomes more intense as labor progresses. An epi- Some women appear to have adequate extent of
dural block that was adequate at 4-cm cervical dilation sensory blockade but still complain of pain. These
may not be adequate at 8-cm cervical dilation. Expecta- women may require more dense analgesia; a larger dose
tions and treatment may be different for women in latent of local anesthetic (10- to 15-mL bolus of 0.125% bupi-
versus active or second-stage labor. The bladder should vacaine or a 5- to 10-mL bolus of 0.25% bupivacaine)
be checked and emptied if distended. The position of the often successfully reestablishes analgesia. Alternatively, a
epidural catheter at the skin should be assessed to exclude lipid-soluble opioid (e.g., fentanyl 50 µg) may be added
the possibility of catheter migration out of the epidural to the solution. The opioid is especially helpful if the
space. Inadequate analgesia may also result from migra- parturient is experiencing back pain because the fetus is
tion of the epidural catheter into a vein or movement of in the occiput posterior position. In some European
the catheter outside of the epidural space. Before giving practices, epidural clonidine (75 µg) is used to treat
a bolus dose of local anesthetic, the anesthesia provider breakthrough pain that occurs during/after epidural
should give a test dose to exclude intravenous migration administration of the standard local anesthetic-opioid
of the catheter. solution.
Some anesthesia providers advocate pulling the epi-
dural catheter 1 to 2 cm out of the epidural space before
Assessment and Management of administering the bolus injection. Beilin et al.347 investi-
BOX 23-7
Inadequate Neuraxial Analgesia gated this practice by randomly assigning women
with incomplete analgesia to one of two treatments:
• Assess progress of labor: (1) immediate injection of 0.25% bupivacaine 5 mL or
• Rule out other causes of pain (distended bladder,
(2) withdrawal of the (multi-orifice) epidural catheter
ruptured uterus).
• Perform an honest evaluation of the anesthetic: 1 cm followed by injection of the same dose of bupiva-
• Is the catheter really in the epidural space? caine. There was no difference in the ability to rescue
• If in doubt, replace the catheter. analgesia between the two treatments (74% versus 77%,
• If the catheter is in the epidural space, but the extent respectively).
of neuroblockade is inadequate (does not extend from Although available data are inconsistent, maternal
T10 to S4, as is required for late labor): position has little effect on the development of an asym-
• Inject a dilute solution of local anesthetic (5 to metric block after a bolus dose of anesthetic solution into
15 mL), with or without an opioid. the epidural space.348,349 Husemeyer and White348 admin-
• Alter maintenance technique (e.g., increase volume, istered 10 mL of epidural 1.5% lidocaine to pregnant
decrease concentration).
women who were in the lateral position; they observed
• If this maneuver is unsuccessful, replace the catheter.
• If catheter is in the epidural space, but the block is greater spread (two to three spinal segments) of anesthe-
asymmetric: sia on the dependent side. In contrast, others have
• Inject a dilute solution of local anesthetic (5 to observed that posture has little influence on the spread
15 mL), with or without an opioid. of local anesthetic within the epidural space.281,350 It is
• Alter maintenance technique (e.g., increase volume, likely that the position of the epidural catheter in relation
decrease concentration). to other epidural space structures (e.g., connective tissue,
• Place the less-blocked side in the dependent position. fatty tissue, blood vessels) affects the spread and quality
• If this maneuver is unsuccessful, replace the catheter. of analgesia to a greater extent than maternal position.
• If the catheter is in the epidural space, but the patient Anatomic barriers (e.g., a longitudinal connective tissue
has breakthrough pain despite adequate extent of
band between the dura and ligamentum flavum) or place-
neuroblockade:
• Inject a more concentrated solution of local anes- ment of the catheter tip in the anterior epidural space or
thetic, with or without an opioid. paravertebral space may explain some cases of single
• Alter maintenance technique (e.g., increase concen- nerve root, unilateral, or asymmetric blockade.351-354
tration of local anesthetic). The response to the bolus dose should be assessed in
a timely fashion, and the epidural catheter should be
486 PART VI Labor and Vaginal Delivery
replaced (with the patient’s consent) if satisfactory anal- within 2 hours of the injection of a lipid-soluble opioid
gesia is not obtained. such as fentanyl or sufentanil. When a lipid-soluble
opioid gains access to the CSF, it is quickly absorbed by
lipophilic body tissues. Subsequent clearance and elimi-
Unintentional Dural Puncture nation are similar to those associated with intravenous
In a meta-analysis of 13 studies that involved more than injection of the same drug. Thus, with spinal or epidural
300,000 obstetric patients, Choi et al.355 determined that injection of a lipid-soluble opioid, the “time window” for
the rate of unintentional dural puncture with an epidural respiratory depression is short. Conversely, with a hydro-
needle or catheter was 1.5% (95% CI, 1.5% to 1.5%) (see philic drug such as morphine, the onset of respiratory
Chapter 31). Dural puncture may be detected at the time depression is delayed. Once a hydrophilic drug such as
of insertion of the epidural needle or after placement of morphine enters the CSF, it tends to stay in the CSF.
the catheter. If dural puncture is detected with the epi- Rostral migration and absorption into the respiratory
dural needle, the anesthesia provider has two primary centers occur over several hours, so respiratory depres-
options. He or she may elect to remove the needle and sion may not occur until 6 to 12 hours after injection of
place an epidural catheter at another interspace; if CSE the drug (see Figure 13-13).
analgesia was planned, the intrathecal dose may be The dose of opioid is a major determinant of the risk
injected through the epidural needle before it is removed for respiratory depression.177 Herman et al.177 observed an
and re-sited at a different interspace. Alternatively, the increase in end-tidal CO2 concentration with intrathecal
anesthesia provider may place a catheter in the subarach- fentanyl doses of 15 µg or higher. The time of maximum
noid space and administer continuous spinal analgesia for end-tidal CO2 was approximately 30 minutes after the
labor and delivery. This latter technique is particularly intrathecal injection. A risk factor for respiratory depres-
advantageous for patients at high risk for repeat dural sion is previous parenteral opioid administration. Several
puncture on a second attempt or in cases in which it may reports have implicated prior intravenous opioid admin-
be difficult to enter either the epidural or subarachnoid istration as a contributing factor to the respiratory arrest
space successfully at an alternative interspace (e.g., in that occurred after intrathecal sufentanil 10 µg adminis-
obese women or in patients with abnormal anatomy of tration in laboring women.357,358 (This dose is higher than
the lumbar spine). It is very important to append a label the currently recommended intrathecal dose range.) For
that clearly identifies the catheter as a spinal catheter to this reason, we refrain from administering a bolus dose of
decrease the risk for injecting an epidural dose of local epidural or spinal opioid to women who have recently
anesthetic into the subarachnoid space. The parturient received systemic opioid analgesia.
and all providers on the labor and delivery unit, including
nurses, midwives, and other anesthesia providers, must Intravascular Injection of
be made aware of the intrathecal catheter, and this infor-
mation must be communicated during any hand-off of Local Anesthetic
care to another provider.
Re-siting the epidural catheter in a different interspace The incidence of fatal local anesthetic systemic toxicity
eliminates the problem of mistaking an intrathecal cath- (LAST) appears to have declined in the past quarter
eter for an epidural catheter. However, local anesthetic century.359 In a prospective audit from the United
or opioid injected through the epidural catheter may pass Kingdom of more than 145,000 obstetric epidural proce-
through the dural puncture site and into the subarach- dures, the incidence of intravascular injection was 1 in
noid space, resulting in unexpectedly high neuroblock- 5000 (Table 23-9). Bupivacaine 0.75% is no longer used
ade.356 This complication is more likely to occur with the
bolus injection of local anesthetic than with an epidural
infusion of local anesthetic. TABLE 23-9 Incidence of Unintentional
If dural puncture is not recognized until CSF is aspi- Intravascular, Intrathecal,
rated from the catheter, or if administration of the test and Subdural Injections
dose results in spinal anesthesia, the anesthesia provider during Attempted Epidural
has the following two options: (1) replace the epidural Labor Analgesia*
catheter at an alternative interspace or (2) provide con- Event Incidence Rate (%)†
tinuous spinal analgesia through the existing catheter.
Intravascular 1 : 5000 0.020 (0.014-0.029)
injection
Respiratory Depression Intrathecal injection 1 : 2900 0.035 (0.027-0.046)
Subdural injection 1 : 4200 0.025 (0.017-0.033)
The administration of opioids by any route entails risk
High/total spinal 1 : 16,200 0.006 (0.003-0.012)
for respiratory depression. Factors that affect the risk for anesthesia
respiratory depression after neuraxial opioid administra-
tion include the choice and dose of drug and its interac- *Prospective data collection of 145,550 epidural procedures for
tion with systemically administered opioids and other obstetric patients in 14 maternity units in the South West
central nervous system depressants (see Chapter 13). The Thames Region (United Kingdom) over a 17-year period.
†
95% confidence intervals shown in parentheses.
most important factor affecting the onset of respiratory Modified from Jenkins JG. Some immediate serious complications
depression is the lipid solubility of the drug.307 In general, of obstetric analgesia and anaesthesia: a prospective study of
if respiratory depression is going to occur, it will do so 145,550 epidurals. Int J Obstet Anesth 2005; 14:37-42.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 487
anesthesia provider must be prepared to maintain oxy- anesthesia and epidural anesthesia (i.e., 10 to 20 minutes)
genation, ventilation, and circulation (Box 23-9). Imme- (Table 23-10).369 Cranial spread is more extensive than
diate management consists of avoidance of aortocaval caudal spread of the local anesthetic, so sacral analgesia
compression, ventilation with 100% oxygen, tracheal typically is absent. The block may involve the cranial
intubation, and administration of intravenous fluids and nerves. (The subdural space, unlike the epidural space,
vasopressors to support the blood pressure as needed. extends intracranially.) Thus, apnea and unconsciousness
The FHR should be monitored continuously. can occur during a subdural block. Horner’s syndrome has
Extensive neuroblockade may also result from subdu- been reported.367 A subdural block usually results in less
ral injection of a local anesthetic.366-368 A subdural injec- intense motor blockade than the blockade that occurs
tion may be difficult to diagnose because onset is later with high or total spinal anesthesia. This difference may
than that with an intrathecal injection and more closely reflect the limited spread of the local anesthetic within the
resembles that associated with epidural neuroblockade. subdural space, which helps spare the anterior motor
The subdural space is a potential space between the fibers.368 Subdural block results in less severe hypotension
dura mater and the arachnoid mater. A retrospective than that with high or total spinal anesthesia, most likely
review of 2182 lumbar epidural injections for pain man- because subdural injection leads to less sympathetic block-
agement found that clinical signs of subdural catheter ade than spinal anesthesia. The unpredictable spread of
placement occurred in approximately 0.82% of patients366; local anesthetic, the slower onset of maximal spread (in
the true incidence is not known, but may be as high as comparison with spinal anesthesia), the patchy nature of
10%.369 Subdural injection of local anesthetic typically the block, and the sacral sparing make it difficult to use a
results in unexpectedly high (but patchy) blockade with an subdural catheter safely during labor and delivery. If it is
onset time that is intermediate between that of spinal suspected that a catheter is positioned within the subdural
space, it should be replaced with an epidural catheter.
Unexpectedly high neuroblockade may result from the
Management of High and Total migration of an epidural catheter into the subdural or
BOX 23-9 subarachnoid space.368 The mechanism by which a soft
Spinal Anesthesia
epidural catheter penetrates the dura or dura-arachnoid
• High spinal anesthesia may occur several minutes after is unclear. Disposable epidural needles are sharp, and
the unintentional intrathecal injection of local anes- insertion of the needle into the epidural space may result
thetic or as a result of overdose of epidural local anes- in an unrecognized nick in the dura, which may create a
thetic. Communication with the patient is important. site for delayed migration of the catheter into the subdural
Agitation, dyspnea, difficulty speaking, and profound or subarachnoid space. Subdural or subarachnoid injec-
hypotension may herald the onset of total spinal tion of local anesthetic also may occur if a multi-orifice
anesthesia.
• Avoid aortocaval compression.
catheter is used, and one orifice is located within the
• Administer 100% oxygen. epidural space while another is located within the subdural
• Provide positive-pressure ventilation, preferably or subarachnoid space. In this situation, the force of injec-
through an endotracheal tube. tion determines the ultimate destination of the local anes-
• Monitor maternal vital signs, electrocardiogram, and thetic. Thus, each bolus injection of local anesthetic
fetal heart rate. should serve as a test dose. During the continuous infusion
• Support maternal circulation with intravenous fluids of a local anesthetic, a gradual increase in the level of
and vasopressors as needed. Do not hesitate to give anesthesia and intensity of motor blockade may indicate
epinephrine if needed. the intrathecal infusion of the local anesthetic solution.
• Maintain verbal communication with the mother, or
administer sedative-hypnotic (after treating any hypo-
tension and hypoxemia) because total spinal anesthesia Extensive Motor Blockade
does not signal brain anesthesia. Patients may lose con-
sciousness and stop breathing because of central Clinically significant motor block may occur after
nervous system hypoperfusion, not brain anesthesia. repeated bolus doses146 or after many hours of a continu-
ous infusion of local anesthetic into the epidural space.370
The administration of bupivacaine with epinephrine may nervous system and so does not impair motor function.
result in a greater likelihood of motor blockade than the Affected patients should be reassured that respiratory
administration of bupivacaine alone.146,371 Extensive efforts are not compromised and that these symptoms
motor blockade is often bothersome for the patient, and will subside in 30 to 60 minutes.376,377
it may impair maternal expulsive efforts during the second In addition to sensory changes, case reports have
stage of labor and increase the likelihood of instrumental described mental status changes, aphasia, and automa-
vaginal delivery (see later discussion). Some obstetricians tisms after the intrathecal injection of fentanyl378 and
argue that pelvic floor relaxation prevents rotation of the sufentanil.379 These symptoms seem to be related to an
fetal head and increases the likelihood of an abnormal opioid effect. In one case, the symptoms were partially
position of the vertex at delivery. reversed by naloxone.378
If intense motor blockade develops during the con-
tinuous epidural infusion of local anesthetic, the infusion
can be discontinued for a short period (e.g., 30 minutes).
Back Pain
Subsequently, the infusion can be restarted at a reduced Approximately 50% of women complain of back pain
rate or with a more dilute solution of local anesthetic. during pregnancy and the puerperium.380,381 The most
Extensive motor blockade does not occur with adminis- significant risk factors for postpartum back pain are
tration of a very dilute solution of local anesthetic com- antepartum back pain and inability to reduce weight
bined with an opioid. to prepregnancy levels.380,382,383 Early retrospective
studies identified an association between epidural anes-
thesia and an increased risk for postpartum back
Prolonged Neuroblockade pain.384,385 However, retrospective studies suffer not only
Rarely, the duration of neuraxial analgesia/anesthesia from patient recall bias (i.e., patients with a problem are
exceeds the time expected. Most cases of unexpectedly much more likely to complete and return the question-
prolonged neuroblockade follow the epidural administra- naire) but also from selection bias in the epidural and
tion of a high concentration of local anesthetic with epi- nonepidural groups. Patients who select epidural analge-
nephrine.372 Abnormal neurologic findings after the sia for labor may have obstetric, orthopedic, social, or
administration of neuraxial anesthesia should prompt the other unidentified factors that predispose them to post-
anesthesia provider to look for evidence of peripheral partum back pain.
nerve injury or an epidural hematoma (see Chapter 32). In an attempt to assess anesthetic factors that might
Factors that argue against the presence of an epidural contribute to postpartum backache (e.g., motor block-
hematoma include (1) the absence of back pain, (2) a uni- ade), Russell et al.383 randomly assigned laboring women
lateral block, and (3) regression (rather than progression) requesting epidural analgesia to receive either bupiva-
of the symptoms. Peripheral nerve injuries typically result caine alone or bupivacaine plus an opioid. Despite the
in a neurologic deficit in the distribution of a specific expected differences in motor blockade, the incidence of
peripheral nerve. Neurologic or neurosurgical consulta- backache did not differ between the two anesthetic groups
tion and immediate imaging studies should be obtained if (bupivacaine alone, 39%; bupivacaine plus an opioid,
there is any question about the etiology of prolonged 30%). In addition, the incidence of backache in both
anesthesia. Avoiding the use of a high concentration of epidural groups was similar to that found in a nonran-
local anesthetic should help minimize the incidence of domized control group of women who labored without
prolonged neuroblockade during and after labor and epidural analgesia (31%).
vaginal delivery. Prospective reports have not shown a significant rela-
tionship between the use of epidural analgesia and long-
term backache. Breen et al.382 observed no difference in
Sensory Changes the incidence of postpartum backache among women
In one of the early studies of intrathecal opioid adminis- who delivered vaginally with or without epidural analge-
tration during labor, Cohen et al.294 observed sensory sia. A prospective Canadian study assessed the relation-
changes in women who received intrathecal sufentanil. ship between postpartum backache and patient-selected
Subsequent studies have demonstrated that these sensory intrapartum analgesia.386 The rate of low back pain was
changes do not result from a local anesthetic effect of greater in the epidural group (53%) than in the nonepi-
sufentanil. Sensory changes do not predict the quality or dural group (43%) on the first postpartum day, but the
duration of analgesia or the extent of hemodynamic rates were similar on postpartum day 7 and at 6 weeks
change.373 Further, intrathecal sufentanil does not cause and 1 year.386 These investigators suggested that the
a sympathectomy.374 Wang et al.375 have provided the best higher incidence of backache immediately after delivery
explanation for these sensory changes. They showed that may have resulted from tissue trauma during epidural
intrathecal opioids block the afferent information from needle placement. Finally, Loughnan et al.387 enrolled
A-delta and C fibers to the spinal cord but that efferent 310 women in a randomized controlled trial that com-
nerve impulses are unaffected. These sensory changes pared epidural bupivacaine with systemic meperidine
can be clinically significant, especially when they extend analgesia. The primary outcome was back pain 6 months
to the cervical dermatomes. In such cases, patients may after delivery. There was no difference between the two
feel that they cannot breathe or swallow, a sensation that groups in the incidence of backache (epidural 48%,
can be quite distressing. Fortunately, neither intrathecal meperidine 50%). Similarly, another randomized con-
sufentanil nor fentanyl affects the efferent limb of the trolled trial of epidural versus nonepidural analgesia found
490 PART VI Labor and Vaginal Delivery
no difference in the incidence of backache at 3 and 12 oxide, or no analgesia). The investigators made the follow-
months388 and several years389 after delivery. ing comments393:
In summary, prospective studies have consistently
shown that no causal relationship exists between epidural Of 245 selected patients, 43 had to be removed from the
analgesia and the development of long-term postpartum trial after labour ensued.…Most of the patients removed
backache. Short-term backache (several days) may be from the non-epidural group were apparently
related to local tissue trauma at the site of skin puncture. experiencing severe pain; they were usually primigravidae
whose baby presented in the occipito-posterior position.…
The majority of patients removed from the epidural group
Pelvic Floor Injury were apparently normal and usually multigravidas; their
Few studies have evaluated the possible effects of epidural labours were so rapid it was not possible to arrange for an
analgesia on postpartum pelvic floor function. In a case- epidural block.
control study, Christianson et al.390 did not identify epi-
dural analgesia as a risk factor for third- or fourth-degree In other words, patients at low risk for operative deliv-
perineal lacerations. Similarly, Sartore et al.391 observed ery were excluded from the epidural group, and patients
no significant difference in the incidence of stress urinary at high risk were excluded from the nonepidural group.
incontinence, anal incontinence, or vaginal prolapse 3 The investigators’ candid comments illustrate that, even
months after vaginal delivery between those women who when a prospective, randomized study is performed, it is
did and those who did not receive epidural analgesia. In difficult to maintain conditions that allow for the com-
a small randomized trial that compared epidural with parison of women at equal risk for abnormal labor and
systemic administration of meperidine, there was no dif- operative delivery.
ference in the rate of perineal trauma between groups.388 Another concern is the external validity of these
Any factor that increases the likelihood of instrumen- studies. Women who agree to participate in research
tal vaginal delivery might be expected to increase the risk trials may be inherently different from women who refuse
for pelvic floor injury and subsequent pelvic floor dys- to participate. Many women make a decision regarding
function (see later discussion). However, to our knowl- labor analgesia well before the onset of labor and are
edge, there is no evidence that epidural analgesia per se unwilling to let chance randomization determine the type
predisposes to pelvic floor injury. of labor analgesia. Thus, the study results may not be
generalizable to the general obstetric population.
Ironically, the effect of systemic opioids on the prog-
EFFECTS OF NEURAXIAL ANALGESIA ON ress and outcome of labor has not been well studied.
THE PROGRESS OF LABOR Furthermore, there may be differences among the
opioids.394 Finally, neuraxial analgesia is not a generic
Neuraxial analgesia during labor is associated with a pro- procedure. Conclusions about the effect of one technique
longed labor and operative delivery. (The term operative on the progress of labor may not be applicable to other
delivery refers to both cesarean delivery and instrumental techniques (see later discussion).
vaginal delivery [e.g., forceps delivery or vacuum extrac- Additional factors prevent rigorous scientific study of
tion]). Controversy exists as to whether there is a cause- this issue. Ideally, a randomized controlled trial should
and-effect relationship between the use of these analgesic be double blinded. This is not possible for studies that
techniques and prolonged labor or operative delivery. compare neuraxial analgesia with another mode of anal-
The understanding of this subject has been limited by the gesia, because of the marked difference in the quality of
difficulty of performing controlled trials in which partu- analgesia. Therefore, the potential for bias on the part of
rients are randomly assigned to neuraxial analgesia or a the parturient, nurses, and anesthesia and obstetric pro-
control group. Ideally, if one wants to study the effect of viders is substantial. Additionally, a number of factors are
neuraxial analgesia on the progress and outcome of labor, known to affect or to be associated with the progress and
the control group would receive no analgesia. However, outcome of labor, including parity, artificial rupture of
such a study is not ethical, and even if it were and women membranes, use of oxytocin, and payer status; these
volunteered to participate in it, the crossover rate would factors should be controlled in well-conducted studies.
probably be high and the data consequently would not One factor known to markedly influence the outcome
be interpretable. Therefore, controlled trials have ran- of labor is the obstetric provider. Neuhoff et al.395 retro-
domly assigned parturients to receive neuraxial analgesia spectively reviewed the records of 607 nulliparous women
or an alternative form of pain relief, usually systemic at term gestation and compared the mode of delivery in
opioid analgesia. However, even when the control group “clinic” patients (whose care was given primarily by resi-
receives some type of analgesia, the crossover rate may dents) and private patients (whose care was provided pri-
be high because the quality of neuraxial analgesia is marily by private obstetricians). Approximately 42% of
markedly superior to that of all other modes of labor patients received epidural analgesia during labor. Five
analgesia.392 percent of patients in the clinic group and 17% of patients
The difficulty in performing and interpreting the in the private group underwent cesarean delivery
results of labor analgesia trials was aptly described by (P < .001). More striking was the difference between
Noble et al.,393 who assessed obstetric outcome in 245 groups in the incidence of cesarean delivery for dystocia
patients randomly assigned to receive either epidural anal- (0.5% versus 13.7%, respectively; P < .001). Similarly,
gesia or “conventional” analgesia (i.e., meperidine, nitrous Guillemette and Fraser396 observed marked obstetrician
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 491
variation in cesarean delivery rates, despite similarities in delivery rate.388,392,403-427 These trials differ in a number of
the use of oxytocin and epidural analgesia. ways, including (1) the population studied (e.g., nullipa-
Several groups of investigators have noted that the rous women or women of mixed parity); (2) onset of labor
timing of cesarean delivery conforms to a “circadian” (spontaneous labor alone or a mix of spontaneous and
rhythm.397,398 For example, investigators in Japan noted a induced labors); (3) type of neuraxial analgesia; (4) density
delivery time rhythm in hospitals, but not birthing centers, of neuraxial analgesia; (5) route of administration of sys-
suggesting that obstetric intervention, not biologic temic analgesia (although all the studies included meperi-
rhythm, partly determines the timing of delivery.399 dine with or without an adjuvant); (6) the crossover rate;
Retrospective studies are difficult to interpret because and (7) management of labor (e.g., active management of
they suffer from selection bias. In some cases, distin- labor, including electronic FHR monitoring, artificial
guishing between anesthesia administered for pain relief rupture of membranes, and oxytocin infusion). All but
during labor and anesthesia administered in preparation one of these studies found no difference in the rate of
for operative delivery is difficult. Moreover, women at cesarean delivery between women randomly assigned to
higher risk for prolonged labor and operative delivery are receive either neuraxial or systemic opioid analgesia.
more likely to request and receive epidural analgesia Four prospective, randomized trials were performed
during labor than women who have a rapid, uncompli- at the University of Texas Southwestern Medical Center,
cated labor.400 Wuitchik et al.400 observed a relationship Parkland Hospital, in Dallas.392,408,422,423 This institution is
between pain and cognitive activity during early labor unique among many others that have performed random-
and the subsequent progress of labor in 115 healthy nul- ized trials, in that the population is composed largely of
liparous women. During the latent phase, higher levels indigent women whose labor is managed by the same
of pain were predictive of longer latent and active phases group of resident physicians and midwives, supervised by
of labor. Those women who reported “horrible” or the same core group of attending obstetricians. In the
“excruciating” pain during the latent phase were more first study, 1330 women of mixed parity were randomly
than twice as likely to require instrumental delivery as assigned to receive either epidural bupivacaine/fentanyl
women who only had “discomfort.” In addition, women or intravenous meperidine for labor analgesia.392 Approxi-
who reported “distress” rather than “coping” had a five- mately one third of the women did not receive the assigned
fold higher incidence of abnormal FHR patterns and a treatment. The cesarean delivery rates were 9.0% in
fourfold higher requirement for assistance from pediatri- women who received epidural analgesia and 3.9% in
cians during neonatal resuscitation. women who received intravenous meperidine. However,
Greater pain intensity during labor appears to be a risk the investigators did not report an intent-to-treat analysis
factor for operative delivery. This fact will significantly of these data; thus, it was unclear whether there was a
bias observational studies of labor analgesia because higher incidence of cesarean delivery in the women ran-
women with greater pain intensity request analgesia, spe- domly assigned to the epidural analgesia group. Subse-
cifically neuraxial analgesia, at a higher rate than women quently, the investigators published a reanalysis of the
with less intense pain. Alexander et al.401 performed a data that included an intent-to-treat analysis (Table
secondary analysis of data from a randomized controlled 23-11).428 The cesarean delivery rate in both groups was
trial in which one group of laboring women received 6%. These analyses support the conclusion that women
patient-controlled intravenous meperidine analgesia. The
rate of cesarean delivery for dystocia was 14% in women
who self-administered 50 mg/h or more of meperidine,
compared with 1.4% in women who self-administered TABLE 23-11 Parkland Hospital Randomized
less than 50 mg/h. In a retrospective study of factors that Controlled Trial of Epidural
predict operative delivery in laboring women, Hess Versus Systemic Opioid
et al.402 found that the cesarean delivery rate in women Analgesia and Rate of Cesarean
who had significant breakthrough pain during low-dose Delivery: Actual Treatment
bupivacaine/fentanyl epidural analgesia was more than Versus Intent-to-Treat Analysis*
twice as high as the rate in women with less breakthrough
Type of Analysis Cesarean Delivery Rate (%)
pain (odds ratio, 2.62; 95% CI, 2.01 to 3.43).
Taken together, these studies suggest that the early EPIDURAL ANALGESIA SYSTEMIC OPIOID
onset of severe pain and the requirement of high doses (n = 664) ANALGESIA (n = 666)
of analgesic agents predict higher risks for abnormal Actual treatment† 9.0 3.9‡
labor, FHR abnormalities, and operative delivery. These Intent-to-treat 6 6
findings may explain the observed association between
neuraxial analgesia and operative delivery. *In the systemic opioid group, 103 women requested and
received epidural analgesia because opioid analgesia was
inadequate. The initial analysis was published in 1995. The
intent-to-treat analysis of the same data was published in 2000.
Cesarean Delivery Rate †
The protocol violation rate was 35%.
‡
P < .05 compared with epidural analgesia group.
Randomized Controlled Trials Data from Ramin SM, Gambling DR, Lucas MJ, et al. Randomized
trial of epidural versus intravenous analgesia during labor.
A number of randomized controlled trials have studied Obstet Gynecol 1995; 86:783-9; and Sharma SK, Leveno KJ.
the effect of neuraxial (primarily epidural) and systemic Update: Epidural analgesia does not increase cesarean births.
opioid (primarily meperidine) analgesia on the cesarean Curr Anesthesiol Rep 2000; 2:18-24.
492 PART VI Labor and Vaginal Delivery
who choose epidural analgesia have an inherent risk Only one randomized trial has compared CSE and
factor(s) for cesarean delivery and that the administration systemic opioid analgesia.408 In this large study (n = 1223),
of neuraxial analgesia per se does not alter this risk. patients of mixed parity were randomly assigned to receive
In an attempt to lower the rate of crossover by provid- CSE analgesia (intrathecal sufentanil 10 µg, followed by
ing better analgesia to the control (meperidine) group, epidural bupivacaine with fentanyl at the second request
the Parkland Hospital investigators performed another for analgesia) or intravenous meperidine (50 mg every
study in which meperidine was administered by PCIA.422 hour on request). Approximately 60% of patients com-
A significant number of women in both groups did not plied with the protocol. An intent-to-treat analysis showed
receive their assigned treatment, although the reason in that there was no difference between groups in the rate
all cases was rapid labor. Only 5 of 357 women randomly of cesarean delivery (CSE 6%, systemic opioid 5.5%).
assigned to the meperidine group crossed over to receive The studies comparing neuraxial with systemic opioid
epidural analgesia. Using an intent-to-treat analysis, the analgesia have been systematically reviewed in several
investigators observed no difference between the groups meta-analyses.3,429 The latest meta-analysis covered out-
in the incidence of cesarean delivery (4% in the epidural comes for 8417 women randomized to receive neuraxial
group and 5% in the PCIA group). There was no differ- or no neuraxial/no analgesia (control) from 27 trials
ence between the two groups in neonatal outcome, except (Figure 23-8).3 The risk ratio for cesarean delivery in
that more neonates of women in the PCIA group received women randomly assigned to receive neuraxial analgesia
naloxone to reverse respiratory depression at birth. compared with those assigned to the control group was
FIGURE 23-8 ■ Meta-analysis of cesarean delivery rate in women randomized to neuraxial or non-neuraxial labor analgesia. The
number of women who had a cesarean delivery, the risk ratio, and 95% confidence interval (CI) of the risk ratio (fixed effect model)
are shown for each study. For studies with no cesarean deliveries the risk ratio could not be calculated. Control, nonepidural anal-
gesia. n, number of events (cesarean delivery) in the neuraxial or non-neuraxial group; N, total number of subjects in the neuraxial
or non-neuraxial group. The scale is logarithmic. (Modified from Anim-Somuah M, Smyth RM, Jones L. Epidural versus non-epidural or
no analgesia in labour. Cochrane Database Syst Rev 2011; [12]:CD000331.)
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 493
50 Impact Studies
Some physicians have questioned whether prospective,
40 * randomized studies provide an accurate representation of
* the effect of neuraxial analgesia on the mode of delivery
in actual clinical practice. They have suggested the pos-
Percentage
30
sibility that prospective studies may introduce a Haw-
thorne effect (which may be defined as the appearance or
20 disappearance of a phenomenon on initiation of a study
to confirm or exclude its existence). An alternative study
10 design is to assess obstetric outcome immediately before
and after a sentinel event, such as the introduction of an
epidural analgesia service in a given hospital. The results
0 of these studies may be generalizable to the general popu-
NSVD IVD CD
lation because patients have not chosen to participate in
Traditional epidural analgesia a study. It also eliminates the problem of treatment group
“Low dose” epidural analgesia crossover because epidural analgesia was not available in
CSE analgesia the control period. One limitation of this study design is
that it assumes that there were no other changes in
FIGURE 23-9 ■ Outcome of labor in the COMET study. Parturients obstetric management in the “after” period.
were randomly assigned to traditional epidural analgesia or to In 1999, Yancey et al.435 published an impact study
one of two “low-dose” neuraxial techniques (see text). There using data from the Tripler Army Medical Center in
was no difference among groups in the cesarean delivery (CD)
rate. *Women who received traditional epidural analgesia had Hawaii. Because of relative homogeneity in socioeco-
a higher rate of instrumental vaginal delivery (IVD) than those nomic status, universal access to health care, and the
who received either “low-dose” technique (P = .04). CSE, com- availability of dedicated health care providers in the pop-
bined spinal-epidural; NSVD, normal spontaneous vaginal ulation served by this hospital, its rate of cesarean deliv-
delivery. (Data from Comparative Obstetric Mobile Epidural Trial
Study Group UK. Effect of low-dose mobile versus traditional epidu-
ery may not be subject to influences common to other
ral techniques on mode of delivery: a randomised controlled trial. hospitals. Prior to 1993 the rate of epidural analgesia was
Lancet 2001; 358:19-23.) less than 1% at Tripler Army Medical Center. In 1993 a
policy change within the U.S. Department of Defense
mandated on-demand availability of neuraxial labor anal-
1.10 (95% CI, 0.97 to 1.25).3 In an individual patient meta- gesia in military hospitals. In nulliparous women in spon-
analysis of the studies performed at Parkland Hospital taneous labor with a singleton infant with a vertex
(n = 4465),429 the odds ratio was 1.04 (95% CI, 0.81 to 1.34). presentation, the rate of epidural labor analgesia rose
from less than 1% to approximately 80% in a 1-year
Mode and Density of Neuraxial Analgesia and Effect period.436 The rate of cesarean delivery was unchanged
on Cesarean Delivery Rate. If neuraxial analgesia during the same period (14.4% versus 12.1%, respec-
adversely affects the outcome of labor, one would expect tively; adjusted RR, 0.8; 95% CI, 0.6 to 1.2).
to observe a dose-response effect. The COMET study In another impact study, Impey et al.437 compared
randomly assigned more than 1000 parturients to one obstetric outcome for the first 1000 nulliparous women
of three groups: (1) “high-dose” epidural analgesia (term gestation, singleton fetus, cephalic presentation,
(traditional epidural analgesia with bupivacaine 0.25%); spontaneous labor) who delivered at the National Mater-
(2) “low-dose” epidural analgesia (bupivacaine 0.1%/fen- nity Hospital in 1987 with the outcome for a similar
tanyl 2 µg/mL bolus, followed by a continuous epidural group of women who delivered in 1992 and 1994. The
infusion); and (3) “low-dose” CSE analgesia (intrathecal epidural analgesia rate rose from 10% in 1987 to 45% in
bupivacaine/fentanyl followed by intermittent boluses of 1992 and 57% in 1994. In each of these 3 years, 82% of
epidural bupivacaine 0.1%/fentanyl 2 µg/mL).430 There women underwent spontaneous vaginal delivery. The
was no difference in cesarean delivery rates among groups cesarean delivery rate was 4% in 1987, 5% in 1992, and
(Figure 23-9). Similarly, several other studies that com- 4% in 1994 (P = NS) (Figure 23-10). The investigators
pared traditional epidural analgesia (using bupivacaine concluded that the consistency of the operative delivery
0.25%) and low-dose CSE techniques found no differ- rates in each of 3 years with very different epidural rates
ence between groups in the cesarean delivery rate.431-433 suggests that epidural analgesia does not increase the
The results of these studies suggest that “high-dose” cesarean delivery rate.
neuraxial analgesia does not entail a higher risk for cesar- Socol et al.438 evaluated the impact of three initiatives
ean delivery than “low-dose” techniques; in other words, to reduce the cesarean delivery rate in their hospital. First,
no dose-response effect has been observed. they strongly encouraged a trial of labor and vaginal birth
There is no evidence that CSE analgesia influences the after cesarean delivery. Second, after the 1988 calendar
mode of delivery, when compared with epidural analgesia year, they circulated data showing the cesarean delivery
alone. Large randomized controlled trials comparing rate of every obstetrician to all obstetricians. Third, they
CSE analgesia with epidural analgesia alone have found recommended the active management of labor as the pre-
no difference between groups in the rate of cesarean ferred method of labor management for term nulliparous
delivery.430-432,434 women. The rates of total, primary, and repeat cesarean
494 PART VI Labor and Vaginal Delivery
60
studies support the results of randomized controlled
Epidural analgesia rate trials—namely, that neuraxial analgesia does not cause an
increase in the cesarean delivery rate.
50 Several studies have assessed whether there is a rela-
tionship between an individual obstetrician’s cesarean
40 delivery rate and the rate of epidural analgesia for his or
her patients.440,441 For example, Lagrew et al.440 divided
Women (%)
FIGURE 23-10 ■ Epidural analgesia and cesarean and instrumen- Timing of Initiation of Neuraxial Analgesia
tal vaginal delivery rates for 1000 consecutive nulliparous
women in spontaneous labor at term during 3 different years at Review of observational data suggests an association
the National Maternity Hospital in Dublin, Ireland. (Modified from between cesarean delivery and the initiation of neuraxial
Impey L, MacQuillan K, Robson M. Epidural analgesia need not
increase operative delivery rates. Am J Obstet Gynecol 2000;
analgesia during early labor (often defined as a cervical
182:358-63.) dilation < 4 to 5 cm).426,432,442 For example, in a retrospec-
tive study of 1917 nulliparous women, the rate of cesar-
ean delivery was twice as high in women who received
0.3
neuraxial analgesia at a cervical dilation less than 4 cm
than in those in whom neuraxial analgesia was initiated
0.25
at a cervical dilation of 4 cm or more (18.9% versus
Cesarean delivery rate
FIGURE 23-12 ■ Meta-analysis of cesarean delivery in women randomized to receive early labor initiation of neuraxial analgesia
(cervical dilation < 4 cm) or late initiation (cervical dilation ≥ 4 cm). The size of the box at the point estimate for each study is pro-
portional to the number of patients in the study. The diamond represents the point estimate of the pooled risk ratio, and the length
of the diamond is proportional to the confidence interval. Control, late epidural analgesia; EA, epidural analgesia; n, number of
events (cesarean delivery) in the treatment or control group; N, total number of patients in the treatment or control group. (Modified
from Wassen MM, Zuijlen J, Roumen FJ, et al. Early versus late epidural analgesia and risk of instrumental delivery in nulliparous women:
a systematic review. BJOG 2011; 118:655-61.)
second study received epidural analgesia alone.22 The use most investigators did not define the criteria for the per-
of oxytocin augmentation was markedly different in the formance of instrumental vaginal delivery. In clinical
two studies (94%21 and 29%22). practice, and in study interpretation, it is often difficult to
Subsequent to the publication of the later studies, the distinguish “indicated” instrumental deliveries from elec-
ACOG446 published an updated Committee Opinion tive instrumental deliveries. Indeed, we have observed
entitled Analgesia and Cesarean Delivery Rates. This revised that indications for instrumental vaginal delivery vary
opinion includes the following statement: markedly among obstetricians. An obstetrician is more
likely to perform an elective instrumental delivery in a
Neuraxial analgesia techniques are the most effective and patient with satisfactory anesthesia than in a patient without
least depressant treatments for labor pain. The American analgesia. In addition, most randomized controlled trials
College of Obstetricians and Gynecologists previously are conducted in teaching institutions that have an obliga-
recommended that practitioners delay initiating epidural tion to teach obstetric residents how to perform instrumen-
analgesia in nulliparous women until the cervical dilation tal vaginal delivery. Instrumental vaginal deliveries
reached 4-5 cm. However, more recent studies have shown performed for the purpose of teaching are more likely to
that epidural analgesia does not increase the risks of be done in women with adequate analgesia.
cesarean delivery. The choice of analgesic technique, agent, Multiple randomized, controlled studies comparing
and dosage is based on many factors, including patient epidural analgesia with systemic opioid analgesia have
preference, medical status, and contraindications. The fear assessed the rate of instrumental vaginal delivery as a sec-
of unnecessary cesarean delivery should not influence the ondary outcome variable.* Most systematic reviews have
method of pain relief that women can choose during labor. concluded that epidural analgesia is associated with a
higher risk for instrumental vaginal delivery than systemic
Later randomized trials in nulliparous women in analgesia.3,429 For example, in a 2011 meta-analysis of 23
both spontaneous24 and induced445 labor, as well as a studies (n = 7935),3 the risk ratio for instrumental vaginal
2011 meta-analysis (five randomized controlled trials; delivery in women randomly assigned to receive epidural
n = 14,836),25 replicated these results. The researchers analgesia or nonepidural/no analgesia was 1.42 (95% CI,
concluded that early initiation of neuraxial analgesia does 1.28 to 1.57) (Figure 23-13). Similarly, in the individual
not increase the rate of cesarean delivery (RR, 1.02 ; 95% patient meta-analysis reported by Sharma et al.,429 the
CI, 0.96 to 1.08) (Figure 23-12).25 adjusted odds ratio was 1.86 (95% CI, 1.43 to 2.40).
In contrast to these studies, many of the impact studies
observed no difference in the instrumental vaginal deliv-
Instrumental Vaginal Delivery Rate ery rate between the control and study periods.435-437,447
Observational data associate neuraxial labor analgesia For example, despite a rise in the epidural analgesia
with a higher rate of instrumental (forceps or vacuum rate from 1% to almost 80% at Tripler Army Medical
extraction) vaginal delivery. The effect of neuraxial anal- Center, the rate of instrumental vaginal delivery did not
gesia on mode of vaginal delivery has not been assessed as change (11.1% versus 11.9%).435 Similarly, despite a
a primary outcome in randomized controlled trials, more than fivefold increase in the epidural analgesia rate
although it has been assessed as a secondary outcome in at the National Maternity Hospital in Dublin (see earlier
multiple trials. Interpretation of these results is clouded
by the fact that most studies have not assessed the quality
of analgesia during the second stage of labor. Further, *References 388, 392, 403-411, 413, 415-417, 419-423, 425-427.
496 PART VI Labor and Vaginal Delivery
FIGURE 23-13 ■ Meta-analysis of instrumental vaginal delivery rate in women randomized to neuraxial or non-neuraxial labor anal-
gesia. The number of women who had an instrumental vaginal delivery, the risk ratio, and 95% confidence interval (CI) of the risk
ratio (fixed effect model) are shown for each study. For studies with no instrumental vaginal deliveries the risk ratio could not be
calculated. n, number of events (instrumental vaginal delivery) in the neuraxial or non-neuraxial group; N, total number of subjects
in the neuraxial or non-neuraxial group. The scale is logarithmic. (Modified from Anim-Somuah M, Smyth RM, Jones L. Epidural versus
non-epidural or no analgesia in labour. Cochrane Database Syst Rev 2011; [12]:CD000331.)
discussion), the instrumental vaginal delivery rate regard to the duration and outcome of the second stage
remained unchanged (see Figure 23-10). A systematic of labor.370,448-452 Chestnut et al.370 randomly assigned
review of seven impact studies439 involving more than women already receiving epidural analgesia at 8 cm of
28,000 patients did not identify a difference in instru- cervical dilation to receive a continuous epidural infu-
mental vaginal delivery rates between periods of low and sion of 0.75% lidocaine or saline until delivery. There
periods of high epidural analgesia rates (mean change, was no difference between groups in the rate of instru-
0.76%; 95% CI, −1.2 to 2.8). mental vaginal delivery, but women in the lidocaine
Studies of early versus late initiation of neuraxial labor group as well as the saline group had inadequate second-
analgesia have not identified an increased risk for instru- stage analgesia. In a similar study in which patients were
mental vaginal delivery in the early analgesia group.21,22,24,445 randomly assigned to receive epidural bupivacaine
Obstetricians and anesthesiologists have suggested 0.125% or saline (control),449 second-stage analgesia was
that multiple factors (e.g., station and position of the clearly better in the bupivacaine group than in the
fetal vertex, maternal pain and the urge to bear down, control group, but the rate of instrumental vaginal deliv-
and neuraxial analgesia–induced motor blockade) may ery was nearly double (52% versus 27%, respectively;
contribute to the outcome of the second stage of labor. P < .05), and the duration of the second stage was longer.
The contribution of these factors to the mode of vaginal In a third study, second-stage analgesia was maintained
delivery, and their interactions, are not well understood with 0.0625% bupivacaine with fentanyl 2 µg/mL or
and these factors have not been well controlled in many saline-placebo.448 There was no difference between
studies. groups in the instrumental vaginal delivery rate, but
Several studies have specifically assessed the effect of analgesia was only marginally better in the treatment
maintenance of neuraxial analgesia until delivery with group.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 497
The effect of neuraxial analgesia on the outcome of between motor blockade and instrumental vaginal deliv-
the second stage of labor may be influenced by the density ery is inconsistent. Smedstad and Morison228 reported a
of neuraxial analgesia. High concentrations of epidural higher incidence of instrumental vaginal delivery when
local anesthetic may cause maternal motor blockade, bupivacaine 0.25% was administered as a continuous epi-
leading to relaxation of pelvic floor musculature, which dural infusion than as intermittent bolus injections. In
in turn may interfere with fetal rotation during descent. contrast, the COMET investigators observed no differ-
Abdominal muscle relaxation may decrease the effective- ence in the instrumental vaginal delivery rate in the two
ness of maternal expulsive efforts. The effects of specific groups who received “low-dose” bupivacaine/fentanyl,
analgesic techniques, concentration of local anesthetic, one by infusion and the other by intermittent bolus.430
total dose of local anesthetic, and degree of motor block- Similarly, in a meta-analysis of PCEA (without back-
ade on the risk for instrumental vaginal delivery are over- ground infusion) compared with continuous epidural
lapping and difficult to study. For example, some studies infusion analgesia,238 the dose of bupivacaine and degree
suggest that administration of epidural analgesia using of motor blockade were significantly lower in the PCEA
higher concentrations of bupivacaine is associated with a group, but the rates of instrumental vaginal delivery did
higher risk for instrumental vaginal delivery compared not differ.
with use of lower concentrations.430,432,433,453 James et al.453 It is possible that the inconsistent results can be
randomly assigned parturients to receive intermittent explained by the actual absolute differences in bupiva-
epidural bupivacaine 0.25% or bupivacaine 0.1% with caine dose and motor blockade. For example, the differ-
fentanyl 2 µg/mL. The severity of motor blockade and ences in dose and motor blockade may have clinically
the incidence of instrumental vaginal delivery were less significant adverse effects on the outcome of the second
in the low-dose group than in the high-dose group (6% stage of labor if bupivacaine 0.25% is compared with
versus 24%, respectively; P = .03). Similarly, in a much bupivacaine 0.125% but not if bupivacaine 0.125% is
larger study that compared CSE (low-dose) with tradi- compared with bupivacaine 0.0625%. Many of the ran-
tional high-dose epidural analgesia, the rate of instru- domized controlled trials included in the meta-analysis
mental vaginal delivery was lower in the CSE group.432 that compared epidural with systemic opioid analgesia
In another large study, Olofsson et al.433 noted a lower used concentrated solutions of bupivacaine for both the
instrumental vaginal delivery rate in women randomly loading and infusion doses (e.g., bupivacaine 0.25% for
assigned to “low-dose” bupivacaine 0.125% with sufent- the loading dose, bupivacaine 0.125% by continuous
anil than in those receiving “high-dose” bupivacaine infusion for maintenance of analgesia.)3
0.25% with epinephrine. Motor blockade may increase the risk for malrotation
In contrast, Collis et al.431 observed no difference in of the fetal vertex. Robinson et al.454 and Le Ray et al.455
mode of delivery between women randomly assigned to observed a higher incidence of occiput malposition at
receive either a high-dose or a low-dose neuraxial tech- delivery in patients who received epidural analgesia
nique. Even more confusing, the COMET investigators before engagement of the fetal head. In contrast, Yancey
reported a lower rate of instrumental vaginal delivery in et al.456 and Sheiner et al.457 noted that the administration
the two groups of women randomly assigned to receive of on-demand epidural analgesia did not increase the
either the low-dose epidural or CSE technique than in frequency of malposition of the fetal head at delivery; the
the group that received 0.25% bupivacaine (see earlier incidence of instrumental vaginal delivery was not related
discussion and Figure 23-9).430 However, the total bupi- to fetal station at initiation of analgesia. In a prospective
vacaine dose in the traditional “high-dose” epidural cohort study using ultrasonography, Lieberman et al.458
group did not actually differ from that in the “low-dose” reported that fetal position changed frequently during
epidural group because the former was administered by labor but that epidural analgesia was associated with a
intermittent injection and the latter by continuous infu- higher incidence of occiput posterior position at delivery
sion. In contrast, the total bupivacaine dose was signifi- (13% versus 3%, P < .002). However, these results should
cantly lower in the CSE group. Finally, in a meta-analysis be interpreted with caution as women were not randomly
of studies that compared CSE and epidural analgesia,27 assigned to the treatment group. Factors that cause
the instrumental vaginal delivery rate was lower in the women to request analgesia when the fetal head is high
CSE group than in the traditional “high-dose” epidural may also be independent risk factors for instrumental
analgesia groups (risk ratio 0.80; 95% CI, 0.65 to 0.98), vaginal delivery. A study from Italy459 in which ultraso-
but there was no difference between “low-dose” epidural nography was used to assess fetal head position found no
and CSE analgesia (risk ratio 1.06; 95% CI, 0.87 to 1.30). association between use of early labor neuraxial analgesia
Together, these data suggest that the specific analgesia and fetal head position at delivery.
technique may influence the risk for instrumental vaginal In an editorial, Chestnut460 concluded that effective
delivery. second-stage analgesia increases the risk for instrumental
In general, the dose of bupivacaine is significantly vaginal delivery. However, effective analgesia is a spec-
lower if epidural analgesia is maintained with an intermit- trum that ranges from complete absence of sensory input
tent bolus technique rather than a continuous infusion (dense analgesia) to perception of uterine contraction
technique (see earlier discussion). Most investigators “pressure” without pain (less dense analgesia). Minimiz-
have noted a difference in motor blockade between the ing the risk for instrumental vaginal delivery while maxi-
two techniques; higher total bupivacaine doses (i.e., con- mizing analgesia is both an art and a science and requires
tinuous infusion techniques) are associated with a greater the attention of the anesthesia provider to the individual
degree of motor blockade. However, the relationship needs of the patient. A single analgesic technique or
498 PART VI Labor and Vaginal Delivery
Anim-Somuah, 2011 3
2981* WMD 19 min (95% CI, –13-50) .25 WMD 14 min (95% CI, 7-21) <.001
4233†
Sharma, 2004429 2703 8.1 ± 5 h 7.5 ± 5 h .01 60 ± 56 min 47 ± 57 min <.001
later time (and lower fetal station) than women with The epidural administration of a local anesthetic with
systemic opioid analgesia. In other words, the patient may epinephrine is followed by systemic absorption of both
be fully dilated for a significant time before cervical exam- drugs. Some physicians have expressed concern that the
ination verifies full cervical dilation. This difference epinephrine may exert a systemic beta-adrenergic toco-
serves to artificially prolong the duration of the first stage lytic effect and slow labor. Early studies, which used large
of labor in the epidural group, although it shortens the doses of epinephrine, suggested that the caudal epidural
apparent duration of the second stage of labor. administration of local anesthetic with epinephrine pro-
Other factors may also influence the duration of the longed the first stage of labor and increased the number
first stage of labor. Some clinicians have noted enhanced of patients who required oxytocin augmentation of
uterine activity in some patients for approximately 30 labor.477 Subsequently, most studies have suggested that
minutes after the initiation of neuraxial analgesia, whereas the addition of epinephrine 1.25 to 5 µg/mL (1 : 800,000
uterine activity appears to be reduced in other patients. to 1 : 200,000) to the local anesthetic solution does not
Schellenberg468 suggested that aortocaval compression is affect the progress of labor or method of delivery.*
responsible for the transient decrease in uterine activity There is no evidence that the specific local anesthetic
that occurs after the administration of epidural analgesia or opioid used for neuraxial analgesia directly or indi-
in some patients. He concluded that this effect does not rectly affects the duration of labor.86,479 In a randomized
occur if aortocaval compression is avoided. Cheek et al.469 controlled trial, Tsen et al.480 observed a higher rate of
noted that uterine activity decreased after the intravenous cervical dilation in women who received CSE analgesia
infusion of 1 L of crystalloid solution, but not after infu- than in those who received epidural analgesia. However,
sion of 0.5 L or maintenance fluid alone. There was no randomized controlled trials that compared CSE and epi-
decrease in uterine activity after the administration of dural analgesia have not found a difference in the dura-
epidural analgesia. Zamora et al.36 made similar observa- tion of labor between the two techniques.430-432,434,481
tions. Miller et al.470 hypothesized that a fluid bolus might New evidence suggests that genetic polymorphism in
inhibit antidiuretic hormone (vasopressin) release from the oxytocin receptor, catechol-O-methyltransferase
the posterior pituitary gland. Because this organ also (COMT), and β2-adrenergic receptor (ADRB2) genes
releases oxytocin, the production of that hormone might affect the progress of labor.482,483 Whether these geno-
also be transiently suppressed; this possible decrease in types interact with neuraxial analgesia to affect the prog-
oxytocin release may partially explain the transient ress of labor requires further study with large numbers
changes in uterine contractility observed in association of parturients.
with epidural analgesia. In summary, neuraxial analgesia appears to have a vari-
In a prospective but nonrandomized study, Rahm able effect on the duration of the first stage of labor. It
et al.471 observed that epidural analgesia (bupivacaine may shorten labor in some women and lengthen it in
with sufentanil) was associated with lower plasma oxyto- others. However, analgesia-related prolongation of the
cin levels at 60 minutes after initiation of analgesia than first stage of labor, if it occurs, is short, has not been
in healthy controls who did not receive epidural analge- shown to have adverse maternal or neonatal effects, and
sia. Behrens et al.472 noted that epidural analgesia during is probably of minimal clinical significance.
the first stage of labor significantly reduced the release of
prostaglandin F2α and “impede[d] the normal progressive Second Stage of Labor
increase in uterine activity.” In contrast, Nielsen et al.473
measured upper and lower uterine segment intrauterine There is little doubt that effective neuraxial analgesia
pressures for 50 minutes before and after the administra- prolongs the second stage of labor. Meta-analyses of ran-
tion of epidural bupivacaine analgesia in 11 nulliparous domized controlled trials that compared neuraxial with
women during spontaneous labor. No significant differ- systemic opioid analgesia support this clinical observation
ence in the number of contractions before and after (see Table 23-12).3,429 The mean duration of the second
epidural analgesia was observed. There was greater intra- stage was 15 to 20 minutes longer in women randomly
uterine pressure in the upper uterine segment than in the assigned to receive neuraxial analgesia than in women
lower segment (consistent with fundal dominance) both assigned to receive systemic opioid analgesia.3,429
before and after initiation of epidural analgesia. Further, The ACOG has defined a prolonged second stage in
fundal dominance was higher after epidural analgesia nulliparous women as lasting more than 3 hours with
than in the preanalgesia period. neuraxial analgesia and more than 2 hours without neur-
Increased uterine activity after the initiation of neur- axial analgesia; for parous women, it is more than 2 hours
axial analgesia has been hypothesized to be an indirect in those with neuraxial analgesia and more than 1 hour
effect of neuraxial analgesia (see later discussion).474 Ini- in those without neuraxial analgesia.484 Zhang et al.485
tiation of neuraxial analgesia is associated with an acute performed a secondary analysis of data from the Consor-
decrease in the maternal plasma concentration of circu- tium on Safe Labor, a large, multicenter study from 19
lating epinephrine.4 Epinephrine is a tocolytic, and the hospitals across the United States, to characterize the
acute decrease in maternal concentration may result in duration of labor in a contemporary cohort of American
greater uterine activity. This may be an explanation women. Data were abstracted for term parturients in
for the salutary effect on the progress of labor that is spontaneous labor with a singleton gestation in the vertex
observed in some women with dysfunctional labor after presentation and with normal perinatal outcome. The
the initiation of neuraxial analgesia475 or in women who
are extremely anxious.476 *References 50, 88, 139, 141, 144, 478.
500 PART VI Labor and Vaginal Delivery
TABLE 23-13 Duration of Second Stage of BOX 23-10 Definition of Second-Stage Arrest
Labor by Parity
No progress (descent or rotation) for:
Parity 0 Parity 1 Parity ≥ 2 • Four hours or more in nulliparous women with
(n = 25,624) (n = 16,755) (n = 16,219) epidural analgesia
• Three hours or more in nulliparous women without
Epidural 1.1 (3.6) 0.4 (2.0) 0.3 (1.6)
Analgesia (h) epidural analgesia
• Three hours or more in parous women with epidural
No Epidural 0.6 (2.8) 0.2 (1.3) 0.1 (1.1)
Analgesia (h) analgesia
• Two hours or more in parous women without epidural
Data are median (95th percentile) duration of the second stage of analgesia
labor in spontaneous laboring women.
Data from Zhang J, Landy HJ, Branch DW, et al. Contemporary Definitions from Spong CY, Berghella V, Wenstrom KD, et al. Preventing
patterns of spontaneous labor with normal neonatal outcomes. the first cesarean delivery. Summary of a joint Eunice Kennedy Shriver
Obstet Gynecol 2010; 116:1281-7. National Institute of Child Health and Human Development, Society for
Maternal-Fetal Medicine, and American College of Obstetricians and
Gynecologists Workshop. Obstet Gynecol 2012; 120:1181-93.
HIGH QUALITY
Goodfellow et al (1979) 2.29 (0.91–5.77) 12/21 4/16 0.33
Buxton et al (1998) 0.47 (0.22–1.03) 6/22 11/19 0.47
Vause et al (1998) 1.05 (0.74–1.48) 34/68 32/67 2.40
Mayberry et al (1999) 1.12 (0.90–1.40) 58/81 46/72 5.84
Fraser et al (2000) 1.09 (1.00–1.18) 544/936 496/926 43.59
Fitzpatrick et al (2002) 0.94 (0.72–1.24) 46/88 50/90 3.86
Plunckett et al (2003) 1.01 (0.84–1.21) 82/117 59/85 8.42
Simpson et al (2005) 1.05 (0.56–1.97) 11/23 10/22 0.73
Gillesby et al (2010) 1.23 (0.92–1.64) 30/38 25/39 3.48
Subtotal (I-squared = 13.6%, P = .321) 1.07 (0.98–1.16) 823/1394 733/1336 69.11
LOW QUALITY
Maresh et al (1983) 1.43 (0.84–2.44) 18/36 14/40 1.00
Hansen et al (multiparous women; 2002) 1.11 (1.00–1.24) 63/65 48/55 23.69
Hansen et al (primiparous women; 2002) 1.15 (0.93–1.43) 48/62 45/67 6.20
Kelly et al (Excluded) 16/16 28/28 0.00
Subtotal (I-squared = 0.0%, P = .515) 1.13 (1.02–1.24) 145/179 135/190 30.89
0.1 1 10
Higher with immediate pushing Higher with delayed pushing
FIGURE 23-14 ■ Meta-analysis of delayed versus immediate pushing on the rate of spontaneous vaginal delivery, stratified by quality
of study. The circle represents the point estimate and the diamond is the point estimate for the pooled risk ratio. The number of
events is the number of spontaneous vaginal deliveries. RR, risk ratio; CI, confidence interval. (Modified from Tuuli M, Frey HA, Odibo
AO, et al. Immediate compared with delayed pushing in the second stage of labor: a systematic review and meta-analysis. Obstet Gynecol
2012; 120:660-8.)
because analgesia/anesthesia may be difficult to reestab- delivery.501 More recently, meta-analysis of a number of
lish if the need for operative delivery arises. randomized controlled trials suggests that active manage-
ment of labor may have little effect on the cesarean deliv-
ery rate.502 Although randomized trials of neuraxial
Third Stage
compared with systemic opioid analgesia have consis-
Rosaeg et al.500 retrospectively reviewed the outcomes of tently found that neuraxial analgesia does not cause an
7468 women who underwent vaginal delivery at their increase in the rate of cesarean delivery (see earlier discus-
hospital between 1996 and 1999. Epidural analgesia was sion), Kotaska et al.503 questioned the external validity of
not associated with a prolonged third stage of labor. these trials because of oxytocin management. In a search
The duration of the third stage of labor was shorter in of the medical literature, they identified 16 randomized
women who received epidural analgesia and subsequently controlled trials; 8 of the 16 trials included descriptions of
required manual removal of the placenta. The research- labor management and these trials were included in the
ers suggested that epidural analgesia “provided a ‘permis- analysis. Seven of the eight trials described active manage-
sive’ role”—in other words, epidural analgesia likely ment of labor and found no difference in the mode of
facilitated and/or encouraged earlier intervention by the delivery between groups. Only one of eight trials described
obstetrician. the use of low-dose oxytocin and reported a markedly
higher rate of cesarean delivery in the neuraxial analgesia
group. Kotaska et al.503 concluded that epidural analgesia
Other Factors and Progress of Labor in the setting of low-dose oxytocin probably increases the
rate of cesarean delivery. The researchers were correct in
Oxytocin
stating that the role of oxytocin in neuraxial analgesia
Active management of labor is a concept that consists of a outcome studies has not been well controlled. However,
disciplined, standardized labor management protocol that their conclusion that epidural analgesia in the setting of
includes early amniotomy and oxytocin augmentation if low-dose oxytocin probably causes an increase in the rate
the cervix fails to dilate at a minimum rate (usually 1 cm/h of cesarean delivery is highly flawed because, in their
in nulliparous women). Early studies suggested that this analysis, the researchers did not include the eight studies
type of labor management decreased the rate of cesarean that did not describe the management of labor. In all
502 PART VI Labor and Vaginal Delivery
probability the management of labor in these studies was of the drug, which has a direct effect on the fetus. Second,
not active (e.g., did not include high-dose oxytocin admin- the effects of neuraxial blockade on the mother may affect
istration), or this would have been described. the fetus indirectly. Effects of local anesthetics and
In randomized controlled trials that compared the opioids on the fetus and neonate are discussed in detail
effects of neuraxial and systemic opioid analgesia on the in Chapter 13.
outcome of labor, women who received neuraxial opioids
had a higher rate of oxytocin augmentation.3,429 In a Direct Effects
meta-analysis that included 13 randomized trials, the risk
ratio was 1.19 (95% CI, 1.03 to 1.39).3 The reason(s) for Direct fetal effects include intrapartum drug effects on
this observation are not clear. the FHR as well as possible respiratory depression after
Randomized controlled trials that compared early and delivery. The determinants of maternal plasma drug con-
late initiation of neuraxial analgesia have used markedly centration, transfer across the placenta, and effects on
different oxytocin protocols, yet all have concluded that the neonate are discussed in Chapters 4 and 13. Deter-
early initiation of neuraxial analgesia does not have an minants of maternal plasma drug concentration include
adverse effect on the outcome of labor. In the study of dose, site of administration, metabolism and excretion of
early CSE analgesia by Wong et al.,21 the rate of oxytocin the drug, and the presence of adjuvants (e.g., epineph-
use was high in both groups (approximately 93%). rine). Factors that influence placental transfer include
However, the maximum oxytocin infusion rate in the maternal and fetal placental perfusion, the physicochem-
control (early systemic opioid) group was significantly ical characteristics of the drug, concentration of the free
higher than that in the early CSE group even though the drug in maternal plasma, and permeability of the pla-
median duration of labor was 81 minutes shorter in the centa. Most anesthetic and analgesic drugs, including
CSE group. In the study of early epidural analgesia by local anesthetics and opioids, readily cross the placenta.
Ohel et al.,22 the rate of oxytocin use in both groups was
much lower (approximately 29%); however, as in the Fetal Heart Rate
study by Wong et al.,21 the duration of labor was signifi-
cantly shorter in the early neuraxial analgesia group. Effects of local anesthetics and opioids on FHR may be
Taken together, the results of these studies do not support direct and indirect (see earlier discussion)474,479; however,
the hypothesis that oxytocin played a major role in the there is little evidence for a direct effect when these drugs
outcomes. are administered as components of neuraxial analgesia.
The ACOG supports the use of oxytocin for the treat- Transient changes in FHR variability and periodic decel-
ment of dystocia or arrest of labor in the first or second erations have been observed during epidural labor anal-
stage, whether or not the patient is receiving neuraxial gesia with bupivacaine and other local anesthetics.479,507,508
analgesia.484 These FHR decelerations were not associated with
maternal hypotension. However, Loftus et al.509 did not
observe FHR decelerations in women who received epi-
Ambulation
dural bupivacaine for elective cesarean delivery, despite
Observational studies suggest that ambulation may be the use of larger doses of bupivacaine and the occurrence
associated with less pain and a shorter duration of labor.504 of more extensive sympathetic blockade in comparison
However, randomized controlled trials that compared with epidural labor analgesia. Of interest, one study noted
ambulation and bed rest during the first stage of labor in that the administration of either epidural bupivacaine or
women with neuraxial analgesia have not demonstrated intrathecal sufentanil was followed by a similar incidence
any advantages of ambulation with regard to the progress of FHR decelerations (23% and 22%, respectively) in
or outcome of labor. Nageotte et al.432 randomly assigned laboring women.510 Other studies have not observed a
505 nulliparous women to receive CSE analgesia either higher incidence of FHR decelerations associated with
with or without ambulation. There was no difference epidural administration of bupivacaine during labor.511
between groups in the mode of delivery or duration of Further, the reports of FHR decelerations after bupiva-
labor. These results agree with those of a meta-analysis caine did not demonstrate adverse neonatal outcome;
of five randomized controlled trials involving 1161 thus, the significance of these decelerations is unclear.
women.505 In addition, there were no differences between There are no published data on the relationship between
groups in the use of oxytocin augmentation, satisfaction the concentration of bupivacaine used for intrapartum
with analgesia, or Apgar scores. No adverse effects were epidural analgesia and the incidence of FHR decelera-
reported. These results are similar to those of trials that tions. Altogether, these data suggest that epidural local
compared ambulation and bed rest in women without anesthetics have minimal, if any, direct effect on FHR.
neuraxial analgesia.506 Similarly, neuraxial opioid administration has little
direct effect on the FHR.109,512,513 In contrast, systemic
meperidine analgesia was associated with a greater reduc-
EFFECTS OF NEURAXIAL ANALGESIA ON tion of FHR variability and fewer FHR accelerations than
THE FETUS AND NEONATE epidural bupivacaine analgesia.514 Spinal administration
of local anesthetics and opioids results in lower maternal
Neuraxial analgesia may affect the fetus directly, indi- plasma concentrations of drug(s) than epidural adminis-
rectly, or both. First, systemic absorption of the anes- tration and is therefore even less likely to cause a direct
thetic agents may be followed by transplacental transfer fetal effect.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 503
opioid combined with a local anesthetic, regardless of the concentration of the maintenance solution may also
stage and phase of labor. Alternatively, epidural analgesia need to be increased.
is initiated with bupivacaine 0.125% combined with fen- This maintenance technique usually results in satisfac-
tanyl 100 µg. tory perineal analgesia for delivery. Occasionally, women
CSE analgesia with both a local anesthetic and an with epidural analgesia require additional (more dense)
opioid is particularly advantageous for parous women in analgesia for delivery, particularly if an instrumental
the late active phase of the first stage of labor and in all vaginal delivery is planned. In this case, we often
women in whom neuraxial analgesia is initiated in the administer 5 to 12 mL of 1% to 2% lidocaine or 2% to
second stage of labor. Sacral neuroblockade is required 3% 2-chloroprocaine. This usually results in satisfactory
for complete analgesia during the second stage of labor; sacral anesthesia in a patient with preexisting epidural
this neuroblockade is difficult to accomplish in a timely labor analgesia.
fashion with an initial (de novo) lumbar epidural injection There is no single correct way to provide neuraxial
of analgesic/anesthetic agents. (For initiation of lumbar labor analgesia, although for particular patients and spe-
epidural anesthesia in late labor, the injection of a large cific clinical conditions some methods may have advan-
volume [≥ 20 mL] of local anesthetic solution may be tages over others. Frequent communication among
required to achieve sacral analgesia, and this injection members of the anesthesia, obstetric, and nursing teams
often results in a mid- or high-thoracic neuroblockade is essential to the safe and satisfactory provision of neur-
that is more extensive than desired. Therefore, when axial labor analgesia. In addition, within each labor and
initiating neuraxial analgesia in late labor, a CSE tech- delivery unit, consistency among anesthesia providers in
nique is preferred). their choice of techniques, specific drugs, and drug doses/
Maintenance epidural analgesia is typically initiated concentrations is likely to result in fewer errors and
soon after the initiation of analgesia (within 15 to 30 higher satisfaction among other caregivers and patients.
minutes) rather than waiting for the neuroblockade to
regress. There are several advantages to this technique.
Most women experience seamless analgesia (i.e., there is
no window of pain as the initial block regresses). The KEY POINTS
workload for the anesthesia provider is lessened, because
he or she can set up and initiate the epidural infusion • Neuraxial analgesia is the most effective form
while monitoring the patient for hypotension after initia- of intrapartum analgesia currently available.
tion of neuroblockade. Finally, an epidural bolus of local • In most cases, maternal request for pain relief
anesthetic is not required to reestablish or extend neuro- represents a sufficient indication for the
blockade, possibly enhancing safety. administration of neuraxial analgesia.
Analgesia is typically maintained with a dilute solution • The safe administration of neuraxial analgesia
of an amide local anesthetic and an opioid, administered requires a thorough (albeit directed) preanesthetic
by continuous infusion or PCEA. My colleagues and evaluation and the immediate availability
I prefer PCEA because it allows patient titration of neu- of appropriate resuscitation equipment.
roblockade and entails less risk for breakthrough pain.
Patient satisfaction is better and the workload for the • Neuraxial labor analgesia is not a generic
anesthesia provider is decreased. At our institution, the procedure. The procedure should be tailored
PCEA infusion pump parameters are the same for all to individual patient needs.
laboring women, so there are fewer errors in pump setup. • The administration of the epidural test dose
However, when a continuous infusion is used without should allow the anesthesia provider to recognize
PCEA to maintain analgesia, it may be necessary to most cases of unintentional intravascular or
titrate the continuous infusion rate to individual patient intrathecal placement of the epidural catheter.
needs. For example, women in early labor require less All therapeutic doses of local anesthetic should
drug to maintain analgesia (6 to 10 mL/h), whereas be administered incrementally.
women in more advanced labor may require a higher • Bupivacaine is the local anesthetic most often
infusion rate (8 to 15 mL/h). Similarly, a parous patient used for epidural analgesia during labor.
may require a higher infusion rate than a nulliparous Ropivacaine and levobupivacaine are satisfactory
patient, even though analgesia is initiated at the same alternatives. Most anesthesia providers reserve
stage of labor. 2-chloroprocaine and lidocaine for cases that
Some parturients experience breakthrough pain. After require the rapid extension of epidural anesthesia
evaluating the nature of the pain, the extent of neuro for vaginal or cesarean delivery.
blockade, and the progress of labor, we usually treat • The addition of a lipid-soluble opioid to a
breakthrough pain with a bolus epidural injection of neuraxial local anesthetic allows the anesthesia
bupivacaine 0.125%, 10 to 15 mL, administered in provider to provide excellent analgesia while
5-mL increments. The patient may benefit from addi- reducing the total dose of local anesthetic and
tional instruction about the optimal use of PCEA. Occa- minimizing the side effects of each agent.
sionally, we may elect to use a more concentrated Perhaps the major advantage of this technique
local anesthetic solution (e.g., bupivacaine 0.25%), is that the severity of motor block can be
particularly in the presence of an abnormal fetal minimized during labor.
position or dysfunctional labor. In this case, the
506 PART VI Labor and Vaginal Delivery
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474. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after versus immediate pushing during second stage of labor for nul-
intrathecal injection of fentanyl for analgesia during labor: a cause liparous women with epidural anesthesia. J Obstet Gynecol Neo-
of fetal bradycardia? Anesthesiology 1994; 81:1083. natal Nurs 2010; 39:635-44.
475. Moir DD, Willocks J. Management of incoordinate uterine action 496. Maresh M, Choong KH, Beard RW. Delayed pushing with
under continuous epidural analgesia. Br Med J 1967; 3:396-400. lumbar epidural analgesia in labour. Br J Obstet Gynaecol 1983;
476. Lederman RP, Lederman E, Work BA Jr, McCann DS. The rela- 90:623-7.
tionship of maternal anxiety, plasma catecholamines, and plasma 497. Hansen SL, Clark SL, Foster JC. Active pushing versus passive
cortisol to progress in labor. Am J Obstet Gynecol 1978; 132: fetal descent in the second stage of labor: a randomized controlled
495-500. trial. Obstet Gynecol 2002; 99:29-34.
23 Epidural and Spinal Analgesia /Anesthesia for Labor and Vaginal Delivery 517
498. Kelly M, Johnson E, Lee V, et al. Delayed versus immediate 513. Wilhite AO, Moore CH, Blass NH, Christmas JT. Plasma con-
pushing in second stage of labor. MCN Am J Matern Child Nurs centration profile of epidural alfentanil. Bolus followed by con-
2010; 35:81-8. tinuous infusion technique in the parturient: effect of epidural
499. Tuuli MG, Frey HA, Odibo AO, et al. Immediate compared with alfentanil and fentanyl on fetal heart rate. Reg Anesth 1994;
delayed pushing in the second stage of labor: a systematic review 19:164-8.
and meta-analysis. Obstet Gynecol 2012; 120:660-8. 514. Hill JB, Alexander JM, Sharma SK, et al. A comparison of the
500. Rosaeg OP, Campbell N, Crossan ML. Epidural analgesia does effects of epidural and meperidine analgesia during labor on fetal
not prolong the third stage of labour. Can J Anaesth 2002; 49: heart rate. Obstet Gynecol 2003; 102:333-7.
490-2. 515. Smith CV, Rayburn WF, Allen KV, et al. Influence of intravenous
501. O’Driscoll K, Meagher D, Boylan P. Active Management of fentanyl on fetal biophysical parameters during labor. J Matern
Labor. 3rd edition. London, Mosby–Year Book, 1993. Fetal Med 1996; 5:89-92.
502. Wei S, Wo BL, Qi HP, et al. Early amniotomy and early oxytocin 516. Scanlon JW, Ostheimer GW, Lurie AO, et al. Neurobehavioral
for prevention of, or therapy for, delay in first stage spontaneous responses and drug concentrations in newborns after maternal
labour compared with routine care. Cochrane Database Syst Rev epidural anesthesia with bupivacaine. Anesthesiology 1976; 45:
2012; (9):CD006794. 400-5.
503. Kotaska AJ, Klein MC, Liston RM. Epidural analgesia associated 517. Elliott RD. Continuous infusion epidural analgesia for obstetrics:
with low-dose oxytocin augmentation increases cesarean births: a bupivacaine versus bupivacaine-fentanyl mixture. Can J Anaesth
critical look at the external validity of randomized trials. Am J 1991; 38:303-10.
Obstet Gynecol 2006; 194:809-14. 518. Abrão KC, Francisco RP, Miyadahira S, et al. Elevation of uterine
504. Lupe PJ, Gross TL. Maternal upright posture and mobility in basal tone and fetal heart rate abnormalities after labor analgesia:
labor—a review. Obstet Gynecol 1986; 67:727-34. a randomized controlled trial. Obstet Gynecol 2009; 113:41-7.
505. Roberts CL, Algert CS, Olive E. Impact of first-stage ambulation 519. Landau R, Carvalho B, Wong C, et al. Elevation of uterine basal
on mode of delivery among women with epidural analgesia. Aust tone and fetal heart rate abnormalities after labor analgesia: a
N Z J Obstet Gynaecol 2004; 44:489-94. randomized controlled trial. Obstet Gynecol 2009; 113:1374.
506. Bloom SL, McIntire DD, Kelly MA, et al. Lack of effect of 520. Albright GA, Forster RM. Does combined spinal-epidural anal-
walking on labor and delivery. N Engl J Med 1998; 339:76-9. gesia with subarachnoid sufentanil increase the incidence of emer-
507. Lavin JP, Samuels SV, Miodovnik M, et al. The effects of bupiva- gency cesarean delivery? Reg Anesth 1997; 22:400-5.
caine and chloroprocaine as local anesthetics for epidural anesthe- 521. Mardirosoff C, Dumont L, Boulvain M, Tramer MR. Fetal bra-
sia of fetal heart rate monitoring parameters. Am J Obstet Gynecol dycardia due to intrathecal opioids for labour analgesia: a system-
1981; 141:717-22. atic review. Br J Obstet Gynaecol 2002; 109:274-81.
508. Boehm FH, Woodruff LF Jr, Growdon JH Jr. The effect of 522. Van de Velde M, Teunkens A, Hanssens M, et al. Intrathecal
lumbar epidural anesthesia on fetal heart rate baseline variability. sufentanil and fetal heart rate abnormalities: a double-blind,
Anesth Analg 1975; 54:779-82. double placebo-controlled trial comparing two forms of combined
509. Loftus JR, Holbrook RH, Cohen SE. Fetal heart rate after epidu- spinal epidural analgesia with epidural analgesia in labor. Anesth
ral lidocaine and bupivacaine for elective cesarean section. Anes- Analg 2004; 98:1153-9.
thesiology 1991; 75:406-12. 523. Sia AT, Chong JL. Epidural 0.2% ropivacaine for labour analgesia:
510. Nielsen PE, Erickson JR, Abouleish EI, et al. Fetal heart rate parturient-controlled or continuous infusion? Anaesth Intensive
changes after intrathecal sufentanil or epidural bupivacaine for Care 1999; 27:154-8.
labor analgesia: incidence and clinical significance. Anesth Analg 524. Smedvig JP, Soreide E, Gjessing L. Ropivacaine 1 mg/mL, plus
1996; 83:742-6. fentanyl 2 µg/mL for epidural analgesia during labour. Is mode
511. Pello LC, Rosevear SK, Dawes GS, et al. Computerized fetal of administration important? Acta Anaesthesiol Scand 2001;
heart rate analysis in labor. Obstet Gynecol 1991; 78:602-10. 45:595-9.
512. Viscomi CM, Hood DD, Melone PJ, Eisenach JC. Fetal heart rate
variability after epidural fentanyl during labor. Anesth Analg 1990;
71:679-83.
C H A P T E R 2 4
Neuraxial analgesic techniques are the most flexible Paracervical block does not adversely affect the prog-
analgesic techniques available for obstetric patients. The ress of labor. Further, it provides analgesia without the
anesthesia provider may use an epidural or a spinal tech- annoying sensory and motor blockade that may result
nique to provide effective analgesia during the first and/ from neuraxial analgesia. The paracervical technique
or second stage of labor. Subsequently, the epidural or does not block somatic sensory fibers from the lower
spinal technique may be used to achieve anesthesia for vagina, vulva, and perineum. Thus, it does not relieve the
either vaginal or cesarean delivery. Unfortunately, some pain caused by distention of these structures during the
maternal conditions (e.g., coagulopathy, hemorrhage) late first stage and second stage of labor. Contemporary
contraindicate the administration of neuraxial analgesia. experience suggests that paracervical block results in sat-
Many parturients do not have access to neuraxial analge- isfactory analgesia during the first stage of labor in 50%
sia, and others do not want it. The purpose of this chapter to 75% of parturients. One study noted that paracervical
is to discuss alternative regional analgesic techniques for block provided better analgesia in nulliparous women
labor and vaginal delivery. than in parous women, probably because paracervical
block does not provide effective analgesia for the sudden
and rapid descent of the presenting part that often occurs
PARACERVICAL BLOCK in parous women.1
In 1981, approximately 5% of laboring women in
During the first stage of labor, pain results primarily from the United States received paracervical block,2 and 2%
dilation of the cervix and distention of the lower uterine to 3% of parturients in the United States received
segment and upper vagina. Pain impulses are transmitted paracervical block during labor in 2001.3 Paracervical
from the upper vagina, cervix, and lower uterine segment block remains more popular in Scandinavian countries.
by visceral afferent nerve fibers that join the sympathetic Approximately 17% of Finnish parturients received
chain at L2 to L3 and enter the spinal cord at T10 to paracervical block during labor in 2004-2005.4 In the
L1. Some obstetricians perform paracervical block to United States, the decline in the popularity of paracervi-
provide analgesia during the first stage of labor. The cal block has resulted from both fear of fetal complica-
goal is to block transmission through the paracervical tions and the greater popularity of neuraxial analgesic
ganglion—also known as Frankenhäuser’s ganglion—which techniques.
lies immediately lateral and posterior to the cervicouter- Jensen et al.5 randomly assigned 117 nulliparous
ine junction. women to receive either bupivacaine paracervical block
518
24 Alternative Regional Analgesic Techniques for Labor and Vaginal Delivery 519
or intramuscular meperidine 75 mg. Women in the para- two groups in the incidence of fetal heart rate (FHR)
cervical block group had significantly better analgesia abnormalities, and there were no cases of fetal bradycar-
than women in the meperidine group at 20, 40, and 60 dia in either group.4
minutes. During the first 60 minutes, pain relief was Kangas-Saarela et al.7 compared neonatal neurobe-
complete or acceptable in 78% of the women in the havioral responses in 10 infants whose mothers received
paracervical block group but in only 31% of the women bupivacaine paracervical block with those in 12 infants
in the meperidine group. Two fetuses in the paracervical whose mothers received no analgesia. The investigators
block group and one in the meperidine group had tran- performed paracervical block while each patient lay in a
sient bradycardia. A total of 6 infants in the paracervical left lateral position, and they limited the depth of the
block group and 16 infants in the meperidine group injection into the vaginal mucosa to 3 mm or less. They
(P < .05) had fetal/neonatal depression, which the inves- observed no significant differences between groups in
tigators defined as an umbilical arterial blood pH of 7.15 neurobehavioral responses at 3 hours, 1 day, 2 days, or 4
or less and/or a 1-minute Apgar score of 7 or less.5 A 2012 to 5 days after delivery. These investigators concluded
Cochrane Review cited this study as evidence that para- that properly performed paracervical block does not
cervical block provides more effective analgesia during adversely affect newborn infant behavior or neurologic
labor than intramuscular meperidine.6 function.7
In a recent study, Junttila et al.4 randomly assigned 122
parous women to receive either bupivacaine paracervical
block or single-shot spinal bupivacaine with sufentanil.
Technique
Single-injection spinal analgesia was superior to that pro- Paracervical block is performed with the patient in a
vided by paracervical block (Figure 24-1), although para- modified lithotomy position. The uterus should be dis-
cervical block resulted in a pain score of 3 or less in 43% placed leftward during performance of the block; this
of the study subjects, and over half of the women in the displacement may be accomplished by placing a folded
paracervical block group indicated that they would be pillow beneath the patient’s right buttock. The physician
happy to receive this method of analgesia during labor in uses a needle guide to define and limit the depth of the
a future pregnancy. There was no difference between the injection and to reduce the risk for vaginal or fetal injury.
The physician introduces the needle and needle guide
into the vagina with the left hand for the left side of the
pelvis and with the right hand for the right side (Figure
24-2). The needle and needle guide are introduced into
10 Pt .001 the left or right lateral vaginal fornix, near the cervix, at
Pg .001 the 4-o’clock or the 8-o’clock position. The needle is
9 Pt*g .001
8
Pain (numerical rating scale)
6
Fetal head
5
4
Needle only into Cervix
3 mucosa (2-4 mm) Index and middle
2 fingers separating
Needle guard cervix and fetal
1 head from needle
PCB
0 SSS
Vagina
Before 15 30 45 60 75 90 105 120
analgesia
Time (minutes after analgesia)
Right hand
NSSS 48 48 47 45 36 29 15 10
NPCB 56 55 54 49 37 23 5 0
FIGURE 24-1 ■ Pain scores over time before and after paracervi- Syringe containing
cal block (10 mL of 0.25% bupivacaine) or single-shot spinal local anesthetic
(intrathecal) injection of bupivacaine 2.5 mg and sufentanil
2.5 µg. Data are median pain scores with the 25th and 75th
percentiles. PCB, paracervical block; SSS, single-shot spinal
analgesia; Pt, P-time; Pg, P-groups; Pt*g, P-time*group. N, number FIGURE 24-2 ■ Technique of paracervical block. Notice the posi-
of parturients at the measurement time points. (From Junttilla tion of the hand and fingers in relation to the cervix and fetal
EK, Karjalainen PK, Ohtonen PP, et al. A comparison of paracervical head. No undue pressure is applied at the vaginal fornix by the
block with single-shot spinal for labour analgesia in multiparous fingers or the needle guide, and the needle is inserted to a
women: a randomized controlled trial. Int J Obstet Anesth 2009; shallow depth. (Redrawn from Abouleish E. Pain Control in Obstet-
18:15-21.) rics. New York, JB Lippincott, 1977:344.)
520 PART VI Labor and Vaginal Delivery
advanced through the vaginal mucosa to a depth of 2 to The incidence of transient FHR abnormalities was 10.4%
3 mm.8 The physician should aspirate before each injec- in the levobupivacaine group and 12.8% in the racemic
tion of local anesthetic. A total of 5 to 10 mL of local bupivacaine group, and that of fetal bradycardia was 2.6%
anesthetic, without epinephrine, is injected on each side.9 in the levobupivacaine group and 3.8% in the racemic
Some obstetricians recommend giving incremental doses bupivacaine group (P = NS).
of local anesthetic on each side (e.g., 2.5 to 5 mL of local Some physicians have suggested that 2-chloroprocaine
anesthetic between the 3-o’clock and 4-o’clock positions, is the local anesthetic of choice for paracervical block.
followed by 2.5 to 5 mL between the 4-o’clock and Published studies suggest but do not prove that post–
5-o’clock positions).8,10,11 paracervical block fetal bradycardia occurs less frequently
After injecting the local anesthetic in either the left with 2-chloroprocaine than with amide local anesthet-
or right lateral vaginal fornix, the physician should wait ics.10,16-18 Weiss et al.16 performed a double-blind study in
5 to 10 minutes and observe the FHR before injecting which 60 patients were randomly assigned to receive
the local anesthetic on the other side.11 Some obstetri- 20 mL of either 2% 2-chloroprocaine or 1% lidocaine
cians do not endorse this recommendation. Van Dorsten for paracervical block. Bradycardia occurred in 1 of the
et al.12 randomly assigned 42 healthy parturients at term 29 fetuses in the 2-chloroprocaine group, compared with
to either of two methods of paracervical block. The study 5 of 31 fetuses in the lidocaine group (P = .14). LeFevre18
group experienced a 10-minute interval between injec- retrospectively observed that fetal bradycardia occurred
tions of local anesthetic on the left and right sides of the after 2 (6%) of 33 paracervical blocks performed with
vagina. The control group had almost simultaneous 2-chloroprocaine versus 44 (12%) of 361 paracervical
injections on the left and right sides. No cases of fetal blocks performed with mepivacaine (P = .29).
bradycardia occurred in either group. The investigators 2-Chloroprocaine undergoes rapid enzymatic hydro-
concluded that patient selection and lateral positioning lysis. Thus it has the shortest intravascular half-life
after the block have a more important role in the preven- among the local anesthetics used clinically. This rapid
tion of post–paracervical block fetal bradycardia than metabolism seems advantageous in the event of uninten-
spacing the injections of local anesthetic. However, tional intravascular or fetal injection. Philipson et al.17
because they studied only 42 patients and had no cases of performed paracervical block with 10 mL of 1%
fetal bradycardia in either group, they could not exclude 2-chloroprocaine in 16 healthy parturients. At delivery,
the possibility that incremental injection might reduce only trace concentrations of 2-chloroprocaine were
the incidence of fetal bradycardia in a larger series of detected in one (6%) of the maternal blood samples and
patients. four (25%) of the umbilical cord venous blood samples.
The investigators concluded17:
Choice of Local Anesthetic In all of the studies of paracervical block with
The physician should administer small volumes of a 2-chloroprocaine, there were no cases in which the
dilute solution of local anesthetic. There is no reason to abnormal fetal heart rate patterns were associated with
inject more than 10 mL of local anesthetic on each side. depressed neonates. This is in contrast to the studies with
Further, there is no indication for the use of concentrated amide local anesthetics and may be explained by the rapid
solutions, such as 2% lidocaine, 0.5% bupivacaine, or 3% enzymatic inactivation of 2-chloroprocaine.
2-chloroprocaine. Nieminen and Puolakka13 observed
that paracervical block with 10 mL of 0.125% bupiva- Some obstetricians dislike 2-chloroprocaine because
caine (5 mL on each side) provided analgesia similar to of its relatively short duration of action. However, in one
that provided by 10 mL of 0.25% bupivacaine. study the mean duration of analgesia was 40 minutes after
The choice of local anesthetic is controversial. The paracervical administration of either 2-chloroprocaine or
North American manufacturers of bupivacaine have lidocaine.16 A 2012 Cochrane Review concluded that the
stated that bupivacaine is contraindicated for the choice of local anesthetic agent did not affect maternal
performance of paracervical block. In contrast, many satisfaction with pain relief after paracervical block.6
European obstetricians—especially those in Finland—
have expressed a preference for bupivacaine for this pro-
cedure. Bupivacaine has greater cardiotoxicity than other
Maternal Complications
local anesthetic agents, and some investigators have sug- Maternal complications of paracervical block are uncom-
gested that its use leads to a higher incidence of fetal mon but may be serious (Box 24-1).19-22 Systemic local
bradycardia or adverse outcome than use of other local anesthetic toxicity may result from direct intravascular
anesthetics for paracervical block. In a review of 50 cases injection or rapid systemic absorption of the local anes-
of perinatal death associated with paracervical block, thetic. Postpartum neuropathy may follow direct sacral
Teramo14 found that the local anesthetic was bupivacaine plexus trauma, or it may result from hematoma forma-
in at least 29 of the 50 cases. tion. Retropsoal and subgluteal abscesses are rare but
Palomäki et al.15 hypothesized that levobupivacaine may result in maternal morbidity or mortality.21,22
might result in a lower incidence of post–paracervical
block fetal bradycardia than racemic bupivacaine. In a
randomized double-blind study of 397 laboring women,
Fetal Complications
paracervical block was performed with 10 mL of either In some cases, fetal injury results from direct injection of
0.25% levobupivacaine or 0.25% racemic bupivacaine. local anesthetic into the fetal scalp during paracervical
24 Alternative Regional Analgesic Techniques for Labor and Vaginal Delivery 521
two anencephalic fetuses. The QRS complex widened, of the vascular endothelium. The presence of vascular
the PR interval lengthened, and both fetuses died, but endothelium may alter the response of vascular smooth
fetal bradycardia did not occur before fetal death. In muscle to local anesthetics.45)
contrast, the investigators observed no widening of the Greiss et al.46 observed that intra-aortic injection of
QRS complex or lengthening of the PR interval in normal lidocaine or mepivacaine led to decreased uterine blood
fetuses demonstrating bradycardia after paracervical flow in gravid ewes. Similarly, Fishburne et al.39 noted
block. Rather, the fetal electrocardiogram (ECG) changes that direct uterine arterial injection of lidocaine, bupiva-
were consistent with sinoatrial node suppression with a caine, or 2-chloroprocaine reduced uterine blood flow in
wandering atrial pacemaker. The investigators concluded gravid ewes. They concluded that only paracervical block
that a mechanism other than direct fetal myocardial “would be expected to produce the high, sustained uterine
depression is responsible for fetal bradycardia after arterial concentrations of anesthetic drugs that cause the
paracervical block. significant reductions in uterine blood flow which we
now feel are the etiology of fetal bradycardia.”39 In a later
Increased Uterine Activity. Increased uterine activity study, Manninen et al.47 observed that paracervical injec-
results in decreased uteroplacental perfusion. Fishburne tion of 10 mL of 0.25% bupivacaine led to an increase in
et al.39 noted that direct uterine arterial injection of the uterine artery pulsatility index—an estimate of uterine
bupivacaine consistently caused a significant increase in vascular resistance—in healthy nulliparous women, sug-
uterine tone in gravid ewes. Uterine arterial injection of gesting that paracervical block may result in uterine
2-chloroprocaine did not affect myometrial tone, whereas artery vasoconstriction.
injection of lidocaine had an intermediate effect. In contrast, Puolakka et al.33 used 133Xe to measure
Myometrial injection of a local anesthetic also may intervillous blood flow before and after the performance
cause greater uterine activity. Morishima et al.40 per- of paracervical block with 10 mL of 0.25% bupivacaine
formed paracervical block with either lidocaine or in 10 parturients. They observed no decrease in mean
2-chloroprocaine in pregnant baboons with normal and intervillous blood flow in these patients. Further, they
acidotic fetuses. A transient increase in uterine activity noted minimal change in intervillous blood flow in the
and a significant reduction in uterine blood flow occurred three patients who had fetal bradycardia after paracervi-
after paracervical block in 73% of the mothers. Approxi- cal block. Using Doppler ultrasonography, Räsänen and
mately 33% of the normal fetuses and all of the acidotic Jouppila48 observed no significant change in either uterine
fetuses had bradycardia after paracervical block. The or umbilical artery pulsatility index after the performance
acidotic fetuses had more severe bradycardia, greater of paracervical block with 10 mL of 0.25% bupivacaine
hypoxemia, and slower recovery of oxygenation com- in 12 healthy parturients. However, fetal bradycardia
pared with fetuses that were well oxygenated before occurred in two patients, and in those two cases, a marked
paracervical block. The researchers concluded that post– increase in umbilical artery pulsatility index occurred.
paracervical block fetal bradycardia is in part a result of Baxi et al.49 performed paracervical block with 20 mL
greater uterine activity, diminished uteroplacental perfu- of 1% lidocaine in 10 pregnant women. They observed
sion, and decreased oxygen delivery to the fetus. They a decrease in fetal transcutaneous Po2 5 minutes after
also concluded that paracervical block should be avoided injecting lidocaine in each of the 10 patients. There was
in the presence of fetal compromise. a maximum decline in transcutaneous Po2 at 11.5 minutes,
and transcutaneous Po2 returned to baseline by approxi-
Uterine and/or Umbilical Artery Vasoconstriction. mately 31 minutes. Some of the patients had increased
The deposition of local anesthetic in close proximity to uterine activity after paracervical block. In contrast,
the uterine arteries may cause uterine artery vasocon- Jacobs et al.50 observed a consistent, sustained decrease
striction, with a subsequent drop in uteroplacental perfu- in fetal transcutaneous Po2 after only 1 of 10 paracervical
sion. At least two studies noted that lidocaine and blocks performed with 10 mL of 0.25% bupivacaine.
mepivacaine caused vasoconstriction of human uterine These investigators attributed their good results to the
arteries in vitro.41,42 (These studies were performed before following precautions: (1) performance of paracervical
recognition of the importance of intact endothelium block only in healthy mothers with normal pregnancies;
during investigation of vascular smooth muscle response.) (2) administration of a small dose of bupivacaine; (3) a
Similarly, Norén et al.43,44 noted that bupivacaine caused limited depth of injection; (4) administration of bupiva-
concentration-dependent contraction of uterine arterial caine in four incremental injections (i.e., two injections
smooth muscle from rats and pregnant women. The on each side); and (5) use of the left lateral position
calcium entry–blocking drugs verapamil and nifedipine immediately after performance of the block. In a later
decreased the vascular smooth muscle contraction caused study, Kaita et al.51 observed that paracervical injection of
by bupivacaine. The researchers concluded that the use 10 mL of 0.25% bupivacaine in 10 healthy parturients
of bupivacaine for paracervical block may cause uterine resulted in a slight (clinically insignificant) increase in
artery vasoconstriction, especially when the bupivacaine fetal Sao2 as measured by fetal pulse oximetry.
is injected close to the uterine arteries. Further, they sug-
gested that the administration of a calcium entry–blocking Summary
drug may successfully eliminate this vasoconstrictive
effect of bupivacaine. (Although these studies were per- Most observers currently believe that post–paracervical
formed in 1991, the researchers did not mention whether block bradycardia results from reduced uteropla-
they preserved, removed, or even observed the presence cental and/or fetoplacental perfusion. Reduction in
24 Alternative Regional Analgesic Techniques for Labor and Vaginal Delivery 523
uteroplacental perfusion may occur because of increased performance of the block. Maintain normal mater-
uterine activity and/or a direct vasoconstrictive effect of nal blood pressure.
the local anesthetic. Likewise, decreased umbilical cord 12. If fetal bradycardia should occur, try to achieve
blood flow may result from increased uterine activity fetal resuscitation in utero. Discontinue oxytocin,
and/or umbilical cord vasoconstriction. Regardless of the administer supplemental oxygen, and ensure that
etiology, the severity and duration of fetal bradycardia the patient is on her left side. Perform operative
correlate with the incidence of fetal acidosis and subse- delivery if the fetal bradycardia persists beyond
quent neonatal depression. Freeman et al.38 reported a 10 minutes.
significant drop in pH and a rise in base deficit only in
fetuses with bradycardia of longer than 10 minutes’ dura-
tion. In an observational study of paracervical block and LUMBAR SYMPATHETIC BLOCK
nalbuphine analgesia during labor, Levy et al.52 observed
no association between paracervical block and low umbil- In 1933, Cleland53 demonstrated that lower uterine
ical arterial blood pH at delivery. and cervical visceral afferent sensory fibers join the
sympathetic chain at L2 to L3. Subsequently, lumbar
sympathetic block was used as an effective—if not
Physician Complications popular—method of first-stage analgesia in some
The performance of paracervical block requires the phy- hospitals.54-57 Like paracervical block, paravertebral
sician to make several blind needle punctures within the lumbar sympathetic block interrupts the transmission of
vagina. The needle guide does not consistently protect pain impulses from the cervix and lower uterine segment
the physician from a needle-stick injury. Thus, the per- to the spinal cord. Lumbar sympathetic block provides
formance of paracervical block may entail the risk for analgesia during the first stage of labor but does not
physician exposure to human immunodeficiency virus relieve pain during the second stage. It provides analgesia
(HIV) or another infectious agent. comparable to that provided by paracervical block but
with less risk for fetal bradycardia.
Lumbar sympathetic block may have a favorable effect
Recommendations on the progress of labor. Hunter58 reported that lumbar
It is difficult for me to offer enthusiasm for the perfor- sympathetic block accelerated labor in 20 of 39 patients
mance of paracervical block in contemporary obstetric with a normal uterine contractile pattern before perfor-
practice. Nonetheless, paracervical block may be an mance of the block. (Indeed, some of the patients in that
appropriate technique in circumstances in which neur- study had a 5- to 15-minute period of uterine hypertonus
axial analgesia is contraindicated or unavailable. The after the block.) Further, he observed that lumbar sym-
following recommendations seem reasonable: pathetic block converted an abnormal uterine contractile
1. Perform paracervical block only in healthy partu- pattern to a normal pattern in 14 of 19 patients. He con-
rients at term who have no evidence of uteropla- cluded that lumbar sympathetic block represents “one of
cental insufficiency or fetal compromise. the most reliable methods reported to actively convert an
2. Continuously monitor the FHR and uterine abnormal labor pattern to a normal pattern.”58 In a later
activity before, during, and after performance of study, Leighton et al.59 randomly assigned 39 healthy
paracervical block. Perform paracervical block nulliparous women at term to receive either epidural
only in patients with a reassuring FHR tracing. analgesia or lumbar sympathetic block. The women who
An obvious exception would be a patient whose received lumbar sympathetic block had a more rapid rate
fetus has an anomaly incompatible with life (e.g., of cervical dilation during the first 2 hours of analgesia,
anencephaly). a shorter second stage of labor, and a nonsignificant trend
3. Do not perform paracervical block when the toward a lower incidence of cesarean delivery for dysto-
cervix is dilated 8 cm or more. cia. However, there was no difference between the groups
4. Establish intravenous access before performing in the rate of cervical dilation during the active phase of
paracervical block. the first stage of labor.
5. Maintain left uterine displacement while perform- Anesthesiologists may successfully perform lumbar
ing the block. sympathetic block when a history of previous back surgery
6. Limit the depth of injection to approximately precludes the successful administration of epidural anal-
3 mm. gesia.60 Some anesthesiologists offer lumbar sympathetic
7. Aspirate before each injection of local anesthetic. block to prepared childbirth enthusiasts who desire first-
8. After injecting the local anesthetic on one side, stage analgesia without any motor block or loss of peri-
wait 5 to 10 minutes and observe the FHR before neal sensation. Meguiar and Wheeler61 stated that the
injecting the local anesthetic on the other side. primary usefulness of lumbar sympathetic block is “in
9. Administer small volumes of a dilute solution of cases where continuous lumbar epidural analgesia is
local anesthetic; 2-chloroprocaine is the agent refused or contraindicated.” They administered 20 mL
of choice. of 0.5% bupivacaine with 1 : 200,000 epinephrine to 40
10. Avoid the administration of epinephrine- nulliparous women. Among these women, 38 experi-
containing local anesthetic solutions. enced good analgesia, and 28 delivered before resolution
11. Monitor the mother’s blood pressure and watch of the block. Pain recurred before delivery in the remain-
for signs of local anesthetic toxicity after ing 12 women; the mean duration of analgesia was 283 ±
524 PART VI Labor and Vaginal Delivery
Anterolateral surface
of L2 vertebral body
Psoas muscle
Sympathetic chain
Aorta
Inferior
vena cava FIGURE 24-3 ■ Lateral view of needle place-
ment for lumbar sympathetic block. The
needle has been advanced so that the tip of
the needle is near the anterolateral surface
of the L2 vertebral body. The figure illustrates
the proximity of the aorta. (Drawing by Naveen
Nathan, MD, Northwestern University Feinberg
School of Medicine, Chicago, IL.)
103 minutes among these patients.61 Leighton et al.59 withdrawn, redirected, and advanced another 5 cm so
administered the same dose of bupivacaine, but they that the tip of the needle is at the anterolateral surface of
observed a shorter duration of analgesia than that the vertebral column, just anterior to the medial attach-
observed by Meguiar and Wheeler.61 ment of the psoas muscle (Figure 24-3). It is possible to
During the last three decades, lumbar sympathetic place the needle within a blood vessel or the subarach-
block has all but disappeared from obstetric anesthesia noid space; thus, the anesthesiologist must aspirate before
practice in the United States, for several reasons. Anes- injecting the local anesthetic. Two 5-mL increments of a
thesiologists may minimize motor block during epidural dilute solution of local anesthetic (with or without epi-
analgesia by giving a dilute solution of local anesthetic, nephrine) are then injected, and the procedure is repeated
with or without an opioid. For those few patients who on the opposite side of the vertebral column.
want to retain full perineal sensation, anesthesiologists
may give an opioid alone, either intrathecally or epidu
rally. Thus, there are few patients for whom lumbar sym-
Complications
pathetic block holds unique advantages. Further, the Modest hypotension occurs in 5% to 15% of patients.58,59,61
procedure often is painful, and few anesthesiologists have The risk for hypotension may be reduced by giving
acquired and maintained proficiency in performing 500 mL of lactated Ringer’s solution intravenously before
lumbar sympathetic block in obstetric patients. performing the block. Less common maternal complica-
Lumbar sympathetic block remains an attractive tech- tions are systemic local anesthetic toxicity, total spinal
nique in a small number of patients.60 Alternatively, anesthesia, retroperitoneal hematoma, Horner’s syn-
two recent reports have described the performance of drome,64 and post–dural puncture headache.65
bilateral lower thoracic paravertebral block in a total of Fetal complications are unlikely unless hypotension
five laboring women in whom epidural analgesia was con- or increased uterine activity results in decreased utero-
traindicated.62,63 As anesthesiologists gain greater profi- placental perfusion.
ciency with thoracic paravertebral block for patients
undergoing breast surgery, perhaps this technique will be
used more often in parturients for whom neuraxial anal- PUDENDAL NERVE BLOCK
gesia is contraindicated.
During the second stage of labor, pain results from dis-
tention of the lower vagina, vulva, and perineum. The
Technique pudendal nerve, which includes somatic nerve fibers from
With the patient in the sitting position, a 10-cm, 22-gauge the anterior primary divisions of the second, third, and
needle is used to identify the transverse process on one fourth sacral nerves, represents the primary source of
side of the second lumbar vertebra. The needle is then sensory innervation for the lower vagina, vulva, and
24 Alternative Regional Analgesic Techniques for Labor and Vaginal Delivery 525
perineum. The pudendal nerve also provides motor the patient complains of vaginal and perineal pain. A
innervation to the perineal muscles and to the external 2004 study suggested that pudendal nerve block does not
anal sphincter. provide reliable analgesia during the second stage of
In 1916, King66 reported the use of pudendal nerve labor but has greater efficacy for episiotomy and repair.73
block for vaginal delivery. This procedure did not become In a randomized, double-blind, placebo-controlled study,
popular until 1953 and 1954, when Klink67 and Kohl68 Aissaoui et al.74 observed that unilateral, nerve stimulator–
described the anatomy and reported modified techniques. guided pudendal nerve block with ropivacaine was associ-
Obstetricians often perform pudendal nerve block in ated with decreased pain and less need for supplemental
patients without epidural or spinal analgesia. The goal is analgesia during the first 48 hours after performance of
to block the pudendal nerve distal to its formation by the mediolateral episiotomy at vaginal delivery.
anterior divisions of S2 to S4 but proximal to its division
into its terminal branches (i.e., dorsal nerve of the clitoris,
perineal nerve, and inferior hemorrhoidal nerve). Puden-
Technique
dal nerve block may provide satisfactory anesthesia for The transvaginal approach is more popular than the
spontaneous vaginal delivery and perhaps for outlet- transperineal approach in the United States. The obste-
forceps delivery, but it provides inadequate anesthesia for trician uses a needle guide (either the Iowa trumpet or
mid-forceps delivery, postpartum examination and repair the Kobak needle guide) to prevent injury to the vagina
of the upper vagina and cervix, and manual exploration and fetus. In contrast to the technique for paracervical
of the uterine cavity.69 block, the needle must protrude 1.0 to 1.5 cm beyond the
needle guide to allow adequate penetration for injection
of the local anesthetic. The obstetrician introduces the
Efficacy and Timing needle and needle guide into the vagina with the left hand
The efficacy of pudendal nerve block varies according to for the left side of the pelvis and with the right hand for
the experience of the obstetrician. Unilateral or bilateral the right side (Figure 24-4). The needle is introduced
failure is common. Thus, obstetricians typically perform through the vaginal mucosa and sacrospinous ligament,
simultaneous infiltration of the perineum, especially if just medial and posterior to the ischial spine. The puden-
the performance of pudendal nerve block is delayed until dal artery lies in close proximity to the pudendal nerve;
delivery. Scudamore and Yates70 reported bilateral success thus, the obstetrician must aspirate before and during the
rates of approximately 50% after use of the transvaginal injection of local anesthetic. The obstetrician typically
route and of approximately 25% after use of the trans- injects 7 to 10 mL of local anesthetic solution on each
perineal route. They concluded70: side. (Some obstetricians inject 3 mL of local anesthetic
just above the ischial spine on each side.75) The obstetri-
The term “pudendal block” is often a misnomer.… If cian should pay attention to the total dose of local anes-
this limitation were more widely appreciated, then many thetic given, especially when repetitive pudendal nerve
mothers would be spared the unnecessary pain which is blocks or both pudendal nerve block and perineal infiltra-
caused when relatively complicated procedures are tion are performed.
attempted under inadequate anesthesia.
of the second stage of labor in 15 healthy parturients. at 6.5 hours. Small scalp puncture wounds suggested
The mean ± SD dose of lidocaine was 79 ± 3 mg, and the that the lidocaine toxicity resulted from direct fetal
mean drug-to-delivery interval was 7.8 ± 7.0 minutes. scalp injection. Pignotti et al.85 reported two cases of
The investigators detected lidocaine in maternal plasma neonatal local anesthetic toxicity. In one case, lidocaine
as early as 1 minute after injection. Peak maternal plasma and prilocaine cream had been applied to the maternal
concentrations of lidocaine occurred between 3 and 15 perineum. In the second case, 10 mL of 2% mepivacaine
minutes after injection. Despite the administration of had been injected into the perineum. Both infants
small doses of lidocaine and the short drug-to-delivery required endotracheal intubation and mechanical ventila-
intervals, there was rapid placental transfer of significant tion, but in both cases, neurodevelopmental outcome
amounts of lidocaine. The mean fetal-to-maternal lido- was normal at 12 months of age. Kim et al.83 suggested
caine concentration ratio of 1.32 was significantly higher that the presence of a molded head in the occiput poste-
than the ratio reported after administration of lidocaine rior position may predispose to unintentional direct
for paracervical block, pudendal nerve block, or epidural injection of the fetal scalp. These cases support the rec-
anesthesia for vaginal or cesarean delivery. There was a ommendation for use of 2-chloroprocaine for perineal
significant correlation between the fetal-to-maternal infiltration.
lidocaine concentration ratio and the length of the second
stage of labor. These investigators speculated that fetal
tissue acidosis increased the fetal-to-maternal lidocaine
ratio after perineal infiltration in this study. Finally,
they noted the persistence of lidocaine and its pharma-
cologically active metabolites for at least 48 hours after
delivery.81 KEY POINTS
Subsequently, Philipson et al.82 evaluated the placental
• Paracervical block and lumbar sympathetic block
transfer of 2-chloroprocaine after perineal administration
may provide effective analgesia for the first stage
of 1% or 2% 2-chloroprocaine to 17 women shortly
of labor. Neither technique relieves pain during
before delivery. The mean ± SD dose of 2-chloroprocaine
the second stage.
was 81.8 ± 27.0 mg, and the mean drug-to-delivery inter-
val was 6.7 ± 4.3 minutes. Perineal infiltration of • Fetal bradycardia is the most worrisome
2-chloroprocaine provided adequate anesthesia for complication of paracervical block.
episiotomy repair except in two patients who required • Paracervical block is contraindicated in patients
additional local anesthetic for repair of fourth- with uteroplacental insufficiency or preexisting
degree lacerations. The investigators did not detect fetal compromise.
2-chloroprocaine in maternal plasma after infiltration or • For patients without epidural or spinal analgesia,
at delivery. Further, they detected 2-chloroprocaine at it is appropriate to perform pudendal nerve block
delivery in only one umbilical cord venous blood sample when the patient complains of pelvic floor pain.
and no 2-chloroprocaine in neonatal plasma. In contrast, • Pudendal nerve block may provide satisfactory
they consistently detected the drug’s metabolite, chloro- anesthesia for spontaneous vaginal delivery and
aminobenzoic acid, in maternal plasma, umbilical cord outlet-forceps delivery, but it provides inadequate
venous plasma, and neonatal urine. The fetal-to-maternal anesthesia for mid-forceps delivery, postpartum
ratio of chloroaminobenzoic acid (0.80) was similar to repair of the cervix, and manual exploration of
that reported after the administration of 2-chloroprocaine the uterine cavity.
for paracervical block and epidural anesthesia for cesar- • Perineal infiltration provides anesthesia only for
ean delivery. The investigators suggested that very episiotomy and repair.
little, if any, unchanged 2-chloroprocaine reaches the
fetus after perineal infiltration. They concluded that • It is unnecessary—and perhaps dangerous—to
2-chloroprocaine may be preferable to lidocaine for ante- give concentrated solutions of local anesthetic
partum perineal infiltration.82 for paracervical block, pudendal nerve block, or
perineal infiltration.
• Some cases of fetal injury result from direct fetal
Complications scalp injection of local anesthetic during
The obstetrician must take care to avoid injecting attempted paracervical block, pudendal nerve
the local anesthetic into the fetal scalp. Kim et al.83 block, or perineal infiltration.
reported a case of newborn lidocaine toxicity after mater- • 2-Chloroprocaine is most likely the safest choice
nal perineal infiltration of 6 mL of 1% lidocaine before of local anesthetic for paracervical block,
vaginal delivery. Similarly, DePraeter et al.84 reported pudendal nerve block, and perineal infiltration.
a case of lidocaine toxicity in a newborn whose mother • The performance of either paracervical block or
received perineal infiltration with 10 mL of 2% lidocaine pudendal nerve block requires the obstetrician to
4 minutes before delivery. In both cases, the infants were make several blind needle punctures within the
initially vigorous but required endotracheal intubation vagina. Thus, there is a risk for physician needle-
15 minutes after delivery. No lidocaine was detected in stick injury during the performance of either
umbilical cord blood, but neonatal blood samples revealed procedure.
concentrations of 14 µg/mL at 2 hours and 13.8 µg/mL
528 PART VI Labor and Vaginal Delivery
26. Shnider SM, Asling JH, Holl JW, Margolis AJ. Paracervical
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C H A P T E R 2 5
CHAPTER OUTLINE
Many parous women choose tubal ligation for permanent 5. If a postpartum tubal ligation is to be performed
contraception. Half are performed postpartum (over before the patient is discharged from the hospital,
350,000 annually in the United States) and half as ambu- the procedure should not be attempted at a time
latory interval procedures.1 Although the interval steril- when it might compromise other aspects of patient
ization rate has declined by 12% in the United States, the care on the labor and delivery unit.
postpartum sterilization rate remains stable, and postpar-
tum sterilization is performed after 8% to 9% of all live
births.1 The considerations and controversies regarding SURGICAL CONSIDERATIONS
the administration of anesthesia for postpartum tubal
sterilization are discussed in this chapter. Tubal sterilization can be performed satisfactorily at any
time, but the early postpartum period has several advan-
tages for women who have had an uncomplicated vaginal
AMERICAN SOCIETY OF delivery.3 The patient avoids the cost and inconvenience
ANESTHESIOLOGISTS GUIDELINES of a second hospital visit. The uterine fundus remains
near the umbilicus for several days postpartum, which
The American Society of Anesthesiologists (ASA) has allows easy access to the fallopian tubes. Minilaparotomy
published “Practice Guidelines for Obstetric Anesthe- and laparoscopy have similar rates of serious complica-
sia,”2 which includes a discussion of postpartum tubal tions (e.g., bowel laceration, vascular injury).4
ligation. (See Appendix B.) The Task Force recommen- There are at least two potential disadvantages to
dations can be summarized as follows: immediate postpartum sterilization. First, parous women
1. For postpartum tubal ligation, the patient should are at increased risk for uterine atony and postpar-
have no oral intake of solid foods within 6 to 8 tum hemorrhage. This risk decreases substantially 12
hours of the surgery, depending on the type of food hours after delivery. Second, immediate surgery results
ingested (e.g., fat content). in sterilization before assessment of the newborn is
2. Aspiration prophylaxis should be considered. complete. Postpartum tubal ligation is not wise if
3. Both the timing of the procedure and the deci- the patient is ambivalent regarding permanent ster-
sion to use a specific anesthetic technique (i.e., ilization. However, women who undergo postpartum
neuraxial versus general) should be individualized, sterilization have a similar probability of regret within
based on anesthetic risk factors, obstetric risk 1 year of delivery (23.7%) as women who undergo
factors (e.g., blood loss at delivery), and patient interval sterilization (22.3%), although the risk is
preferences. markedly increased when the woman is younger than
4. Neuraxial techniques are preferred to general anes- 25 years of age.5
thesia for most postpartum tubal ligations. The Several techniques are used for postpartum tubal ster-
anesthesia provider should be aware that gastric ilization (Figure 25-1).6 Puerperal sterilization has a
emptying will be delayed in patients who have failure rate that is lower than most interval procedures,
received opioids during labor and that an epidural and the failure rate is lowest (approximately 0.75%) if
catheter placed for labor may be more likely to fail some form of tubal resection occurs.7 With the Irving
with longer postdelivery time intervals. procedure, the obstetrician buries the cut ends of the
530
25 Postpartum Tubal Sterilization 531
NONMEDICAL ISSUES
Nonmedical issues affect decisions regarding the timing
A Irving B Pomeroy
of tubal sterilization. The obstetrician must obtain and
document informed consent for surgery.5 Tubal ligation
should be considered an irreversible procedure. There-
fore, most obstetricians require a discussion with the
patient before labor and delivery. Postpartum partial sal-
pingectomy has 5-year and 10-year failure rates of 6.3
and 7.5 per 1000 patients, respectively, the lowest of all
sterilization procedures.5 Physicians should be aware of
state laws or insurance regulations that may require a
C Parkland D Madlener
specific interval between obtaining consent and perfor-
mance of sterilization procedures. Regulations often do
not allow the woman to give consent while in labor or
immediately after delivery. For example, the Medicaid
reimbursement program includes the following require-
ments for sterilization8:
• The patient must be at least 21 years of age and
mentally competent when consent is obtained.
E Kroener fimbriectomy • Informed consent may not be obtained while the
patient is in labor or during childbirth.
FIGURE 25-1 ■ Techniques for tubal sterilization. A, Irving proce-
dure. The medial cut end of the oviduct is buried in the myo- • Consent may not be obtained while the patient is
metrium posteriorly, and the distal cut end is buried in the undergoing an abortion or under the influence of
mesosalpinx. B, Pomeroy procedure. A loop of oviduct is alcohol or other substances.
ligated, and the knuckle of tube above the ligature is excised. • A total of 30 days must pass between the date the
C, Parkland procedure. A midsegment of tube is separated from
the mesosalpinx at an avascular site, and the separated tubal
consent is signed and the date the procedure is per-
segment is ligated proximally and distally and then excised. formed. (Exceptions to the 30-day waiting period
D, Madlener procedure. A knuckle of oviduct is crushed and can be made for preterm delivery or emergency
then ligated without resection; this technique has an unaccept- abdominal surgery.)
ably high failure rate of approximately 7%. E, Kroener proce- • Consent is valid for only 180 days.
dure. The tube is ligated across the ampulla, and the distal
portion of the ampulla, including all of the fimbria, is resected; In some cases the obstetrician may schedule a patient
some studies have reported an unacceptably high failure rate for a postpartum tubal ligation because of a fear that the
with this technique. (From Cunningham FG, MacDonald PC, Gant patient will not return for interval tubal sterilization 6
NF, et al. Williams Obstetrics, 20th edition. Stamford, CT, Appleton weeks after delivery. Concerns regarding patient compli-
& Lange, 1997:1376.)
ance should not prompt the performance of postpartum
tubal ligation in patients with significant medical or
obstetric complications. However, women who request
postpartum tubal sterilization but do not receive it are
tubes in the myometrium and mesosalpinx. This tech- more likely to become pregnant within 1 year of delivery
nique is least likely to fail, but it requires more extensive (46.7%) than are women who did not request the proce-
exposure and increases the risk for hemorrhage. The dure (22.3%).9
Pomeroy procedure is simplest. The surgeon ligates a
loop of oviduct and excises the loop above the suture.
With the Parkland procedure, the obstetrician ligates the PREOPERATIVE EVALUATION
tube proximally and distally and then excises the midseg-
ment. The last two methods are most commonly per- The patient scheduled for postpartum tubal ligation
formed during postpartum tubal ligations. Regardless of requires a thorough preoperative evaluation, and a
the technique, the obstetrician should document that reevaluation should be performed even if the patient
fimbriae are present to preclude ligation of another struc- is known to the anesthesia provider as a result of
ture such as the round ligament. The excised portions the provision of labor analgesia. A cursory evaluation
typically are sent to a pathologist for verification. should not be performed simply because the patient
A randomized clinical trial found a significantly is young and healthy. Patients with pregnancy-induced
increased risk for pregnancy at 24 months after use of the hypertension may safely receive neuraxial or general
titanium clip for postpartum tubal occlusion (i.e., a cumu- anesthesia for postpartum tubal ligation provided that
lative pregnancy rate of 1.7 pregnancies per 1000 women there is no evidence of pulmonary edema, oliguria, or
who had titanium tubal occlusion versus 0.04 pregnancies thrombocytopenia.10
532 PART VI Labor and Vaginal Delivery
Physicians and nurses often underestimate blood loss and degree of ionization.12 Typically, the amount of
during delivery.11 Excessive blood loss from uterine atony drug present in breast milk is small. Opioids, barbitu-
is not uncommon in parous women. Orthostatic changes rates, and propofol administered during anesthesia are
in blood pressure and heart rate should be excluded, excreted in insignificant amounts. (See Chapter 14 for
especially if an immediate postpartum procedure is to be a detailed discussion of interactions between drugs and
performed. At the University of Colorado, for surgery breast-feeding.)
performed the day after delivery, the patient’s hematocrit
is determined several hours after delivery (to allow for
equilibration) and compared with the antepartum mea- RISK FOR ASPIRATION
surement. A hematocrit is not obtained before an imme-
diate postpartum tubal sterilization (performed < 8 hours Historically, anesthesiologists have considered maternal
after delivery), provided that the antepartum hematocrit aspiration the major risk associated with anesthesia for
was acceptable, there are no orthostatic vital sign changes, postpartum tubal ligation, although the evidence for
and there was no evidence of excessive blood loss during this is scant and conflicting. A review of anesthesia-
delivery. related maternal mortality found no maternal deaths
No absolute value of hematocrit requires a delay associated with aspiration during postpartum tubal liga-
of surgery, but physical signs of hemodynamic insta- tion, despite tracking deaths for 1 year after delivery.13
bility or laboratory evidence of excessive blood loss However, several factors may place the pregnant woman
should prompt postponement of the procedure until at increased risk for aspiration. Some but not all of
6 to 8 weeks postpartum. Fever may signal the pres- these factors are resolved at delivery. The placenta is
ence of endometritis or urinary tract infection and the primary site of progesterone production, and pro-
also may require postponement of surgery until a gesterone concentrations fall rapidly after delivery of
later date. Finally, the condition of the neonate should the placenta (Figure 25-2).14,15 Typically, progesterone
be confirmed before surgery to exclude any unexpected concentrations decline within 2 hours of delivery; and
problems. by 24 hours postpartum, progesterone concentrations
Mothers may be concerned that medications admin- are similar to those found during the luteal phase of
istered during surgery might affect their ability to the menstrual cycle.
breast-feed or that these medications might harm the Two important questions to address during the pre-
newborn. Any drug present in the mother’s blood will anesthetic evaluation are (1) What is the duration of the
be present in breast milk, with the concentration depen- fast for solids? (2) Were parenteral opioids administered
dent on factors such as protein binding, lipid solubility, during labor?
40
Maximum
35 Average
Minimum
30
Progesterone (mg/100 mL plasma)
25
20
15
10
Gastric Emptying
20
et al.25 observed that epidural administration of 10 mL TABLE 25-1 Gastric Volume and pH at
of 0.375% bupivacaine with fentanyl 100 µg caused a Intervals after Delivery
modest prolongation of gastric emptying during labor
when compared with epidural administration of bupiva- Volume
caine alone. However, Kelly et al.26 found that intrathe- > 25 mL (%) pH < 2.5 (%) At Risk* (%)
cal, but not epidural, fentanyl delayed gastric emptying. Group 1 73 100 73
Metoclopramide may not accelerate gastric emptying in (1-8 h)
patients who have received an opioid. Group 2 40 100 40
(9-23 h)
Group 3 73 80 67
Gastric Volume and pH (24-45 h)
There is little evidence that postpartum women are at Group 4 67 80 60
(control)
greater risk for sequelae of aspiration than patients
undergoing elective surgery based solely on pregnancy- *Gastric contents with pH < 2.5 and volume > 25 mL.
induced changes in gastric pH and volume. The conven- From James CF, Gibbs CP, Banner T. Postpartum perioperative
tional wisdom is that a gastric volume of more than risk of aspiration pneumonia. Anesthesiology 1984; 61:756-9.
25 mL and a gastric pH of less than 2.5 are risk factors
for aspiration pneumonitis. Coté27 noted that this dogma
was derived from unpublished animal studies and that it Gastroesophageal Reflux
assumes that every milliliter of gastric fluid is directed
into the trachea. A marked disparity exists between Women in the third trimester of pregnancy have
the incidence of patients labeled “at risk” and the inci- decreased lower esophageal barrier pressures as com-
dence of patients with clinically significant aspiration pared with nonpregnant controls.31 Those with symp-
pneumonitis. toms of heartburn have even lower pressures and a higher
Blouw et al.28 measured gastric volume and pH in incidence of gastric reflux. Vanner and Goodman32 asked
nonpregnant women undergoing gynecologic surgery parturients to swallow a pH electrode to measure lower
and postpartum women 9 to 42 hours after delivery. They esophageal pH at term and on the second postpartum
found no significant difference between the groups. day. Patients were placed in four positions: supine with
Approximately 75% of women in both groups had a tilt, left lateral, right lateral, and lithotomy, and were then
gastric pH of less than 2.5. When the combination of asked to perform a Valsalva and other maneuvers to
volume and pH was used to determine the risk for aspi- promote reflux. A total of 17 of 25 patients had reflux at
ration, 64% of the control patients but only 33% of term, whereas only 5 of 25 had reflux after delivery. The
postpartum patients were at risk. The researchers con- investigators concluded that the incidence of reflux
cluded that 8 hours after delivery, postpartum patients returns toward normal by the second day after delivery.
are not at greater risk than nonpregnant patients under- However, this conclusion is arguable given the fact that
going elective surgery. They did not examine patients they did not determine normal by defining the incidence
earlier than 8 hours after delivery. In addition, they of reflux before or 6 to 8 weeks after pregnancy.
acknowledged that a large number of patients in both
groups are at risk.
James et al.29 attempted to determine the “safe”
Summary
interval after delivery. They compared gastric pH and No data indicate that the postpartum patient’s safety is
gastric volume in postpartum women 1 to 8 hours, 9 enhanced by delaying surgery or is compromised by pro-
to 23 hours, and 24 to 45 hours after delivery with a ceeding with surgery immediately after delivery. This
control group of nonpregnant women undergoing elec- situation has led to confusion and inconsistency in the
tive surgery. There were no significant differences in development of policies for the performance of postpar-
either parameter between the group of patients under- tum tubal ligation.33 No waiting interval guarantees that
going elective surgery and any of the postpartum groups the postpartum patient is free of risk for aspiration. It is
(Table 25-1). Approximately 60% of all patients were probably prudent to use some form of aspiration prophy-
considered “at risk” for aspiration pneumonitis. The laxis in all patients undergoing postpartum tubal ligation.
investigators concluded that there was no difference in However, significant aspiration pneumonitis is so rare
the risk for sequelae if aspiration should occur, but that it will be difficult to document cost-effectiveness and
they speculated that hormonal changes or mechanical decreased rates of morbidity and mortality from the use
factors might make aspiration more likely during the of these measures. H2-receptor antagonists and antacids
postpartum period. do not reduce the possibility of regurgitation and aspira-
Finally, Lam et al.30 administered 150 mL of water to tion, but they may make the consequences less severe.
50 women 2 to 3 hours before tubal ligation that was Metoclopramide (a prokinetic agent) may decrease the
performed 1 to 5 days postpartum. Another 50 postpar- incidence of reflux by increasing lower esophageal sphinc-
tum and 50 nonpregnant women fasted after midnight. ter tone and hastening gastric emptying.32 None of these
The authors found no differences in gastric pH or volume medications can guarantee that gastric contents will not
among the postpartum-water group, the postpartum- enter the lungs. Aspiration is best prevented by an expe-
fasted group, and the group of nonpregnant controls rienced anesthesia provider using careful airway manage-
undergoing elective surgery. ment and/or by use of a neuraxial anesthetic technique.
25 Postpartum Tubal Sterilization 535
Performance of an immediate postpartum tubal liga- reasonable to give all postpartum patients some form of
tion (within 8 hours of delivery) may decrease both the aspiration prophylaxis. This may include a clear (nonpar-
length of the hospital stay and hospital costs. In this era ticulate) antacid, an H2-receptor antagonist, and/or
of health care cost-containment, any decision to post- metoclopramide to increase lower esophageal sphincter
pone surgery that requires an extra day of hospitalization tone and hasten gastric emptying. Metoclopramide also
must be evaluated carefully. Anesthesia providers and may prevent emesis during and after surgery. Patients
obstetricians have questioned the need to wait 8 or more with additional risk factors for aspiration (e.g., morbid
hours after delivery if gastric emptying time and gastric obesity, diabetes mellitus) warrant prophylaxis with all
volume and pH are no different in the postpartum patient three classes of drugs. Tubal sterilization does not require
from those in nonpregnant women. Possible reasons to administration of preoperative antibiotics.34
consider an 8-hour delay are as follows. First, women
may remain at increased risk for gastroesophageal reflux Local Anesthesia
immediately after delivery. Second, delays in gastric emp-
tying due to the antepartum administration of opioids Local anesthesia is used for more than 75% of tubal
will resolve during this period. Third, an 8-hour delay sterilizations worldwide, although neuraxial anesthesia is
allows the administration of aspiration prophylaxis drugs, most often administered for postpartum tubal steriliza-
although they might also be given during labor. Fourth, tion in the United States.3 Several reports have docu-
maximal hemodynamic stress and potential instability mented the efficacy and safety of local anesthesia for
occur immediately postpartum when central blood postpartum or laparoscopic tubal ligation in the hospital
volume suddenly increases because of contraction of the operating room or a free-standing outpatient facility.
evacuated uterus, relief of aortocaval compression, and Cruikshank et al.35 described the use of intraperitoneal
loss of the low-resistance placental circuit; indeed, the lidocaine for postpartum tubal ligation. After intravenous
patient with cardiovascular disease is at greatest risk for administration of diazepam, lidocaine 100 mg was used
hemodynamic decompensation immediately postpartum. to infiltrate the skin and subcutaneous tissue. The peri-
Fifth, if there are concerns about excessive blood loss at toneum was entered, and 400 mg of lidocaine (80 mL of
delivery, an 8-hour delay allows the physician to assess 0.5% solution) was instilled into the peritoneal cavity. A
serial hemodynamic measurements (including the pres- Pomeroy tubal ligation was performed 5 minutes later.
ence or absence of orthostatic changes), obtain an equili- All patients had complete peritoneal anesthesia, and all
brated postpartum hematocrit, and, if necessary, restore patients stated they would have the same procedure
intravascular volume. Sixth, delay allows a more thor- again. None recalled any pain or discomfort 24 hours
ough evaluation of the infant. Finally, delay allows the later. There were no signs of lidocaine toxicity in any
woman more time to assess her decision. patient, and the maximum lidocaine blood level obtained
In summary, at the University of Colorado, immediate was 5.3 µg/mL. Surgeons rated the conditions excellent.
postpartum tubal ligation is performed in patients who This study was published in 1973 when anesthesiologists
have a functioning epidural catheter in place. These may or may not have been involved and before ASA
patients are given an H2-receptor antagonist and meto- monitoring standards such as pulse oximetry existed.
clopramide intravenously during labor, and a clear (non- Poindexter et al.36 described almost 3000 laparoscopic
particulate) antacid is administered just before taking the tubal sterilization procedures performed with local anes-
patient to the operating room. In other patients who do thesia in an ambulatory surgical facility. After intravenous
not want (or are unable to receive) epidural analgesia for sedation with midazolam (5 to 10 mg) and fentanyl (50
labor, an H2-receptor antagonist and metoclopramide are to 100 µg), the skin was infiltrated with 10 mL of 0.5%
given intravenously after delivery followed by a wait of bupivacaine. After insertion of the trocar, the abdomen
at least 1 hour for a therapeutic effect. This is an elective was insufflated with nitrous oxide. Each tube was sprayed
procedure, and patients should not consume solid food with 5 mL of 0.5% bupivacaine, and a Silastic ring was
for 6 to 8 hours preoperatively. (NPO policies for post- applied. Patients were discharged home after approxi-
partum tubal sterilization should not differ from those mately 1 hour in the postanesthesia care unit. The authors
used for elective surgery in the main operating rooms.) reported a technical failure rate of 0.14% and no unin-
Before surgery, estimated blood loss is reviewed and tended laparotomies or intraoperative complications.
orthostatic vital signs are assessed. A clear antacid is given They reported that this technique reduced surgical time
just before the patient goes to the operating room. Most by 33% and cost by 68% to 85% when compared with
of these patients (without preexisting epidural analgesia) general anesthesia. The investigators presented no data
receive spinal anesthesia for postpartum tubal ligation. regarding patient satisfaction, and they made no comment
However, general anesthesia can be provided using rapid- on the use of pulse oximetry or blood pressure monitors.
sequence induction with cricoid pressure. Four percent of patients, however, required oxygen
therapy for “adequate tissue perfusion.” This study was
done in the 1980s, before many ambulatory surgery facil-
ANESTHETIC MANAGEMENT ities had institutional guidelines for sedation.
in 1983 indicating that morbidity and mortality were University of Colorado, rapid-sequence induction (with
much higher when general anesthesia was used. The cricoid pressure) is performed and all patients undergo
first report involved 3500 interval (not postpartum) lapa- tracheal intubation during administration of general
roscopic tubal sterilizations at nine university medical anesthesia for postpartum tubal ligation.
centers.37 Among all patients, the risk for intraoperative Volatile anesthetic agents cause uterine relaxation
or postoperative complications was 1.75%, but the risk and could potentially increase the risk for postpartum
was five times higher with general anesthesia than with hemorrhage if administered to women in the imme-
local anesthesia. (In this report, local anesthesia included diate postpartum period. Therefore, the question arises
local, epidural, and spinal anesthesia.) The reason(s) for as to whether the anesthesia provider should use an
the difference was unclear. In the second report, the inhalation or an intravenous technique to maintain
U.S. Centers for Disease Control and Prevention exam- general anesthesia for postpartum tubal ligation. Marx
ined deaths attributed to tubal sterilization procedures et al.39 measured postpartum uterine activity and the
from 1977 to 1981.38 Both immediate postpartum response to oxytocin with different concentrations of
laparotomies and interval laparoscopic procedures were halothane or enflurane (Figure 25-4). Impairment of
included. Of the 29 deaths, 11 followed complications spontaneous uterine activity occurred at 0.5 minimum
of general anesthesia and were caused by hypoventilation alveolar concentration (MAC) of both agents, and
or cardiorespiratory arrest. Aspiration was not reported loss of the response to oxytocin occurred near 1.0
as a cause of death. Of the six patients whose deaths MAC. Spontaneous contractions reappeared when
were definitely attributed to hypoventilation, none had anesthetic concentrations were reduced below these
undergone tracheal intubation. Five of the 11 deaths levels. Parous women are at risk for postpartum
attributed to general anesthesia occurred during post- uterine atony, and administration of a high concen-
partum laparotomy. Of these, only one woman had tration of a volatile halogenated agent may precipitate
undergone tracheal intubation; all others underwent postpartum hemorrhage.
mask ventilation. The investigators concluded, “It Two studies have determined the MAC of isoflurane
appears that for tubal sterilization, like abortion, the during the postpartum period. Chan et al.40 found a posi-
greatest risk for death is that associated with the anes- tive correlation between MAC and the length of time
thesia used during the procedure.”39 after delivery, with nonpregnant values achieved by 72
These reports preceded the mandatory use of pulse hours postpartum. Zhou et al.41 determined that MAC of
oximetry and capnography and do not reflect modern isoflurane was approximately 0.75% in the first 12 hours
anesthesia care. In the 30 years since those reports, postpartum and 1.04% in patients who were 12 to 24
appropriate airway management with tracheal intubation hours postpartum. No significant difference in MAC
has become standard practice. Thorough adherence to existed between the latter group and a control group of
ASA standards for basic anesthesia monitoring (including nonpregnant gynecologic patients. Together these results
use of pulse oximetry and capnography to monitor oxy- demonstrate that the reduced MAC observed during
genation and ventilation) should help prevent morbidity pregnancy persists for a variable period between 12 and
and mortality associated with general anesthesia. At the 36 hours postpartum.
Drip
Pitocin 10 mU
Uterine pressure
100
(torr)
60
20
2 1 0.5
Delivered halothane (vol%)
Blood halothane
14
(mg/100 mL)
10
6
2
0 5 10 15 20 25 30 35
Time (min)
FIGURE 25-4 ■ Halothane anesthesia blocked the normal response to oxytocin when arterial blood levels exceeded 10.5 mg/100 mL
or approximately 0.8 MAC. (From Marx GF, Kim YI, Lin CC, et al. Postpartum uterine pressures under halothane or enflurane anesthesia.
Obstet Gynecol 1978; 51:697.)
25 Postpartum Tubal Sterilization 537
10. Vincent RD, Martin RQ. Postpartum tubal ligation after preg-
• Postpartum sterilization offers the advantages of nancy complicated by preeclampsia or gestational hypertension.
convenience for the patient and technical Obstet Gynecol 1996; 88:119-22.
11. Toledo P, McCarthy RJ, Hewlett BJ, et al. The accuracy of blood
simplicity for the surgeon. loss estimation after simulated vaginal delivery. Anesth Analg
• Postpartum patients do not have lower gastric 2007; 105:1736-40.
pH or higher gastric volumes than nonpregnant 12. Ito S. Drug therapy: drug therapy for breast-feeding women. N
Engl J Med 2000; 343:118-25.
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studies suggest that gastric emptying is delayed nal mortality in the United States. Obstet Gynecol 2011;
postpartum only if the patient has received an 117:69-74.
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and 5 alpha-pregnane-3,20-dione during labor and early post
• The incidence of gastroesophageal reflux returns partum. Acta Obstet Gynecol Scand 1990; 69:123-6.
toward normal by the second postpartum day. 15. Llauro JL, Runnebaum B, Zander J. Progesterone in human
• Modern anesthetic drugs do not appear in breast peripheral blood before, during and after labor. Am J Obstet
Gynecol 1968; 101:867-73.
milk in amounts that affect the newborn. 16. O’Sullivan GM, Sutton AJ, Thompson SA, et al. Noninvasive
• The duration of succinylcholine-, rocuronium-, measurement of gastric emptying in obstetric patients. Anesth
mivacurium-, and vecuronium-induced Analg 1987; 66:505-11.
neuromuscular blockade is prolonged during the 17. Gin T, Cho AMW, Lew JKL, et al. Gastric emptying in the post-
partum period. Anaesth Intens Care 1991; 19:521-4.
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action for atracurium is unchanged and that of of gastric emptying times in pregnancy and the puerperium.
cisatracurium is shorter. Anaesthesia 1993; 48:53-7.
19. Sandhar BK, Elliott RH, Windram I, Rowbotham DJ. Peripartum
• An epidural catheter placed for labor may be changes in gastric emptying. Anaesthesia 1992; 47:196-8.
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for anesthesia failure may be greater if surgery water in term pregnancy. Anesthesiology 2002; 96:1395-1400.
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of water in obese pregnant women at term. Anesth Analg 2007;
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Anaesthesia 1999; 54:329-34.
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542 PART VI Labor and Vaginal Delivery
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to tubal sterilization in the United States, 1977 to 1981. Am J epidural catheters associated with patient movement. Anesthesiol-
Obstet Gynecol 1983; 146:131-6. ogy 1997; 86:778-84.
39. Marx GF, Kim YI, Lin CC, et al. Postpartum uterine pressures 60. Abouleish EI, Elias M, Nelson C. Ropivacaine-induced seizure
under halothane or enflurane anesthesia. Obstet Gynecol 1978; after extradural anaesthesia. Br J Anaesth 1998; 80:843-4.
51:695-8. 61. Vixcomi CM, Rathmell JP. Labor epidural catheter reactivation
40. Chan MTV, Gin T. Postpartum changes in the minimum alveolar or spinal anesthesia for delayed postpartum tubal ligation: a cost
concentration of isoflurane. Anesthesiology 1995;82:1360-3. comparison. J Clin Anesth 1995; 7:380-3.
41. Zhou HH, Norman P, DeLima LGR, et al. The minimum alveo- 62. Assali NS, Prystowsky H. Studies on autonomic blockade. I. Com-
lar concentration of isoflurane in patients undergoing bilateral parison between the effects of tetraethylammonium chloride
tubal ligation in the postpartum period. Anesthesiology 1995; (TEAC) and high selective spinal anesthesia on blood pressure of
82:1364-8. normal and toxemic pregnancy. J Clin Invest 1950; 29:1354-66.
42. Dailland P, Cockshott ID, Lorzin JD, et al. Intravenous propofol 63. Abouleish EI. Postpartum tubal ligation requires more bupiva-
during cesarean section: placental transfer, concentrations in caine for spinal anesthesia than does cesarean section. Anesth
breast milk, and neonatal effects. A preliminary study. Anesthesi- Analg 1986; 65:897-900.
ology 1989; 71:827-34. 64. Datta S, Hurley RJ, Naulty JS, et al. Plasma and cerebrospinal
43. Evans RT, Wroe JM. Plasma cholinesterase changes during preg- fluid progesterone concentrations in pregnant and nonpregnant
nancy. Anaesthesia 1980;35:651-4. women. Anesth Analg 1986; 65:950-4.
44. Ganga CC, Heyduk JV, Marx GF, Sklar GS. A comparison of the 65. Huffnagle S, Norris MC, Leighton BL, et al. Do patient variables
response to suxamethonium in postpartum and gynaecological influence the subarachnoid spread of hyperbaric lidocaine in the
patients. Anaesthesia 1982; 37:903-6. postpartum patient? Reg Anesth 1994; 19:330-4.
45. Leighton BL, Cheek TG, Gross JB, et al. Succinylcholine phar- 66. Wong CA, Slavenas P. The incidence of transient radicular irrita-
macodynamics in peripartum patients. Anesthesiology 1986; tion after spinal anesthesia in obstetric patients. Reg Anesth Pain
64:202-5. Med 1999; 24:55-8.
46. Kao YJ, Turner DR. Prolongation of succinylcholine block by 67. Philip J, Sharma SK, Gottumukkala VNR, et al. Transient neuro-
metoclopramide. Anesthesiology 1989; 70:905-8. logic symptoms after spinal anesthesia with lidocaine in obstetric
47. Woodworth GE, Sears DH, Grove TM, et al. The effect of patients. Anesth Analg 2001; 92:405-9.
cimetidine and ranitidine on the duration of action of succinyl- 68. Schneider MC, Birnbach DJ. Lidocaine neurotoxicity in the
choline. Anesth Analg 1989; 68:295-7. obstetric patient: is the water safe? Anesth Analg 2001; 92:
48. Puhringer FK, Spart HJ, Mitterschiffthaler G, et al. Extended 287-90.
duration of action of rocuronium in postpartum patients. Anesth 69. Sharma SK, Gajraj NM, Sidawi JE. Prevention of hypotension
Analg 1997; 84:352-4. during spinal anesthesia: a comparison of intravascular adminis-
49. Gin T, Derrick JL, Chan MTV, et al. Postpartum patients have tration of hetastarch versus lactated Ringer’s solution. Anesth
slightly prolonged neuromuscular block after mivacurium. Anesth Analg 1997; 84:111-14.
Analg 1998; 86:82-5. 70. Suelto MD, Vincent RD, Larmon JE, et al. Spinal anesthesia for
50. Hawakins JL, Adenwala J, Camp C, Joyce TH. The effect of postpartum tubal ligation after pregnancy complicated by pre-
H2-receptor antagonist premedication on the duration of eclampsia or gestational hypertension. Reg Anesth Pain Med
vecuronium-induced neuromuscular blockade in postpartum 2000; 25:170-3.
patients. Anesthesiology 1989; 71:175-7. 71. Norris MC, Honet JE, Leighton BL, et al. A comparison of
51. Khuenl-Brady KS, Koller J, Mair P, et al. Comparison of meperidine and lidocaine for spinal anesthesia for postpartum
vecuronium and atracurium-induced neuromuscular blockade in tubal ligation. Reg Anesth 1996; 21:84-8.
postpartum and nonpregnant patients. Anesth Analg 1991; 72. Malinow AM, Mokriski BLK, Nomura MK, et al. Effect of epi-
72:110-13. nephrine on intrathecal fentanyl analgesia in patients undergoing
52. Pan PH, Moore C. Comparison of cisatracurium-induced neuro- postpartum tubal ligation. Anesthesiology 1990; 73:381-5.
muscular blockade between immediate postpartum and nonpreg- 73. Habib AS, Muir HA, White WD, et al. Intrathecal morphine for
nant patients. J Clin Anesth 2001; 13:112-17. analgesia after postpartum bilateral tubal ligation. Anesth Analg
53. Gin T, Chan MTV, Chan KL, et al. Prolonged neuromuscular 2005; 100:239-43.
block after rocuronium in postpartum patients. Anesth Analg 74. Marcus RL, Wong CA, Lehor A, et al. Postoperative epidural
2002; 94:686-9. morphine for postpartum tubal ligation analgesia. Anesth Analg
54. Camann W, Cohen MB, Ostheimer GW. Is midazolam desirable 2005; 101:876-81.
for sedation in parturients (letter)? Anesthesiology 1986; 65:441. 75. Alexander CD, Wetchler BV, Thompson RE. Bupivacaine infiltra-
55. Vincent RD, Reid RW. Epidural anesthesia for postpartum tubal tion of the mesosalpinx in ambulatory surgical laparoscopic tubal
ligation using epidural catheters placed during labor. J Clin Anesth sterilization. Can J Anaesth 1987; 34:362-5.
1993; 5:289-91. 76. Wittels B, Faure EAM, Chavez R, et al. Effective analgesia after
56. Lawlor M, Weiner M, Fantauzzi M, Johnson C. Efficacy of epi- bilateral tubal ligation. Anesth Analg 1998; 87:619-23.
dural anesthesia for post-partum tubal ligation utilizing indwelling 77. American Academy of Pediatrics Committee on Drugs. The
labor epidural catheters. Reg Anesth 1994; 19:54. transfer of drugs and other chemicals into human milk. Pediatrics
57. Goodman EJ, Dumas SD. The rate of successful reactivation of 1994; 93:137-50.
labor epidural catheters for postpartum tubal ligation surgery. Reg
Anesth Pain Med 1998; 23:258-61.
58. Beilin Y, Bernstein HH, Zucker-Pinchoff B. The optimal distance
that a multiorifice epidural catheter should be threaded into the
epidural space. Anesth Analg 1995; 81:301-4.
PA RT V I I
CESAREAN DELIVERY
Donald Caton, MD
During most of the nineteenth century, physicians per- anesthesia was not available before 1900. Ether and
formed very few cesarean deliveries because the mortality chloroform were the only two potent agents available
rate was so high. For example, in his case books, John for general anesthesia until the addition of cyclopropane.
Snow mentions more than 90 patients anesthetized for Until curare was introduced to clinical practice, use of
vaginal delivery, but not one cesarean delivery.1 The pro- these agents necessitated achieving an anesthetic depth
cedure was reserved for desperate situations. One physi- sufficient to obtain abdominal relaxation.
cian quipped that a woman had a better chance of Only in the past five decades have there been incen-
surviving an abdominal delivery if she performed the tives to develop better anesthetic techniques for cesarean
surgery herself, or if her abdomen were accidentally delivery. First, obstetricians began to perform cesarean
ripped open by the horn of a bull.2 delivery more often to deal with fetal and maternal prob-
Hemorrhage and infection caused most deaths. The lems. Second, physicians developed a better understand-
use of anesthesia allowed surgeons to develop techniques ing of the physiology of pregnancy, especially the nature
to deal with these problems. Italian surgeon Eduardo of risks associated with anesthesia. Third, anesthesiolo-
Porro made the first important innovation in 1876. To gists and obstetricians began to place greater emphasis
limit hemorrhage, he excised the uterus after delivering on the well-being of the neonate, a change that required
the child. Others had left the uterine incision open in the the development of anesthetic techniques that would
belief that it would heal better. In 1882, German surgeon protect the mother but have the least possible effect on
Max Sänger advised closing the uterus with sutures, the child.
thereby obviating the need for a hysterectomy. Sänger, REFERENCES
benefiting from the advances in bacteriology, also devised 1. Ellis RH, editor. The case books of Dr. John Snow. Med Hist Suppl
techniques to limit the risk of infection.3 1994:14
In 1910, J. Whitridge Williams of Johns Hopkins still 2. Williams JW. Obstetrics: A Textbook for the Use of Students and
called cesarean delivery a “dangerous procedure” despite Practitioners. New York, D: Appleton and Company, 1907.
the fact that the maternal mortality rate had fallen to 400-11.
3. O’Dowd M, Philipp EE. The History of Obstetrics and Gynaecol-
10%. He performed it only for the most severe cases of ogy. New York: Parthenon Publishing, 1994:157-65.
contracted pelvis.2,4 In fact, Williams warned that a cesar- 4. Loudon I. Death in Childbirth: An International Study of Maternal
ean delivery “should never be performed when the child Care and Maternal Mortality, 1800-1850. New York: Oxford Uni-
is dead or in serious danger.” Even in 1970, cesarean versity Press, 1992:132-9.
5. Hellman LM, Pritchard JA, Wynn RM. Williams Obstetrics. New
delivery rates remained below 7% in the United States, York: Appleton-Century-Crofts, 1971:1007-167.
and at less than 2% in many European countries.5
With few agents to choose from, anesthetic techniques
for cesarean delivery also evolved slowly. Regional
C H A P T E R 2 6
CHAPTER OUTLINE
50 40
Primary Cesarean Delivery
Percent of all deliveries
30
Percent
20
20
10 10
0 0
Africa Asia Oceania Europe Latin North
1970 1980 1990 2000 2006
America America
FIGURE 26-2 ■ Rates of primary cesarean delivery, total cesarean
FIGURE 26-1 ■ The range of cesarean delivery rates by world
delivery, and vaginal birth after cesarean delivery (VBAC) in the
region as collected in surveys or vital registration system
United States, 1970 to 2006. (Data for 1970-1988 from the National
reports. (Data modified from Gibbons L, Belizan JM, Lauer JA, et al.
Hospital Discharge Survey; data for 1989-2006 from the National
Inequities in the use of cesarean section deliveries in the world. Am
Vital Statistics System, Centers for Disease Control and Prevention.
J Obstet Gynecol 2012; 206:331.e1-19.)
Available at http://www.cdc.gov.)
INDICATIONS
of maternal and fetal indications but may need to be
The common indications for cesarean delivery include conducted in an urgent or emergent manner. A prior
dystocia, malpresentation, nonreassuring fetal status, and cesarean delivery does not necessitate cesarean delivery
previous cesarean delivery (Box 26-2). An elective cesarean in a subsequent pregnancy. A trial of labor after cesarean
delivery can be performed for obstetric or medical indica- (TOLAC), which if successful is called a vaginal birth
tions or at the request of a pregnant patient, and it is after cesarean (VBAC), is an alternative option; the use
typically planned and performed prior to the onset of of TOLAC, once growing in popularity, has declined in
labor.5 A cesarean delivery performed during labor for a recent years for a variety of reasons (Figure 26-2) (see
planned vaginal delivery can also occur for a wide range Chapter 19).
26 Anesthesia for Cesarean Delivery 547
Complications of Cesarean
OPERATIVE TECHNIQUE BOX 26-3
Delivery
The technical aspects of performing a cesarean delivery INTRAOPERATIVE COMPLICATIONS
are comparable worldwide, with minor variations. A Hemorrhage
midline vertical abdominal incision allows rapid access and
• Uterine atony
greater surgical exposure; however, the horizontal supra- • Uterine lacerations
pubic (Pfannenstiel) incision offers better cosmesis and • Broad ligament hematoma
wound strength. Similarly, a low transverse uterine inci-
sion, in comparison with a vertical incision, allows for a Infection
lower incidence of uterine dehiscence or rupture in sub- • Endometritis
sequent pregnancies, as well as a reduction in the risks of • Wound infection
infection, blood loss, and bowel and omental adhesions.
POSTOPERATIVE COMPLICATIONS
Vertical uterine incisions are most often used in the fol-
lowing situations: (1) when the lower uterine segment is • Cardiovascular: venous thromboembolism
underdeveloped (before 34 weeks’ gestation), (2) in deliv- • Gastrointestinal: ileus, adhesions, injury
• Genitourinary: bladder or ureteral injury
ery of a preterm infant in a woman who has not labored, • Respiratory: atelectasis, aspiration pneumonia
and (3) in selected patients with multiple gestation and/ • Chronic pain
or malpresentation. In some cases, a vertical uterine inci-
sion is performed high on the anterior uterine wall (i.e., FUTURE PREGNANCY RISKS
classic incision), especially in the patient with a low-lying • Placenta previa
anterior placenta previa or when a cesarean hysterectomy • Placenta accreta
is planned. • Uterine rupture
Uterine exteriorization following delivery facilitates • Obstetric hysterectomy
visualization and repair of the uterine incision, particu-
larly when the incision has been extended laterally.
Although the effect of exteriorization on blood loss and
febrile morbidity remains controversial,6 higher rates of
intraoperative nausea, emesis, and venous air embolism
as well as postoperative pain have been observed.7,8 Clark et al.12 identified the causes of maternal death
in a retrospective study of 1.5 million deliveries that
occurred between 2000 and 2006 within a health care
MORBIDITY AND MORTALITY network composed of primary, secondary, and tertiary
care hospitals in 20 states (Table 26-1). Only 15% of
Complications of cesarean delivery include hemorrhage, maternal deaths were related to preexisting medical con-
infection, thromboembolism, ureteral and bladder injury, ditions; most deaths occurred in women classified as
abdominal pain, uterine rupture in subsequent pregnan- being at low risk at the beginning of pregnancy. The
cies, and death (Box 26-3).9 Nonelective cesarean delivery investigators concluded that 17 deaths (18%) could have
is associated with a greater risk for maternal morbidity been prevented by provision of more appropriate medical
than elective cesarean delivery; a 2008 study of all deliv- care. (Causality was determined by evaluating whether
eries in Finland indicated that the rates of severe mater- the maternal death could have been avoided with the
nal morbidity were 5.2, 12.1, and 27.2 per 1000 vaginal, use of an alternative route of delivery, with the assump-
elective cesarean, and nonelective cesarean deliveries, tion that all other details remained the same prior to
respectively.10 delivery.) The preventable deaths were associated with
Maternal mortality has decreased during the past 75 postpartum hemorrhage (8), preeclampsia (5), medica-
years (see Chapter 40). Since 1937, when the maternal tion error (3), and infection (1). Cesarean delivery was
mortality rate for nulliparous women undergoing cesar- determined to be directly responsible for maternal death
ean delivery in the United States was 6%, the risk for in four cases, including hemorrhage from surgical vas-
death associated with the procedure has decreased by cular injury in three cases and sepsis from surgical injury
a factor of nearly 1000 owing to the availability of to the bowel in the fourth. Deaths associated with, but
blood transfusions, antibiotics, safer anesthetic tech- not directly caused by, cesarean delivery were associated
niques, and critical care units.11 Maternal morbidity and with perimortem procedures or caused by thromboem-
mortality vary widely from country to country. In most bolic phenomena; of the nine patients who died of
developed nations, the rate of maternal death associated thromboembolic phenomena, none had received peri-
with all cesarean deliveries remains higher than that partum mechanical or pharmacologic thromboprophy-
associated with vaginal deliveries.3,12 The risk for mater- laxis. The investigators concluded that cesarean delivery
nal death for a planned, elective primary cesarean deliv- per se was only rarely the causative factor in maternal
ery may not differ from that associated with a planned death; in the majority of cases, death was related to the
vaginal delivery, but performance of cesarean delivery indication for the cesarean delivery rather than the opera-
places the mother at higher risk for morbidity (and tive procedure. Nonetheless, these investigators also
perhaps mortality) in subsequent pregnancies and cesar- concluded that the risk for death caused by cesarean
ean deliveries.13 delivery is approximately 10 times higher than that for
548 PART VII Cesarean Delivery
BOX 26-5 Elements of Informed Consent A survey conducted among obstetric anesthesia pro-
viders in the United Kingdom and Ireland found a con-
THRESHOLD ELEMENTS sensus that the following neuraxial anesthetic risk factors
• Patient is competent to provide consent (i.e., refers to should be disclosed: (1) the possibility of intraoperative
the patient’s legal authority to make decisions regard- discomfort and a failed/partial blockade, (2) the potential
ing her health care). need to convert to general anesthesia, (3) the presence of
weak legs, (4) hypotension, and (5) the occurrence of an
INFORMATION ELEMENTS unintentional dural puncture (with the use of an epidural
• Provider discloses information about material risks. technique).41 Backache and urinary retention were con-
• Patient understands information. sidered “optional” for discussion, and the risk for para-
CONSENT ELEMENTS plegia was considered unworthy of mention unless the
patient specifically asked about it.41
• Provider offers information in a noncoercive manner.
• Patient gives authorization voluntarily.
Among obstetric patients, the desire for risk disclosure
varies. In a study from Australia, Bethune et al.42 reported
Information from Barkham M, Peters G, Pace N. Ethical and medico-legal a significant range (between 1 : 1 and 1 : 1 billion) in the
aspects of obstetric anaesthesia. Anaesth Intensive Care Med 2005; level of risk for complications of epidural analgesia at
6:127-129. which pregnant women wished to be informed. In a
similar study from the United Kingdom in which the
risks associated with general anesthesia were discussed,
Jackson et al.43 found that 50% of pregnant women
Threshold Elements wished to know all risks that occurred at a frequency of
greater than 1 : 1000. Overall, pregnant women appear to
Threshold elements include the ability of the patient to want more rather than less information regarding the
meet the basic definition of competence, which refers to risks of anesthetic interventions.44
the patient’s legal authority to make a decision about her
health care. Although some cognitive functions may be Consent Elements
compromised by the effects of pain, exhaustion, and anal-
gesic drugs,38 evidence suggests that most laboring In obtaining consent, care must be taken to preserve
women retain the capacity to hear and comprehend patient autonomy by providing information in a nonco-
information during the consent process.36 ercive, nonmanipulative manner (i.e., avoiding a pater-
nalistic or maternalistic approach). Barkham et al.37
observed that there are occasions when noncoercive
Information Elements
forms of influence may be appropriate and that reasoned
The premise that a patient should be informed about the argument can be used to persuade patients of the merits
risks of a planned procedure in a language that she under- of a particular course of action. For example, a woman
stands is the basis for the information elements of the with anatomy consistent with a difficult airway who is
consent process. In part, the difficulty with obtaining requesting general anesthesia for an elective cesarean
informed consent for anesthesia lies in determining the delivery may reconsider her choice after rational
incidence of anesthesia-related morbidity and mortality. persuasion.
Jenkins and Baker39 surveyed the risks associated with In many cases, the course of action most appropriate
anesthesia and compared them with risks inherent in for maternal health is also beneficial to the fetus. In some
daily living to provide contextual comparisons for cases, however, the best interests of the mother may con-
patients. The investigators concluded that the percep- flict with those of the fetus. For example, emergency
tions regarding anesthesia risks held by anesthesia pro- cesarean delivery with general anesthesia is often per-
viders, surgeons, and the public are somewhat optimistic formed primarily for the benefit of the fetus but may
and that the consent process should include a more real- involve higher risk to the mother than a nonemergency
istic and comprehensive disclosure. procedure performed with neuraxial anesthesia. This
A second difficulty is determining what risks require conflict in relative risks and benefits will most likely
disclosure. White and Baldwin40 stated: intensify in the future as intrauterine fetal surgery
becomes more common.
Anesthesia is by nature a practical specialty; every
procedure [is] performed carrying a range of risks, which Informed Refusal
may be minor or major in consequence, common or rare
in incidence, causal or incidental to the harm sustained (if The National Institute of Clinical Excellence (NICE) is
any), convenient or inconvenient in timing, expected or a part of the National Health Service in the United
unexpected, relative or absolute, operator-dependent or Kingdom. The NICE guidelines for cesarean delivery
any combination of the above. In addition, there are state that “after providing the pregnant woman with
significant difficulties in communicating risk, caused by evidence-based information and in a manner that respects
patient perceptions, anaesthetist perceptions and the the woman’s dignity, privacy, views, and culture whilst
doctor-patient interaction, and complicated by the range of taking into consideration the clinical situation … a com-
communication methods (numerical, verbal, or petent pregnant woman is entitled to refuse treatment,
descriptive). even when the treatment would clearly benefit her or her
26 Anesthesia for Cesarean Delivery 551
Selected Risk Factors for Preparation for obstetric hemorrhage includes (1)
BOX 26-6 reviewing the patient’s history for anemia or risk factors
Peripartum Hemorrhage
for hemorrhage (e.g., placenta previa, prior uterine
• Abnormal placentation surgery, possible placenta accreta); (2) consulting with the
• Advanced maternal age obstetric team regarding the presence of risk factors;
• Anticoagulation (3) reviewing reports of ultrasonographic or magnetic
• Bleeding disorder resonance images of placentation; (4) obtaining a blood
• Chorioamnionitis sample for a type and screen or crossmatch; (5) contact-
• Fetal demise ing the blood bank to ensure the availability of blood
• Fetal malpresentation products; (6) obtaining and checking the necessary equip-
• General anesthesia
• Increased parity/grand multiparity
ment (blood filters and warmers, infusion pumps and
• Instrumental vaginal delivery tubing, compatible fluids and medications, and standard
• Internal trauma (e.g., curettage, internal version) clinical laboratory collection tubes [to check hemoglobin,
• Oxytocin augmentation of labor platelets, electrolytes, and coagulation factors]); and (7)
• Placental abruption consulting with a blood bank pathologist, hematologist,
• Precipitous delivery and/or interventional radiologist in selected cases (Box
• Preeclampsia (thrombocytopenia, coagulopathy) 26-7).
• Premature rupture of membranes Currently, there is a lack of consensus as to which
• Previous uterine surgery (cesarean delivery, patients require a blood type and screen and which
myomectomy) patients require a crossmatch.34 The maternal history
• Prolonged labor
• Retained placenta
(previous transfusion, existence of known red blood cell
• Tocolytic therapy antibodies) and anticipated hemorrhagic complications,
• Trauma (blunt or penetrating) as well as local institutional policies, should guide
• Uterine distention (e.g., macrosomia, multiple gesta- decision-making. In certain high-risk cases (e.g., sus-
tion, polyhydramnios) pected placenta accreta), blood products (i.e., 2 to 4 units
• Uterine leiomyoma of packed red blood cells) should be physically present
near or in the operating room before making the surgical
incision, if possible.
If an interventional radiologist plans to place prophy-
baby’s health. Refusal of treatment needs to be one of the lactic intravascular balloon occlusion catheters before
woman’s options.”45 Although compliance with maternal surgery, and if neuraxial anesthesia is planned, the
requests is the usual course of action, a court-based deci- anesthesia provider should place an epidural catheter
sion is sometimes made on behalf of the unborn infant prior to placement of the balloon catheters (see later
(see Chapter 33). discussion).50
The anesthesia provider is not obliged to honor a
patient’s or obstetrician’s request (e.g., general anesthesia Monitoring
in a morbidly obese patient with a difficult airway), par-
ticularly when it conflicts with the clinician’s experience Attention should be given to the availability and proper
and knowledge of acceptable risks and benefits.46 functioning of equipment and monitors for the provision
Overall, anesthesia providers are encouraged to (1) of anesthesia and the management of potential complica-
engage in, rather than withhold, a discussion of anes- tions (e.g., failed intubation, cardiopulmonary arrest).34
thetic risks; (2) recognize that their own biases may influ- Equipment should be checked on a daily basis and ser-
ence the presentation of risks; (3) understand how the viced at recommended intervals. The equipment and
perception of risks is modified by the situation; and (4) facilities available in the labor and delivery operating
provide contextual explanation of risks, to help place room suite should be comparable to those available in the
potential complications in perspective.39 When recog- main operating room.34
nized as an opportunity to foster a closer patient-physician The ASA standards for basic monitoring apply to the
relationship and greater involvement of the patient in her provision of anesthesia for all patients.51 Within obstet-
care, rather than simply as a tool to avoid litigation, rics, basic monitoring consists of maternal pulse oxime-
informed consent can help guide the decision-making try, electrocardiogram (ECG), and noninvasive blood
associated with anesthesia care. pressure monitoring,* as well as fetal heart rate (FHR)
monitoring.
Blood Products
Peripartum hemorrhage remains a leading cause of
maternal mortality worldwide (see Chapters 38 and 40).47 *Outside the operating room, and before the onset of labor, maternal
There is little difference in blood loss between an uncom- blood pressure is ideally measured (using an appropriately sized cuff
plicated elective cesarean delivery and an uncomplicated with a bladder length that is 80% and a width that is at least 46% of
planned vaginal birth48; however, a cesarean delivery per- the arm circumference) after a rest period of 10 minutes or more,
with the pregnant woman sitting or lying on her left side with her
formed during labor is associated with greater blood arm at the level of the right atrium. The onset (phase 1) and disap-
loss.49 Risk factors for peripartum hemorrhage are listed pearance (phase 5) of Korotkoff sounds correspond to systolic and
in Box 26-6. diastolic pressures, respectively.52
552 PART VII Cesarean Delivery
of the neuraxial technique and until the abdominal skin located on a separate floor but shares a common operat-
preparation for cesarean delivery has begun.45 ing room facility (used for other surgical procedures),
In most cases of emergency cesarean delivery, a previ- whereas in others it is a geographically separate, self-
ously placed fetal scalp (or buttock) ECG electrode can contained unit with its own operating room facilities.
be used to monitor the FHR before, during, and after the Regardless of location, the equipment, facilities, and
initiation of anesthesia. Typically, the fetal scalp electrode support personnel available in the labor and delivery
is removed when the surgical drapes are applied to the operating room should be comparable to those available
abdomen, but in some cases the scalp electrode may be in the main operating room.34 In addition, personnel and
left in place until just before delivery, when the circulat- equipment should be available to care for obstetric
ing nurse reaches under the drapes to disconnect the patients recovering from major neuraxial or general
electrode. anesthesia.
In cases of emergency cesarean delivery, continuous Resources for the conduct and support of neuraxial
FHR monitoring is useful for at least three reasons. First, anesthesia and general anesthesia should include those
the FHR abnormality often resolves; in some cases, the necessary for the basic delivery of anesthesia and airway
obstetrician will then elect to forgo the performance of a management as well as those required to manage com-
cesarean delivery. In other cases, the obstetrician may plications (e.g., failed tracheal intubation). The immediate
continue with plans to perform a cesarean delivery but availability of these resources is particularly important,
continuous FHR monitoring may facilitate the adminis- given the frequency and urgency of anesthesia care.
tration of neuraxial anesthesia. For example, an improved Consideration should be given to having some of the
FHR tracing allows time for extension of adequate epi- equipment and supplies immediately available in one
dural anesthesia or administration of spinal anesthesia. location or in a cart (e.g., difficult airway cart, massive
Second, continuous FHR monitoring may guide man- hemorrhage cart, malignant hyperthermia box) specifi-
agement in cases of failed tracheal intubation. If intuba- cally located on the labor and delivery unit. Equipment
tion fails and there is no evidence of fetal compromise, and supplies should be checked on a frequent and regular
both the anesthesia provider and the obstetrician will basis. Securing special-situation equipment and supplies
have greater confidence in a decision to awaken the in a cart with a single-use breakthrough plastic tie helps
patient and proceed with an alternative anesthetic tech- ensure that the cart is kept in a fully stocked state.
nique. By contrast, if there is evidence of ongoing fetal
compromise, the anesthesia provider may decide to Aspiration Prophylaxis
provide general anesthesia by means of a face mask or
supraglottic airway (e.g., laryngeal mask airway [LMA]), The patient should be asked about oral intake, although
and the obstetrician may proceed with cesarean delivery insufficient evidence exists regarding the relationship
(see Chapter 30). Third, intraoperative FHR monitoring between recent ingestion and subsequent aspiration
allows the obstetrician to modify the surgical technique pneumonitis (see Chapter 29). Gastric emptying of clear
according to the urgency of delivery. liquids during pregnancy occurs relatively quickly; the
residual content of the stomach (as measured by the
cross-sectional area of the gastric antrum 60 minutes
Medication Availability and Storage after the ingestion of 300 mL of water) does not appear
The drugs used for the provision of general and neur- to be different from baseline fasting levels in either lean
axial anesthesia, including vasopressors and emergency or obese nonlaboring pregnant women.68,69 Moreover,
medications, should be readily available. The Joint Com- when measured by serial gastric ultrasonographic exami-
mission65 mandates that all medications should be nations and acetaminophen absorption, the gastric emp-
secured. Currently, only Schedule II controlled sub- tying half-time of 300 mL of water is shorter than that
stances as classified by the Drug Enforcement Agency66 of 50 mL of water in healthy, nonlaboring, nonobese
need to be secured in a “substantially constructed locked pregnant women (24 ± 6 versus 33 ± 8 minutes,
cabinet.”67 Other drugs and products, including anes- respectively).68
thetic medications, should be “reasonably secure” but The healthy patient undergoing elective cesarean deliv-
not necessarily locked. These drugs include the Schedule ery may drink modest amounts of clear liquids up to 2
III drug thiopental, as well as succinylcholine and vaso- hours before induction of anesthesia.34 Examples of clear
pressor agents. The Joint Commission has defined “rea- liquids are water, fruit juices without pulp, carbonated
sonably secure” as storage in areas not readily accessible beverages, clear tea, black coffee, and sports drinks. The
or easily removed by the public. Federal law requires volume of liquid ingested is less important than the
that all hospitals receiving Medicare funding adhere to absence of particulate matter. Patients with additional
conditions of participation, which state that “drugs and risk factors for aspiration (e.g., morbid obesity, diabetes,
biologicals must be kept in a secure area, and locked difficult airway) or laboring patients at increased risk for
when appropriate.”67 This rule applies to noncontrolled cesarean delivery (e.g., nonreassuring FHR pattern) may
substances. have further restrictions of oral intake, determined on a
case-by-case basis.34
Ingestion of solid foods should be avoided in laboring
Equipment patients and patients undergoing elective surgery
Labor and delivery units may be adjacent to or remote (e.g., scheduled cesarean delivery or postpartum tubal
from the operating rooms. In some facilities, the unit is ligation). A fasting period for solids of 6 to 8 hours,
554 PART VII Cesarean Delivery
depending on the fat content of the food, has been the minimum inhibitory tissue concentration for gram-
recommended.34 negative rods was not achieved at the time of skin incision
A reduction in gastric content acidity and volume is or closure in 20% of obese women and 33% of morbidly
believed to decrease the risk for damage to the respira- obese women.
tory epithelium if aspiration should occur. Oral admin- The optimal timing of antibiotic administration
istration of a nonparticulate antacid (0.3 M sodium (before skin incision versus after clamping of the umbili-
citrate, pH 8.4) causes the mean gastric pH to increase cal cord) and the potential value of more broad-spectrum
to greater than 6 for 1 hour; it does not affect gastric antibiotics remain controversial. In the past, prophylactic
volume.70,71 H2-receptor antagonists (ranitidine, antibiotics typically have been administered after umbili-
famotidine), proton pump inhibitors (omeprazole), cal cord clamping, because of concern that fetal antibiotic
and metoclopramide reduce gastric acid secretion and exposure might mask a nascent infection and/or increase
volume but require at least 30 to 40 minutes to exert the likelihood of a neonatal sepsis evaluation. However,
their effects.72 In a systematic review of interventions in a meta-analysis, Costantine et al.81 concluded that pre-
used to reduce the risk for aspiration pneumonitis in incision antibiotic prophylaxis reduces the incidence of
women undergoing cesarean delivery, Paranjothy et al.73 postcesarean endometritis and total maternal infectious
found a significant reduction in the risk for gastric pH morbidity, without evidence of adverse neonatal effects.
less than 2.5 with antacids (relative risk [RR], 0.17; 95% Although earlier studies suggested that ampicillin and
confidence interval [CI], 0.09 to 0.32), H2-receptor first-generation cephalosporins are similar in efficacy to
antagonists (RR, 0.09; 95% CI, 0.05 to 0.18), and proton- more broad-spectrum agents,77 more recent trials have
pump antagonists (RR, 0.26; 95% CI, 0.14 to 0.46), suggested that there is benefit associated with extended-
compared with no treatment or placebo. The combined spectrum antibiotic prophylaxis that includes the addition
use of an antacid and an H2-receptor antagonist was of an agent that covers other organisms such as Urea-
found to be more effective in reducing pH less than 2.5 plasma.79,82 Further investigation is necessary to deter-
than administration of placebo or an antacid alone.73 mine whether more broad-spectrum prophylactic
Sodium citrate was associated with a higher incidence antibiotic coverage improves maternal and fetal outcomes
and severity of nausea than an H2-receptor antagonist in mothers with active or presumed infection (e.g.,
(famotidine).74 Metoclopramide is a promotility agent chorioamnionitis).
that hastens gastric emptying, increases lower esophageal
sphincter tone, and decreases nausea and vomiting.75,76
Prior to surgical procedures, the timely administration
Aseptic Technique
of a nonparticulate antacid, an H2-receptor antagonist, In the early 19th century, Ignác Semmelweis observed
and metoclopramide should be considered, especially for that puerperal fever, known as “childbed fever,” was most
nonelective procedures.34 likely transmitted when the first stage of labor was pro-
longed and multiple individuals performed vaginal exam-
inations with contaminated hands. Since that time, the
Prophylactic Antibiotics practice of hand hygiene has caused a significant reduc-
With both elective (nonlaboring) and nonelective (labor- tion in maternal and neonatal infectious morbidity.
ing) cesarean deliveries, a 60% decrease in the incidence Epidural abscess and meningitis have been reported as
of endometritis, a 25% to 65% decrease in the incidence complications of neuraxial procedures in obstetric patients
of wound infection, and fewer episodes of fever and (see Chapter 32). These cases have prompted questions
urinary tract infections have been demonstrated after regarding the best antiseptic solution for disinfecting the
prophylactic antibiotic administration.77 The ACOG78 skin,83 provider attire, and the appropriate dressing for
has recommended the prophylactic administration of a the neuraxial catheter insertion site (see Chapters 12 and
narrow-spectrum antibiotic, such as a first-generation 32). There is wide variation in aseptic practices. Regret-
cephalosporin, within 1 hour of the start of cesarean tably, some anesthesia providers do not wear a face mask,
delivery. whereas others wear a gown, face mask, and hat.84 “Rapid-
Antibiotics with efficacy against gram-positive, gram- sequence spinal” has been described for cases of emer-
negative, and some anaerobic bacteria are commonly gency cesarean delivery in which the use of draping is
used for prophylaxis for cesarean delivery. Appropriate omitted and a single-wipe skin preparation is used85;
coverage includes intravenous ampicillin 2 g, cefazolin however, many obstetric anesthesia providers would
1 g, or ceftriaxone 1 g. Appropriate antibiotic coverage argue that this practice is unwise.
should last for 3 to 4 hours; therefore, ampicillin may be Subtle changes in circulating immunoglobulin levels
less appropriate owing to a shorter half-life.78,79 In partu- induced by pregnancy may affect the risk associated with
rients with a significant allergy to beta-lactam antibiotics exposure to infectious pathogens.86 As a consequence,
(e.g., history of anaphylaxis, angioedema, respiratory dis- obstetric anesthesia providers should always give careful
tress, or urticaria), intravenous clindamycin with genta- attention to aseptic technique, especially during perfor-
micin is a reasonable alternative. mance of a neuraxial technique. Proper sterile technique
Because of the greater volume of distribution, higher consists of wearing a face mask, giving careful attention
doses of antibiotics should be considered in women with to hand hygiene, and donning sterile gloves before initi-
a body mass index (BMI) greater than 30 kg/m2 or an ating neuraxial blockade.87
absolute weight greater than 100 kg.78,80 After adminis- Attention should also be given to the careful prepara-
tration of cephazolin 2 g, Pevzner et al.80 observed that tion of anesthetic drugs during administration of either
26 Anesthesia for Cesarean Delivery 555
general or neuraxial anesthesia. Although many local crystalloid solution at the time of the intrathecal injection
anesthetics have bactericidal properties that appear con- (“co-load”) was more efficacious than prehydration in
centration dependent,88 propofol and other anesthetic preventing hypotension,94 later studies did not support
agents can support bacterial growth.89 An increasing this finding,95 likely because the infusion rate was too
number of institutions are using premixed solutions of slow.93 Colloid, administered before or at the time of the
local anesthetic and opioid (prepared under aseptic con- intrathecal injection, is more effective than crystalloid for
ditions in a hospital or compounding pharmacy) to limit preventing hypotension.96 Colloid administered before
breaches in aseptic technique during the administration the intrathecal injection (preload) is equally efficacious to
of neuraxial anesthesia. administration at the time of injection (co-load).95
In healthy patients, we rapidly administer approxi-
Intravenous Access and Fluid mately 1 L of crystalloid at the time of initiation of neur-
axial anesthesia. For patients at high risk for hypotension
Management or the consequences of hypotension, colloid may be
The establishment of functional intravenous access is of administered before or at the time of initiation of neuro-
critical importance to the successful outcome of many blockade.93 Hypotension despite fluid administration is
clinical situations in obstetric anesthesia practice. Accord- treated with vasopressors (see later discussion).
ing to the Hagen-Poiseuille equation, the infusion rate
of fluid through a catheter is directly related to the pres-
sure gradient of the fluid and the fourth power of the
Supplemental Medications for Anxiety
catheter’s radius, and inversely related to the viscosity of The administration of benzodiazepines, even low doses
the fluid and the catheter’s length. Because the size of the (e.g., midazolam 0.02 mg/kg), may result in amnesia97,98;
catheter, more than the size of the vein, dictates the flow as a consequence, benzodiazepines are typically avoided
rate, the use of a short, large-diameter catheter (e.g., 16- during awake cesarean delivery. However, on occasion,
or 18-gauge) is associated with the best flow.90 particularly in women with severe anxiety or undergoing
In general, a smaller but functional catheter is more an emergency cesarean delivery, the use of low doses of
important than a larger catheter that is unreliable or intravenous midazolam or an opioid may facilitate per-
requires frequent manipulation. Smaller catheters may be formance of a neuraxial technique, awake tracheal intuba-
acceptable in an emergency; volume and blood resuscita- tion, or the induction of general anesthesia. Anxiolytics
tion can be satisfactorily achieved using 20- and 22-gauge may also assist in mitigating the feelings of distress during
catheters (without evidence of greater red blood cell the birthing experience, which may lessen the risk for
destruction) with the use of dilution, pressurization, or developing post-traumatic stress disorder.99 The use of
both.91 However, when large-bore peripheral venous low doses of sedative or anxiolytic agents has minimal to
access is problematic, especially when large blood loss is no neonatal effects. Frölich et al.100 observed no differ-
anticipated, or administration of multiple blood products ences in neonatal Apgar scores, neurobehavioral scores,
is required, the anesthesia provider may choose to insert or oxygen saturation among women who were random-
a central venous catheter. ized to receive either intravenous midazolam (0.02 mg/
Although the administration of intravenous fluids may kg) and fentanyl (1 µg/kg) or saline before administration
decrease the incidence of neuraxial anesthesia–associated of spinal anesthesia for cesarean delivery.
hypotension, initiation of anesthesia should not be
delayed to administer a fixed volume of fluid,34 particu-
larly in the case of an emergency cesarean delivery, in
Positioning
which the life and health of the mother and the infant are After 20 weeks’ gestation, all pregnant women should be
best preserved with timely delivery. Vasopressors can be positioned with left uterine displacement to minimize
used for both prophylaxis and treatment of hypotension. aortocaval compression. The supine hypotension syn-
The type of fluid (crystalloid, colloid) and the volume, drome, which is caused by compression of the aorta and
rate, and timing of administration are relevant factors in inferior vena cava by the gravid uterus, can manifest as
the prevention and treatment of hypotension.92,93 In most pallor, tachycardia, sweating, nausea, hypotension, and
situations, a balanced salt solution such as lactated Ring- dizziness.101,102 Uteroplacental blood flow is compro-
er’s solution is acceptable. Blood products are most often mised by decreased venous return and cardiac output,
administered with normal saline. Crystalloid or colloid increased uterine venous pressure, and compression of
solutions that contain calcium or glucose should not be the aorta or common iliac arteries.103
administered with blood products, owing to the risks for The full lateral position minimizes aortocaval com-
clotting (due to reversal of the citrate anticoagulant) and pression but does not allow performance of cesarean
clumping of red blood cells, respectively. delivery. In an editorial, Kinsella104 concluded that
Traditionally, approximately 1 L of crystalloid 15 degrees of left lateral tilt (left uterine displace-
solution has been administered intravenously (as “prehy- ment) significantly reduces the adverse hemodynamic
dration” or “preload”) to prevent or reduce the incidence consequences of the supine position, although both the
and severity of hypotension during neuraxial anesthesia aorta and inferior vena cava may remain partially com-
for cesarean delivery. However, prehydration, even with pressed. However, most anesthesia providers underesti-
large volumes (30 mL/kg), is minimally effective in pre- mate the degree of lateral tilt. In a systematic review,
venting neuraxial anesthesia–induced hypotension. Cluver et. al.105 observed no differences in maternal and
Although an initial study found that administering early neonatal outcomes among various maternal
556 PART VII Cesarean Delivery
positions for cesarean delivery, but acknowledged that the recumbent to the sitting position. In contrast, Andrews
small sample size in their study was a serious shortcoming et al.120 observed a greater decrease in cardiac output in
that limited the applicability of their observations. They parturients placed in the left lateral position than in those
also acknowledged that the effect of maternal position in the sitting position during initiation of epidural anal-
may vary with different clinical situations and that aorto- gesia. Using substernal Doppler ultrasonography, Arm-
caval compression may be more problematic in women strong et al.121 observed that maternal cardiac index,
with multiple gestation, fetal macrosomia, or polyhy- stroke volume index, heart rate, and systolic blood pres-
dramnios.105 Anesthesia providers should recognize that sure were higher by approximately 8% in the right or left
(1) individual susceptibility to aortocaval compression lateral positions than in the sitting or supine positions;
varies,106 (2) visual estimates of lateral tilt may be in however, there were no significant differences among
error,107 and (3) in symptomatic women, increasing the positions in fetal heart rate, pulsatility index, or resistivity
extent of left uterine displacement may be beneficial. index.
Lateral tilt should be used in all women in mid to late Some parturients find the lateral position more com-
pregnancy after the administration of neuraxial or general fortable during administration of neuraxial anesthesia122;
anesthesia, with greater tilt used when feasible if aorto- this position may also limit side-to-side and front-to-back
caval compression is suspected as the cause for maternal patient motion during needle insertion. Moreover,
or fetal compromise.108 because uterine compression of the vena cava diverts
The use of a slight (10 degrees) head-up position may blood into the epidural venous plexus,123 the use of the
help reduce the incidence of hypotension after initiation lateral position can reduce hydrostatic pressure and
of hyperbaric spinal anesthesia.109 The use of a more return the engorged epidural venous plexus to its size in
significant head-up position (30 degrees) has been the nonpregnant state.124 Bahar et al.125,126 observed that
observed to significantly increase functional residual fewer needle/catheter replacements occurred for needle-
capacity in parturients compared with the supine posi- or catheter-induced venous trauma when epidural proce-
tion, with the effect diminishing with increasing BMI.110 dures were performed in the lateral recumbent head-down
In morbidly obese patients receiving general anesthesia, position than in either the sitting or the lateral recumbent
the 30-degree head-up position may be particularly useful horizontal position in both obese and nonobese
to improve preoxygenation, denitrogenation, and the parturients.
view of the glottis during direct laryngoscopy111; this can The lateral position may also be of value during epi-
be accomplished with blankets or commercially available dural needle placement because it minimizes the promi-
devices (see Chapters 30 and 50). If blankets are used to nence of the dural sac. On the other hand, a bulging dural
create the ramp position, they should be stacked rather sac might be preferable during administration of spinal
than interlaced, to allow for rapid readjustment of the or CSE anesthesia. Magnetic resonance imaging and
head and neck position if necessary. Ideal positioning computed tomography studies have indicated that the
leads to the horizontal alignment between the external cross-sectional area and the anteroposterior diameter of
auditory meatus and the sternal notch; this position (1) the dural sac at the level of the L3-L4, L4-L5, and L5-S1
aligns the oral, pharyngeal, and tracheal axes (“sniffing interspaces are significantly influenced by posture.127
position”) and (2) facilitates insertion of the laryngoscope Lumbar cerebrospinal fluid (CSF) pressure is lower and
blade (see Chapter 30).112 dural sac cross-sectional area smaller in the recumbent
Theoretically, the Trendelenburg (head-down) position than in the upright position.127 Bulging of the
position may augment venous return and increase cardiac lumbar dural sac—particularly in the sitting position—
output. The value of this approach in preventing hypoten- may decrease the force required to create a dural punc-
sion during neuraxial anesthesia has been questioned.105 ture with a Tuohy epidural needle, but this possibility is
After the initiation of hyperbaric spinal anesthesia, the unproven.
Trendelenburg position has been reported to result in In a randomized controlled trial, Yun et al.128 observed
more cephalad spread of anesthesia in one study113 but that the severity and duration of hypotension were greater
not in others.114,115 However, this position had no effect in women randomly assigned to receive CSE anesthesia
on the incidence of hypotension after administration of (hyperbaric spinal bupivacaine with fentanyl) in the
hyperbaric spinal anesthesia.113,115 sitting position than in those in the lateral position,
The optimal patient position for insertion of a neur- despite no differences in the level of sensory blockade.
axial needle (or catheter) may depend on clinical circum- The sitting position may offer some advantages (e.g.,
stances and the preferences and skills of the anesthesia physical landmark recognition in obese parturients, prac-
provider. Whether the use of the lateral or the sitting titioner preference).117 However, anesthesia providers
position is best for routine initiation of neuraxial should be facile with the placement of needles for neur-
anesthesia is controversial.116,117 Advocates of the lateral axial techniques in both the sitting and lateral positions,
position cite a reduction of vagal reflexes, which can because the sitting position should not be used in some
result in dizziness, diaphoresis, pallor, bradycardia, and situations (e.g., fetal head entrapment, umbilical cord
hypotension.118 Moreover, the lateral position may allow prolapse, footling breech presentation).116
better uteroplacental blood flow than the sitting position.
Using technetium Tc 99m–radiolabeled isotopes in preg-
nant women in the third trimester, Suonio et al.119
Supplemental Oxygen
observed a 23% reduction in uteroplacental blood flow The routine administration of supplemental oxygen
when pregnant patients moved from the left lateral during elective cesarean delivery with neuraxial
26 Anesthesia for Cesarean Delivery 557
anesthesia has been a common practice since publication In summary, no significant improvement in maternal-
of the seminal report by Fox and Houle129; their report fetal oxygen transfer occurs until very high levels of
demonstrated improved oxygenation, better umbilical maternal Fio2 are used. At these levels, the resulting
cord blood acid-base measurements, and less time to sus- hyperoxia creates reactive oxygen species. Preterm fetuses
tained respiration in the neonate, when mothers under- in nonlaboring mothers are the population at highest risk
going cesarean delivery with neuraxial anesthesia breathed for hyperoxia-induced injury. Nonetheless, the emer-
100% oxygen instead of air for at least 10 minutes. gency cesarean delivery of the compromised fetus should
However, later evidence suggested that routine oxygen include maternal administration of a high Fio2. The
administration may be unnecessary and ineffective130 and greater maternal oxygen consumption and reduced fetal
may even be detrimental.131 The use of a fractional oxygen delivery associated with uterine contractions may
inspired concentration of oxygen (Fio2) of 0.35 to 0.4 exacerbate the fetal compromise; in these situations, sup-
(which cannot be obtained by a nasal cannula or a simple plemental oxygen may augment fetal oxygenation and,
face mask with a flow rate less than 6 L/min132) does not perhaps, reduce the severity of fetal hypoxia. However,
improve fetal oxygenation during labor or elective cesar- diminishing fetal benefit appears to occur after 10
ean delivery. Although respiratory function can deterio- minutes.
rate in parturients receiving neuraxial anesthesia,133,134 All women who are at risk for requiring general anes-
maternal or fetal hypoxemia does not normally occur thesia for emergency cesarean delivery should receive an
when parturients breathe room air.134 An Fio2 of 0.6 in Fio2 of 1.0 after transfer to the operating table. Denitro-
nonlaboring women undergoing elective cesarean deliv- genation should always be performed; if it is not per-
ery with spinal anesthesia increases the umbilical venous formed, the mother is at risk for hypoxemia during apnea
oxygen content by only 12%; an increase in oxygen before intubation, in turn putting the fetus at risk. When
content is not observed when the uterine incision-to- general anesthesia is administered in a patient with fetal
delivery (U-D) interval exceeds 180 seconds.135 compromise, the mother should receive an Fio2 of 1.0
Supplemental oxygen has both beneficial and detri- before and immediately after induction of anesthesia,
mental effects. Through normal biologic processes, even though the subsequent increases in umbilical venous
oxygen is converted to reactive oxygen species, including and arterial oxygen content are not dramatic.
free radicals. The reactive oxygen species cause lipid per- The value of supplemental maternal oxygen during
oxidation, alteration of cellular enzymatic functions, and elective cesarean delivery of a noncompromised fetus is
destruction of genetic material136; these adverse effects questionable. The only reason some obstetric anesthesia
occur with the restoration of perfusion after a period of providers place nasal cannulae in patients undergoing
ischemia (i.e., ischemia-reperfusion injury), including elective cesarean delivery with neuraxial anesthesia is to
intermittent umbilical cord occlusion and perhaps during facilitate the monitoring of expired carbon dioxide (to
uterine contractions.137 Reactive oxygen species are monitor the parturient’s ventilation).
present during hyperoxia (causing such disorders as neo-
natal retinopathy and bronchopulmonary dysplasia) and
in the setting of prolonged labor, oligohydramnios, inter- ANESTHETIC TECHNIQUE
mittent umbilical cord compression, and/or fetal com-
promise.137,138 Hyperoxia in these settings (i.e., during the Providing anesthesia to the parturient is a dynamic, mul-
period of reperfusion following ischemia) results in a tistep process (Table 26-2). The most appropriate anes-
higher level of lipid peroxidation.131,138 thetic technique for cesarean delivery depends on
Term (but not preterm) fetuses may be able to with- maternal, fetal, and obstetric factors (Table 26-3). The
stand the adverse effects of these reactive oxygen species urgency and anticipated duration of the operation play
through a compensatory increase in antioxidants during an important role in the selection of an anesthetic
labor.139,140 Antioxidants, the defense against reactive technique.
oxygen species, consist of enzymatic inactivators (super- In cases of dire fetal compromise, the anesthesia
oxide dismutase, catalase, peroxidase) and scavengers provider may need to perform a preanesthetic evalua-
(ascorbate, glutathione, transferrin, lactoferrin, cerulo- tion simultaneously with other tasks (i.e., establishing
plasmin). The activity of these compensatory mechanisms intravenous access and placing a blood pressure cuff,
and their relationships to gestational age and labor suggest pulse oximeter probe, and ECG electrodes). Regardless
that the highest risk for ischemia-reperfusion injury occurs of the urgency, the anesthesia provider should not
in preterm fetuses before the onset of labor.131,140 compromise maternal safety by failing to obtain critical
The use of a very high Fio2 improves oxygen delivery information about previous medical and anesthetic
to hypoxic fetuses for a limited period (approximately history, allergies, and the airway. Effective communica-
10 minutes); beyond this time, continued hyperoxia, tion with the obstetric team is critical to establish the
especially in the setting of restored perfusion, increases degree of urgency, which helps guide decisions regard-
reactive oxygen species, placental vasoconstriction, and ing anesthetic management. Further, contemporary
fetal acidosis.141,142 A lower Fio2 may be of benefit in some standards for patient safety require that all members of
situations. When asphyxiated infants are immediately the surgical team participate in a pre–cesarean delivery
resuscitated at birth with air instead of 100% oxygen, “time-out” to verify (1) the correct patient identity,
better short-term outcomes have been observed143,144; this position, and operative site; (2) agreement on the pro-
finding may be a result of the shift in the balance between cedure to be performed; and (3) the availability of
beneficial oxygenation and detrimental free radicals. special equipment, if needed.
558 PART VII Cesarean Delivery
*Procedures, techniques, and drugs may need to be modified for individual patients and circumstances.
†Evidence now suggests that administration of prophylactic antibiotics before incision (rather than after cord clamping) reduces the
incidence of postcesarean endometritis and total maternal infectious morbidity.78
26 Anesthesia for Cesarean Delivery 559
*Many indications for or contraindications to specific anesthesia techniques are relative, and the choice of anesthetic must be tailored to
individual circumstances.
In cases of emergency cesarean delivery, the emotional especially spinal anesthesia, for both elective and emer-
needs of the infant’s mother and father are also impor- gency cesarean deliveries (Figure 26-3).20 Neuraxial anes-
tant. Parental distress commonly occurs in this setting, thesia has been used for more than 80% of cesarean
and the anesthesia provider is often the best person to deliveries since 1992. Similar increases have occurred in
give reassurance. All members of the obstetric care team the United Kingdom and in other developed as well as
should remember that chaos does not need to accompany developing countries.145,146
urgency. The greater use of neuraxial anesthesia for cesarean
delivery has been attributed to several factors, including
(1) the growing use of epidural techniques for labor anal-
Neuraxial versus General Anesthesia gesia, (2) an awareness of the possibility that an in situ
Overall, neuraxial (epidural, spinal, CSE) techniques are epidural catheter (even if not used during labor) may
the preferred method of providing anesthesia for cesar- decrease the necessity for general anesthesia in an urgent
ean delivery; specific benefits and risks of each technique situation, (3) improvement in the quality of neuraxial
dictate the eventual choice. In contemporary practice, anesthesia with the addition of an opioid to the local
neuraxial anesthesia is administered to some patients who anesthetic, (4) appreciation of the risks of airway compli-
would have received general anesthesia in the past. cations during general anesthesia in parturients, (5) the
Umbilical cord prolapse, placenta previa, and severe desire for limited neonatal drug transfer, and (6) the
preeclampsia are no longer considered absolute indica- ability of the mother to remain awake to experience
tions for general anesthesia. For example, in some cases childbirth and to have a support person present in the
a prolapsed umbilical cord can be decompressed, and if operating room. Spinal anesthesia is considered an appro-
fetal status is reassuring, a neuraxial technique can be priate technique even in the most urgent settings; in a
used. In an analysis of obstetric anesthesia trends in the tertiary care institution with an average of 9500 cesarean
United States between 1981 and 2001, a progressive deliveries annually, neuraxial anesthesia was used in more
increase was noted in the use of neuraxial anesthesia, than 99% of cesarean deliveries over a 6-year period.147
560 PART VII Cesarean Delivery
70
and neonatal outcomes with the use of neuraxial anesthe-
General sia and general anesthesia for cesarean delivery, Afolabi
60 Epidural et al.152 found less maternal blood loss and shivering
50
Spinal but more nausea in the neuraxial anesthesia group. The
CSE
intraoperative “perception” of pain was greater in the
40 neuraxial group, but the time elapsed before the first
Percent
TABLE 26-4 Advantages and Disadvantages of Neuraxial Anesthetic Techniques for Cesarean
Delivery
Neuraxial Technique Advantages Disadvantages
Epidural No dural puncture required Slow onset of anesthesia
Can use in situ catheter placed for earlier Larger drug doses required than for spinal
administration of labor analgesia techniques:
Ability to titrate extent of sensory blockade • Greater risk for maternal systemic toxicity
Continuous intraoperative anesthesia • Greater fetal drug exposure
Continuous postoperative analgesia
Combined spinal-epidural May be technically easier than spinal Delayed verification of functioning epidural
anesthesia in obese patients catheter
Low doses of local anesthetic and opioid
Rapid onset of dense lumbosacral and
thoracic anesthesia
Ability to titrate extent of sensory blockade
Continuous intraoperative anesthesia
Continuous postoperative analgesia
Continuous spinal Low doses of local anesthetic and opioid Large dural puncture increases risk for
Rapid onset of dense anesthesia post–dural puncture headache
Ability to titrate extent of sensory blockade Possibility of overdose and total spinal
Continuous intraoperative anesthesia anesthesia if the spinal catheter is mistaken
for an epidural catheter
Single-shot spinal Technically simple Limited duration of anesthesia
Low doses of local anesthetic and opioid Limited ability to titrate extent of sensory
Rapid onset of dense lumbosacral and blockade
thoracic anesthesia
more cephalad than that identified by light touch. A sub- technique, resulting in a reduced need for supplemental
sequent study of spinal anesthesia in parturients undergo- intravenous analgesics or conversion to general anesthe-
ing cesarean delivery indicated that although sensory sia.159,160 Only a small amount of local anesthetic is needed
blockade to light touch differed from sensory blockade to establish functional spinal blockade; therefore, spinal
to pinprick or cold sensation by 0 to 11 spinal segments, anesthesia is associated with negligible maternal risk for
no constant relationship among these levels could be systemic local anesthetic toxicity and with minimal drug
determined.156 The investigators concluded that a T6 transfer to the fetus.161,162 Given these advantages, spinal
blockade to touch would likely provide a pain-free cesar- anesthesia is now the most commonly used anesthetic
ean delivery for most women. technique for cesarean delivery in the developed
In a survey performed in the United Kingdom, the world.20,145 Spinal anesthesia is also associated with pre-
majority of anesthesiologists used the absence of cold dictable and relatively prompt recovery that enables
temperature sensation to a T4 level to indicate adequate patients to quickly transition through the postanesthesia
cephalad extent of sensory blockade for cesarean deliv- care unit (PACU); in some settings, such a recovery may
ery.157 Sensory examination should move caudad to ceph- result in a cost savings to the institution.159
alad in the midaxillary line on the lower extremities but Spinal anesthesia is usually administered as a single-
can be performed in the midclavicular line on the torso. injection procedure (“single-shot” technique) through a
The time at which an adequate block is achieved, as well non-cutting, pencil-point needle that is 24-gauge or
as the cephalad level of the block and the presence of smaller. A number of different needle designs are avail-
surgical anesthesia of the lower abdomen, should be doc- able (see Chapter 12)163; the size and design of the needle
umented on the anesthetic record. tip affect the incidence and severity of post–dural punc-
Because the undersurface of the diaphragm (C3 to C5) ture headache (see Chapter 31).
and the vagus nerve may be stimulated by surgical manip- The spinal technique should be performed at the
ulation during cesarean delivery,158 maternal discomfort L3-L4 interspace or below (see Chapter 12). This space
(including shoulder pain) and other symptoms (e.g., is used to avoid the potential for spinal cord trauma;
nausea and vomiting) may occur despite a T4 level of although the spinal cord ends at L1 in most adults, it
blockade. Neuraxial or systemic opioids help prevent or extends to the L2-L3 interspace in a small minority
alleviate these symptoms (see later discussion). (see Chapter 32). Additionally, anesthesia providers often
misidentify the location of the needle insertion site on
the spinal column, and the needle is more frequently
Spinal Anesthesia introduced at a higher level than intended.
Spinal anesthesia is a simple and reliable technique that On occasion, a continuous spinal anesthetic technique
allows visual confirmation of correct needle placement is used, particularly in the setting of an unintentional
(by visualization of CSF) and is technically easier to dural puncture with an epidural needle. Intentional con-
perform than an epidural technique. Spinal anesthesia tinuous spinal anesthesia may be desirable in certain set-
provides rapid onset of dense neuroblockade that is typi- tings, when the reliability of a spinal technique and the
cally more profound than that provided with an epidural ability to precisely titrate the initiation and duration of
562 PART VII Cesarean Delivery
anesthesia are strongly desired (e.g., a morbidly obese nerve fibers to the local anesthetic during pregnancy.164
patient with a difficult airway). Although microcatheters Overall, the mass of local anesthetic, rather than the
(27- to 32-gauge) were used to provide spinal analgesia concentration or volume, is thought to influence the
and anesthesia in the 1980s, the U.S. Food and Drug spread of the resulting blockade165; however, the specific
Administration (FDA) removed these catheters from the influence of the dose/concentration and baricity on
market because of concerns about cauda equina syn- the efficacy of the block is controversial. The necessary
drome; the catheters are still being used in Europe, par- dose may be influenced by other factors, such as
ticularly in Germany. Currently the administration of co-administration of neuraxial opioids and surgical tech-
continuous spinal anesthesia in the United States requires nique. (Exteriorization of the uterus during closure of the
the use of a 17- or 18-gauge epidural needle and a 19- or uterus is more stimulating than closure in situ.) Carvalho
20-gauge catheter; this technique is associated with a et al.166 demonstrated that the effective dose for 95% of
high incidence of post–dural puncture headache. recipients (ED95) for plain bupivacaine with fentanyl
10 µg* and morphine 0.2 mg in women undergoing
cesarean delivery (n = 48) was 13 mg; the effective dose
Local Anesthetic Agents
for 50% of recipients (ED50) was 7.25 mg. By contrast,
The choice of local anesthetic agent (and adjuvants) used Sarvela et al.167 demonstrated that spinal hyperbaric or
to provide spinal anesthesia depends on the expected plain bupivacaine 9 mg with fentanyl 20 µg provided sat-
duration of the surgery, the postoperative analgesia plan, isfactory anesthesia for all but one of 76 subjects. Anes-
and the preferences of the anesthesia provider. For cesar- thesia characteristics and hemodynamic changes were
ean delivery, the local anesthetic agent of choice is typi- similar in the hyperbaric and plain bupivacaine groups;
cally bupivacaine (Table 26-5). In the United States, more than 50% of patients in both groups required vaso-
spinal bupivacaine is formulated as a 0.75% solution in pressor support.
dextrose 8.25%. Intrathecal administration of bupiva- Vercauteren et al.168 demonstrated that hyperbaric
caine results in a dense block of long duration. bupivacaine 6.6 mg with sufentanil 3.3 µg provided
The dose of intrathecal bupivacaine that has been suc- better anesthesia and less hypotension than the same dose
cessfully used for cesarean delivery ranges from 4.5 to of plain bupivacaine. Ben-David et al.169 reported that
15 mg. In general, pregnant patients require smaller reducing the dose of plain bupivacaine from 10 to 5 mg
doses of spinal local anesthetic than nonpregnant patients. decreased the incidence of hypotension and nausea;
Reasons include (1) a smaller CSF volume in pregnancy, however, these findings were obscured by the variable use
(2) cephalad movement of hyperbaric local anesthetic in of opioids in the low-dose group. Finally, Bryson et al.170
the supine pregnant patient, and (3) greater sensitivity of compared plain bupivacaine 4.5 mg with hyperbaric
bupivacaine 12 mg (both with fentanyl 50 µg and mor-
phine 0.2 mg); they observed similar cephalad sensory
levels (C8), incidence of hypotension (approximately
TABLE 26-5 Drugs Used for Spinal Anesthesia 75%), side effects, and rates of patient satisfaction with
for Cesarean Delivery the two approaches. Five of 27 (19%) patients in the
bupivacaine 4.5-mg group and 1 of 25 (4%) patients in
Drug Dose Range Duration (min)* the bupivacaine 12-mg group required supplemental
Local Anesthetics
analgesia; no conversions to general anesthesia occurred.
Lidocaine 60-80 mg 45-75
Altogether, these data indicate that lower anesthetic
Bupivacaine 7.5-15 mg 60-120
doses can be used; whether they should be used is contro-
Levobupivacaine 7.5-15 mg 60-120
versial. The anesthesia provider should consider whether
Ropivacaine 15-25 mg 60-120
adjuvant drugs will be used and whether the risks of
giving supplemental analgesia or conversion to general
Opioids anesthesia that are associated with low doses of bupiva-
Fentanyl 10-25 µg 180-240 caine outweigh the potential benefits (i.e., less hypoten-
Sufentanil 2.5-5 µg 180-240 sion, faster recovery).
Morphine 100-200 µg 720-1440
(0.1-0.2 mg)
Meperidine† 60-70 mg 60
*The Institute of Safe Medicine Practices (ISMP) has recommended
Adjuvant Drugs that health care providers never use µg as an abbreviation for micro-
Epinephrine‡ 100-200 µg grams, but rather they should use mcg (http://www.ismp.org/tools/
(0.1-0.2 mg) errorproneabbreviations.pdf, Accessed February 2013). The use of
the symbol µg is frequently misinterpreted and involved in harmful
*For the local anesthetics, the duration is defined as the time to medication errors. The abbreviation may be mistaken for mg (mil-
two-segment regression. For the opioids, the duration is defined ligrams), which would result in a 1000-fold overdose. The symbol µg
as the period of analgesia (or time to first request for a should never be used when communicating medical information,
supplemental analgesic drug). including pharmacy and prescriber computer order entry screens,
†Meperidine has both local anesthetic and opioid properties and computer-generated labels, labels for drug storage bins, and medica-
can provide surgical anesthesia without the addition of a local tion administration records. However, most scholarly publications
anesthetic. The dose indicated represents meperidine used have continued to use the abbreviation µg. The editors have chosen
without a local anesthetic. to retain the use of the abbreviation µg throughout this text. However,
‡The addition of epinephrine may augment the duration of local the editors recommend the use of the abbreviation mcg in clinical
anesthetics by 15 to 20 minutes. practice.
26 Anesthesia for Cesarean Delivery 563
The intrathecal administration of an alpha-adrenergic overall use of epidural anesthesia is becoming less
agonist (e.g., epinephrine, clonidine) increases the density common for elective cesarean delivery when an epidural
of sensory and motor blockade and may prolong the catheter is not already in situ (e.g., for labor analgesia or
duration of blockade as well as contribute to postcesarean as a potential mode of anesthesia in a laboring individual
analgesia. Abouleish197 observed that intrathecal epi- at high risk for urgent cesarean delivery) (see Figure
nephrine 0.1 to 0.2 mg, when combined with hyperbaric 26-3), in part because the resulting block is less reliable
bupivacaine, improved the quality of intraoperative anal- than that with spinal anesthesia. Initiation of CSE anes-
gesia and prolonged both sensory and motor blockade by thesia offers both rapid onset and reliable spinal anesthe-
approximately 15% in comparison with bupivacaine sia coupled with the ability to augment or prolong the
alone. However, Randalls et al.198 observed that the addi- blockade through the epidural catheter. The dural punc-
tion of epinephrine 0.3 mg to hyperbaric bupivacaine ture performed as part of CSE anesthesia may enhance
12.5 mg for elective cesarean delivery increased the inci- movement of drugs injected into the epidural space across
dence of nausea. the dura-arachnoid into the subarachnoid space.203 Epi-
Spinal clonidine, in doses of 60 to 150 µg, improves dural local anesthetic and opioid doses are generally 5 to
intraoperative analgesia, decreases shivering, and reduces 10 times greater than doses given intrathecally; this dif-
peri-incisional hyperalgesia in women undergoing cesar- ference results from the requirement for penetration of
ean delivery; however, it has been associated with hypo- nerve roots as they traverse the epidural space, the greater
tension and sedation.199 This agent is not used commonly capacity of the epidural space, and the presence of the
in the United States, although it may be considered in epidural venous plexus, which becomes progressively
specific circumstances (e.g., when neuraxial opioid anal- more engorged during pregnancy. Greater systemic
gesia is contraindicated). The FDA has issued a “black absorption of anesthetic agents occurs with epidural
box” warning against its use in obstetric patients because anesthesia than with spinal anesthesia, and the risk for
of concerns about hemodynamic instability. local anesthetic toxicity is a real possibility with local
In women undergoing cesarean delivery, spinal neo- anesthetic injection for epidural anesthesia, but not for
stigmine in doses up to 100 µg significantly reduced spinal anesthesia.
postoperative pain with no effect on FHR or Apgar Possible advantages of the epidural technique include
scores; however, 100% of patients who received 100 µg a slower onset of sympathetic blockade; this may allow
complained of nausea.200 Chung et al.201 observed that compensatory mechanisms to attenuate the severity of
74% of parturients undergoing cesarean delivery with hypotension. A catheter-based technique also allows
spinal neostigmine 25 µg with hyperbaric bupivacaine titration of the level, density, and duration of anesthesia.
12 mg had significant nausea and vomiting, which per- Continuous postcesarean analgesia can be provided
sisted for greater than 1 hour despite multiple antiemetic through an epidural catheter.
agents. In a dose-response investigation in nonpregnant
healthy volunteers, spinal doses of neostigmine as low as Local Anesthetic Agents
6.25 µg were associated with a high incidence of side
effects, including prolonged motor blockade, nausea, and The most common local anesthetic used for the initiation
vomiting.202 Collectively, these studies suggest that the and maintenance of epidural anesthesia for cesarean
high incidence of nausea associated with intrathecal neo- delivery is 2% lidocaine with epinephrine (see Table
stigmine limits its clinical use. 26-6). The epidural administration of lidocaine in con-
At many institutions, the spinal agents and doses are centrations less than 2%, or without the addition of
standardized so that consistent results are obtained during epinephrine (which augments the analgesia through
the provision of spinal anesthesia for cesarean delivery. alpha-adrenergic receptor blockade204), may result in
Such standardization enables the anesthesia, obstetric, anesthesia that is inadequate for surgery.205 Hillyard
and nursing staff to anticipate predictable onset and et al.206 observed a significantly lower incidence of intra-
recovery characteristics and respond to physiologic operative block supplementation with 2% lidocaine with
responses that are outside the norm. Standardization of epinephrine 1 : 200,000 or 0.75% ropivacaine compared
drugs and doses may also result in fewer errors. At our with 0.5% bupivacaine or 0.5% levobupivacaine.
institution, spinal anesthesia for cesarean delivery is pro- A 3% solution of 2-chloroprocaine has the most
vided with 0.75% hyperbaric bupivacaine 12 mg, fen- rapid onset and the shortest duration of action of avail-
tanyl 10 µg, and morphine 0.2 mg. Administration of able local anesthetics given epidurally. These character-
these doses of fentanyl and morphine allows administra- istics make it an excellent choice for emergency cesarean
tion of the same volume (0.2 mL) of fentanyl 50 µg/mL delivery (see later discussion) because the dose is admin-
and morphine 1 mg/mL, thereby helping to prevent istered rapidly, and even if unintentional intravenous
dosing errors. The use of a tuberculin or insulin syringe administration of drug were to occur, the sequelae would
to prepare the opioids further improves measurement likely be less severe than the similar administration of an
accuracy. amide local anesthetic agent. Administration of 2-
chloroprocaine has been associated with neurologic
sequelae, possibly associated with the antioxidant sodium
Epidural Anesthesia bisulfite, and paralumbar muscle spasms and pain, believed
The use of epidural anesthesia for nonelective cesarean to be a result of calcium chelation by the preservative
delivery has increased, primarily as a result of the greater EDTA. Current preparations of 2-chloroprocaine do not
use of epidural analgesia during labor. However, the contain either an antioxidant or a preservative (see
566 PART VII Cesarean Delivery
provides better postoperative analgesia than epidural prior to administration results in a solution that has a
morphine 4 mg, with no differences in nausea, pruritus, higher pH than commercially prepared epinephrine-
or sedation scores.223 containing products, which use (low-pH) antioxidants to
Epidural diamorphine (2.5 to 3 mg) is commonly preserve the efficacy of the epinephrine (see Chapter 13).
used in the United Kingdom for providing prolonged Thus, use of freshly prepared solutions hastens the onset
postcesarean analgesia.224 Optimal dose-finding studies of of anesthesia.
epidural diamorphine have not been performed; however, The addition of sodium bicarbonate results in a solu-
Bloor et al.225 observed that duration and quality of anal- tion with more local anesthetic molecules in a non-
gesia from epidural diamorphine 3 mg was similar to that ionized state, which hastens the onset and augments the
provided by spinal diamorphine 0.3 mg, with signifi- quality of the local anesthetic blockade, particularly if
cantly less pruritus. sodium bicarbonate is added to a low-pH solution (see
Epidural clonidine (75 to 200 µg) combined with later discussion).
morphine or fentanyl reduces the requirement for post-
cesarean morphine analgesia.226 Eisenach et al.226 demon-
strated an additive rather than synergistic effect of
epidural clonidine and fentanyl in producing postcesar-
Combined Spinal-Epidural Anesthesia
ean analgesia. Common side effects include hypotension The CSE technique incorporates the rapid and predict-
and sedation. Currently, epidural clonidine has only one able onset of spinal blockade with the ability to augment
specific neuraxial indication in the United States (intrac- anesthesia by injection of additional drug through the
table cancer pain), and the package insert has a “black epidural catheter.236,237 In 1981, Brownridge236 reported
box” FDA warning stating that “epidural clonidine is not the first use of the CSE technique for cesarean delivery
recommended for obstetrical, postpartum and periopera- through separate spinal and epidural needles introduced
tive pain management.” at different interspaces. Carrie and O’Sullivan237 subse-
Epidural neostigmine produces a modest amount of quently described the needle-through-needle technique
postcesarean analgesia when given after umbilical cord via a single interspace for cesarean delivery; this has
clamping. Kaya et al.227 investigated the administration of become the more popular technique. Compared with a
75, 150, or 300 µg of epidural neostigmine in women conventional epidural anesthetic technique for cesarean
undergoing elective cesarean delivery. An increase in delivery, Davies et al.238 reported that the CSE technique
intraoperative shivering and sedation was observed in the resulted in a faster onset, greater motor blockade, and
300-µg group only; a dose-independent reduction in lower pain scores at delivery; moreover, no differences
postoperative pain and sedation was observed in all were observed in the incidence of maternal hypotension,
groups. nausea, or headache, the use of supplemental analgesics,
Epinephrine is frequently added to the local anes- or overall patient satisfaction.
thetic agent to minimize systemic absorption and peak Additional advantages of the CSE technique include
blood level of local anesthetic, increase the density of (1) use of the epidural needle as an introducer for a longer
sensory and motor blockade, and prolong the duration of spinal needle when attempts with a traditional introducer
anesthesia.204,228,229 Bernards et al.230 observed that the and spinal needle have failed and (2) use of a spinal needle
pharmacokinetic effects of epinephrine co-administered (and return of CSF through the needle) to “confirm” the
with an opioid vary with the opioid and the sampling site. correct positioning of the epidural needle in the epidural
In the lumbar epidural space, epinephrine lengthened the space. The CSE technique also allows use of a low dose
mean residence time of morphine but shortened that of of local anesthetic to initiate spinal anesthesia (associated
fentanyl and sufentanil. with a lower incidence of hypotension), followed by use
The epidural administration of epinephrine in pre- of the epidural catheter to extend intraoperative anesthe-
eclamptic women is controversial (see Chapter 36).231 sia or provide postoperative analgesia.
Animal and clinical studies suggest that epidural epineph- Conventional spinal doses (e.g., 12 mg) of hyperbaric
rine 0.1 mg does not decrease uterine blood flow.232,233 bupivacaine are most often used to provide CSE anesthe-
Alahuhta et al.234 used maternal Doppler ultrasonogra- sia for cesarean delivery; however, a satisfactory block has
phy and fetal M-mode echocardiography to evaluate the been reported with plain bupivacaine drug doses as low
hemodynamic effects of the addition of epidural epineph- as 4.5 mg.170 Although the use of lower amounts of local
rine 5 µg/mL (1 : 200,000) to 0.5% bupivacaine for cesar- anesthetic is enabled by the presence of the epidural
ean delivery; maternal diastolic pressure, but not systolic catheter (because additional agents can be administered
pressure or uterine blood flow, was decreased with the if discomfort occurs), the block achieved with the CSE
addition of epinephrine. By contrast, in a similar study in technique may be inherently different from the block
hypertensive women, Alahuhta et al.235 observed that the achieved with a single-shot spinal technique with the
addition of epidural epinephrine 5 µg/mL (1 : 200,000) to same dose(s) of medication. Goy et al.239 positioned men
0.5% bupivacaine significantly reduced uteroplacental undergoing surgery in the right lateral position for
blood flow but did not affect umbilical arterial blood flow initiation of neuraxial anesthesia and demonstrated that
or pH measurements at delivery. the median effective doses of intrathecal hyperbaric bupi-
When combined with local anesthetic for epidural vacaine (to achieve a T6 sensory level of anesthesia for
anesthesia, the usual epinephrine concentration is 2.5 or 60 minutes) for the CSE and spinal techniques were
5 µg/mL (i.e., 1 : 400,000 or 1 : 200,000). The addition of 9.2 mg and 11.4 mg, respectively. The investigators spec-
epinephrine to a solution of plain local anesthetic just ulated that the use of the loss-of-resistance to air (during
568 PART VII Cesarean Delivery
introduction of the epidural needle) resulted in a reduc- Extension of Epidural Labor Analgesia
tion in lumbar CSF volume and a subsequently higher
sensory blockade. Similarly, after initiating neuraxial The extension of epidural labor analgesia to surgical anes-
analgesia with intrathecal bupivacaine 10 mg in parturi- thesia sufficient for cesarean delivery can be accomplished
ents undergoing elective cesarean delivery, Ithnin et al.240 with one of several local anesthetic agents. The selection
observed median sensory levels of C6 and T3 with the of agent often depends on the urgency of the case. Exten-
CSE and spinal techniques, respectively. The CSE tech- sion of epidural analgesia can be initiated as preparations
nique was performed with loss-of-resistance to air (2 mL); are being made to move the patient from the labor room
however, after administration of the spinal medications, to the operating room. Whether an in situ epidural cath-
the epidural catheter was not inserted. The investigators eter should be used for an extension attempt depends on
speculated that the loss of negative pressure in the epi- a number of factors, including the quality of the existing
dural space created by the introduction of the epidural labor analgesia. If obtaining satisfactory epidural labor
needle was responsible for the observed differences. analgesia has been problematic (e.g., one-sided or
However, when investigators from the same institution “patchy” analgesia), replacing the catheter and using a
performed the same anesthetic techniques for cesarean spinal or CSE technique may be a better method to attain
delivery in laboring women, no differences in the block rapid and effective anesthesia. In a systematic review and
characteristics were observed.241 The reasons for these meta-analysis, Bauer et al.246 observed that the incidence
different results are unclear. of failed conversion of labor analgesia to cesarean deliv-
The sequential CSE technique uses a lower dose of ery anesthesia is greater when an increasing number of
spinal bupivacaine (7.5 to 10 mg) followed by incre- epidural boluses have been required to produce sufficient
mental injection of local anesthetic through the epidural labor analgesia, a greater urgency for cesarean delivery
catheter to achieve a T4 level of anesthesia.242,243 The exists, and a nonobstetric anesthesiologist is managing
purported advantage of this approach is a lower incidence the case.
of hypotension. Thoren et al.243 observed a more gradual Specific local anesthetic and adjuvant solutions may
onset of hypotension and a lower initial sensory level influence whether the quality and level of epidural anes-
with the CSE compared with the single-shot spinal thesia is adequate for cesarean delivery. Lucas et al.247
technique (T7 and T4, respectively); however, all par- compared the extension of existing labor epidural anal-
turients in the CSE group required additional doses of gesia among three solutions: 0.5% bupivacaine, 2% lido-
local anesthetic through the epidural catheter. The caine with epinephrine 5 µg/mL (1 : 200,000), and a
sequential CSE technique may be of particular advantage 50 : 50 combination of the two solutions. They observed
in high-risk parturients (e.g., significant cardiac disease) no difference among groups in the time required to
in whom avoidance of severe hypotension can be vitally obtain a bilateral loss to cold sensation at T4. Similarly,
important. although the study was likely underpowered, Bjornestad
Another CSE technique is the extradural volume exten- et al.248 observed no significant difference in onset of
sion (EVE) technique.242,244 Intrathecal administration of anesthesia between epidural administration of 3%
a small dose of local anesthetic is followed by the admin- 2-chloroprocaine and that of 2% lidocaine with freshly
istration of saline through the epidural catheter. In a added epinephrine 5 µg/mL; median onset was 8 minutes
review of this technique, McNaught and Stocks242 (range of 4 to 13 minutes) in the 2-chloroprocaine group
observed a higher cephalad spread of one to four derma- and 5 minutes (range of 2 to 22 minutes) in the lidocaine
tomal segments. However, the effect of EVE may group. However, given the time taken to prepare the
depend on the initial dose and baricity of local anes- lidocaine with epinephrine solution, the investigators
thetic, the time interval between spinal and epidural concluded that use of a pre-prepared solution, such as
injection, the volume of epidural saline, and the out- 2-chloroprocaine, may be preferred. Of interest, 30%
comes measured. Kucukguclu et al.244 found no clinical and 20% of patients in the 2-chloroprocaine and lido-
differences when 10 mL of epidural saline was adminis- caine groups, respectively, required intravenous alfentanil
tered within 5 minutes of intrathecal injection of either for supplementation of anesthesia.
hyperbaric or plain 0.5% bupivacaine 8 to 9 mg with Alkalinization of the local anesthetic solution not only
fentanyl 20 µg. Similarly, Loubert et al.245 found no dif- increases the speed of onset but also improves the quality
ference in sensory or motor blockade when spinal hyper- and prolongs the duration of neuroblockade.249 Alkalini-
baric bupivacaine 7.5 mg was administered with or zation shifts more of the local anesthetic molecules to the
without 5 mL of epidural saline injected immediately non-ionized, lipid-soluble form, which allows the local
after the spinal dose. anesthetic to pass more easily through the lipid neuronal
Potential drawbacks of CSE techniques include an membrane surrounding the sodium channel. Although
untested epidural catheter and hypotension. Yun et al.128 this phenomenon can be demonstrated for all local anes-
reported greater severity and duration of hypotension thetics, alkalinization is most often performed with local
when the CSE technique was administered in the sitting anesthetic agents of short and medium duration (e.g.,
position than in the lateral decubitus position. The hypo- 2-chloroprocaine, lidocaine). Typically, 1 mL of 8.4%
tension may be related to the delay in moving the patient sodium bicarbonate (1 mEq/mL) is added to 10 mL of
from the sitting to the supine (with leftward tilt) position. lidocaine or 2-chloroprocaine. Longer-acting agents
Alternatively, greater hypotension may result from a (e.g., bupivacaine, ropivacaine, levobupivacaine) easily
higher level of sympathetic blockade with the CSE precipitate with the addition of sodium bicarbonate. Pre-
technique. cipitation occurs with the addition of less than 0.2 mEq
26 Anesthesia for Cesarean Delivery 569
of bicarbonate to 20 mL of 0.5% bupivacaine.250 Alkalini- emergency cesarean delivery, we often initiate the exten-
zation exerts the greatest effect when it is freshly mixed sion of epidural anesthesia in the labor room by giving
with the local anesthetic solution; however, the mixture 5 to 10 mL of alkalinized 2% lidocaine (with epineph-
is relatively stable. Tuleu et al.251 evaluated the stability rine) or 3% 2-chloroprocaine. The sensory blockade is
of pH-adjusted lidocaine with epinephrine, prepared assessed after transfer of the patient to the operating
with 2 mEq of sodium bicarbonate added to 20 mL of room; if the blockade is bilateral and moving in a cepha-
2% lidocaine and epinephrine 0.1 mg. Although the local lad direction, an additional 5 to 10 mL is administered
anesthetic activity was unchanged, the epinephrine to bring the sensory level to T4. The use of this frac-
showed evidence of partial degradation at 6 hours. tionated dosing schedule offers several advantages,
Lam et al.249 evaluated the extension of a T10 level of including (1) greater hemodynamic stability during
epidural labor analgesia with the addition of 1.2 mL patient transfer; (2) assessment of the evolving sensory
of 8.4% sodium bicarbonate (or saline) to 12 mL of level before administration of the full dose of local anes-
premixed 2% lidocaine with epinephrine 5 µg/mL thetic; (3) minimization of dural sac compression (by a
(1 : 200,000) and fentanyl 75 µg (Figure 26-6). The mean large volume epidural injection),254 which enables a less
times to attain a T6 anesthesia level with and without difficult and safer conversion to spinal anesthesia if exten-
bicarbonate were 5.2 minutes and 9.7 minutes, respec- sion of epidural anesthesia is not successful (see later
tively. Gaiser et al.252 evaluated the addition of 2 mL of discussion); and (4) early sensory blockade at the incision
8.4% sodium bicarbonate to 23 mL of either 1.5% lido- site, so that surgery can be initiated in emergency cases
caine with epinephrine 5 µg/mL (1 : 200,000) or 3% before establishment of a full T4 sensory level. The
2-chloroprocaine; the mean onset time to extend the T10 extension of epidural analgesia to epidural anesthesia in
analgesia level to a surgical level of anesthesia was 4.4 the labor room is controversial.255 Some anesthesia pro-
minutes for lidocaine and 3.1 minutes for 2-chloroprocaine. viders delay epidural administration of additional local
Malhotra and Yentis253 evaluated the use of 20 mL of anesthetic until the patient has arrived in the operating
0.5% levobupivacaine, with and without fentanyl 75 µg, room. However, this practice may increase the risk for
to extend a T9 labor analgesia level to a T4 sensory level. failed epidural anesthesia, necessitating the induction of
The onset time did not differ between groups, averaging general anesthesia with its attendant risks (see later
10 to 11 minutes. discussion).
Extension of a T10 level of analgesia to a T4 level of
anesthesia typically requires a volume of 15 to 20 mL of
local anesthetic with one or more adjuvants. At our
General Anesthesia
institution the extension of epidural labor analgesia Although neuraxial techniques are typically preferred
begins with assessment of the quality of analgesia. For when anesthesia is provided for cesarean delivery, there
are some clinical situations in which the administration
of general anesthesia is considered the most appropriate
option (see Table 26-3). In addition, general anesthesia
10 † offers an advantage in cases in which uterine relaxation
would be beneficial (e.g., cesarean delivery as part of an
8 ex utero intrapartum treatment [EXIT] procedure).
The basic elements for preparation and care of the
obstetric patient undergoing cesarean delivery also apply
Minutes
6
†
* to the patient undergoing general anesthesia (Box 26-8;
4 see Table 26-2). The preanesthetic evaluation should
*
focus on assessment of physical characteristics (e.g.,
2 airway) and comorbidities. The consent process should
feature the risks associated with airway management,
0 aspiration, and awareness. The importance of a careful
3% Chloro 1.5% Lido 2% Lido 2% Lido
+ Bicarb + Bicarb + Bicarb + Epi airway evaluation cannot be overemphasized (see Chapter
+ Epi 30); pregnancy-induced changes in the upper airway may
be exacerbated during labor. Kodali et al.256 used acoustic
FIGURE 26-6 ■ Onset time for extension of existing labor analge- reflectometry to show that soft tissue mucosal edema in
sia blockade (T10 sensory level) with different local anesthetic
preparations. Results between the two studies cannot be directly both the oral (incisor teeth to oropharyngeal junction)
compared owing to differences in labor analgesia regimens, and pharyngeal (oropharyngeal junction to the glottis)
different sensory testing methods and target levels, and pres- tissue increases during labor; these changes occurred over
ence of epidural opioids. The 2% lidocaine with epinephrine an average labor duration of 11 hours, of which 75
solution was premixed. The epinephrine concentration was
5 µg/mL. Chloro, 2-chloroprocaine; Bicarb, bicarbonate; Lido,
minutes was in the second stage, and resulted in worsen-
lidocaine; Epi, epinephrine 5 µg/mL. *To T4 sensory level. (Data ing of the airway classification compared with the
modified from Gaiser RR, Cheek TG, Gutsche BB. Epidural lidocaine prelabor evaluation. Failed intubation, failed ventilation
versus 2-chloroprocaine for fetal distress requiring urgent cesarean and oxygenation, and pulmonary aspiration of gastric
section. Int J Obstet Anesth 1994; 3:208-10.) †To T6 sensory level. contents remain leading anesthesia-related causes of
(Data modified from Lam DT, Ngan Kee WD, Khaw KS. Extension
of epidural blockade in labour for emergency Caesarean section maternal death.150 If the airway evaluation suggests the
using 2% lidocaine with epinephrine and fentanyl, with or without possibility of a difficult intubation, consideration
alkalinisation. Anaesthesia 2001; 56:790-4.) should be given to the placement of a neuraxial catheter
570 PART VII Cesarean Delivery
BOX 26-8 Steps for Initiating General Anesthesia for Cesarean Delivery*
1. Discuss the operative plan with the multidisciplinary b. Thiopental 4 to 5 mg/kg or propofol 2 to 2.8 mg/kg
team. and succinylcholine 1 to 1.5 mg/kg; wait 30 to 40
2. Perform preanesthetic assessment and obtain informed seconds.§
consent. 14. Perform tracheal intubation. Confirm correct placement
3. Prepare necessary medications and equipment. of endotracheal tube.
4. Place patient supine with left uterine displacement. 15. Provide maintenance of anesthesia:
5. Secure 16- or 18-gauge intravenous access. Send blood a. Use isoflurane, sevoflurane, or desflurane (approxi-
specimen for baseline laboratory measurements; consider mately 1 MAC) in 100% oxygen, or oxygen/nitrous
type and screen (or crossmatch) if risk factors for peripar- oxide (up to 50%).
tum hemorrhage are present. b. Treat hypotension (e.g., phenylephrine, ephedrine).
6. Give metoclopramide 10 mg and/or ranitidine 30 mg c. If additional muscle relaxant (e.g., rocuronium,
intravenously more than 30 minutes before induction, if vecuronium) is necessary, titrate dose according to
possible. response to peripheral nerve stimulator.
7. Give a nonparticulate antacid orally less than 30 minutes 16. Observe delivery of infant.
before induction.† 17. Administer a bolus and/or a continuous infusion of oxy-
8. Administer antibiotic prophylaxis (with 60 minutes prior tocin; consider other uterotonic agents (e.g., methylergo-
to incision).‡ novine, 15-methyl prostaglandin F2α, misoprostol) if
9. Initiate monitoring. uterine tone is inadequate. Monitor blood loss and
10. Perform a team “time-out” to verify patient identity, posi- respond as necessary.
tion, and operative site; procedure to be performed; and 18. Adjust maintenance technique after delivery of the infant:
availability of special equipment, if needed. a. Administer a reduced concentration of a volatile halo-
11. Provide 100% oxygen with a tight-fitting face mask for 3 genated agent (0.5 to 0.75 MAC).
minutes or longer, when possible, for denitrogenation/ b. Supplement anesthesia with nitrous oxide and an intra-
preoxygenation. Otherwise, instruct the patient to take venous opioid.
four to eight vital-capacity breaths immediately before c. Give attention to risk for awareness and recall.
induction of anesthesia. Consider administration of a benzodiazepine (e.g.,
12. After the abdomen has been prepared and operative midazolam).
drapes are in place, verify that the surgeon and assistant 19. Perform extubation when neuromuscular blockade is fully
are ready to begin surgery. reversed and the patient is awake and responds to
13. Initiate rapid-sequence induction: commands.
a. Cricoid pressure 10 N while awake; increase to 30 N 20. Evaluate postoperative issues (e.g., pain, nausea).
after loss of consciousness.
during early labor, even if it is not used to provide labor If the patient has airway characteristics that herald
analgesia.34 difficult mask ventilation or intubation, preparations
should be made to perform an awake tracheal intubation
(see Chapter 30). Preparations include administering an
Preparation
antisialagogue (e.g., glycopyrrolate), judicious sedation
All pregnant patients requiring surgical anesthesia should (e.g., midazolam), and topical airway anesthesia (e.g.,
be considered at risk for pulmonary aspiration of gastric aerosolized lidocaine). Glossopharyngeal and laryngeal
contents (see Chapter 29). Attempts should be made to nerve blocks may also be considered.
minimize both the risk for maternal aspiration and the The patient should be placed supine with left uterine
risk for pulmonary injury if aspiration occurs. Fasting displacement. The head, neck, and shoulders should be
policies should be shared with all members of the obstet- optimally positioned for airway management (i.e., the
ric care team. We administer metoclopramide 10 mg sniffing position) (see Figure 30-8). Routine monitoring
and ranitidine 50 mg intravenously between 30 and 60 should be established, including ECG, pulse oximetry,
minutes before induction of general anesthesia, to dimin- blood pressure, and capnography. Preoxygenation (deni-
ish gastric volume and gastric acid secretion, respec- trogenation) with 100% oxygen should be performed to
tively.73 A clear, nonparticulate antacid (sodium citrate delay the onset of hypoxemia during apnea; this hypox-
30 mL) should also be administered within 30 minutes of emia occurs more rapidly due to the pregnancy-induced
surgery to neutralize gastric acid71; the antacid may be decrease in functional residual capacity and increase in
particularly relevant in the emergent situation when oxygen consumption. In a computer simulation of the
metoclopramide and ranitidine have not had the neces- respiratory and cardiovascular systems during pregnancy,
sary time to exert their pharmacologic effects. McClelland et al.257 noted that the presence of labor,
26 Anesthesia for Cesarean Delivery 571
high BMI, and sepsis further accelerated oxyhemoglobin commonly used to induce general anesthesia for cesarean
desaturation during apnea; by contrast, multiple gesta- delivery. Propofol, in a dose sufficient for induction and
tion and hemorrhage appeared to have minimal effects. to prevent maternal awareness (2.5 mg/kg), depresses the
Ideally, preoxygenation is accomplished by 3 minutes of infant more than thiopental. In the presence of hemody-
tidal-volume breathing with a tight-fitting face mask.258 namic instability, ketamine (1 to 1.5 mg/kg) or etomi-
Although four maximal deep breaths over 30 seconds date (0.3 mg/kg) should be substituted for propofol.
with an Fio2 of 1.0 can achieve a similar Pao2, the same Paralysis is achieved by succinylcholine (1 to 1.5 mg/kg)
protection against rapid oxyhemoglobin desaturation is in 30 to 40 seconds; a peripheral nerve stimulator can be
not afforded, owing to differences in tissue and venous used to confirm neuromuscular blockade, because the
compartment oxygen reserves.257,258 The method of eight presence of fasciculations is an unreliable sign. Adminis-
deep breaths over 1 minute appears to provide better tration of a defasciculating dose of a nondepolarizing
protection from oxyhemoglobin desaturation during muscle relaxant is not recommended, because it may delay
apnea than the four deep breath over 30-second method.259 the onset of neuromuscular blockade with succinylcho-
In contrast to most surgical procedures, the patient’s line. Pregnancy appears to be associated with less severe
abdomen is prepared and draped before induction of succinylcholine-induced fasciculations and muscle pain.262
general anesthesia to minimize fetal exposure to general Rocuronium (1 mg/kg) may provide intubating con-
anesthesia. After the surgical drapes have been applied ditions similar to those provided with succinylcholine
and the operating personnel are ready at the tableside, (1 mg/kg) for cesarean delivery263 and is a viable alterna-
the surgeon should be instructed to delay the incision tive in situations in which succinylcholine should be
until the anesthesia provider confirms correct placement avoided (e.g., malignant hyperthermia, myotonic dystro-
of the endotracheal tube and gives verbal instructions to phy, spastic paraparesis). The use of a priming preinduc-
proceed with surgery. tion dose of a nondepolarizing muscle relaxant is not
recommended during pregnancy, because it may result in
complete paralysis and increase the risk for aspiration.264
Induction
Enhanced activity of nondepolarizing agents may also
A rapid-sequence induction is initiated with be observed in patients receiving magnesium sulfate
denitrogenation/preoxygenation followed by administra- (e.g., for seizure prophylaxis in preeclamptic women or
tion of an induction agent, paralysis, and cricoid pressure; for fetal neuroprotection).265 Sugammadex, a modified
mask ventilation is not performed, to prevent uninten- gamma-cyclodextrin, has been demonstrated to be effec-
tional insufflation of the stomach. Whether rapid- tive in providing rapid recovery (a train-of-four ratio of
sequence induction should be employed, particularly in greater than 0.9) without recurarization from moderate
an appropriately fasted, nonlaboring patient presenting and profound rocuronium-induced neuromuscular block-
for elective cesarean delivery, has been questioned.260 ade in parturients undergoing cesarean delivery.266
Further, the value of cricoid pressure has been challenged Sugammadex has not been approved for use in all coun-
owing to (1) physiologic evidence demonstrating that tries owing to concerns regarding hypersensitivity and
cricoid pressure reduces lower esophageal sphincter pres- allergic reactions.
sure, (2) anatomic investigations showing an inability to A small-diameter cuffed endotracheal tube (i.e., 6.5 or
completely occlude the esophagus, (3) a lack of clinical 7.0 mm) should be used during pregnancy; the use of a
outcome data that confirm that cricoid pressure reduces flexible stylet within the endotracheal tube optimizes the
the incidence of aspiration, and (4) the frequent misap- first attempt at intubation. Tissue trauma and airway
plication of the technique itself.261 The technique for edema may occur with repeated attempts at intubation.
cricoid pressure begins with an assistant applying 10 Correct endotracheal tube placement should be con-
newtons (N) of force, with one N being the unit of force firmed by auscultation in both axillae and over the
required to accelerate a mass of 1 kilogram 1 meter per stomach to detect inadvertent endobronchial and esopha-
second squared. (Force cannot be represented by mass geal intubation, respectively. Expired end-tidal carbon
alone, but as a practical guide to the amount of force to dioxide may be detected transiently with an esophageal
apply, 10 N is approximately equivalent to the downward intubation; thus, the anesthesia provider should observe
force exerted by a weight of 1 kg.) Following loss of ongoing evidence of a normal capnographic tracing and
consciousness, the amount of force is increased to 30 N. adequate maternal oxyhemoglobin saturation as well as
Application of the full amount of force while the patient bilateral thoracic movement and breath sounds. If doubts
is still awake can provoke active retching and regurgita- persist, the anesthesia provider can perform direct laryn-
tion. In some cases, cricoid pressure may be briefly goscopy or fiberoptic bronchoscopy to confirm the
released to enable a successful intubation; not infre- correct placement of the endotracheal tube in the trachea.
quently the benefit of release outweighs the risk for If incorrect endotracheal tube placement is promptly rec-
regurgitation. Cricoid pressure should then be reapplied ognized, extubation (with continued cricoid pressure)
until the correct endotracheal tube position is will often allow another attempt without the need for
confirmed. additional muscle relaxant.
Historically, thiopental (4 to 5 mg/kg) has been the Anticipation of a difficult endotracheal intubation, or
most frequently used induction agent. Because of recent a failed intubation attempt, should invoke the difficult
lack of availability, and also lack of familiarity, it is now airway algorithm and a call for assistance (see Chapter
rarely used in the United States, although it is still used 30). Options include (1) allowing the patient to awaken,
in other countries. Propofol (2 to 2.8 mg/kg) is now (2) using alternative techniques to place an endotracheal
572 PART VII Cesarean Delivery
tube, and (3) using alternative airway devices. The laryn- the effect of oxytocin on uterine tone and lead to greater
geal mask airway (LMA) does not prevent pulmonary blood loss after delivery.274 A bispectral index measure-
soiling with gastric contents as efficiently as an endotra- ment less than 60 typically requires more than 0.75 MAC
cheal tube, but it can be a lifesaving device in situations of a volatile halogenated agent combined with 50%
of failed intubation. Han et al.267 reported clinically effec- nitrous oxide and has been suggested to prevent intraop-
tive airway management with a classic LMA, which was erative awareness and recall in parturients undergoing
placed successfully on the first attempt in 98% of 1067 general anesthesia275; however, this target bispectral index
healthy parturients undergoing elective cesarean delivery value requires further study in pregnant women. Yoo
with general anesthesia. Cricoid pressure was maintained et al.276 observed lower bispectral index values with a
throughout the cesarean delivery, and no adverse sequelae standardized sevoflurane–50% nitrous oxide anesthetic in
occurred. Utilizing an LMA with a higher seal pressure women with prior labor compared with women without
than a simple LMA, and a built-in gastric draining tube, prior labor; in addition, plasma norepinephrine concen-
Halaseh et al.268 reported successful placement of the trations were higher at both baseline and delivery in the
LMA in 98% of 3000 healthy parturients undergoing laboring group. Similarly, Erden et al.277 observed lower
elective cesarean delivery; they observed only one case of volatile agent requirements to maintain a target bispec-
regurgitation without aspiration. Cricoid pressure was tral index value between 40 and 55 in parturients who
not maintained after confirmation of successful LMA were in labor compared with nonlaboring women; this
placement. In both of these studies, patients were excluded finding could not be explained by differences in plasma
if they had symptoms of gastropharyngeal reflux, known/ concentrations of progesterone, prolactin, or cortisol.277
predicted difficult airway, and a prepregnancy BMI Postoperative analgesia requirements for the first 24
greater than 30 kg/m2. A number of variations to the hours were also less in the group who had labored.276
classic LMA have been developed that may facilitate In clinical practice, approximately 1.0 MAC of a vola-
airway management in specific situations (see Chapter tile halogenated agent is typically administered between
30). Emergency airway equipment should be immedi- tracheal intubation and delivery, and the concentration
ately available in all obstetric operating rooms.34 of the volatile agent is then reduced to 0.5 to 0.75 MAC
after delivery. Nitrous oxide 50% in oxygen is often
added to reduce the required concentration of volatile
Maintenance
agent, thereby mitigating adverse effects on uterine
The goals for anesthetic maintenance include (1) ade- tone. The administration of a benzodiazepine (e.g., mid-
quate maternal and fetal oxygenation, with maintenance azolam) after delivery may reduce the risk for maternal
of normocapnia for pregnancy; (2) appropriate depth of awareness.
anesthesia to promote maternal comfort and a quiescent Intravenous opioids are often withheld until after
surgical field and to prevent awareness and recall; (3) delivery to minimize the potential for neonatal respira-
minimal effects on uterine tone after delivery; and (4) tory depression; however, there may be circumstances in
minimal adverse effects on the neonate. which maternal hemodynamic stability or blunting of
Fetal oxygenation appears maximal when a maternal responses to airway manipulation and surgical stimula-
Fio2 of 1.0 is used269; however, in the absence of fetal tion favor the administration of opioids during the induc-
compromise, an Fio2 of 0.3 appears to provide sufficient tion of general anesthesia. The rapid onset and efficacy
oxygenation while minimizing the production of oxygen of intravenous lipid-soluble agents (e.g., remifentanil,
free radicals (see earlier discussion). Although the use of fentanyl, alfentanil) make them ideal for mitigating the
a higher Fio2 can increase maternal arterial and umbilical responses to laryngoscopy and intubation.278 Intraopera-
venous blood oxygen content, this action has not been tively, the prolonged activity of water-soluble agents (e.g.,
observed to result in differences in 1- or 5-minute Apgar morphine, hydromorphone) can be useful to minimize
or neurobehavioral scores.270,271 As a consequence, in the volatile anesthetic use and for the provision of intraop-
absence of fetal compromise, inspired oxygen concentra- erative and postoperative analgesia (see Chapter 27).
tions should be guided by pulse oximetry rather than Given the pregnancy-induced stretching of the
provision of an arbitrarily set level of Fio2. abdominal wall, additional neuromuscular blockade is
Maternal ventilation should maintain normocapnia, seldom necessary in the parturient who has an adequate
which at term gestation is a Paco2 of 30 to 32 mm Hg. depth of anesthesia (with administration of both a volatile
Excessive ventilation can cause uteroplacental vasocon- agent and an opioid). A small dose of a short-acting non-
striction and a leftward shift of the oxyhemoglobin dis- depolarizing agent (or an infusion of succinylcholine)
sociation curve, which may result in compromised fetal may be administered, with maternal response monitored
oxygenation.272 On the other hand, hypercapnia can lead with a peripheral nerve stimulator, if additional muscle
to maternal tachycardia and is also undesirable. relaxation is indicated.
Initially, high fresh-gas flows should be used to ensure Although differences in maternal and umbilical artery
an adequate end-tidal concentration of the volatile halo- acid-base status have been observed in women who
genated agent. No specific volatile halogenated agent has underwent elective general anesthesia compared with
been demonstrated to be superior to another. The anes- epidural anesthesia for cesarean delivery, similar neonatal
thetic requirements for volatile halogenated agents are outcomes were demonstrated.279 With any anesthetic
diminished 25% to 40% during pregnancy.273 End-tidal technique, consideration should be given to the duration
levels of halogenated agent greater than 1 to 1.5 times of the U-D interval; in a study evaluating spinal anesthe-
the minimum alveolar concentration (MAC) may reduce sia, when the U-D interval was longer than 180 seconds,
26 Anesthesia for Cesarean Delivery 573
lower Apgar scores and greater fetal acidosis were neonatal depression. With a maternal induction dose of
observed.137 (This result most likely reflects difficulty in 4 mg/kg, umbilical vein concentrations of thiopental are
delivering the baby rather than a direct effect of the well below the arterial plasma concentrations necessary
anesthetic agents.) General anesthetic agents can redis- to produce anesthesia in adults.285 However, with large
tribute from the neonatal fat to the central circulation induction doses (8 mg/kg), thiopental can produce sig-
and lead to secondary depression of neonatal ventilatory nificant neonatal depression.286
effort; thus, the presence of a pediatrician (or another The following theories have been proposed to explain
neonatal provider) is advisable until a normal ventilatory the clinical occurrence of an unconscious mother but an
pattern is observed. awake neonate: (1) preferential uptake of thiopental by
the fetal liver, which is the first organ perfused by blood
coming from the umbilical vein286; (2) the higher relative
Emergence and Extubation
water content of the fetal brain287; (3) rapid redistribution
When the patient awakens, extubation should be under- of the drug into the maternal tissues, which causes a rapid
taken with the patient in a semirecumbent position. The reduction in the maternal-to-fetal concentration gradi-
patient should demonstrate purposeful response to verbal ent; (4) nonhomogeneity of blood flow in the intervillous
commands and return of protective airway reflexes before space; and (5) progressive dilution by admixture with the
tracheal extubation. In a review of anesthesia-related various components of the fetal circulation. Because of
maternal deaths between 1985 and 2003 in the state of this rapid equilibration of thiopental and the low fetal
Michigan, Mhyre et al.280 observed that deaths associated brain concentration of thiopental, there is no advantage
with hypoventilation or airway obstruction did not occur in delaying delivery until thiopental concentrations
at induction and tracheal intubation but rather during decline. There is no evidence that thiopental causes
emergence, extubation, or recovery from anesthesia. Risk adverse fetal effects when the I-D time is prolonged.
factors associated with mortality were obesity and African-
American race, which may have delayed the visual recog- Propofol. Propofol is an intravenous induction agent
nition of cyanosis; medical management and medication with a rapid onset, rapid recovery, and favorable side-
issues were also identified. The American Society of effect profile, which includes a low incidence of nausea
Anesthesiologists Practice Guidelines for Postanesthetic and vomiting. Induction with propofol can result in pain
Care suggest that pulse oximetry is associated with early on injection and a reduction in maternal blood pressure
detection of hypoxemia; the guidelines recommend peri- and cardiac output. The pharmacokinetics of propofol
odic assessment of airway patency, respiratory rate, and are similar in pregnant and nonpregnant women, except
oxygen saturation during emergence and recovery.281 If for a more rapid clearance observed during pregnancy,
repeated airway manipulation, massive hemorrhage, or which may partially reflect drug removal through blood
emergency hysterectomy has occurred, delayed extuba- loss and the delivery of the infant and placenta.
tion and/or transfer to an intensive care unit (ICU) When given as an intravenous bolus, by continuous
should be considered. infusion, or both, propofol rapidly crosses the placenta
and results in an umbilical vein–to–maternal vein (UV/
MV) ratio of approximately 0.7.288 In an in vitro human
Pharmacology
placenta study, Soares de Moura et al.289 observed that
Thiopental. Historically, the barbiturates (e.g., thio- propofol produced vasodilation of fetal placental blood
pental [thiopentone], methohexital, thiamylal) have been vessels and decreased the effect of various vasoconstric-
the induction agents most commonly used for cesarean tors, most likely through the inhibition of calcium influx
delivery. Extensive published data have confirmed the through the smooth muscle sarcolemma; intralipid, the
safety and efficacy of thiopental for induction of anesthe- propofol carrier solution, was not responsible for these
sia in patients undergoing cesarean delivery at various effects. Celleno et al.290 randomly assigned 40 mothers
gestational ages. Thiopental 4 mg/kg provides a rapid undergoing cesarean delivery with general anesthesia to
and reliable induction of anesthesia. As a negative ino- receive either propofol 2.8 mg/kg or thiopental 5 mg/kg
trope and vasodilator, thiopental can cause decreased for induction of anesthesia; they observed significantly
cardiac output and blood pressure,282 which may result in lower Apgar and neurobehavioral scores in the propofol
significant hypotension in hypovolemic patients. Some group. The I-D and U-D intervals in the two groups
investigators have attempted to minimize this effect by were nearly identical. Five infants exposed to propofol
using a lower dose of thiopental in combination with had profound muscular hypotonus at birth and at 5
ketamine or propofol, with varying success. minutes, and one newborn was somnolent. Other studies
Thiopental rapidly crosses the placenta. In 11 healthy have found no effect of propofol on neurobehavioral
subjects who underwent induction of general anesthesia scores or the time to sustained spontaneous respiration
with thiopental, the mean umbilical artery–to–umbilical with induction bolus doses of propofol 2.5 mg/kg or with
vein ratio was 0.87 with an induction-to-delivery (I-D) infusion doses less than 6 mg/kg/h.291,292 However, higher
interval that ranged from 8 to 22 minutes.283 Fetal-to- doses of propofol (9 mg/kg/h) have been correlated with
maternal concentration ratios after a single thiopental a low Neurologic and Adaptive Capacity Score (NACS).293
dose exposure in other studies in term infants exhibited Compared with thiopental, propofol results in a
a range of 0.43 to 0.96.284 The equilibration of thiopental greater incidence of maternal hypotension,294 which may
occurs relatively rapidly in the fetus; however, fetal brain more effectively attenuate the response to laryngoscopy
concentrations rarely exceed the threshold required for and intubation at the risk of reduced uteroplacental blood
574 PART VII Cesarean Delivery
flow. Moreover, in women undergoing cesarean delivery, reported.305 Apgar scores and umbilical cord blood gas
Celleno et al.295 demonstrated that propofol 2.4 mg/kg, and pH measurements at delivery with ketamine are
in comparison with thiopental 5 mg/kg, resulted in elec- similar to those with thiopental.306,307 A formulation of
troencephalographic patterns consistent with a lighter the purified S+ isomer of ketamine is available for clinical
depth of anesthesia, which was confirmed by the presence use in some countries outside the United States. In
of clinical signs of light anesthesia in 50% of the patients. chronically instrumented pregnant sheep, Strumper
Other studies have not observed significant hypotension et al.308 found that the effects of the isomer were similar
after the administration of propofol (2 to 2.8 mg/kg) or to those of the racemic mixture in terms of maternal and
lower umbilical cord blood gas and pH measurements fetal hemodynamics and uterine perfusion; however, the
than after administration of thiopental (4 to 5 mg/ S+ isomer was associated with a smaller increase in
kg)291,296 or thiamylal (3 to 4 mg/kg).297 However, one maternal and fetal Pco2 than that seen with racemic ket-
report noted a transient but severe episode of maternal amine in spontaneously breathing animals.
bradycardia after administration of propofol followed by The emergence delirium and hallucinations experi-
succinylcholine for rapid-sequence induction.298 This enced with ketamine, particularly in the unpremedicated
effect has also been demonstrated in pregnant ewes; one patient, have limited the adoption of this drug as a routine
animal experienced severe bradycardia that led to a sinus induction agent for cesarean delivery. If ketamine is used,
arrest.299 a benzodiazepine should be administered to decrease the
In a study of nonpregnant women, the interaction of incidence of these psychomimetic effects.309 Maternal
propofol and ketamine was found to be additive at hyp- awareness may still occur after an induction dose of
notic and anesthetic endpoints; the cardiostimulant ketamine 1 to 1.5 mg/kg,310 but the incidence is lower
effects of ketamine appear to offset the cardiodepressant than with thiopental 4 mg/kg or a mixture of ketamine
effects of propofol.300 0.5 mg/kg and thiopental 2 mg/kg.311 The incidence of
Propofol provides a vehicle for bacterial growth, has maternal awareness can also be diminished with the
undergone less investigation in pregnant women (espe- co-administration of a benzodiazepine.
cially preterm parturients), is painful on administration, When used to maintain general anesthesia with 50%
and may lead to a higher incidence of adverse maternal nitrous oxide in oxygen for cesarean delivery, a continu-
and neonatal effects. Thus, propofol does not offer a ous infusion of ketamine (70 µg/kg/minute) was followed
significant benefit over thiopental for the induction of by a higher incidence of factual recall and postoperative
general anesthesia for cesarean delivery. pain than seen with a volatile anesthetic technique.312
Ngan Kee et al.306 found that patients who received ket-
Ketamine. The sympathomimetic properties of ket- amine 1 mg/kg for induction had lower postoperative
amine make it an ideal induction agent in the setting of consumption of morphine than patients who received
an urgent cesarean delivery in a patient with hypotension thiopental 4 mg/kg for induction (anesthesia was main-
or an acute exacerbation of asthma.301 Ketamine is an tained with nitrous oxide and isoflurane). Some investiga-
analgesic, hypnotic, and amnestic agent associated with tors have suggested that lower doses of ketamine (0.5 to
minimal respiratory depression; it is often used to supple- 0.7 mg/kg) combined with thiopental or propofol may be
ment a neuraxial technique that may not be providing preferable to the administration of any one individual
optimal anesthesia. Ketamine’s effect is likely related agent. There appears to be limited advantage to this
to antagonism of the N-methyl-d-aspartate (NMDA) approach with thiopental in terms of maternal recall,
receptor. maternal hemodynamic status, and neonatal neurobehav-
An induction dose of ketamine 1 mg/kg is associated ioral scores.313,314 Whether ketamine, given as a bolus or
with an increase in blood pressure immediately after infusion initiated after infant delivery, can provide post-
induction, and a further increase is observed after cesarean analgesia and modulate pain remains controver-
laryngoscopy and intubation.302 Such an increase can sial (see later discussion).
be desirable in the bleeding hypotensive patient but
should be avoided in the parturient with hypertension Etomidate. Etomidate is an intravenous induction agent
(e.g., preeclampsia). However, in experimental animal that produces rapid onset of anesthesia with minimal
models, ketamine was sometimes associated with direct effects on cardiorespiratory function. This property
myocardial depression, decreased cardiac output, and makes it ideal for parturients who are hemodynamically
hypotension.282 unstable or who would not tolerate hemodynamic aber-
Studies in pregnant ewes suggest that the use of ket- rations well (e.g., patients with severe cardiac disease).315
amine is not associated with a reduction in uterine blood With an induction dose of 0.2 to 0.3 mg/kg, etomidate
flow.303 Ketamine is associated with dose-dependent undergoes rapid hydrolysis, thereby allowing rapid recov-
increases in uterine tone, but a single induction dose does ery.316 Intravenous administration of etomidate may cause
not increase uterine tone at term gestation.304 Using an pain and involuntary muscle movements in unpremedi-
induction dose of ketamine 0.7 mg/kg, Craft et al.303 cated patients; etomidate is also associated with nausea
observed a 39% increase in resting uterine tone with no and vomiting, potential activation of seizures in patients
effect on uterine blood flow in gravid ewes. with an epileptogenic foci, and an impaired glucocorti-
Ketamine rapidly crosses the placenta. No neonatal coid response to stress.317
depression is observed with doses less than 1 mg/kg.305 Etomidate crosses the placenta rapidly; however, large
At higher doses, low Apgar scores, neonatal respiratory variations in the UV/MV ratio (0.04 to 0.5) have been
depression, and need for resuscitation have been reported.316 Downing et al.318 observed that an induction
26 Anesthesia for Cesarean Delivery 575
dose of etomidate 0.3 mg/kg was associated with better Rocuronium is a suitable alternative to succinylcho-
neonatal acid-base measurements and overall clinical line when a nondepolarizing agent is preferred for
condition than with thiopental 3.5 mg/kg. A transient rapid-sequence induction (e.g., history of malignant
(< 6 hours) reduction in neonatal cortisol production hyperthermia). Abouleish et al.325 observed that
has been observed when an induction dose of etomidate rocuronium (0.6 mg/kg) administered with an induction
is used for cesarean delivery319; however, the clinical dose of thiopental (4 to 6 mg/kg) provided good to excel-
relevance of this finding is unclear. lent intubating conditions in pregnant women after a
mean interval of 79 seconds and maximal intubating con-
Midazolam. Midazolam is a short-acting, water-soluble ditions in 98 seconds. Rocuronium did not adversely
benzodiazepine that has few adverse hemodynamic effects affect neonatal Apgar scores, acid-base measurements,
and provides hypnosis and amnesia. Although most com- time to sustained respiration, or neurobehavioral scores.
monly used as a premedicant prior to anesthesia, mid- Neuromuscular blockade was reversed satisfactorily at
azolam can be used as an induction agent for cesarean the end of cesarean delivery. Magorian et al.326 demon-
delivery. Crawford et al.320 observed that induction with strated that rocuronium 1.2 mg/kg resulted in an onset
either midazolam 0.3 mg/kg or thiopental 4 mg/kg of paralysis similar to that provided by succinylcholine
resulted in similar maternal hemodynamic responses and (55 seconds), but it had a significantly longer clinical
Apgar scores. By contrast, Bland et al.321 reported that duration of action.
midazolam 0.2 mg/kg for induction of anesthesia resulted Vecuronium 0.1 mg/kg may be administered when
in a higher incidence of low Apgar scores and longer time the use of succinylcholine is contraindicated; however, its
to spontaneous respiration in the neonates than thiopen- onset of action is significantly slower than that of
tal 3.5 mg/kg. Umbilical cord blood gas measurements rocuronium (144 seconds).326 Hawkins et al.327 evaluated
did not differ between the two groups; however, the the use of two methods of vecuronium administration for
infants exposed to midazolam had lower neurobehavioral rapid-sequence induction of anesthesia for elective cesar-
scores, body temperature, general body tone, and arm ean delivery. One group of women received vecuronium
recoil. These differences did not persist at 4 hours after 0.01 mg/kg as a priming dose before administration of
delivery. There are few indications for the use of mid- 0.1 mg/kg 4 to 6 minutes later; the other group received
azolam for the induction of general anesthesia for cesar- 0.2 mg/kg as a single bolus. The mean onset time for
ean delivery; it should be used only when there are both groups (177 seconds and 175 seconds, respectively)
relative or absolute contraindications to the use of other was much longer than that for succinylcholine; moreover,
agents. the duration of blockade was prolonged (73 minutes in
the priming group and 115 minutes in the bolus group).
Muscle Relaxants. Muscle relaxants are commonly The same group performed a separate study in women
used before delivery to provide optimal intubation and undergoing postpartum tubal ligation; the mean duration
operating conditions. Most muscle relaxants are highly of action of vecuronium was significantly longer in these
ionized with low lipid solubility; thus, they do not undergo women (57 minutes) than in nonpregnant controls (35
significant placental transfer. minutes).328 Vecuronium crosses the placenta in small
The depolarizing agent succinylcholine (1 to 1.5 mg/ amounts; however, neonatal outcome, as assessed by
kg) is the muscle relaxant of choice for most parturients Apgar scores and NACS, does not appear to be adversely
undergoing rapid-sequence induction of general anesthe- affected.329
sia. Maternal administration provides adequate intubat- Atracurium is a less desirable agent for rapid-sequence
ing conditions within approximately 45 seconds of induction because the high dose required for a rapid
intravenous administration. Succinylcholine is a highly onset of action may result in significant histamine release,
ionized and water-soluble molecule, and only small which may cause hypotension. The isomer cisatracur
amounts cross the placenta. Although high doses of suc- ium does not have these undesirable side effects, but its
cinylcholine (2 to 3 mg/kg) can result in detectable levels relatively slow onset makes it less optimal than other
in umbilical cord blood, very large doses (10 mg/kg) are alternatives.330
required to lead to placental transfer sufficient to cause Regardless of the choice of agent, laryngoscopy and
neonatal muscle weakness.322 intubation should not be attempted until adequate muscle
Succinylcholine is rapidly metabolized by plasma relaxation has occurred. The use of a nerve stimulator
pseudocholinesterase, the concentration of which is allows an objective assessment of the onset and duration
decreased during pregnancy; however, in most patients of the neuromuscular blockade. Residual neuromuscular
this effect is offset by the pregnancy-induced increase in blockade can be reversed with neostigmine and glycopyr-
volume of distribution. Thus, recovery from succinylcho- rolate. To diminish the risk for aspiration, the anesthesia
line is not prolonged, unless the patient has extremely provider should confirm that the patient responds appro-
low levels of pseudocholinesterase or atypical pseudocho- priately to verbal commands before tracheal extubation.
linesterase.323 The administration of metoclopramide
may also prolong succinylcholine-induced neuromuscu- Nitrous Oxide. Nitrous oxide is an inhalational agent
lar blockade, perhaps by inhibiting plasma pseudocholin- commonly used in the setting of a cesarean delivery
esterase324; this effect is rarely (if ever) clinically significant. because of its minimal effects on maternal blood pressure
The return of neuromuscular function should be con- and uterine tone. The use of nitrous oxide allows for a
firmed before additional doses of muscle relaxant are reduction in the concentration of the volatile halogenated
given. agent. (High concentrations of a volatile halogenated
576 PART VII Cesarean Delivery
agent decrease uterine tone.) Administration of 50% to contractions were affected in a dose-dependent manner
67% nitrous oxide in oxygen without another anesthetic and were completely inhibited at 2 MAC.337 The same
agent does not provide complete anesthesia and can group of investigators also reported that 1 MAC of des-
result in maternal awareness in 12% to 26% of cases.331,332 flurane inhibits the amplitude of oxytocin-induced myo-
Nitrous oxide is transferred rapidly across the pla- metrial contractions to a lesser extent than sevoflurane338
centa, where fetal tissue uptake reduces the fetal arterial and that pregnant myometrium is more sensitive than
concentration for the first 20 minutes. Karasawa et al.333 nonpregnant myometrium to the inhibitory effects of
evaluated the relationship between duration of exposure volatile halogenated agents.339 These effects may influ-
to nitrous oxide 67% and the resulting UV/MA nitrous ence maternal blood loss after delivery.
oxide concentration ratios; they observed different ratios Lower amounts of volatile halogenated agents are
according to duration of exposure: 2 to 9 minutes (0.37), required during pregnancy. Gin et al.340 demonstrated
9 to 14 minutes (0.61), and 14 to 50 minutes (0.70). Apgar a 28% lower MAC for isoflurane in pregnant women
scores at 1 minute inversely correlated with duration of at 8 to 12 weeks’ gestation than in nonpregnant women.
anesthesia, an effect observed in other studies.334 The use The same group of investigators found a 27% and 30%
of a lower concentration (e.g., 50%) of nitrous oxide may decrease in MAC of halothane and enflurane, respec-
reduce but not eliminate these neonatal effects. Piggott tively.341 These findings were correlated with an increase
et al.269 randomly assigned parturients undergoing in progesterone level. In an animal model, Datta et al.342
general anesthesia to receive either 100% oxygen or 50% demonstrated that long-term administration of proges-
nitrous oxide in oxygen, both supplemented by isoflurane terone was associated with a reduction in the MAC of
(1.5 MAC for the first 5 minutes and 1.0 MAC thereaf- halothane in rabbits. Chan and Gin343 observed that
ter). Neonates exposed to nitrous oxide required more the reduction in MAC persists for 24 to 36 hours post-
resuscitation, although no significant differences were partum, with a gradual return to normal values by 72
observed in Apgar scores. hours.
Volatile Halogenated Agents. Volatile halogenated Opioids. All opioids, particularly those with high lipid
agents are perhaps the most commonly used agents for solubility (e.g., remifentanil, fentanyl, sufentanil), readily
maintaining general anesthesia for cesarean delivery. pass through the placenta to the fetus. As a consequence,
Volatile halogenated agents produce central nervous the administration of opioids is usually avoided until after
system and cardiovascular effects in a dose-dependent delivery to reduce the risk for neonatal depression.
manner; of particular concern for the obstetric patient However, the hemodynamic stability provided by opioids
are the resulting decreases in blood pressure (which may during airway manipulation and surgery may be valuable
result in reduced uterine blood flow) and uterine tone. in select settings, particularly in the presence of maternal
The uptake and delivery of a volatile halogenated agent cardiac disease, neurologic conditions, and preeclampsia
is determined by inspired partial pressure, blood flow, or hypertension.
and the blood/gas/tissue partition coefficient. The alveo- The administration of remifentanil has been observed
lar partial pressure of volatile agents during pregnancy to mitigate the hemodynamic responses to intubation and
follows known patterns of equilibration; the following surgery but result in significant neonatal depression.
commonly used agents are listed in order of more rapid Even with the administration of relatively low doses of
to slower equilibration: nitrous oxide, desflurane, sevo- remifentanil (0.5 µg/kg bolus followed by 0.15 µg/kg/
flurane, and isoflurane. Volatile halogenated agents cross min continuous infusion until peritoneal incision), Draisci
the placenta rapidly and equilibrate quickly with fetal et al.344 observed that Apgar scores and umbilical cord
tissues.335 Neonatal depression may occur. This is typi- blood pH measurements were lower in the infants
cally not a clinical issue when volatile anesthetic agents exposed to remifentanil than in the infants whose mothers
are used for emergency cesarean delivery, because the received fentanyl 5 µg/kg after delivery; some neonates
delivery usually occurs before much of the volatile agent exposed to remifentanil required tracheal intubation.
crosses the placenta (particularly if uteroplacental insuf- There were no significant differences between groups in
ficiency is the reason for emergency delivery). Also, the maternal hemodynamics or maternal plasma concentra-
maternal hemodynamic response to laryngoscopy and tions of catecholamines and growth hormone.
intubation typically offsets any hypotension that might The highly lipid-soluble agent fentanyl rapidly crosses
result from administration of a volatile halogenated agent the placenta. Fentanyl is 60% to 80% protein bound;
before delivery. thus, approximately one third is available for transfer
Munson and Embro336 evaluated three concentrations across the placenta.345 Despite its low lipid solubility,
(0.5, 1.0, and 1.5 MAC) of isoflurane, enflurane, and morphine has a fetal-to-maternal blood concentration
halothane in an in vitro study of gravid and nongravid ratio of 0.96 at 5 minutes346; this rate of equilibration and
uterine myometrial strips; the amount of depression of the production of active metabolites are relevant consid-
uterine contractile activity was dose related for each erations in the use and timing of intravenous morphine
agent and was similar for the three agents. In a similar administration.
study, Dogru et al.337 evaluated the effect of 0.5, 1.0, and Meperidine is highly lipid soluble and is 50% to 70%
2.0 MAC of desflurane and sevoflurane on gravid uterine protein bound; maternal administration results in a mean
myometrial strips; a dose-dependent decrease in uterine fetal-maternal blood concentration ratio of 0.75.347 The
contractions was observed. Importantly, the duration, production of the active metabolite normeperidine,
amplitude, and frequency of oxytocin-induced uterine which can accumulate in both the mother and neonate
26 Anesthesia for Cesarean Delivery 577
and result in respiratory and neurobehavioral alterations, Ideally, the obstetrician should then wait for 3 to 4
limits the use of meperidine as a principal analgesic agent minutes to allow the local anesthetic agent to exert its
during cesarean delivery; however, after delivery of the effect before making the skin incision.
neonate, an intravenous dose of 12.5 to 25 mg is useful A vertical skin incision is made between the umbilicus
for treatment of shivering in the mother. and the symphysis pubis and is extended down to the
Maternal respiratory depression, as well as nausea and rectus fascia. The obstetrician then infiltrates local anes-
emesis during the intraoperative and postoperative thetic into the rectus fascia and rectus muscles by making
periods, represent significant concerns in parturients three to five laterally directed injections on each side.
given intravenous opioids. The needle should be passed between the rectus sheath
and the transversus muscle at an angle of 10 to 15 degrees
and a depth of 3 to 5 cm; aspiration is performed, and 2
Local Anesthesia to 3 mL of local anesthetic is injected at each site with
As a method used primarily for supplementation of neur- an additional 1 mL injected with needle withdrawal. The
axial anesthesia, the infiltration of local anesthesia can obstetrician should also make oblique injections at the
also be used to facilitate an emergency cesarean delivery. upper and lower poles of the incision. The local anes-
This latter technique has been well described and is used thetic will spread freely in the rectus sheath, but it takes
predominantly in developing countries, where contem- 4 to 5 minutes for anesthesia to be complete. The supra-
porary anesthesia techniques may not be readily available. pubic area must also be generously infiltrated to ensure
Few contemporary obstetricians are familiar or proficient blockade of the branches of the iliohypogastric nerve.
with this technique in developed countries. The disadvantage of the rectus sheath block is the large
The success of local infiltration depends on the obste- volume (40 to 50 mL) of local anesthetic required; a less
trician’s making a midline abdominal incision, avoiding effective alternative that requires less volume and time is
use of retractors, and not exteriorizing the uterus. In set- to raise a longitudinal paramedian wheal in the rectus
tings in which an anesthesia provider might not be readily fascia on each side of the midline and to infiltrate the
available, the obstetrician might begin surgery with the suprapubic region.
aid of local infiltration; after delivery of the infant, the The obstetrician then extends the incision through the
achievement of temporary hemostasis, and the arrival of rectus sheath, and the peritoneum is grasped with forceps
the anesthesia provider, surgery may be completed once clamps. If the patient has pain, the parietal peritoneum
general anesthesia has been induced. may be infiltrated with 5 to 10 mL of local anesthetic and
Local infiltration is performed in sequential steps as then incised. The visceral peritoneum overlying the area
the operation progresses (Box 26-9).348 The use of 0.5% of the uterine incision is injected with 10 mL of local
lidocaine with epinephrine is recommended; the use of a anesthetic and is then incised and reflected appropriately.
more concentrated solution is likely to result in systemic Paracervical infiltration with 5 to 10 mL of local anes-
toxicity. A 25-gauge spinal needle is used to make the thetic may block pain impulses from the uterus and
intracutaneous injection; the needle is inserted just below cervix.
the umbilicus and is directed in the midline toward the A uterine incision is made, and the infant is delivered.
symphysis pubis. Approximately 10 mL of local anes- The surgeon must avoid forceful retraction and blunt
thetic is required to create a skin wheal that extends from dissection of tissue planes, and uterine manipulation
the symphysis pubis to the umbilicus. The subcutaneous should be kept to a minimum. A support person at the
injection is also performed for the full length of the head of the table who can provide coaching and reassur-
planned incision with 10 to 20 mL of local anesthetic. ance to the mother is invaluable.
The major disadvantages of local infiltration anesthe-
sia are patient discomfort and the potential for systemic
local anesthetic toxicity, given that as much as 100 mL of
local anesthetic solution is required. The latter disadvan-
Steps for Initiating Local tage may be especially problematic in the absence of a
BOX 26-9 Infiltration Anesthesia for skilled anesthesia provider to assist with maternal resus-
Cesarean Delivery citation. Another disadvantage is the amount of time
1. Professional support person with patient required for maximal anesthesia to develop; maternal dis-
2. Infiltration with 0.5% lidocaine with epinephrine comfort often accompanies an urgent delivery performed
(total dose should not exceed 500 mg) with this form of anesthesia. Finally, local infiltration
3. Intracutaneous injection in the midline from the does not provide satisfactory operating conditions in the
umbilicus to the symphysis pubis event of a surgical complication (e.g., uterine laceration,
4. Subcutaneous injection broad ligament hematoma).
5. Incision down to the rectus fascia Cesarean delivery with use of local infiltration, if suc-
6. Rectus fascia blockade cessful, has the advantages of preserving maternal cardio-
7. Parietal peritoneum infiltration and incision
vascular stability and a patent airway while allowing the
8. Visceral peritoneum infiltration and incision
9. Paracervical injection initiation of surgery in emergency cases. However, the
10. Uterine incision and delivery technique is frequently associated with incomplete mater-
11. Administration of general anesthesia for uterine nal anesthesia, which subsequently presents significant
repair and abdominal closure, if needed management issues, because the surgical procedure has
commenced, positioning options are limited, and the
578 PART VII Cesarean Delivery
during hypotension or hemorrhage, (5) the presence of a a volatile halogenated agent may not reliably provide
partial neuraxial blockade in parturients requiring con- adequate depth of anesthesia to consistently prevent
version to general anesthesia after failed neuraxial anes- maternal awareness. Robins and Lyons62 have recom-
thesia, and (6) the (mistaken) assumption that high mended a larger induction dose of barbiturate (e.g., thio-
baseline sympathetic tone is responsible for intraopera- pental 5 to 7 mg/kg instead of 3 to 4 mg/kg), an end-tidal
tive tachycardia in parturients. volatile anesthetic concentration greater than 0.8 MAC,
Concern about neonatal depression and uterine atony the highest concentration of nitrous oxide compatible
associated with volatile halogenated agents has led to with appropriate oxygenation, and the administration of
administration of relatively low doses of these agents. an opioid and a benzodiazepine after delivery. Intrave-
Administration of a barbiturate induction agent followed nous induction or infusion techniques that may reduce
by nitrous oxide 50% in oxygen resulted in maternal the risk for maternal awareness include the administra-
awareness in 12% to 26% of cases.331,332 Using an isolated tion of repeat doses of thiopental,365 the use of ketamine,310
forearm technique, King et al.360 assessed 30 women or a combination of thiopental and ketamine.313 Mid-
undergoing cesarean delivery with thiopental 250 mg, azolam 0.075 mg/kg provides 30 to 60 minutes of antero-
succinylcholine infusion, and 0.5% halothane in 50% grade amnesia when given to women undergoing elective
nitrous oxide; the majority of patients signaled pain in cesarean delivery under epidural anesthesia.367 Induction
the first minute. The incidence of recall with this anes- of general anesthesia with propofol 2.4 mg/kg compared
thetic regimen was approximately 1%.361 The use of with thiopental 5 mg/kg has been associated with a sig-
higher concentrations of a volatile halogenated agent has nificantly greater incidence (50% versus 10%) of rapid
subsequently become a more common practice, leading low-voltage (8-9 Hz) waves, suggestive of a light plane of
to an incidence of maternal awareness of approximately anesthesia.295 Infusion of propofol 8 mg/kg/h with 67%
0.26%.62 However, the result of increasing the depth of nitrous oxide has also been used with satisfactory amnes-
maternal anesthesia is that neonates born to women who tic effect.368 Propofol exhibits an amnestic effect that is
receive general anesthesia tend to have lower Apgar and not dependent on the degree of sedation; however, the
neurobehavioral scores, particularly when the I-D inter- effect is significantly less than that with midazolam.369
val exceeds 8 minutes.362 The psychological morbidity associated with aware-
The optimal doses and concentrations of anesthetic ness should not be underestimated.62 Further investiga-
agents to prevent awareness remain unclear, in part tions into the anesthetic regimens and monitoring
because of the difficulty in assessing awareness. Studies necessary to prevent awareness and recall in pregnant
have evaluated several tools for assessment of depth of women undergoing operative procedures are needed.
maternal anesthesia, including the electroencephalo- These studies should incorporate the growing data on
gram, brainstem auditory evoked potentials, and the gender- and pregnancy-related differences in pharmaco-
bispectral index.62,276,311 The bispectral index is an empiri- kinetics and pharmacodynamics of drugs used for
cally derived electroencephalographic parameter in which anesthesia.370,371
values less than 60 are suggested to predict a low prob- Paradoxically, the issue of recall is not limited to the
ability of intraoperative recall and awareness.363 With administration of general anesthesia. In women undergo-
each of these monitoring devices, the threshold for ing cesarean delivery with a neuraxial technique who
awareness will need further validation, particularly during desire treatment for anxiety, the administration of anxio-
pregnancy364; moreover, many of these devices are not lytic or hypnotic agents may result in a lack of recall of
suitable for the emergency conditions under which delivery, which is typically undesirable.
most general anesthetics for cesarean delivery are
administered.
Yeo et al.365 evaluated 20 women undergoing cesarean
Dyspnea
delivery and noted that an end-tidal concentration of 1% After the initiation of neuraxial anesthesia, the patient
sevoflurane (approximately 0.5 MAC) with 50% nitrous may complain of dyspnea. The most common cause of
oxide resulted in a range of bispectral index values this complaint is hypotension (causing hypoperfusion of
between 52 and 70; no patient experienced intraoperative the brainstem); therefore, the complaint of difficulty in
dreams, recall, or awareness. Using a similar regimen, breathing should prompt immediate assessment of blood
Yoo et al.276 demonstrated that bispectral index values pressure and treatment, if appropriate. Other causes of
were lower during general anesthesia in women who were dyspnea are the blunting of thoracic proprioception, the
in labor prior to cesarean delivery than in nonlaboring partial blockade of abdominal and intercostal muscles,
women; the nonlaboring group did not reliably have and the recumbent position, which increases the pressure
values less than 60, and the mean value at tracheal intuba- of the abdominal contents against the diaphragm. The
tion was 64 ± 10. Ittichaikulthol et al.366 found that mean sensation of dyspnea appears related to the cephalad
bispectral index values in women undergoing cesarean extent of the sensory blockade and may be mitigated by
delivery with 3% and 4.5% desflurane in 50% nitrous using a low-dose hyperbaric spinal bupivacaine technique
oxide were 62 ± 8 and 49 ± 12, respectively. Chin et al.275 in women undergoing cesarean delivery.372
observed that an 80% probability of maintaining bispec- Despite these changes, significant respiratory com-
tral index values less than 60 required a sevoflurane con- promise is unlikely, primarily because the neuraxial
centration of at least 1.2% to 1.3%. blockade rarely affects the cervical nerves that control
Although pregnancy diminishes anesthetic require- the diaphragm. Lirk et al.373 evaluated the effects of
ments by 25% to 40%,273 administration of 0.5 MAC of spinal bupivacaine 10 mg, ropivacaine 20 mg, and
580 PART VII Cesarean Delivery
levobupivacaine 10 mg, all with fentanyl 15 µg, on anesthesia; however, the investigators found that patients
women undergoing cesarean delivery. Reductions in the with a baseline heart rate higher than 90 bpm had a 83%
functional vital capacity (3 to 6%) and peak expiratory chance (positive predictive value) of experiencing marked
flow rate (6 to 13%) were observed; however, the find- hypotension (decrease in blood pressure > 30%), whereas
ings had no apparent clinical significance, were similar patients with a baseline heart rate lower than 90 bpm had
for all local anesthetics, and did not differ for sensory a 75% chance (negative predictive value) of not experi-
blockade that extended higher, versus no higher, than encing marked hypotension.
the T4 dermatome. Dahlgren et al.384 hypothesized that the response of
If the patient loses the ability to vocalize, demonstrate pregnant women to a preoperative supine stress test would
a strong hand grip, and/or maintain normal oxyhemoglo- predict the occurrence of maternal symptoms, a need
bin saturation (e.g., symptoms suggestive of high spinal for ephedrine, or a decrease in blood pressure below
anesthesia), a rapid-sequence induction with cricoid pres- 80 mm Hg during administration of spinal anesthesia
sure and placement of an endotracheal tube should be for cesarean delivery. The supine stress test was consid-
performed to maintain ventilation and prevent pulmo- ered positive if it was associated with (1) an increase in
nary soiling with gastrointestinal contents. maternal heart rate greater than 10 bpm, (2) a decrease
in systolic blood pressure of more than 15 mm Hg, or
(3) signs and symptoms related to the supine position
Hypotension (e.g., nausea, dizziness). These investigators found that
Hypotension is a common sequela of neuraxial anesthesia the preoperative stress test had a sensitivity of 69% and
and, if severe and sustained, may lead to impairment of a specificity of 92% in identifying those who would have
uteroplacental perfusion and result in fetal hypoxia, aci- hypotension.
dosis, and neonatal depression or injury.374 Severe mater- Investigators have used other methods, including
nal hypotension can also have adverse maternal outcomes, assessment of heart rate variability385,386 and noninvasive
including altered consciousness, pulmonary aspiration, measurements of systemic vascular resistance (e.g., tho-
apnea, and cardiac arrest. racic impedance387) in an attempt to identify parturients
Although not universally accepted, most investigators at risk for neuraxial anesthesia–induced hypotension for
accept the following definitions for maternal hypoten- cesarean delivery. Hanss et al.385,388 suggested that the
sion: (1) a decrease in systolic blood pressure of more low- to high-frequency ratio of heart rate variability
than 20% to 30% from baseline measurements or (2) a could identify pregnant patients at risk for severe spinal
systolic blood pressure lower than 100 mm Hg.375 Neur- anesthesia–induced hypotension and could guide prophy-
axial anesthetic techniques produce hypotension through lactic treatment with fluid and vasopressors. To date, pre-
blockade of sympathetic nerve fibers, which control vas- dicting which parturients will have hypotension after
cular smooth muscle tone. Several studies using nonin- neuraxial anesthesia for cesarean delivery has not proven
vasive measures of cardiac output have demonstrated that feasible clinically and will likely require more sophisti-
cardiac output commonly increases after spinal anesthesia, cated studies that employ a number of different method-
even in the presence of a phenylephrine infusion and fluid ologies; the reason may be the myriad of factors that
administration.376-378 These studies emphasize that spinal control the autonomic, physiologic, and hormonal
anesthesia–induced hypotension is principally related to changes and hemodynamic responses that occur during
a marked decrease in systemic vascular resistance, rather pregnancy.
than decreased cardiac output. The rate and extent of the
sympathetic involvement, and subsequently the severity Prevention of Hypotension
of hypotension, are determined by the onset and spread
of the neuraxial blockade379; hypotension may be less A number of strategies can mitigate hypotension after
common with epidural anesthesia than with spinal anes- spinal anesthesia for cesarean delivery, including fluid
thesia because of the slower onset of neuroblockade and administration, vasopressor administration, lower local
the earlier recognition and treatment.380 anesthetic doses, leg elevation or wrapping, and left
uterine displacement.
Risk Factors for Hypotension The use of intravenous fluid to prevent hypotension
can be manipulated by (1) timing of administration,
A number of studies have attempted to identify pregnant either prior to (preload) or coincident with (co-load) the
women at increased risk for development of hypotension. intrathecal injection, and/or (2) type of fluid, either crys-
Of interest, women with severe preeclampsia381 or in talloid or colloid. Rate of fluid administration may also
established labor appear less likely to experience hypo- play a role. A crystalloid preload is minimally effective,
tension during administration of spinal anesthesia for even when volumes as great as 30 mL/kg are infused.93
cesarean delivery. By contrast, a colloid preload consistently reduces the
Using a modified orthostatic challenge (i.e., “tilt test”), incidence and severity of hypotension. Ueyama et al.389
Kinsella and Norris382 were unable to establish a correla- compared the administration of 1500 mL of lactated
tion in the observed change in blood pressure or heart Ringer’s solution and 500 mL and 1000 mL of hydroxy-
rate with hypotension after spinal anesthesia. Similarly, ethyl starch solution (HES) 6% prior to spinal anesthesia
Frölich and Caton383 could not establish a correlation for cesarean delivery; the incidence of hypotension (sys-
between orthostatic blood pressure and heart rate tolic blood pressure < 100 mm Hg and < 80% of baseline)
changes and the hypotension that developed after spinal was 75%, 58%, and 17%, respectively. Significant
26 Anesthesia for Cesarean Delivery 581
60
1.0 Liter HES sion for women undergoing cesarean delivery. Although
greater doses of ephedrine provided more effective pro-
45
phylaxis, hypotension was still observed and reactive
30 hypertension and umbilical artery metabolic acidosis
15
were more common.
Traditionally, ephedrine was used to prevent and treat
0 the hypotension associated with neuraxial anesthesia
–15 because of fear that pure alpha-adrenergic agonists would
0 5 10 15 20 25 30 decrease uterine blood flow. However, phenylephrine is
Percent change in blood volume equally efficacious to ephedrine for the prevention and
treatment of hypotension, and it is less likely to depress
FIGURE 26-7 ■ The relationship between the changes (%) in
blood volume and cardiac output after volume preload in par-
umbilical arterial blood pH and base excess.392 Phenyl-
turients undergoing spinal anesthesia. Cardiac output (CO) was ephrine crosses the placenta at a lower rate than ephed-
estimated with indocyanine green pulse spectrophotometry rine and undergoes greater fetal metabolism than
methodology. HES, hydroxyethyl starch solution; LR, lactated ephedrine.393 Presumably, fetal ephedrine contributes to
Ringer’s solution. (Modified from Ueyama H, He Y, Tanigami H, stimulation of fetal metabolism, resulting in lower pH
et al. Effects of crystalloid and colloid preload on blood volume in
the parturient undergoing spinal anesthesia for elective cesarean and base excess than phenylephrine.394
section. Anesthesiology 1999; 91:1571-6.) There is some controversy as to whether vasopressors
should be administered as a continuous infusion or bolus,
particularly for the prevention of hypotension. When
administered as an infusion, phenylephrine infusion rates
increases in intravascular volume and cardiac output, as of 25 to 100 µg/min are usually used to prevent hypoten-
measured by indocyanine green spectrophotometry, were sion.395,396 However, the number of interventions to
observed in the HES groups (Figure 26-7). At 30 minutes, maintain systolic blood pressure within 20% of baseline
100% of the HES volume, versus 28% of the lactated are lower for phenylephrine infusions of 25 and 50 µg/
Ringer’s volume, remained within the intravascular space. min than for infusions of 75 and 100 µg/min because of
In one trial,94 the rapid administration of a crystalloid the number of interventions required to treat hyperten-
co-load (20 mL/kg in 10 minutes, initiated immediately sion with the higher doses. Using an up-down sequential
on induction of spinal anesthesia) was more effective than allocation study design, the effective phenylephrine bolus
crystalloid preload in preventing hypotension; however, dose for preventing hypotension in 95% of patients
a meta-analysis of randomized trials comparing crystal- (ED95) was estimated at 159 µg (95% CI, 122 to
loid preload to co-load did not find a difference in the 371 µg).397 Reflex decreases in heart rate and reductions
incidence of hypotension.95 Similarly, no difference in the in cardiac output may occur with phenylephrine; however,
incidence of hypotension is observed with a colloid this does not appear to affect umbilical cord blood gas
preload versus co-load, likely reflecting the intravascular measurements or neonatal Apgar scores in uncompro-
dwell time of colloid.95 Additionally, co-load administra- mised infants delivered via elective cesarean delivery.396
tion of colloid is as effective, and likely more effective, The effect on infants that have been subjected to intra-
than co-load administration of crystalloid.376 uterine compromise remains unclear.
The cost and associated pruritus, mild coagulation One study demonstrated a salutary effect of a prophy-
abnormalities, and potential for allergic reaction to lactic infusion of ephedrine combined with phenyleph-
colloid starch solutions, particularly with first-generation rine compared with infusion of ephedrine alone.398
agents, have tempered their widespread use. Possible However, another study comparing infusions of different
fetal and neonatal effects related to the type and timing ephedrine-to-phenylephrine ratios found that as the pro-
of maternal fluid administration deserve further investi- portion of ephedrine increased, the incidence of hypoten-
gation; for example, the rapid administration of 1500 to sion and nausea/vomiting also increased, whereas
2000 mL of fluid can release atrial natriuretic peptide, umbilical cord blood pH and base excess were decreased.399
which may result in vasodilation and reduced sensitivity The titration of vasopressor infusions often requires
to vasoconstrictors.390 Our current practice is to admin- frequent infusion rate adjustments, and this mode of
ister a rapid crystalloid co-load (approximately 15 mL/ administration may be more cumbersome than bolus
kg) to healthy parturients undergoing elective cesarean administration of the same agents. Thus, some clinicians
delivery with spinal anesthesia. Parturients at high risk prefer to administer a bolus dose of vasopressor to prevent
for hypotension (e.g., history of supine hypotension syn- or treat hypotension. Loughrey et al.400 tested various
drome), or at high risk for the adverse consequences of ratios of ephedrine combined with phenylephrine, admin-
hypotension (e.g., hypertrophic cardiomyopathy), receive istered as a bolus, but were unable to identify a combina-
a colloid preload (500 mL). tion that reliably prevented hypotension yet avoided
Vasopressor agents, including ephedrine and phen- hypertension. Methods under investigation include a
ylephrine, can be titrated to maintain maternal blood closed-loop feedback computer-controlled infusion of
pressure and have been observed to be more effective phenylephrine for maintaining blood pressure during
than crystalloid solution or placebo in preventing spinal spinal anesthesia.401
582 PART VII Cesarean Delivery
The combination of fluid and vasopressor administra- efficacy and apparent superiority (over other agents)
tion may be the most effective regimen to prevent hypo- in protecting and/or restoring uterine blood flow in
tension. Ngan Kee et al.402 reduced the incidence of gravid ewes and other pregnant animal models.405 By
spinal anesthesia–associated hypotension to almost zero contrast, other agents, including metaraminol and phen-
(1.9%) by combining a rapid crystalloid co-load with ylephrine, while restoring maternal blood pressure, were
a prophylactic phenylephrine infusion (beginning at associated with a decrease in uterine artery blood flow
100 µg/min); the incidence of hypotension was 28% in and fetal pH.405
the women who received phenylephrine without the Contemporary animal studies have provided a mecha-
co-load. No difference in neonatal outcome was observed nistic understanding of these effects. During pregnancy
between groups. vasopressors appear to constrict the femoral artery more
The use of lower doses of spinal local anesthetic is than the uterine artery, which increases blood pressure
associated with a lower incidence of hypotension, par- and protects uterine blood flow. This differential pressor
ticularly when high and low doses are compared (e.g., effect is greater for ephedrine than metaraminol.406 A
hyperbaric bupivacaine 6.5 versus 9.5 mg, or 3.75 versus second mechanism appears to be the up-regulation of
9 mg; and plain bupivacaine 5 versus 10 mg combined nitric oxide synthase (NOS) in the uterine artery during
with fentanyl 25 µg).403 However, the desire to use a low pregnancy.407 The presence of NOS potentially makes
dose of spinal local anesthetic (e.g., bupivacaine ≤ 8 mg) this artery less sensitive to vasopressors; this effect may
should be tempered by the potential for an increased be further augmented by ephedrine, a drug observed to
requirement for intraoperative supplemental analgesia or independently cause the release of NOS.
conversion to general anesthesia.404 The optimal local In a quantitative systematic review, Lee et al.392 noted
anesthetic dose is likely influenced by a number of factors, that the use of ephedrine for treatment of maternal hypo-
including technical factors (e.g., precision of dose, spinal tension during administration of spinal anesthesia for
level of injection, concomitant opioid use, positioning of cesarean delivery was associated with lower umbilical
patient during and after the block), and other factors cord blood pH measurements than the use of phenyleph-
(e.g., genetic sensitivity, patient expectations, differences rine. This surprising clinical result (which differs from
in operative technique); these factors are often not con- results in animal studies) may reflect interspecies differ-
trolled in studies of local anesthetic dose.403 Anesthesia ences in vascular smooth muscle physiology, control of
providers who administer an intermediate or low dose of blood flow, and drug metabolism. Also, this result may
local anesthetic should consider the use of a catheter- reflect the fetal effects of ephedrine given to the mother.
based technique (continuous spinal or CSE anesthesia), Cooper et al.394 developed a measurement index by sub-
given the frequent need (up to 40%) for supplemental tracting the umbilical vein Pco2 from the umbilical artery
administration of additional local anesthetic through the Pco2 to determine the amount of CO2 generated by the
catheter.403 fetus; the index indicated a higher metabolic production
Physical methods to prevent hypotension include the of CO2 in fetuses whose mothers received ephedrine.
use of lower limb compression bandages or pneumatic Ngan Kee et al.393 observed that the greater depression
compression devices, which have demonstrated some of fetal pH and base excess with ephedrine compared
success375 and may assist in preventing thromboembolic with phenylephrine appears related to its ability to cross
complications. Compared with the supine position, left the placenta to a greater extent, undergo less early metab-
uterine displacement does not consistently reduce the olism or redistribution in the fetus, and consequently
occurrence of maternal hypotension during cesarean produce greater fetal concentrations of lactate, glucose,
delivery,375 most likely reflecting the variable presence and catecholamines.
and significance of supine hypotension syndrome. The NICE guidelines state that phenylephrine and
However, in some studies, adequate left uterine displace- ephedrine are equally effective as vasopressors.408 Given
ment was associated with higher umbilical arterial blood the efficacy of phenylephrine in the treatment of hypo-
pH measurements and better neonatal outcomes than the tension and the better umbilical cord blood acid-base
supine position, indicating that maternal blood pressure measurements associated with its use in clinical studies,
measured at the level of the brachial artery may not many anesthesia providers now use phenylephrine as a
always predict uteroplacental perfusion. It is not known first-line agent for the prevention and treatment of
a priori who will experience hypotension; more impor- maternal hypotension.409 Regardless of the vasopressor
tant, diminished uterine blood flow may occur in the agent selected to treat hypotension, therapy should be
presence or absence of maternal hypotension. Thus, we administered as soon as the blood pressure begins to
consider the use of left uterine displacement mandatory decrease, rather than after the occurrence of clinically
during anesthesia for cesarean delivery. significant hypotension.410 In addition, vasopressor
administration strategies can optimize maternal, and
potentially fetal, hemodynamics and well-being by main-
Treatment of Hypotension
taining blood pressure near baseline, instead of lower
The ideal treatment of hypotension would be reliable, target goals such as 80% or 90% of baseline measure-
titratable, easy to use, and devoid of maternal and ments.411 Ephedrine is usually administered intravenously
fetal side effects. Almost 40 years ago, ephedrine, a in bolus doses of 5 to 10 mg. Phenylephrine may be
mixed alpha- and beta-adrenergic receptor agonist, administered intravenously in bolus doses of 50 to 100 µg
emerged as the leading choice for the treatment of or by continuous infusion beginning at 25 to 50 µg/
hypotension on the basis of studies demonstrating its min,395 with titration to maintain maternal arterial blood
26 Anesthesia for Cesarean Delivery 583
pressure at or near baseline and avoidance of maternal Management of breakthrough pain should begin with
bradycardia.378 Administration of ephedrine may lead to acknowledgement of the patient’s discomfort and a con-
tachycardia, as well as tachyphylaxis. By contrast, phen- sideration of the fetal (e.g., presence of nonreassuring
ylephrine may result in reflex maternal bradycardia, fetal status), surgical (e.g., ongoing or anticipation of
which, if treated with an anticholinergic agent in the prolonged surgery), and anesthetic (e.g., maternal airway
absence of hypotension, may result in significant examination, BMI) implications, as well as the anesthesia
hypertension. provider’s experience. Emergent or ongoing surgery may
require administration of general anesthesia. If no block
exists, the surgery has not begun, and time allows, neur-
Failure of Neuraxial Blockade axial anesthesia can be repeated; whether an epidural or
“Failed” neuraxial anesthesia can be defined as neuro spinal technique is attempted depends on the previously
blockade insufficient in extent, density, or duration to mentioned factors. If an inadequate, partial block exists
provide anesthesia for cesarean delivery. Four to 13 in an elective situation, either the surgery can be
percent of epidural anesthetics and 0.5% to 4% of spinal postponed (to allow resolution of the partial block)
anesthetics fail to provide sufficient anesthesia for the or a second neuraxial technique may be performed with
initiation or completion of cesarean delivery.412,413 Epidu- caution.
ral techniques are more often associated with failure, The disadvantages of replacing a failed neuraxial block
given that the catheter is often placed during early labor, with epidural anesthesia include (1) the potential for
and over time the catheter may migrate out of the epi- local anesthetic toxicity (particularly after epidural
dural space. Factors that may correlate with failed exten- administration of a large dose of local anesthetic for the
sion of labor epidural anesthesia for cesarean delivery initial attempt), (2) the time required to establish an
include a higher number of bolus doses for the provision adequate block, and (3) the unpredictable reliability and
of labor analgesia (i.e., treatment of breakthrough pain), quality of the resulting block. As a consequence, many
patient characteristics (e.g., obesity, distance from the practitioners intent on replacing a failed epidural tech-
skin to the epidural space), and the time elapsed between nique suggest the cautious use of a technique with an
placement of the epidural catheter and cesarean intrathecal component (i.e., spinal, CSE, or continuous
delivery.413 spinal technique).414
The causes of failure of neuraxial techniques include The performance of a spinal technique in the setting
anatomic, technical, and obstetric factors. Steps to reduce of a partial but failed epidural or spinal anesthetic tech-
the likelihood of epidural block failure include meticu- nique is controversial. In this setting, intrathecal admin-
lous attention to technical detail, the administration of a istration of a standard intrathecal dose of bupivacaine
solution that contains both a local anesthetic and an may result in a high spinal block.415 Radiographic evi-
opioid, and a better understanding of the characteristics dence suggests that the dural sac is compressed by prior
of epidural versus spinal blockade. Moreover, the patient epidural drug administration.254 Thus, when performing
should be prepared to expect the sensation of deep pres- a spinal anesthetic technique after failed epidural or
sure and movement yet be reassured that reports of dis- spinal anesthesia, the anesthesia provider should consider
comfort or pain will be addressed promptly. Initiation of (1) using a different interspace to avoid the anatomic
surgery should be delayed until adequate thoracic and distortions (e.g., from the loss of resistance to saline or
sacral sensory blockade has been achieved; on rare occa- previous needle passes) or difficulties; (2) reducing the
sions, in the setting of an urgent procedure for which a dose of bupivacaine (with the chosen dose depending on
developing epidural block is present at T10 but has yet the extent of existing neuroblockade); (3) placing the
to achieve a T4 level, surgery can commence with the patient in a semi-sitting (Fowler’s) position to limit ceph-
understanding that adjuvant treatments or alternative alad spread of the local anesthetic; (4) using a CSE tech-
forms of anesthesia may be required. nique with a small intrathecal dose of local anesthetic,
Evaluation of intraoperative pain requires (1) determi- and, if necessary, titrating the sensory level with addi-
nation of the location and extent of discomfort, (2) evalu- tional drugs administered through the epidural catheter;
ation of the sensory level of anesthesia, (3) assessment of and (5) intentionally placing an epidural catheter into the
the current status of the surgery (e.g., incision, delivery, intrathecal space for administration of continuous spinal
uterine repair, skin closure), and (4) assessment of the anesthesia. This last strategy may be especially useful in
presence of confounding factors (e.g., hemorrhage, obese patients in whom the technical difficulty of the
anxiety). Shoulder pain can originate from irritation of neuraxial approach may otherwise limit success.
the diaphragm (usually by amniotic fluid or blood) and is If discomfort is reported after the start of surgery, it is
mediated by the phrenic nerve (C3 to C5); prolonged often helpful to ask the surgeons to halt the operation
abduction and extension of the arms can also cause dis- while an assessment is made. If an epidural catheter is in
comfort. Additional discomfort can occur from visceral place, an alkalinized local anesthetic with an opioid (e.g.,
stimulation such as uterine manipulation, which often 3% 2-chloroprocaine with fentanyl) should be adminis-
involves the greater splanchnic nerve (T5 to T10). Alter- tered. The density of epidural anesthesia may be improved
natively, the extent of the block may be adequate but the by “repainting the fence.” An additional dose of local
density of neuroblockade of the large nerve fibers in the anesthetic (20% to 30% of the initial dose [e.g., 4 to
lumbosacral plexus may be inadequate. Inadequate anes- 7 mL]) is administered approximately 20 minutes after
thesia can result from regression of the block from a the initial dose. This second dose serves to improve the
cephalad or caudad direction. density of neuroblockade without extending the sensory
584 PART VII Cesarean Delivery
level. Some anesthesia providers routinely administer this and spinal nerves to the abdominal muscles, which causes
supplemental dose, without waiting for a patient’s com- the physical act of vomiting.
plaint of breakthrough pain.
Intravenous administration of an opioid (fentanyl), Preoperative Nausea and Vomiting
inhalation of nitrous oxide (40% to 50% in oxygen),
or intravenous anxiolysis (midazolam) may be helpful Nausea and vomiting may occur separately or in com-
for the treatment of breakthrough pain. Severe pain bination and are not uncommon during pregnancy. A
may require intravenous ketamine in 5- to 10-mg incre- number of metabolic, endocrine, and anatomic changes
ments. However, care should be taken, because the have been implicated in the genesis of gestational nausea
administration of multiple agents can result in significant and vomiting, including human chorionic gonadotropin,
sedation, loss of consciousness, and the presence of estrogen, progesterone, prostaglandins, and immune
psychomimetic and amnestic effects. The obstetrician system dysregulation.416 When vomiting is sufficiently
can infiltrate the wound or instill the peritoneal cavity severe to produce weight loss, dehydration, acidosis
with local anesthetic; however, at this point, the induc- from starvation, alkalosis from loss of hydrochloric acid
tion of general anesthesia with tracheal intubation is in vomitus, and hypokalemia, it is referred to as hyper-
often necessary. emesis gravidarum (see Chapter 16). This disorder most
If the anesthesia provider anticipates that the duration commonly occurs in early pregnancy, but as many as
of the surgical procedure will be longer than the pre- 10% of pregnant women have nausea and vomiting
dicted duration of epidural or CSE anesthesia, additional that persist beyond 22 weeks’ gestation.416 Severe and
local anesthetic (with or without an opioid) should be persistent hyperemesis may result in maternal and fetal
administered before anticipated regression of neuroblock- morbidity.
ade (see Table 26-6). The usual dose to maintain neuro- The presence of delayed gastric emptying during labor
blockade is half of the initial dose. and administration of opioids are risk factors for nausea
and vomiting before cesarean delivery.
High Neuraxial Blockade
Intraoperative Nausea and Vomiting
It is not uncommon for the parturient to report mild
dyspnea or reduced ability to cough, especially if the Intraoperative nausea and vomiting associated with cesar-
neuraxial blockade has achieved a T2 sensory level. If ean delivery can be variable in incidence and presenta-
impaired phonation, unconsciousness, respiratory depres- tion, depending on preexisting symptoms, anesthetic and
sion, or significant impairment of ventilation occurs, obstetric techniques, and preventive and therapeutic
administration of general anesthesia should be performed. measures. The incidence of nausea may be as high as
High neuraxial blockade may also result in cardiovascular 80%, particularly when the anesthesia provider specifi-
sequelae, including bradycardia and hypotension. An easy cally assesses for the presence of intraoperative symp-
method to diagnose a clinically significant high neuraxial toms; symptoms occur frequently with exteriorization of
blockade is to ask the patient to make a fist (“squeeze your the uterus.7 Anesthetic causes of intraoperative nausea
fingers”). A weak hand grasp indicates high thoracic and and vomiting include hypotension and increased vagal
cervical motor blockade. activity; nonanesthetic causes include surgical stimuli,
High neuraxial block can be caused by several mecha- bleeding, medications (e.g., uterotonic agents, antibiot-
nisms, including an exaggerated spread of spinal or epi- ics), and motion at the end of surgery.417 Many of these
dural drugs and unintentional intrathecal or subdural elements occur simultaneously.
administration of an “epidural dose” of local anesthetic. Hypotension is among the most common sequelae
The rapid epidural administration of a large volume of associated with the administration of neuraxial anesthe-
local anesthetic solution in the presence of a large-bore sia. Centrally, hypotension may lead to cerebral and
dural puncture (e.g., after a “wet tap”) may also result in brainstem hypoperfusion, which results in stimulation of
high neuroblockade. the medullary vomiting center. Peripherally, hypotension
may cause gut ischemia with release of emetogenic sub-
stances (e.g., serotonin) from the intestine.418 Strict main-
Nausea and Vomiting tenance of intraoperative blood pressure can reduce the
Nausea and vomiting are regulated by the chemoreceptor occurrence of emesis; Datta et al.410 observed that the
trigger zone and the vomiting center, which are located incidence of intraoperative nausea and vomiting was 66%
in the area postrema and the medullary lateral reticular when the blood pressure decreased more than 30% from
formation, respectively. The vomiting center receives baseline, but was less than 10% when blood pressure was
impulses from the vagal sensory fibers in the gastrointes- maintained at baseline with ephedrine. Similarly, Ngan
tinal tract, the semicircular canals and ampullae (laby- Kee et al.411 demonstrated progressive increases in intra-
rinth) of the inner ear, higher cortical centers, the operative nausea and vomiting when blood pressure
chemoreceptor trigger zone, and intracranial pressure control with an infusion of phenylephrine was less aggres-
receptors. Impulses from these structures are influenced sive; the incidence of nausea and vomiting was 4% when
by dopaminergic, muscarinic, tryptaminergic, histaminic, blood pressure was maintained at 100% of baseline, 16%
and opioid receptors, which are subsequently the targets when maintained at 90% of baseline, and 40% when
for antiemetic agents. Efferent impulses from the vomit- maintained at 80% of baseline during spinal anesthesia
ing center are transmitted through the vagus, phrenic, for cesarean delivery.
26 Anesthesia for Cesarean Delivery 585
Uterotonic agents may also contribute to intraopera- sickness or postoperative nausea and vomiting, (3) non-
tive nausea and vomiting. Ergot alkaloids may cause smoking status, and (4) the use of perioperative opioids.
nausea and vomiting by interacting with dopaminergic The incidence of postoperative nausea and vomiting
and serotoninergic receptors. Oxytocin causes nausea was 10% if the patient had no risk factors, 21% for
and vomiting primarily as a result of the hypotension one, 39% for two, 61% for three, and 79% for four.
produced through release of nitric oxide and atrial A subset of pregnant women may have a lower threshold
natriuretic peptide.419 A 29% incidence of nausea and for nausea and vomiting associated with motion.416
a 9% incidence of vomiting have been reported with Changes in position and transfer to and on the stretcher
an intravenous bolus of oxytocin 5 units during elective may stimulate afferent neural pathways that trigger
cesarean delivery with neuraxial anesthesia.420 Admin- emesis. Because the histamine-1 (H1) and muscarinic
istration of 15-methyl prostaglandin F2α causes nausea cholinergic pathways play primary roles in this response,
through the stimulation of smooth muscles of the gas- antihistamine and anticholinergic agents should be con-
trointestinal tract; a 10% incidence of nausea and vom- sidered first-line treatments.424 Postoperative nausea and
iting has been observed after administration of 250 µg vomiting may be related to postoperative ileus, which
intramuscularly.417 in turn is influenced by the effect of opioids on the
Surgical stimuli, including exteriorization of the gastrointestinal tract, the activation of the sympathetic
uterus, intra-abdominal manipulation, and peritoneal nervous system, the occurrence of intestinal wall inflam-
traction, can cause visceral pain and subsequent nausea mation, and the presence of volume overload or edema.416
through the stimulation of vagal fibers and activation of
the vomiting center; despite high levels of thoracic Prophylaxis and Treatment of Nausea
sensory block obtained for cesarean delivery anesthesia, and Vomiting
visceral pain may still occur, particularly after the neur-
axial administration of a local anesthetic without opioid.421 Preventing maternal hypotension may be the best means
The administration of neuraxial opioids reduces visceral of preventing nausea and vomiting (see earlier). Several
pain–induced nausea and vomiting. Neuraxial fentanyl options exist for the pharmacologic prophylaxis of nausea
both improves the quality of neuraxial anesthesia and and vomiting, and several different classes of drugs are
decreases intraoperative nausea; the minimal effective available (Table 26-7). Although various algorithms have
doses are 6.25 µg given intrathecally and 50 µg given been developed to prevent postoperative nausea and
epidurally, respectively.180 vomiting, primarily targeting the nonpregnant patient
population, none has been universally successful.425
However, the prophylactic use of these agents either
Postoperative Nausea and Vomiting
before or after umbilical cord clamping during cesarean
Risk factors for postoperative nausea and vomiting have delivery with neuraxial anesthesia has been demonstrated
not been specifically studied in obstetric patients; to be highly effective. Balki and Carvalho417 suggested an
however, studies have identified risk factors in nonob- algorithm consisting of metoclopramide as a first-line
stetric patients receiving general or neuraxial anesthesia agent, dimenhydrinate as a second-line agent, and ondan-
(Box 26-10).422,423 Apfel et al.423 identified the following setron or granisetron as a third-line agent. Multimodal
four highly predictive factors for postoperative nausea therapies may eventually prove the most effective.
and vomiting in nonobstetric patients after general Metoclopramide is the agent most frequently given,
anesthesia, which may have relevance in the pregnant owing to its favorable prokinetic effects. Common side
population: (1) female gender, (2) history of motion effects include dizziness, drowsiness, and fatigue; more
rare side effects include extrapyramidal reactions and
acute dystonias. In a meta-analysis of 11 studies of 702
Risk Factors for Nausea patients undergoing cesarean delivery, Mishriky and
BOX 26-10
and Vomiting Habib75 found that intravenous metoclopramide 10 mg,
administered before neuraxial blockade, resulted in a sig-
GENERAL ANESTHESIA–RELATED FACTORS nificant reduction in intraoperative nausea (RR, 0.27;
• Female gender 95% CI, 0.16 to 0.45) and vomiting (RR, 0.14; 95% CI,
• History of motion sickness or postoperative nausea and 0.03 to 0.56) when metoclopramide, rather than placebo,
vomiting was administrated before neuraxial blockade. This
• Nonsmoking status
• Use of perioperative opioids
approach was more effective than giving metoclopramide
after delivery, an approach that also resulted in a signifi-
SPINAL ANESTHESIA–RELATED FACTORS cant reduction in perioperative nausea and vomiting.
• Block height of T5 or higher Early postoperative nausea (RR, 0.47; 95% CI, 0.26 to
• History of motion sickness 0.87) and vomiting (RR, 0.45; 95% CI, 0.21 to 0.93) were
• Hypotension also reduced with metoclopramide.
• Omission of neuraxial opioids Abouleish et al.426 found that ondansetron was more
effective than placebo for the prevention of intraopera-
Information from Gan TJ. Risk factors for postoperative nausea and tive nausea and vomiting during cesarean delivery with
vomiting. Anesth Analg 2006; 102:1884-98; and Apfel CC, Laara E,
Koivuranta M, et al. A simplified risk score for predicting postoperative spinal anesthesia. Pan and Moore427 observed that when
nausea and vomiting: conclusions from cross-validations between two administered after umbilical cord clamping, ondansetron
centers. Anesthesiology 1999; 91:693-700. 4 mg was more effective than metoclopramide 10 mg
586 PART VII Cesarean Delivery
TABLE 26-7 Agents for Prevention of Nausea and Vomiting in Women Undergoing Cesarean
Delivery with Neuraxial Anesthesia*
Optimal or Recommended
Drug Dose Timing Comments
Dexamethasone 4-8 mg IV Unknown for patients undergoing Delayed onset of action; used
cesarean delivery† infrequently in patients undergoing
cesarean delivery
Dimenhydrinate‡ 25-50 mg IV Unknown for patients undergoing Antihistamine
cesarean delivery
Dolasetron 12.5 mg IV After umbilical cord clamping Serotonin antagonist; not effective in
the single published randomized
controlled trial
Droperidol 0.625-1.25 mg IV End of surgery Butyrophenone with a package insert
that contains an FDA “black box”
warning regarding prolongation of
corrected QT interval on
electrocardiogram
Ephedrine‡ 0.5 mg/kg IM End of surgery Vasopressor
Granisetron 40 µg/kg IV After umbilical cord clamping Serotonin antagonist
Metoclopramide 10 mg IV Prior to surgery or after umbilical Benzamide
cord clamping
Ondansetron 4 mg IV After umbilical cord clamping Serotonin antagonist
Scopolamine 1.5-mg transdermal Unknown Muscarinic antagonist
patch
in preventing nausea (26% versus 51%) but not vomit- subgroup analysis, the authors identified a lower inci-
ing (15% versus 18%). In a systematic review, Griffiths dence of postoperative nausea and vomiting in women
et al.428 concluded that the use of a serotonin antagonist who received epidural morphine; however, they were
(e.g., ondansetron, granisetron) in women undergoing unable to draw definitive conclusions regarding the effect
neuraxial anesthesia for cesarean delivery was associated of dexamethasone on postoperative nausea and vomiting
with a reduction in intraoperative nausea (but not vom- in women who received spinal morphine because of the
iting) and postoperative nausea and vomiting, compared small sample size.
with placebo. Furthermore, serotonin antagonists were Harnett et al.431 observed that the administration of a
found to be more effective in reducing postoperative transdermal scopolamine 1.5-mg patch after umbilical
nausea than dopamine antagonists (e.g., metoclopramide, cord clamping was as effective as ondansetron 4 mg in
droperidol).428 the prevention of nausea and vomiting after cesarean
In an animal toxicology study that was followed by a delivery with spinal anesthesia (bupivacaine 12 mg with
human clinical trial, Han et al.429 demonstrated no his- fentanyl 10 µg and morphine 0.2 mg); compared with
tologic changes in spinal cord tissues after epidural placebo, both drugs resulted in a reduction in the inci-
administration of ondansetron in rats. Moreover, in 80 dence of postoperative emesis from approximately 60%
women undergoing elective cesarean delivery with CSE to approximately 40%. The use of scopolamine may be
anesthesia, the incidence of postoperative nausea was limited by side effects, particularly dry mouth and blurry
lower in women randomized to receive an epidural infu- vision. The results of a systematic review suggest that the
sion of ondansetron than in women who received an use of an anticholinergic agent (e.g., scopolamine, glyco-
intravenous infusion (8 mg over 48 hours) at both 24 and pyrrolate) in women undergoing neuraxial anesthesia for
48 hours.429 However, future investigations are needed to cesarean delivery results in a significant reduction in
validate the safety of the neuraxial administration of intraoperative nausea but not vomiting.428
ondansetron before this route of administration can be Alternative therapies may play a role in preventing
recommended. or treating perioperative nausea and vomiting. Several
In a meta-analysis, Allen et al.430 found that a single studies have found a favorable effect of acupressure on
intravenous dose of dexamethasone 5 to 10 mg (but not the P6 acupoint (on the inner aspect of the wrist). After
2.5 mg) compared with placebo reduced the incidence of spinal anesthesia for cesarean delivery, acupressure has
postoperative nausea (23% versus 41%, respectively) and been observed to result in a lower incidence of nausea
vomiting (20% versus 36%, respectively) in women who (36% and 15%, respectively) and vomiting (17% and 9%,
received neuraxial morphine for cesarean delivery. In a respectively), when compared with placebo.432 Two
26 Anesthesia for Cesarean Delivery 587
systematic reviews of randomized controlled trials involv- management considerations. For example, an epidural
ing a total of 649 women undergoing neuraxial anesthesia catheter–based technique may be optimal for the patient
for cesarean delivery concluded that despite heterogene- with a significant pain history (e.g., sickle cell vaso-
ity in the data, P6 stimulation (compared with placebo) occlusive crises, chronic pain syndromes, drug-seeking
appears to reduce intraoperative nausea but not intraopera- behavior) so that the epidural catheter may be used for
tive vomiting or postoperative nausea or vomiting.428,433 postoperative pain management.
One study found that the administration of supple- By directly activating spinal and supraspinal opioid
mental oxygen (Fio2 of 0.7) between umbilical cord receptors, epidurally and spinally administered opioids
clamping and the end of cesarean delivery with neuraxial blunt nociceptive input and produce analgesia of greater
anesthesia was not associated with a lower incidence of intensity than parenterally or intramuscularly adminis-
nausea and vomiting than the administration of room tered doses.214 A number of opioids have been used in the
air.434 This finding is consistent with a meta-analysis435 of epidural and spinal spaces; however, morphine has
randomized controlled trials in the nonobstetric popula- emerged as the leading agent for postcesarean analgesia,
tion; there was no difference in the incidence of nausea owing to its long duration of action and low cost (see
and vomiting with the use of supplemental oxygen (Fio2 Chapter 28). When morphine is administered intrathe-
of 0.8) compared with the use of lower oxygen concentra- cally or epidurally, doses of 0.1 mg and 3.75 mg, respec-
tions (Fio2 of 0.3 to 0.4).435 tively, appear to provide optimal analgesia after cesarean
A systematic review428 suggests that the administration delivery.192,222 Neuraxial morphine has a peak analgesic
of subhypnotic doses of propofol (0.5 to 1.5 mg/kg/h) effect at 60 to 90 minutes but continues to provide effec-
for the reduction of intraoperative and postoperative tive analgesia for up to 24 hours.222 Thus, intrathecal
nausea and vomiting in women undergoing neuraxial morphine is often co-administered with the local anes-
anesthesia for cesarean delivery is more effective than thetic and lipid-soluble opioid administered for spinal
placebo; however, there are insufficient data to compare anesthesia, and epidural morphine is administered intra-
this method with other therapies.428 operatively, after the umbilical cord is clamped, to allow
sufficient time for the onset of epidural morphine anal-
gesia before the regression of epidural anesthesia.
Perioperative Pain The local anesthetic selected for epidural anesthesia
In contrast to surveys performed in the general surgical may influence postoperative analgesia. The epidural
patient population, in which patients have revealed a administration of 2-chloroprocaine has been observed to
primary concern for postoperative nausea and vomiting, adversely affect the subsequent efficacy of epidural mor-
a survey performed in obstetric patients during their phine analgesia,438 although this remains a matter of some
expectant parent class indicated that pain during and after dispute.439 The mechanism for this potential interaction
cesarean delivery was their greatest concern.436 Inade- remains unknown, however, the use of 2-chloroprocaine
quate neuraxial anesthesia leading to pain during labor or should be limited to emergency situations in which rapid
cesarean delivery was the most frequent “damaging augmentation of epidural anesthesia is desired (see earlier
event” in obstetric claims (31%) against the National discussion).
Health Service in the United Kingdom from 1995 to Adverse effects of neuraxial morphine include pruri-
2007.437 Although pain during cesarean delivery was gen- tus, nausea and vomiting, urinary retention, and delayed
erally classified as “mild” or “moderate” (when accompa- respiratory depression. Frequent evaluations (hourly for
nied by post-traumatic stress disorder), it represented an the first 12 hours, and then every 2 hours for another
especially frequent cause of low-severity obstetric 12 hours) should be conducted.440 Postpartum women
claims.437 Pain due to inadequate neuraxial anesthesia is who are morbidly obese or have preexisting respiratory
also a common cause of obstetric complaints in the issues (sleep apnea) are at greater risk for respiratory
American Society of Anesthesiologists Closed-Claims depression.
Project database (see Chapter 33). Postoperative pain has at least two components,
A preoperative discussion about pain and discomfort somatic and visceral. A multimodal approach with differ-
can help allay patient concerns. The anesthesia provider ent agents (e.g., ketamine) and techniques (e.g., infiltra-
should (1) explain that there may be some deep pressure, tion, peritoneal spraying, transversus abdominis plane
pain, or discomfort during cesarean delivery performed [TAP] block) provides the most effective postcesarean
with a neuraxial technique; (2) reassure the patient that analgesia (see Chapters 27 and 28). The administration
the anesthesia provider will be present throughout the of nonsteroidal anti-inflammatory drugs has been associ-
operation to administer additional analgesics or general ated with potential adverse effects (platelet dysfunction,
anesthesia if necessary; (3) ensure and document ade- uterine atony), and some investigators have expressed
quacy of neuraxial blockade before the start of surgery; concerns related to neonatal exposure through breast
(4) communicate with the patient frequently during the milk. However, the American Academy of Pediatrics441
procedure, specifically about pain or discomfort; and (5) has stated that ibuprofen and ketorolac are compatible
treat pain when it arises, in agreement with the patient’s with breast-feeding.
wishes. During the postoperative visit, the anesthesia
provider should address any concerns that may have
arisen during or after surgery.
Pruritus
The anesthetic technique for the cesarean delivery The incidence of pruritus with the administration of
may be altered because of postoperative pain opioids can be as high as 30% to 100%, and pruritus is
588 PART VII Cesarean Delivery
more commonly observed when opioids are administered infusion of any of these agents may reverse analgesia.
intrathecally than epidurally. Pruritus may be generalized Because the primary mechanisms of opioid-induced pru-
or localized to regions of the nose, face, and chest and is ritus appears unrelated to histamine release, antihista-
typically self-limited in duration. The particular combi- mines seldom represent a viable treatment option,
nations and doses of opioid and local anesthetic may although some benefit may be derived from the accom-
influence the incidence and severity of pruritus, and the panying sedative qualities of these agents.
addition of epinephrine to an opioid–local anesthetic
solution has been observed to worsen pruritus.442 Pruritus Hypothermia and Shivering
does not represent an allergic reaction to the neuraxial
opioid. If flushing, urticaria, rhinitis, bronchoconstric- Perioperative hypothermia and shivering are commonly
tion, or cardiac symptoms also occur, an allergic reaction observed in women undergoing cesarean delivery, with a
to another substance should be considered. reported incidence of 66% and 85%, respectively.445,446
The cause of neuraxial opioid–induced pruritus is not Hypothermia has been associated with a number of
known, although multiple theories have been proposed. adverse outcomes in nonpregnant surgical patients,
They include µ-opioid receptor stimulation at the medul- including wound infection, coagulopathy, increased
lary dorsal horn, antagonism of inhibitory transmitters, blood and transfusion requirements, increased oxygen
and activation of an “itch center” in the central nervous consumption, decreased metabolism, and prolonged
system.443 Pharmacologic prophylaxis or treatment of recovery.447 In a systematic evaluation of randomized
pruritus may include an opioid antagonist, an opioid trials of normothermic and mildly hypothermic (34° C to
agonist/antagonist, droperidol, a serotonin antagonist 36° C) nonpregnant surgical patients, Rajagopalan et al.448
(e.g., ondansetron), and/or a subhypnotic dose of propo- observed that even hypothermia less than 1° C below
fol (Table 26-8).443 Intravenous administration of granis- normal body temperature was associated with a 16%
etron 3 mg may reduce the severity but not the incidence increase in blood loss (95% CI, 4% to 26%) and a 22%
of intrathecal morphine–induced pruritus when com- increase in risk for transfusion (95% CI, 3% to 37%).
pared with administration of ondansetron 8 mg.444 Dexa- Normally, core body temperature is tightly regulated
methasone in doses of 2.5 to 10 mg has not been found within a narrow range of 36° C to 37° C. During preg-
to reduce the incidence of pruritus associated with neur- nancy, despite an increase in maternal basal metabolic
axial morphine in women undergoing cesarean deliv- rate and energy released by the developing fetal and
ery.430 Although opioid antagonists, such as naltrexone uteroplacental unit, maternal core temperature decreases,
and naloxone, and partial agonist/antagonists, such as reaching a nadir at 12 weeks postpartum (36.4° C).449
nalbuphine, are currently the most effective treatments Major causes of hypothermia during cesarean delivery are
for pruritus, a single dose or continuous intravenous most likely related to core-to-periphery heat redistribu-
tion due to diminished vasoconstriction and shivering,
particularly after neuraxial blockade, and impairment of
centrally mediated thermoregulatory control.447
The onset and severity of hypothermia and shivering
TABLE 26-8 Agents for Prevention or are associated with the patient’s baseline thermal status,
Treatment of Pruritus in Women the perioperative environment, and the anesthetic tech-
Undergoing Cesarean Delivery nique and agents selected. Saito et al.450 observed that
Drug Class Drug and Dose Comments spinal anesthesia reduced the initial core temperature of
patients undergoing cesarean delivery more rapidly than
Opioid Naloxone May reverse
antagonists infusion analgesia
epidural anesthesia, but the overall incidence of shivering
1-2 µg/kg/h IV was similar. However, the severity of shivering was sig-
Naltrexone nificantly less in the spinal group, possibly through the
6-9 mg PO induction of a lower shivering threshold or the inhibition
Opioid agonist/ Nalbuphine of thermoregulatory control as a function of the number
antagonist 2.5-5 mg IV of blocked dermatomes.451
Sedative/ Propofol Subhypnotic dose The effect of neuraxial opioids on thermoregulation
hypnotic 10-20 mg IV with conflicting
agent evidence regarding and shivering in patients undergoing cesarean delivery is
efficacy in treating not fully understood. Intravenously administered meper-
pruritus idine 12.5 to 25 mg is one of the most effective antishiv-
Serotonin Ondansetron Conflicting evidence ering drugs known and is unique among opioids in
antagonist 0.1 mg/kg IV regarding efficacy producing this effect at doses not typically associated with
in treating pruritus
respiratory depression. The mechanism of this effect
Butyrophenone Droperidol Package insert
1.25 mg IV contains an FDA
does not appear to be related to κ-opioid receptor activity
“black box” or inhibition of cholinergic receptors; instead, central
warning regarding α2B-adrenergic receptor stimulation may be involved.452
prolongation of The α2-adrenergic receptor agonists clonidine (150 µg)
corrected QT and dexmedetomidine are effective antishivering agents
interval on
electrocardiogram that can lower the shivering threshold,452 although both
agents may have limited use during pregnancy because
IV, intravenously; PO, orally. of the potential to cause sedation, bradycardia, and
26 Anesthesia for Cesarean Delivery 589
hypotension. Other modalities have been used to prevent myometrium less responsive to additional oxytocin but
and treat hypothermia and shivering. Preoperative patient not to other uterotonic agents.462 Pregnancy causes a
warming using forced air has been shown to reduce the 180-fold increase in the concentration of oxytocin recep-
incidence of perioperative and postoperative core hypo- tors with a significant proportion of this increase occur-
thermia and shivering in patients undergoing cesarean ring just before the onset of labor463; this change in
delivery with epidural anesthesia.453 In contrast, a subse- receptor number may have relevance to parturients who
quent study found that perioperative forced-air warming are delivering preterm infants.
did not prevent maternal hypothermia after cesarean Tsen and Balki455 have suggested a “rule of 3’s” (oxy-
delivery with spinal anesthesia.445 Lower limb wrapping tocin 3 units, 3-minute evaluation intervals, 3 total doses,
has also been observed to have no effect on the incidence and oxytocin 3 units/h for maintenance) protocol for the
of hypothermia or shivering.454 administration of oxytocin after delivery. The oxytocin 3
units is given as a slow bolus or as an infusion (30 units
oxytocin in 500 mL of normal saline [50 mL]), at a rate
no faster than over a period of 15 seconds. Uterine tone
OBSTETRIC COMPLICATIONS is reassessed again at 3 and 6 minutes; if inadequate, an
Postpartum Hemorrhage additional dose of oxytocin 3 units is given. If uterine
atony persists after three total doses of oxytocin, other
A leading cause of maternal and fetal morbidity and mor- uterotonic agents should be employed (see later discus-
tality worldwide, mild to moderate obstetric hemorrhage sion). The specific timing of the initial dose of oxytocin
can be masked by pregnancy-related physiologic changes. varies by individual practitioner; insufficient data are
Underestimation of blood loss and inadequacy of resus- available to determine whether oxytocin administration
citation remain common problems (see Chapter 38). immediately on emergence of the infant’s shoulder or
Failure of the uterus to contract (uterine atony) after body or after placental delivery makes a difference in
delivery accounts for most cases of postpartum hemor- overall blood loss during cesarean delivery. After the
rhage and remains a leading cause of postpartum hys- establishment of adequate uterine tone, an infusion of 3
terectomy and blood transfusion. Each minute, 600 to units/h for up to 5 hours is recommended.455
700 mL of blood flows through the placental intervil- The administration of oxytocin as a rapid intravenous
lous spaces; thus, obstetric hemorrhage can rapidly result bolus causes hypotension and may result in cardiovascu-
in maternal shock. Uterine atony occurs more commonly lar collapse464,465; patients with preeclampsia may have an
after cesarean delivery than after vaginal delivery, unpredictable hemodynamic response to oxytocin admin-
perhaps as a reflection of the condition(s) that prompted istration (i.e., decrease in cardiac output).466 Oxytocin has
the cesarean delivery or possibly because surgery disrupts a direct relaxing effect on the vascular smooth muscle,
the normal postpartum response to uterotonic hormones which leads to decreased systemic vascular resistance,
and pharmacologic agents. Risk factors for uterine atony hypotension, and tachycardia.467 Tachycardia also may
include (1) high parity, (2) an overdistended uterus result from a direct effect on specific oxytocic receptors
(multiple gestation, macrosomia, polyhydramnios), (3) in the myocardium and subsequently result in alterations
prolonged labor (augmented by oxytocin), (4) chorio- in atrioventricular conduction and myocardial repolariza-
amnionitis, (5) abnormalities in placentation (placenta tion.467 Chest pain and signs suggestive of myocardial
accreta, increta, or percreta), (6) retained placental tissue, ischemia and anaphylaxis may occur. Owing to the struc-
and (7) poor perfusion of the uterine myometrium (e.g., tural similarity of oxytocin to vasopressin, water intoxica-
with hypotension). tion may occur and, when severe, can lead to hyponatremia,
Initial efforts to control uterine atony include uterine confusion, convulsions, and coma.
massage and exogenous oxytocin administration. Post- If oxytocin proves ineffective, the ergot alkaloid deriv-
partum oxytocin is administered in a wide range of doses, ative methylergonovine (0.2 mg) may be given intra-
methods, and timing patterns (e.g., before or after deliv- muscularly to enhance uterine tone; onset time is within
ery of the placenta),455 although small doses of oxytocin 10 minutes and the effect persists for 3 to 6 hours. Intra-
are sufficient to produce adequate uterine contraction venous administration (in small divided doses) should be
after cesarean delivery in most women.455 The effective performed only with great caution, because intense vaso-
bolus dose necessary for adequate uterine tone in 90% constriction may lead to acute hypertension, seizures,
(ED90) of nonlaboring women undergoing cesarean cerebrovascular accident, retinal detachment, and myo-
delivery oxytocin is 0.35 unit456; in laboring women who cardial arrest468; this possibility is of special concern in
have received approximately 10 hours of oxytocin aug- patients with preeclampsia or cardiac disease. Methyler-
mentation, the ED90 is 2.99 units.457 George et al.458 esti- gonovine also has additive hemodynamic effects when
mated the ED90 of an oxytocin infusion to be 0.29 unit/ given with sympathomimetic agents, such as ephedrine
min (95% CI, 0.15 to 0.43). and phenylephrine. Nausea and vomiting are common
Women receiving oxytocin augmentation for labor side effects, which most likely reflect a direct central
have greater blood loss despite higher oxytocin doses; this nervous system effect. The co-administration of oxytocin
appears to originate from signal attenuation and desensi- and ergometrine has been demonstrated to improve
tization of the oxytocin receptors in a time- and uterine contractions (as measured by the requirement for
concentration-dependent manner.459-462 Continued high- additional uterotonic agents) compared with the admin-
dose oxytocin exposure in the postpartum period can istration of oxytocin alone; however, the estimated blood
lead to acute receptor desensitization and render the loss was not different between groups, and nausea and
590 PART VII Cesarean Delivery
vomiting were more prevalent with the oxytocin- erythropoietin. This novel protein may be useful in the
ergometrine combination.469 setting of anticipated or actual obstetric hemorrhage if
Uterine sensitivity to prostaglandins increases with concerns about its adverse effects are alleviated.475
advancing gestation. 15-Methyl prostaglandin F2α The efficacy of preoperative autologous blood dona-
causes a dose-dependent increase in the force and the tion is limited by the maximum life span of stored blood;
frequency of uterine contractions. The initial recom- collection can start no sooner than 6 weeks before a
mended dose is 250 µg given intramuscularly; this planned delivery, with an average unit collection interval
dose can be repeated if necessary at 15- to 90-minute of 3 to 7 days. This method may be of some use in a
intervals up to a maximum of eight doses.470 Whether woman with maternal antibodies to red blood cell anti-
15-methylprostaglandin F2α is more effective than oxy- gens. The technique seems safe but has limited applica-
tocin is controversial471; however, it clearly has a role bility and efficacy in obstetric patients (see Chapter 38).
in the treatment of refractory uterine atony.472 In Acute normovolemic hemodilution has the advan-
approximately 20% of women, the following side effects tage of reducing the risk for administrative errors and
occur (listed in descending order of frequency): diar- bacterial contamination and allowing the infusion of
rhea, hypertension, vomiting, fever, flushing, and tachy- whole blood replete with functional coagulation factors
cardia.472 Bronchospasm, pulmonary vasoconstriction, and platelets. This technique may reduce the need for
and oxyhemoglobin desaturation may also occur. transfusion in selected patients, and it may be acceptable
Rectal or sublingual administration of prostaglandin to Jehovah’s Witness patients at increased risk for blood
E1 (misoprostol) is a uterotonic agent with a rapid onset loss during cesarean delivery.
of action. A systematic review of prophylactic misopros- The use of intraoperative red blood cell salvage in
tol (given orally or sublingually in doses ranging from obstetric patients is gaining greater acceptance.478 In the
400 to 800 µg) administered for the active management past, obstetric anesthesia providers have expressed
of the third stage of labor concluded that it is more effec- concern that intraoperative cell salvage might precipitate
tive than placebo in preventing severe postpartum hem- amniotic fluid embolism. Allam et al.478 noted that “exist-
orrhage but less effective than conventional injectable ing cell salvage systems differ in their ability to clear
uterotonic agents.473 Several large studies have assessed contaminants and all require the addition of a leucocyte
misoprostol’s role in the treatment of postpartum hemor- depletion filter.” The cell salvage process does not remove
rhage. An editorial concluded that the drug was no more all fetal red blood cells and hemoglobin, and maternal
effective than oxytocin and was associated with more side isoimmunization may occur.479 Intraoperative cell salvage
effects.474 These side effects include hyperthermia and may be used to prevent morbidity and mortality in par-
severe shivering. There may be a prophylactic role for turients who refuse homologous blood or in cases of
this drug in low-resource settings where oxytocin is not intractable hemorrhage that may overwhelm blood bank
available. supplies (see Chapter 38).34
heart rate, blood pressure, and transthoracic or trans- with a dilute solution of local anesthetic and a lipid-
esophageal echocardiography (TTE or TEE)481 assess- soluble opioid, similar to that used for labor analgesia.
ments can assist in the rapid evaluation of the adequacy The epidural catheter, regardless if used for analgesia, is
of volume resuscitation. typically kept in place until the uterine balloon is deflated
Fortunately, most pregnant women are healthy and to allow for rapid transition to surgical anesthesia if
tolerate modest blood loss well. Also, concerns about necessary.
uteroplacental perfusion and fetal oxygenation are no The treatment of postpartum hemorrhage with human
longer present after delivery of the infant. The ASA Task recombinant factor VIIa (rFVIIa), a vitamin K–
Force on Blood Component Therapy482 has concluded dependent protein licensed for the treatment of bleeding
that transfusion of packed red blood cells is rarely indi- episodes in patients who have hemophilia A or B with
cated when the hemoglobin concentration is greater than inhibitors to factor VIII or factor IX, remains controver-
10 g/dL and is almost always indicated when the hemo- sial (see Chapter 38). Off-label administration of rFVIIa
globin concentration is less than 6 g/dL. Transfusion of has resulted in cessation or reduction of severe bleeding
platelets is rarely indicated unless the platelet count is refractory to standard hematologic or hemostatic support
less than 100,000/mm3 (unless platelet dysfunction and in a variety of animal and human trials and case reports
microvascular bleeding are present), and replacement of or series.486 Administration of rFVIIa promotes clotting
fibrinogen is rarely indicated unless the fibrinogen con- primarily through the extrinsic (tissue factor) pathway
centration is less than 150 mg/dL in the presence of with some activation of the intrinsic pathway and should
microvascular bleeding. However, decreases in fibrino- be combined with best practice use of blood products
gen concentrations at levels higher than this threshold (i.e., blood product component therapy). Administered as
may serve as an early predictor of the severity of obstetric an intravenous dose of 60 to 100 µg/kg, rFVIIa has been
hemorrhage.483 observed to have a clinical effect within 10 minutes in
The prophylactic placement of intravascular balloon some cases. The half-life of the drug is 2 to 6 hours, and
occlusion catheters can facilitate the timely control of side effects consist primarily of hypertension, hypoten-
obstetric bleeding in some parturients at high risk for sion, bradycardia, renal dysfunction, and thromboembo-
hemorrhage.484 Harnett et al.50 have recommended the lism.486 Observational trials in the setting of traumatic
placement of an epidural catheter prior to an intravascu- injury are being performed, but to date there have been
lar balloon catheter for the following reasons: (1) once no large randomized studies of rFVIIa in obstetric
the balloon catheter is placed, flexion of the hips (during patients.
positioning for a neuraxial anesthetic technique) is dis-
couraged, because it may result in balloon dislodgement
or occlusion and subsequent thrombosis; (2) epidural
Obstetric Hysterectomy
anesthesia seems preferable to the use of local anesthesia The incidence of cesarean hysterectomy and emergency
with sedation for balloon catheter placement; (3) during postpartum hysterectomy ranges from 0.03% to 0.33%
balloon catheter placement, small amounts of heparin are in different hospital settings and countries.487 Over a
sometimes used, and it seems preferable to have the epi- 14-year period in the United States, the rate of peripar-
dural catheter in place prior to anticoagulation; and (4) tum hysterectomy per 100,000 deliveries increased from
should untoward events (e.g., fetal compromise, vessel 71.6 (1994 to 1995) to 82.6 (2006 to 2007); this increased
rupture) occur during the procedure, the epidural cath- rate was associated with an increased rate of abnormal
eter allows for rapid extension of anesthesia for cesarean placentation (e.g., placenta previa, placenta accreta) from
delivery. With prior planning, operative procedures, 32.9 to 40.5 and an increased rate of uterine atony from
including cesarean delivery, can be performed success- 11.2 to 25.9 per 100,000 deliveries.488 Increasing rates
fully under neuraxial anesthesia in the interventional of cesarean delivery, failed trial of labor, infection,
radiology suite.50 intrauterine fetal death, and disseminated intravascular
When uterine bleeding occurs postpartum, the use of coagulation are other factors associated with cesarean
uterine tamponade balloon catheters has been demon- hysterectomy. Improvements in ultrasonography, color
strated to tamponade and potentially treat intrauterine flow Doppler ultrasonography, and magnetic resonance
sources of bleeding and allow time to correct coagulopa- imaging have allowed earlier identification of some
thy.485 A number of balloon catheters have been used by women with placenta accreta; however, limitations in
practitioners for uterine tamponade (e.g., Sengstaken- diagnostic sensitivity and specificity exist.489
Blakemore esophageal balloon, Foley urinary catheters). Cesarean hysterectomy is considered a high-risk pro-
Commercial balloon catheters designed specifically for cedure owing to the vascularity and size of the uterus and
uterine tamponade are now available. Some of the cath- the distorted anatomic relationships. Bladder and ure-
eter designs allow for uterine cavity drainage, with vari- teral injuries are common. Prior to performance of hys-
able success in function and ability to identify ongoing, terectomy, various conservative medical and surgical
significant bleeding.485 The balloons are often left in treatment modalities may be attempted (see Chapter 38).
place for 24 to 48 hours, along with a vaginal pack and The ligation or embolization of major and collateral
continued antibiotic administration. Distention of the uterine vessels with the assistance of an interventional
uterus causes discomfort, and pain relief should be pro- radiologist is becoming more common, particularly in
vided, either with systemic agents or epidural analgesia if tertiary care settings.484
a catheter is in situ. We typically provide continuous epi- The amount of blood loss depends in part on whether
dural analgesia, or patient-controlled epidural analgesia, the hysterectomy is elective or an emergency. In a
592 PART VII Cesarean Delivery
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C H A P T E R 2 7
CHAPTER OUTLINE
0.10
PREDICTORS OF PAIN
0.05
Intrinsic Patient Factors
0.00 The likelihood of developing chronic pain after child-
0 2 4 6 8 10 birth may be influenced by multiple factors. There is
Post Delivery Pain (0 - 10 NRS) evidence for heritability in labor pain. Studies of non-
pregnant patients have shown that patients who carry a
Vaginal Delivery Cesarean Delivery common polymorphism in the μ-opioid receptor gene
(OPRM1: A118G [substitution of guanine for adenine at
FIGURE 27-1 ■ Distribution of numerical rating scale (NRS) scores nucleotide position 118; Rs 1799971]) have an altered
(0, no pain; 10, worst pain imaginable) of average pain for the response to exogenous opioids.22 Landau et al.23 studied
first 24 hours after vaginal and cesarean delivery. (From Eisenach the ED50 (median effective dose) of intrathecal fentanyl
JC, Pan PH, Smiley R, et al. Severity of acute pain after childbirth,
but not type of delivery, predicts persistent pain and postpartum for labor analgesia in women who were homozygous for
depression. Pain 2008; 140:87-94.) the wild-type allele compared with women who carried
the A118G polymorphism. Women who carried at least
one copy of the G-allele had a lower ED50 and requested
analgesia at a greater cervical dilation than women with
complication of childbirth. The idea that acute pain two copies of the wild-type allele.23 However, in another
during and immediately after delivery may have long- study, the duration of intrathecal fentanyl analgesia did
term consequences was not evaluated until the early not vary according to the OPRM1 genotype.24
2000s, when investigators noted that severe pain after In contrast to the findings of Landau et al.,23 in which
some types of surgery was associated with a high inci- women with the G-allele had a lower ED50 for intrathecal
dence of persistent chronic pain.14,15 fentanyl for labor analgesia, Sia et al.25 observed that
women who carried the G-allele self-administered a
higher dose of morphine to treat breakthrough pain after
Pain after Cesarean Delivery intrathecal morphine administration for postcesarean
In a prospective study, the prevalence of persistent pain analgesia. The reasons for these seemingly disparate
8 weeks after cesarean delivery was 9.2%; the risk for results have yet to be elucidated.26
experiencing pain at 8 weeks was associated with the Elevated concentrations of endorphins and enkepha-
severity of acute postpartum pain.14 In a retrospective lins are found in the plasma and cerebrospinal fluid (CSF)
survey, the incidence of persistent pain 1 year after deliv- of parturients, and opioid antagonists abolish pregnancy-
ery was 10% after vaginal delivery and 18% after cesar- induced analgesia to visceral stimulation in experimental
ean delivery.16 Another retrospective study reported a 6% animals (see Chapter 2). Given our current knowledge of
incidence of daily or almost daily pain 6 to 18 months the influence of genetic variability on response to exog-
after cesarean delivery.17 In these studies,16,17 the inci- enous opioids, it would not be surprising if some of the
dence of persistent pain after cesarean delivery was com- variability in labor pain and acute postpartum pain is a
parable to that reported 4 months after a hysterectomy.18 result of differing responses to endogenous and exoge-
By contrast to the results of retrospective studies,16,17 a nous opioids. Other genes may also play a role. β2-
prospective study observed that the incidence of persis- Adrenergic receptor polymorphisms have been associated
tent pain 1 year after either cesarean or vaginal delivery with preterm labor27 and labor progress.28,29 Slower
was less than 1%.19 development of pain during labor may be associated with
slower labor progress.28
Long-standing psychological factors and mental prep-
Pain after Vaginal Delivery aration for labor influence labor pain or its expression
In the absence of analgesia, almost all patients experience during labor. Catastrophizing (i.e., the unfounded belief
severe pain at some point during labor and vaginal deliv- that something will be worse than it is) has been associ-
ery (see Chapter 20).20,21 The severity of acute pain after ated with labor pain and request for treatment.30,31 There
vaginal delivery is highly variable.14 Most patients experi- is evidence that even the way that the practitioner asks
ence some degree of cramping pain from uterine involu- about pain influences the response. When the negative
tion. Severe pain may result from episiotomy, perineal word “pain” was used in a postcesarean visit, 54% of
lacerations, and/or perineal hematoma. This pain is women reported pain. By comparison, when patients
transmitted primarily via the pudendal and iliohypogas- were asked, “Are you comfortable,” only 28% reported
tric nerves and the sacral and lumbar plexuses. Such pain pain directly or indirectly (P < .001).32 Preexisting
606 PART VII Cesarean Delivery
depression and anxiety impact the outcome after surgery; but there is no reason to expect that the common stress-
affected patients report more severe pain and are at ors that accompany a significant life change such as child-
increased risk for analgesic drug abuse.33 birth, as well as specific individual stressors, would not
Women who abuse illegal drugs are at increased risk have a similar impact on postcesarean pain and conver-
for adverse pregnancy outcomes.34 These patients have sion to chronic pain.
particularly high risk for inadequate treatment of intra- In summary, the presence of intrinsic and extrinsic
partum and postpartum pain. Although a large propor- factors predicts severe acute pain after cesarean delivery.
tion of pregnant women who abuse drugs deny doing Similarly, conversion to chronic pain is associated with
so,35 it is important to identify these patients antenatally the presence of these factors and the presence of
to devise an analgesia plan. Buprenorphine and metha- severe acute postoperative pain. Patients may have an
done are the most common drugs used for treatment of intrinsic tendency toward severe pain in response to
opioid addiction during pregnancy. Both drugs are effec- injury. This tendency may be inherited as a genetic or
tive and are not associated with respiratory depression in epigenetic phenomenon, or it may be acquired through
the neonate, although these infants usually require treat- life experiences. Assessment of these predictive factors
ment of opioid withdrawal.36 Women who use opioids, with validated scales may identify a subset of women
cocaine, and/or amphetamines during pregnancy require for whom aggressive multimodal treatment of acute
more analgesia during labor than nonusers.37 Patients postoperative pain may prevent conversion of acute to
on opioid maintenance programs should receive their chronic pain.41
normal maintenance dose of opioid and should receive Depression, anxiety, sleep deprivation, and disability
additional medication to treat postpartum pain. A multi- are also predictable consequences of severe pain, thus creat-
modal analgesia strategy that includes NSAIDs is benefi- ing a positive reinforcing cycle. Interruption of this cycle
cial in this setting. by predicting and treating severe postcesarean pain may
Women with preexisting chronic pain syndromes may help prevent the development of chronic pain. In addi-
have significant anxiety regarding childbirth pain. Anxiety tion, identification and treatment of coexisting psycho-
itself is a predictor of labor pain.38 Patients with chronic logical distress and sleep disorders may help prevent
pain syndromes who are treated with chronic opioid conversion of acute pain to chronic pain.
therapy are likely to develop opioid tolerance similar to In 2001, The Joint Commission announced new pain
patients who use opioids recreationally. Thus, patients management standards.42 These standards recognize the
with chronic pain syndromes should be maintained on right of patients to receive appropriate assessment and
their therapeutic regimen throughout the course of labor, management of pain. The standards require accredited
delivery, and recovery; additional medication will likely organizations to screen patients for pain during the initial
be necessary to treat postpartum pain. assessment, to reassess pain periodically, and to educate
patients about pain management options. Fulfillment of
these requirements in the obstetric setting is challenging
Environmental Factors because pain is expected during childbirth. Nonetheless,
Sleep deprivation accentuates responses to noxious the mandate for pain assessment is not controversial. As
stimuli. Research subjects who sleep less than 6.5 hours occurs with all other types of surgery, obstetric patients
per day have greater areas of secondary hyperalgesia in should be assessed for postpartum pain at regular inter-
response to a heat test after capsaicin treatment. Addi- vals and offered treatment. Multimodal pharmacologic
tionally, those deprived of sleep have a lower threshold and nonpharmacologic treatment for pain is the optimal
for pressure pain.39 Sleep deprivation accentuates pain, approach and should be offered whenever feasible and
and pain interrupts sleep. This association creates a medically indicated.
vicious cycle that commonly accentuates pain after cesar-
ean delivery. Prolonged labor may precede cesarean
delivery. Afterward, care of the newborn requires fre- SYSTEMIC OPIOID ANALGESIA
quent interruptions in sleep. It is important to facilitate
sleep as a therapeutic intervention as much as possible by Neuraxial opioid administration currently represents
decreasing environmental stimuli and reducing light the “gold standard” for providing effective postcesarean
during the evening. analgesia. Intrathecal and epidural opioid administration
Stress is also an important factor that can worsen provide analgesia that is superior to intramuscular opioid
postoperative pain and can facilitate conversion to chronic and intravenous opioid patient-controlled analgesia
pain. Antepartum stressors induced by fear of surgery, (PCA) after cesarean delivery (see Chapter 28, Figure
parenting, or other changes that are associated with 28-1).43-45 A 2010 systematic review found that a single
childbirth and cesarean delivery may accentuate postop- bolus dose of epidural morphine provides better analgesia
erative pain. In patients undergoing back surgery, preop- than parenteral opioids after cesarean delivery.46 In the
erative report of worry or intrusive memories was United States, most women who undergo cesarean deliv-
associated with chronic preoperative pain, failed back ery with neuraxial anesthesia receive neuraxial opioids for
syndrome, and chronic postoperative pain.40 Further, postcesarean analgesia. Multimodal analgesic strategies
biochemical evidence of preoperative stress, as measured are used to augment the analgesic effect of neuraxial
by abnormal reactivity of the hypothalamic-pituitary- opioids in this setting. Some women may have break-
adrenal axis, was also associated with chronic pain after through pain using this analgesia strategy and may require
surgery.40 Evidence specific to obstetric surgery is limited, augmentation with systemic opioids.
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 607
*Nonopioid analgesic options should be considered to limit opioid-related side effects. All adverse events should be carefully evaluated to
rule out other potential causes.
Courtesy of the Dana Farber Cancer Institute Pain and Palliative Care Program and the Brigham and Women’s Hospital Pain Committee.
Modified with permission from Bridget C. Fowler, Pharm. D., Clinical Pharmacy Manager, Dana Farber Cancer Institute.
Some women are not candidates for postoperative opioids; the primary limiting factor is the occurrence of
neuraxial analgesia; for example, they may have a contra- side effects (Table 27-1).
indication to a neuraxial procedure and therefore receive Patients with hepatic or renal dysfunction (which may
general anesthesia for their cesarean delivery. These occur with severe preeclampsia), morbid obesity, and/or
women require multimodal analgesia that usually includes obstructive sleep apnea are particularly susceptible to the
systemic opioid administration. respiratory depressant effects of opioids. Patients who
Although pain after vaginal delivery is usually less have never received opioids may be especially prone to the
severe than pain after cesarean delivery, its severity is occurrence of side effects. It is important to monitor the
highly variable. A large episiotomy with a third- or respiratory rate and sedation level before giving an addi-
fourth-degree perineal laceration may warrant adminis- tional dose or adjusting the bolus dose that the patient can
tration of a single dose of a neuraxial opioid for postpar- self-administer. After adjusting the dose, the clinician
tum analgesia.47 must document the respiratory rate and pattern, sedation
The analgesic effect of opioids can vary significantly level, and analgesic response. The use of a multimodal
among patients; one study observed a fivefold difference analgesic approach helps provide adequate analgesia while
in the maximum blood drug concentration still associated limiting opioid-related side effects (see later discussion).
with pain (MCP).48 The MCP decreases over time after
a surgical procedure. The goal of opioid administration Intravenous Patient-Controlled
is to achieve a minimum effective analgesic concentration
(MEAC) with minimal side effects.49 Because both the
Analgesia
MEAC and the MCP vary greatly among patients, an In the past, opioids were commonly administered intra-
individualized approach to pain control is required. muscularly or subcutaneously; these simple routes of
There are no maximum allowable doses for specific administration do not require the postoperative return of
608 PART VII Cesarean Delivery
bowel activity or the use of sophisticated equipment. were threefold to fourfold higher in the intravenous
Intramuscular and subcutaneous medications are inex- group. The two groups had similar pain and sedation
pensive, easy to administer, and associated with a long scores, but patients in the intravenous group reported
history of safety. Disadvantages of this approach include more frequent drowsiness and less pruritus.54
the need for repeated painful injections, a delayed (and Several studies have compared intravenous morphine
sometimes erratic) absorption of drug, and an inconsis- PCA to single-shot epidural morphine for postcesarean
tent analgesic response due to variations in plasma opioid analgesia.45,55,56 Although the incidence of pruritus was
concentrations. higher with epidural morphine than with intravenous
A number of studies have compared intravenous opioid morphine PCA, analgesia and patient satisfaction were
PCA to traditional nurse-administered parenteral analge- better with epidural morphine.45,55,56 The incidence of
sia. A 2006 meta-analysis concluded that intravenous nausea was not different between groups45,55,56; sedation
PCA provided better postoperative analgesia and greater was greater in the intravenous PCA group.45
patient satisfaction than conventional nurse-administered
opioid analgesia.50 Although the use of intravenous PCA Choice of Opioid
was associated with greater opioid use and a higher inci-
dence of pruritus, the incidence of other side effects was Overall, factors that affect the choice of opioid are speed
not different between groups.50 The American Society of of onset, duration of action, overall efficacy, and the type
Anesthesiologists (ASA) Task Force for Acute Pain Man- and frequency of side effects (Table 27-2). If side effects
agement in the Perioperative Setting51 recommends that prevent adequate analgesia, other opioids or nonopioid
“these modalities [epidural or intrathecal opioids, sys- adjuvants should be used. Patient preferences based on
temic opioid PCA, and peripheral regional techniques] past experiences and desired analgesia should also be
should be used in preference to intramuscular opioids considered.
ordered ‘as needed.’ ” Historically, meperidine has been a popular opioid
PCA has been used with intravenous and epidural for postoperative analgesia. It is the least potent of the
routes of administration after cesarean delivery. In a study opioids used clinically, and it has a long-acting active
of intravenous versus epidural meperidine PCA, higher metabolite, normeperidine, that is excitotoxic to the
pain scores with rest and movement, greater sedation, central nervous system. In the past two decades a con-
and lower patient satisfaction were observed with the certed effort has been made to decrease the use of meper-
intravenous route of administration.52 Moreover, plasma idine for postoperative analgesia.57 In 1999, the American
meperidine and normeperidine concentrations were Pain Society stated that “meperidine should not be used
almost double with the intravenous route.52 Similarly, for more than 48 hours for acute pain…[it] should be
another study that compared intravenous versus epidural reserved for brief courses in otherwise healthy patients
fentanyl PCA after cesarean delivery reported higher who have demonstrated an unusual reaction or allergic
pain scores and greater fentanyl consumption with the response to other opioids.”58 The American College of
intravenous route, although patient satisfaction ratings Obstetricians and Gynecologists (ACOG)59 has discour-
were similar in the two groups.53 Another study com- aged the use of meperidine because of the accumulation
pared intravenous versus epidural hydromorphone PCA of normeperidine in the neonate and its subsequent effect
after cesarean delivery.54 Hydromorphone requirements on neurobehavioral scores.
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 609
Recorded as: PCA bolus dose/lockout interval/4-hour limit/continuous infusion rate. A continuous background infusion is typically avoided
except in selected cases (e.g., opioid tolerance).
IV, intravenous; PCA, patient-controlled analgesia.
Courtesy of the Dana Farber Cancer Institute Pain and Palliative Care Program and the Brigham and Women’s Hospital Pain Committee.
Modified with permission from Bridget C. Fowler, PharmD, Clinical Pharmacy Manager, Dana Farber Cancer Institute.
analgesia did not vary among groups despite the overall adequate pain relief. Patients use PCA bolus demands
higher use of morphine in the group that received the for different reasons, including worsening pain at rest,
largest bolus dose. In addition, there were no differences pain with movement or coughing, and anticipation of an
among groups in patient satisfaction or side effects. In an activity that is likely to produce pain.61 Inadequate anal-
earlier study, Owen et al.63 observed that the patient- gesia most likely can be improved by an increase in the
administered morphine dose did not differ in patients ran- demand bolus dose, a shorter lockout interval, or a change
domized to receive patient-administered bolus morphine of opioid. Patients also should be encouraged to use
compared with patient-administered bolus morphine demand bolus doses before movement or activity.
with a continuous basal infusion (morphine 1.5 mg/h). A commonly neglected but important guideline is the
Moreover, the quality of analgesia was similar in the two achievement of adequate analgesia and the initiation of
groups despite a twofold higher total dose of morphine in intravenous PCA before the patient is discharged from the
the group receiving a continuous infusion. postanesthesia care unit (PACU). Although there is sig-
Controversy exists regarding the use of a continuous nificant variation in individual perception of pain and
basal infusion during administration of intravenous response to analgesia, the assessment of pain scores can
opioid PCA. Studies of patients undergoing gynecologic facilitate evaluation of the adequacy of analgesia. In a
surgery do not support the use of a continuous back- study of postoperative patients after general anesthesia
ground infusion to provide better postoperative analge- (the surgical procedures were not disclosed), Aubrun
sia. Parker et al.64 evaluated 230 women who had et al.68 demonstrated that the relationship between visual
undergone an abdominal hysterectomy; one group analog pain scores (VAPS, 0 to 100 scale) and morphine
received a demand bolus dose of morphine (1 to 2 mg) requirements was represented by a sigmoid curve; they
without a continuous infusion, and the other three groups observed one plateau below a score of 40 and another
received a continuous infusion of morphine (0.5, 1, or plateau above a score of 80. Although patients with a
2 mg/h) in addition to the demand bolus dose. No dif- VAPS of 70 or higher were considered to have severe pain
ferences in the number of demand or delivered doses per and required a larger total dose of morphine to obtain a
hour, pain scores, or overall morphine consumption were VAPS lower than 50, a smaller total dose of morphine
observed, except that an overall higher dose of morphine was required to reduce a VAPS of 50 to a score of 30 or
was administered in the 2 mg/h continuous infusion less.68 This study suggests that pain scores are slow to
group than in the demand bolus–only group. A subse- change when severe pain exists but that the scores decline
quent study by the same investigators in a similar patient rapidly once pain begins to improve. Other investigators
population compared a group receiving an intravenous have identified relevant VAPS thresholds associated with
PCA morphine (2 mg demand bolus dose) regimen with changes in intravenous PCA dose requirements after
a group receiving the same intravenous PCA regimen and intra-abdominal surgery as 30 or less, 31 to 70, and more
a nighttime continuous infusion of morphine (1 mg/h).65 than 70.69 Only 4% of patients with a VAPS of 30 or less
There were no differences between groups in postopera- requested an increase in analgesic dose, whereas 80% of
tive pain, sleep patterns, demand or delivered bolus doses patients with a VAPS higher than 70 requested a higher
per hour, opioid consumption, or recovery from surgery. dose. Among patients with a VAPS between 31 and 70,
The investigators reported that the use of a continuous those whose scores improved at least 10 points were less
infusion resulted in six errors during the programming likely to request additional analgesia than those with little
of the device and that three patients required discontinu- change or an increase in VAPS.69 Thus, a patient’s per-
ation of the continuous infusion because of significant ception of pain improvement may depend, in part, on her
oxyhemoglobin desaturation.65 initial pain score.
Thus, a continuous basal infusion is often avoided in Severe pain most likely antagonizes the sedative and
opioid-naive patients because of concern about the risks respiratory depressant side effects of opioids, a possibility
of oversedation and respiratory depression. The ASA that becomes increasingly important in patients request-
Task Force on Acute Pain Management51 concluded that ing higher doses of opioids. Therefore, a transition from
intravenous PCA with a continuous background infusion an opioid-only to a multimodal, balanced analgesia
of morphine results in use of a larger total dose of anal- approach should be employed to optimize pain control
gesic drug than intravenous PCA without a background and minimize opioid-related side effects. The morbidity
infusion; the findings were equivocal regarding compari- associated with high doses of opioids should invoke the
sons of quality of analgesia and the incidence of nausea, application of algorithms for pain assessment, manage-
vomiting, pruritus, and sedation.51 The Task Force con- ment, and monitoring. At many institutions, postcesarean
cluded that special caution should be taken when a con- patients are assessed every 4 hours for respiratory rate
tinuous infusion is used, owing to the potential for adverse and quality, oxygen saturation, pain score, and sedation
effects from opioid accumulation.51 The American Pain level. Patients are asked whether their level of pain relief
Society has also urged caution in the use of a continuous is acceptable; and if not, an adjustment of analgesic dose
basal infusion in opioid-naive patients receiving intrave- is performed and documented. The pain score is reas-
nous opioid PCA.66 sessed within 15 to 30 minutes before additional inter-
With the use of PCA, the ratio of patient demands to ventions are made. High-risk patients, including those
bolus doses delivered appears to be a good measure of with hepatic or renal dysfunction, obstructive sleep
analgesia and is strongly correlated with pain scores.67 apnea, and/or morbid obesity, are assessed every 2 hours
A high ratio is likely to reflect patient misunderstanding for 12 hours after initiation of intravenous PCA therapy
or inadequate analgesia, but a ratio close to 1 signifies and then every 4 hours if the respiratory rate is 8 breaths/
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 611
Subcutaneous/ 120
Diclofenac has also been extensively studied and combination of NSAIDs and acetaminophen is synergis-
found to be effective for postcesarean analgesia. Diclof- tic in human experimental pain studies.89
enac rectal suppositories (100 mg twice a day) decreased Intravenous acetaminophen has gained popularity
morphine consumption (14 mg versus 22 mg in 32 hours) owing to reports of slower absorption of oral acetamino-
compared with placebo in patients who had undergone phen in patients treated with morphine90 and higher peak
cesarean delivery.79 A single dose of diclofenac rectal sup- plasma and CSF levels of acetaminophen after intrave-
pository 100 mg prolonged the mean time to first anal- nous administration.91 However, in patients with a func-
gesic administration by more than 5 hours in patients tioning gastrointestinal system, there is no documented
who received intrathecal morphine for postcesarean anal- analgesic advantage in using intravenous rather than oral
gesia.80 Patients who received intrathecal morphine doses administration.
as small as 25 µg (0.025 mg) required no rescue analgesic
when intramuscular diclofenac 75 mg was administered
every 8 hours.81
α2-Adrenergic Receptor Agonists
Parenteral ketorolac is another NSAID that is useful α2-Adrenergic agonists have been used for the treatment
in the treatment of postpartum pain. In a randomized, of acute and chronic pain in nonobstetric patients.92
controlled study, Lowder et al.82 provided evidence that Intravenous dexmedetomidine has been used as an
ketorolac decreased pain scores at 2, 3, 4, 6, 12, and 24 adjunct to opioids for labor analgesia and as a component
hours after cesarean delivery and also significantly of general anesthesia for cesarean delivery.93 Dexmedeto-
decreased opioid consumption. Unlike other NSAIDs, midine may be preferred over clonidine for intrapartum
the U.S. Food and Drug Administration (FDA) has a intravenous administration because an isolated, perfused
mandated black box warning that states that ketorolac is human placenta model suggested that less dexmedetomi-
“contraindicated in nursing mothers because of the poten- dine is transferred across the placenta to the fetus. The
tial adverse effects of prostaglandin-inhibiting drugs on investigators noted that more dexmedetomidine was
neonates.”83 This warning was mandated in spite of a retained in the placenta, which they attributed to its
study showing minimal to undetectable ketorolac levels in higher lipophilicity.94
breast milk.84 The American Academy of Pediatrics (AAP) Neuraxial clonidine has been used for labor analgesia
considers ketorolac safe for nursing mothers.85 but is not commonly used for analgesia after cesarean
delivery. The epidural formulation of clonidine carries
the following “black box” warning from the U.S. FDA95:
Selective Cyclooxygenase-2 Inhibitors
COX-2 specific inhibitors have a potential benefit com- Clonidine hydrochloride injection (epidural clonidine)
pared with traditional nonselective NSAIDS in that they is not recommended for obstetrical, postpartum or
have minimal effects on platelet adhesion and thus are perioperative pain management. The risk of hemodynamic
less likely to interfere with blood clot formation and instability, especially hypotension and bradycardia,
contribute to hemorrhage. However, concerns about from epidural clonidine may be unacceptable in these
the potential to increase the risk for cardiovascular and patients. However in a rare obstetrical, postpartum or
thrombotic events, combined with the baseline elevated perioperative patient, potential benefits may outweigh the
risk for these events during pregnancy and postpartum, possible risks.
have prevented COX-2 inhibitors from playing a major
role in postpartum analgesia. Celecoxib is the only The combination of intrathecal clonidine (150 µg) and
widely available COX-2 selective inhibitor in the United bupivacaine compared with sufentanil combined with
States. The breast milk content of valdecoxib and bupivacaine has been shown to reduce peri-incisional
its pro-drug precursor parecoxib was studied after a hyperalgesia but does not alter pain scores or opioid
single 40-mg intravenous dose of parecoxib following consumption after elective cesarean delivery.96 These
cesarean delivery. The breast milk concentration was findings suggest that intrathecal clonidine might be ben-
very low, and neonatal neurologic and adaptive scores eficial in a patient who is at risk for the development of
were normal.86 chronic pain after cesarean delivery. Another randomized
trial compared intrathecal clonidine 75 µg combined
with hyperbaric bupivacaine to saline combined with
Acetaminophen bupivacaine.97 Clonidine prolonged the duration of anal-
Despite widespread popularity, few published data gesia, but there was no difference in the need for rescue
support the use of acetaminophen (paracetamol) for post- analgesia. Epidural clonidine (75 µg and 150 µg) added
cesarean analgesia. A 2012 meta-analysis identified four to a mixture of morphine, bupivacaine, and epinephrine
randomized controlled trials evaluating acetaminophen prolonged the duration of analgesia and reduced mor-
and its effect on opioid consumption after major surgery; phine consumption without a significant increase in the
only one study included obstetric patients.87 The meta- incidence of side effects in patients who had undergone
analysis revealed that acetaminophen was less effective cesarean delivery.98 However, given the availability of
than NSAIDs in decreasing opioid consumption and other agents and the lack of overwhelming evidence in
postoperative nausea and vomiting.87 A comparison of favor of α2-agonists, routine use of these agents in the
intravenous acetaminophen with oral ibuprofen in post- postpartum period should be restricted to patients in
cesarean patients failed to show an advantage in pain whom other agents are contraindicated or in those with
scores, opioid consumption, or patient satisfaction.88 The risk factors for chronic pain.
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 613
Gabapentin
NON-NEURAXIAL REGIONAL
Gabapentin is an anticonvulsant that has analgesic prop-
erties, particularly in the setting of neuropathic pain.
ANALGESIC TECHNIQUES
Although extensively studied in the management of Transversus Abdominis Plane Block
chronic pain, its mechanism of action is uncertain. As part
of a multimodal analgesic regimen in patients undergoing The transversus abdominis plane (TAP) block is a regional
cesarean delivery, a preoperative dose of oral gabapentin anesthetic technique in which local anesthetic is injected
600 mg was associated with significantly lower pain between the internal oblique and the transversus abdomi-
scores with movement and at rest; however, the incidence nis muscle layers to block the plexus of nerves supplying
of sedation was greater in the gabapentin group than in the anterior abdominal wall (Figure 27-3). In a trial in
the placebo group (19% versus 0%).8 In a follow-up patients undergoing elective cesarean delivery, women
study, placebo was compared with two doses of gabapen- randomized to receive a TAP block with 0.75% ropiva-
tin (300 mg and 600 mg) in the hope of finding an effica- caine required significantly less morphine, had a longer
cious dose associated with less sedation. Unfortunately time before first analgesic request, and had lower pain
the trial failed to show efficacy in either gabapentin scores than women who received a block procedure with
group.103 Limited evidence of efficacy and concerns about saline.108 In another trial, bilateral TAP block with ropi-
excessive sedation limit enthusiasm for routine use of vacaine 0.5% was compared with saline; the ropivacaine
gabapentin for postcesarean analgesia. group consumed less morphine (ropivacaine group,
18 mg; saline group, 32 mg; P < .05) and reported greater
patient satisfaction.109
Ketamine and Dextromethorphan Several trials have compared intrathecal morphine
Ketamine, an N-methyl-d-aspartate (NMDA) antago- analgesia to a TAP block after cesarean delivery.110,111 In
nist, has analgesic properties and may play a role in the one such trial, patients who received intrathecal mor-
treatment of acute postoperative pain and prevention or phine 0.2 mg had a longer time to first analgesic request
reversal of central sensitization.104 It also is used as an (8 hours versus 4 hours; P = 0.005) and decreased anal-
intraoperative adjuvant to neuraxial anesthesia in patients gesic requirements in the first 12 hours compared with
undergoing cesarean delivery; small intravenous doses those who received a TAP block.110 However, the inci-
provide significant analgesia with minimal respiratory dence of nausea, vomiting, and pruritus was greater in
depression. An evaluation of low-dose ketamine for the intrathecal morphine group.110 Similarly, Loane
postcesarean analgesia compared intravenous ketamine et al.111 randomized patients to receive intrathecal mor-
0.15 mg/kg, intrathecal fentanyl 10 µg, and placebo.105 phine 0.1 mg or a TAP block; intrathecal morphine
The study demonstrated a prolonged duration of analge- resulted in lower opioid consumption and pain scores but
sia in both the fentanyl and ketamine groups compared was associated with a greater incidence of nausea, vomit-
with the placebo group (time to first analgesic request: ing, and pruritus.111 Finally, Costello et al.112 found that
614 PART VII Cesarean Delivery
TA EO
IO
LS
PM
QL
ST
LD N
IL
MM
Skin
FIGURE 27-3 ■ Line drawing of a transverse section through the abdominal wall at the level of the lumbar triangle of Petit (TOP). The
floor of the triangle is composed, from superficial to deep, of the fascial extensions of external oblique, internal oblique, and trans-
versus abdominis, respectively, and the peritoneum. The needle is inserted through the triangle, using the loss-of-resistance tech-
nique. The needle is shown in the transversus abdominis plane, and the fascial layers have separated as a result of the injection
of local anesthetic. LS, lumbar spine; LD, latissimus dorsi; PM, psoas major; QL, quadratus lumborum; MM, multifidus muscle;
IL, longissimus, iliocostalis; TA, transversus abdominis; IO, internal oblique; EO, external oblique; N, 50-mm blunt-tipped needle;
ST, subcutaneous tissue. (From McDonnell JG, Curley G, Carney J, et al. The analgesic efficacy of transversus abdominis plane block after
cesarean delivery: a randomized controlled trial. Anesth Analg 2008; 106:186-91.)
the combination of intrathecal morphine and TAP block is advanced through the muscle layers until it is posi-
did not provide better postcesarean analgesia than intra- tioned in the fascial plane between the internal oblique
thecal morphine alone.112 Thus, TAP block represents a and transversus abdominis muscles. A small amount of
reasonable alternative for patients who are unable to saline is injected to verify hydrodissection of the plane.
receive neuraxial morphine, but TAP block should not After correct identification of the plane, 15 to 20 mL of
replace neuraxial opioid analgesia as the gold standard for local anesthetic solution is incrementally injected into the
postcesarean analgesia. plane, again with ultrasonographic guidance.
Complications of the block include intravascular injec-
tion resulting in local anesthetic systemic toxicity (LAST)
Technique
and bowel perforation. The local anesthetic dose/volume/
The TAP block can be performed blindly using surface concentration−response relationships have not been well
landmarks or with ultrasonographic guidance.113 Con- studied. Griffiths et al.115 performed bilateral TAP blocks
tinuous infusion of local anesthetic has been described, with a total ropivacaine dose of 2.5 mg/kg (diluted with
but the block is usually performed as a single-shot 0.9% saline to a total volume of 40 mL) in women who
technique. The originally described landmark/loss-of- had spinal anesthesia for elective cesarean delivery. (This
resistance technique involves introduction of the needle dose corresponds to 20 mL of 0.5% ropivacaine on each
into the triangle of Petit.114 Using ultrasonographic guid- side for an 80-kg patient.) The mean (± SD) peak plasma
ance, an anterior oblique-subcostal approach, a midaxil- ropivacaine concentration (30 minutes after injection)
lary approach, and a posterior approach have been was 1.82 ± 0.69 µg/mL. Although this concentration is
described.114 The pattern of local anesthetic spread within below the reported threshold for systemic toxicity (2.2 µg/
the transversus abdominis plane may vary depending on mL), 12 of 30 patients had peak concentration measure-
the site of injection; thus, the block characteristics, ments above this threshold (maximum, 3.76 µg/mL), and
including extent of analgesia, may also vary depending on 3 patients had symptoms of LAST (perioral tingling,
the specific technique.114 metallic taste).115 These findings suggest that ropivacaine
The classic, midaxillary, ultrasonography-guided TAP doses less than 2.5 mg/kg should be used and that patients
block is performed with the patient in the supine posi- should be observed for at least 30 minutes after the block
tion. An area of skin on the lateral abdominal wall between is performed.
the subcostal margin and the iliac crest is prepared with
antiseptic solution. Using a high-frequency (8 to 12 MHz)
linear array ultrasound probe, the abdominal wall is
Wound Infusion Catheters
scanned between the anterior and posterior axillary line Wound infusion catheters have gained popularity for pain
(Figure 27-4). The muscle layers are identified, and the relief after general and orthopedic surgery as ambulatory
needle (usually a 21- to 22-gauge, 80- to 100-mm short- disposable pumps have become widely available. However,
bevel needle with extension tubing attached to a syringe data are conflicting regarding the efficacy of these cath-
with saline solution) is inserted in-plane from medial to eters. In a study comparing pain control provided by
lateral. Using ultrasonographic guidance, the needle tip wound infusion and epidural levobupivacaine, the
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 615
External Internal
oblique oblique
Posterior
B
Transversus
abdominis
epidural group had less pain only at the 4-hour time incidence of nausea and vomiting compared with epidural
point. There were no significant differences between morphine 2 mg administered every 12 hours.117 Carvalho
groups in opioid consumption.9 In another study com- et al.118 added ketorolac to bupivacaine for wound infu-
paring intrathecal morphine and wound infusion with sion; compared with infusion of bupivacaine alone, pain
ropivacaine or saline,116 more oxycodone was required in scores and opioid consumption were decreased, as were
the ropivacaine wound infusion group than in the intra- local inflammatory mediators collected from the wound.118
thecal morphine group during the first 24 hours (48 mg The addition of hydromorphone to bupivacaine did not
versus 26 mg; P = .004); there was no difference in oxy- alter these outcomes.118
codone use between the ropivacaine wound infusion and Some of the differences in outcomes among these
saline-control groups.116 By contrast, another group of studies may be due to differences in catheter insertion
investigators found that wound infusion with ropivacaine technique, local anesthetic concentration, and rate of
0.2% at 5 mL/h provided superior analgesia and a lower infusion; however, current evidence does not support the
616 PART VII Cesarean Delivery
superiority of local anesthetic wound infusion over neur- medication is immediately after breast-feeding or just
axial opioid administration. Although some centers use before the infant takes a nap.85
wound infusion catheters, the additional cost of the pump The two most important items needed to determine
and the inconvenience may be prohibitive. the potential neonatal risks of maternal drug administra-
tion are the amount of medication excreted in breast
milk and the therapeutic effect of that medication when
Local Infiltration given to the infant.126 Some investigators have arbitrarily
Local infiltration of the wound is a relatively simple com- defined a breast milk concentration lower than 10%
ponent of multimodal postoperative analgesia. In a study of the therapeutic infant plasma concentration (or a
of patients who did not receive neuraxial morphine for breast milk dose less than 10% of the weight-normalized
postcesarean analgesia, infiltration of 0.25% bupivacaine maternal dose) as a safe level of exposure. In breast-
with epinephrine (40 mL) before wound closure was feeding infants, the estimated absolute infant drug dose is
associated with decreased opioid requirements in the first calculated by multiplying the average infant breast milk
12 hours compared with saline-placebo.119 However, intake by the average concentration of the drug in the
wound infiltration with 30 mL bupivacaine 0.5% did not milk (area under the pharmacokinetic curve). The abso-
provide additional analgesia when combined with neur- lute infant drug dose is then expressed as a percentage
axial opioid administration.120 of the maternal dose, normalized by weight (mg/kg/
day), to yield the relative infant dose. If the relative infant
dose is high and the drug has potential to harm the
Ilioinguinal-Iliohypogastric Block infant, or if side effects attributed to the drug are
Ilioinguinal-iliohypogastric block is useful for post detected in the infant, clinicians should consider discon-
operative analgesia after lower abdominal surgery. Similar tinuing the drug, modifying the dose, or changing to a
to TAP blocks, these blocks can be performed with different drug.
ultrasonographic guidance. Evidence is inconsistent as to Persistent pain is associated with sympathetic nervous
whether ilioinguinal-iliohypogastric blocks improve system activation, vasoconstriction, and decreased breast
analgesia provided by neuraxial morphine.121,122 In a study milk production in animal models.127 Better pain manage-
of women who did not receive neuraxial morphine, bilat- ment after cesarean delivery is associated with more
eral, multilevel ilioinguinal-iliohypogastric blocks were episodes of breast feeding.128 Clearly, pain requires treat-
associated with lower systemic opioid use, but a decrease ment after cesarean delivery, and the optimal method
in opioid side effects was not observed.123 or methods to prevent adverse neonatal effects through
breast milk transfer is an important consideration.
Because significantly smaller total opioid doses are
NONPHARMACOLOGIC INTERVENTIONS required in women who receive neuraxial opioids, less
opioid is available for transfer to breast milk. In a parturi-
Nonpharmacologic interventions may play a role as ent treated with continual intrathecal morphine for
adjuvant treatments in the management of postcesarean chronic pain, minimal morphine concentrations were
pain, but these interventions have not been subjected detected in the neonate, and neurobehavioral scores
to rigorous investigation. Acupuncture has been used were normal.129 A relatively small amount (1.6%) of the
to treat pain after cesarean delivery. In one trial, patients maternal dose of hydrocodone is transferred to the
treated with acupuncture used 30% less opioid in neonate as hydromorphone in breast milk.130 In general,
24 hours and reported lower pain scores at 2 hours.124 the small amounts of analgesic drugs that are transferred
Foot and hand massage has been reported to reduce to breast milk in the postpartum period are not harmful
reported pain scores and the need for rescue pain to the neonate.
medication.125 Standard references, including the AAP list of drugs
that are usually compatible with breast-feeding,85 should
be consulted before prescribing drugs to breast-feeding
IMPACT OF PAIN AND ANALGESIC women.131
TREATMENT ON BREAST-FEEDING
The AAP strongly supports breast-feeding because of its MATERNAL ANESTHESIA
benefits to the infant, mother, and society. However, AND BREAST-FEEDING
patients may discontinue breast-feeding when taking
analgesic medications because of incomplete or incorrect Surgeons and breast-feeding mothers often have ques-
information regarding neonatal health. The AAP Com- tions about whether breast-feeding should be interrupted
mittee on Drugs recommends that physicians take the when the mother undergoes anesthesia for a surgical pro-
following steps before prescribing medications to breast- cedure. Short-term administration of other potent medi-
feeding women: (1) determination of the reasons for the cations commonly used for sedation and analgesia (e.g.,
medication, (2) identification of the safest available medi- midazolam, propofol, fentanyl) has been found to result
cation in a particular category, and (3) measurement of in breast milk doses less than 1.25% of the weight-
blood concentrations of drug in those neonates for whom normalized maternal dose.132 Thus, women do not have
the drug presents a significant risk.85 The AAP has also to “pump and dump” because of concerns of infant expo-
suggested that the best time for the mother to take a sure to anesthetic agents.
27 Postoperative and Chronic Pain: Systemic and Regional Analgesic Techniques 617
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effects modeling. Anesth Analg 2012; 114:837-44. 108. McDonnell JG, Curley G, Carney J, et al. The analgesic efficacy
87. Rawlinson A, Kitchingham N, Hart C, et al. Mechanisms of transversus abdominis plane block after cesarean delivery: a
of reducing postoperative pain, nausea and vomiting: a randomized controlled trial. Anesth Analg 2008; 106:186-91.
systematic review of current techniques. Evid Based Med 2012; 109. Belavy D, Cowlishaw PJ, Howes M, Phillips F. Ultrasound-guided
17:75-80. transversus abdominis plane block for analgesia after Caesarean
88. Alhashemi JA, Alotaibi QA, Mashaat MS, et al. Intravenous acet- delivery. Br J Anaesth 2009; 103:726-30.
aminophen vs oral ibuprofen in combination with morphine PCIA 110. Kanazi GE, Aouad MT, Abdallah FW, et al. The analgesic efficacy
after Cesarean delivery. Can J Anaesth 2006; 53:1200-6. of subarachnoid morphine in comparison with ultrasound-guided
89. Ing Lorenzini K, Besson M, Daali Y, et al. A randomized, transversus abdominis plane block after cesarean delivery: a ran-
controlled trial validates a peripheral supra-additive antihyperal- domized controlled trial. Anesth Analg 2010; 111:475-81.
gesic effect of a paracetamol-ketorolac combination. Basic Clin 111. Loane H, Preston R, Douglas MJ, et al. A randomized controlled
Pharmacol Toxicol 2011; 109:357-64. trial comparing intrathecal morphine with transversus abdominis
90. Petring OU, Dawson PJ, Blake DW, et al. Normal postoperative plane block for post-cesarean delivery analgesia. Int J Obstet
gastric emptying after orthopaedic surgery with spinal anaesthesia Anesth 2012; 21:112-8.
and i.m. ketorolac as the first postoperative analgesic. Br J Anaesth 112. Costello JF, Moore AR, Wieczorek PM, et al. The transversus
1995; 74:257-60. abdominis plane block, when used as part of a multimodal regimen
91. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal inclusive of intrathecal morphine, does not improve analgesia after
fluid pharmacokinetic parameters after single-dose administration cesarean delivery. Reg Anesth Pain Med 2009; 34:586-9.
of intravenous, oral, or rectal acetaminophen. Pain Pract 2012; 113. Sharkey A, Finnerty O, McDonnell JG. Role of transversus
12:523-32. abdominis plane block after caesarean delivery. Curr Opin Anaes-
92. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of peri- thesiol 2013; 26:268-72.
operative systemic alpha2-agonists on postoperative morphine 114. Carney J, Finnerty O, Rauf J, et al. Studies on the spread of
consumption and pain intensity: systematic review and meta- local anaesthetic solution in transversus abdominis plane blocks.
analysis of randomized controlled trials. Anesthesiology 2012; Anaesthesia 2011; 66:1023-30.
116:1312-22. 115. Griffiths JD, Le NV, Grant S, et al. Symptomatic local anaesthetic
93. Palanisamy A, Klickovich RJ, Ramsay M, et al. Intravenous toxicity and plasma ropivacaine concentrations after transversus
dexmedetomidine as an adjunct for labor analgesia and cesarean abdominis plane block for Caesarean section. Br J Anaesth 2013;
delivery anesthesia in a parturient with a tethered spinal cord. Int 110:996-1000.
J Obstet Anesth 2009; 18:258-61. 116. Kainu JP, Sarvela J, Halonen P, et al. Continuous wound infusion
94. Ala-Kokko TI, Pienimaki P, Lampela E, et al. Transfer of cloni- with ropivacaine fails to provide adequate analgesia after caesarean
dine and dexmedetomidine across the isolated perfused human section. Int J Obstet Anesth 2012; 21:119-24.
placenta. Acta Anaesthesiol Scand 1997; 41:313-9. 117. O’Neill P, Duarte F, Ribeiro I, et al. Ropivacaine continuous
95. Duraclon (clonidine hydrochloride injection). Package insert. wound infusion versus epidural morphine for postoperative anal-
Bioniche Pharma. Available at http://www.bionichepharmausa gesia after cesarean delivery: a randomized controlled trial. Anesth
.com/pdf/Duraclon_Xanodyne_PI.pdf. Accessed May 2013. Analg 2012; 114:179-85.
96. Lavand’homme PM, Roelants F, Waterloos H, et al. An evaluation 118. Carvalho B, Lemmens HJ, Ting V, Angst MS. Postoperative
of the postoperative antihyperalgesic and analgesic effects of subcutaneous instillation of low-dose ketorolac but not
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hydromorphone reduces wound exudate concentrations of 125. Abbaspoor Z, Akbari M, Najar S. Effect of foot and hand massage
interleukin-6 and interleukin-10 and improves analgesia following in post-cesarean section pain control: a randomized control trial.
cesarean delivery. J Pain 2013; 14:48-56. Pain Manag Nurs 2013:Epub ahead of print.
119. Niklasson B, Borjesson A, Carmnes UB, et al. Intraoperative 126. Ito S. Drug therapy for breast-feeding women. N Engl J Med
injection of bupivacaine-adrenaline close to the fascia reduces 2000; 343:118-26.
morphine requirements after cesarean section: a randomized con- 127. Morales T, Shapiro E, Marina N, Mena F. Sympathetic innerva-
trolled trial. Acta Obstet Gynecol Scand 2012; 91:1433-9. tion of mammary glands mediates suckling-induced reflex inhibi-
120. Pavy T, Gambling D, Kliffer P, et al. Effect of preoperative skin tion of milk yield in rats. Physiol Behav 2001; 74:37-43.
infiltration with 0.5% bupivacaine on postoperative pain following 128. Woods AB, Crist B, Kowalewski S, et al. A cross-sectional analysis
cesarean section under spinal anesthesia. Int J Obstet Anesth 1994; of the effect of patient-controlled epidural analgesia versus patient
3:199-202. controlled analgesia on postcesarean pain and breastfeeding.
121. Vallejo MC, Steen TL, Cobb BT, et al. Efficacy of the bilateral J Obstet Gynecol Neonatal Nurs 2012; 41:339-46.
ilioinguinal-iliohypogastric block with intrathecal morphine for 129. Oberlander TF, Robeson P, Ward V, et al. Prenatal and breast milk
postoperative cesarean delivery analgesia. Scientific World Journal morphine exposure following maternal intrathecal morphine
2012; 2012:107316. treatment. J Hum Lact 2000; 16:137-42.
122. Wolfson A, Lee AJ, Wong RP, et al. Bilateral multi-injection 130. Sauberan JB, Anderson PO, Lane JR, et al. Breast milk hydroco-
iliohypogastric-ilioinguinal nerve block in conjunction with neur- done and hydromorphone levels in mothers using hydrocodone
axial morphine is superior to neuraxial morphine alone for post- for postpartum pain. Obstet Gynecol 2011; 117:611-7.
cesarean analgesia. J Clin Anesth 2012; 24:298-303. 131. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and
123. Bell EA, Jones BP, Olufolabi AJ, et al. Iliohypogastric-ilioinguinal Lactation. 9th edition. Philadelphia, Wolters Kluwer Health/
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decreases morphine use but not opioid-related side effects. Can J 132. Nitsun M, Szokol JW, Saleh HJ, et al. Pharmacokinetics of mid-
Anaesth 2002; 49:694-700. azolam, propofol, and fentanyl transfer to human breast milk. Clin
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cesarean section pain. Chin Med J (Engl) 2009; 122:1743-8.
C H A P T E R 2 8
CHAPTER OUTLINE
The cesarean delivery rate in the United States has Joint Commission also proposed the goal of having
steadily increased as a result of changing patterns in patients experience uniformly low postoperative pain
obstetric practice,1 and recent data indicate that more scores of less than 3 (based on a numerical pain scale
than 1 million cesarean deliveries are now performed [0 to 10] at rest and with movement). In the United
annually in the United States.2 With cesarean delivery Kingdom, the Royal College of Anaesthetists8 has pro-
accounting for an ever-increasing proportion of all posed the following standards for adequate postcesarean
deliveries in the United States and in many other analgesia:
developed countries,3 strategies for reducing adverse 1. More than 90% of women should have a pain score
postcesarean maternal outcomes, including postopera- of less than 3 (as measured by a numerical pain scale
tive pain, have important clinical and public health [0 to 10]).
implications. 2. More than 90% of women should be satisfied with
Postoperative pain after cesarean delivery can be mod- their pain management.8
erate to severe and is equivalent to that reported after A 2007 study suggested that these goals for postcesar-
abdominal hysterectomy.4 Management of postoperative ean analgesia and maternal satisfaction are frequently not
pain is frequently substandard, with 30% to 80% of attained.9 A sample of expectant mothers attending birth-
patients experiencing moderate to severe postoperative ing classes identified pain during and after cesarean deliv-
pain.5,6 In an effort to improve pain management in the ery as their most important concern (Table 28-1).10
United States, The Joint Commission has stated that Effective pain management should be highlighted as an
postoperative pain should be the “fifth vital sign.”7 The essential element of postoperative care.
621
622 PART VII Cesarean Delivery
Percentage of patients
80 Moderate (4-7)
Delivery* Severe (8-10)
60%†
60
Outcome Rank† Relative Value‡ 49%
45%
Pain during cesarean delivery 8.4 ± 2.2 27 ± 18 40 33%
Pain after cesarean delivery 8.3 ± 1.8 18 ± 10
Vomiting 7.8 ± 1.5 12 ± 7 20
Nausea 6.8 ± 1.7 11 ± 7 11%
4% 7% 6%
Cramping 6.0 ± 1.9 10 ± 8 0
Itching 5.6 ± 2.1 9 ± 8 Epidural PCA IM
Shivering 4.6 ± 1.7 6 ± 6
Anxiety 4.1 ± 1.9 5 ± 4 FIGURE 28-1 ■ Randomized trial of postcesarean analgesia with
Somnolence 2.9 ± 1.4 3 ± 3 epidural analgesia, intravenous patient-controlled analgesia
(PCA), or intramuscular (IM) administration of morphine. Per-
Normal 1 0 centage of patients reporting mild, moderate, or severe discom-
fort during a 24-hour study period. *P < .05, epidural versus PCA
*Data are mean ± standard deviation. and IM; †P = NS, PCA versus IM. (From Harrison DM, Sinatra RS,
†Rank = 1 to 10 from the most desirable (1) to the least desirable Morgese L, et al. Epidural narcotic and PCA for postcesarean section
(10) outcome. pain relief. Anesthesiology 1988; 68:454-7.)
‡Relative value = dollar value patients would pay to avoid an
outcome (e.g., they would pay $27 of a theoretical $100 to
avoid pain during cesarean delivery).
From Carvalho B, Cohen SE, Lipman SS, et al. Patient preferences
for anesthesia outcomes associated with cesarean delivery. A CSE technique incorporates the rapid onset of
Anesth Analg 2005; 101:1182-7. spinal anesthesia with placement of an epidural catheter
for supplementation of intraoperative anesthesia and/or
for provision of postoperative analgesia. The CSE tech-
nique is increasingly used when prolonged duration of
NEURAXIAL TECHNIQUES FOR surgery is anticipated (e.g., obesity, multiple previous sur-
CESAREAN DELIVERY geries).16 After surgery, patients with an epidural catheter
in situ may benefit from intermittent bolus injection or
In the United States and the United Kingdom, most continuous epidural infusion of local anesthetic and/or
cesarean deliveries are performed with neuraxial anes- opioid for postoperative analgesia.
thesia (spinal, epidural, or combined spinal-epidural
[CSE] techniques).11-13 A meta-analysis found no differ-
ences between spinal and epidural anesthetic techniques EFFICACY AND BENEFITS OF
with regard to failure rate, additional requests for intra- NEURAXIAL ANALGESIA
operative analgesia, need for conversion to general
anesthesia, maternal satisfaction, postoperative analgesic Neuraxial opioid administration currently represents the
requirements, or neonatal outcomes.14 There may be “gold standard” for providing effective postcesarean
other nonclinical factors that influence the choice of analgesia. A meta-analysis of studies involving a broad
neuraxial anesthetic technique for cesarean delivery. population of patients undergoing a variety of surgical
Spinal anesthesia has been shown to be more cost effec- procedures confirmed that opioids delivered by either
tive than epidural anesthesia for cesarean delivery, patient-controlled epidural analgesia (PCEA) or continu-
because needle placement is technically less challenging ous epidural infusion (CEI) provide postoperative pain
and adequate surgical anesthesia is achieved more relief that is superior to that provided by intravenous
rapidly.15 These advantages, combined with the low patient-controlled analgesia (PCA).17 Similar results have
incidence of post–dural puncture headache with non- been reported in studies comparing intrathecal and epi-
cutting spinal needles (see Chapter 12), have increased dural opioid administration with intravenous opioid PCA
the popularity of spinal-based anesthetic techniques for or intramuscular opioid administration after cesarean
patients undergoing cesarean delivery. A 2008 survey delivery (Figure 28-1).18-21 A 2010 systematic review
of members of the Society for Obstetric Anesthesia and found that neuraxial morphine provides better analgesia
Perinatology found that 85% of elective cesarean deliv- than parenteral opioids after cesarean delivery.22 Neur-
eries are performed with spinal anesthesia.13 A workforce axial opioids also provide postcesarean analgesia that is
survey in the United States demonstrated that the major- superior to that provided by local anesthetic techniques
ity of laboring women receive epidural analgesia.11 If a (e.g., transversus abdominis plane blocks) and oral anal-
patient receiving epidural analgesia during labor subse- gesics (e.g., nonsteroidal anti-inflammatory drugs
quently requires a cesarean delivery, most anesthesia [NSAIDs], opioids) (see Chapter 27).23-26 Wound infiltra-
providers choose to administer medications through tion of a local anesthetic has been proposed as an alterna-
the epidural catheter to achieve adequate surgical tive to an epidural technique for postcesarean analgesia27,28;
anesthesia (see Chapter 26).11-13 however, the efficacy and reliability of this technique are
28 Postoperative Analgesia: Epidural and Spinal Techniques 623
variable.29-31 Intrathecal morphine is particularly effective reduction in postoperative pain with neuraxial analgesia,
after abdominal surgery.32 Although neuraxial analgesia there is less consistent evidence linking neuraxial anes-
offers important benefits in optimizing postoperative thesia with a reduction in postoperative morbidity and
analgesia, multimodal analgesic strategies should be used mortality.52,55
to augment the analgesic effect of neuraxial opioids in Most patients undergoing cesarean delivery are young,
this setting.25 healthy, and at low risk for major perioperative morbidity
Persistent and chronic incisional and pelvic pain have and mortality. For this patient population, the benefits of
been described after cesarean delivery, with an incidence neuraxial analgesia include better postoperative analge-
of 1% to 15%.33-41 Psychosocial and pathophysiologic sia, increased functional ability, earlier ambulation, and
factors may also increase the likelihood of chronic post- earlier return of bowel function.56-59 However, differences
operative pain.42,43 Severe acute postoperative pain is one in postcesarean complication rates with the use of neur-
of the most prominent associated factors.34,37,42,44 The axial versus systemic opioid analgesia have not been
development of chronic pain after surgery has been asso- definitively demonstrated.56,60 Surgical trauma and post-
ciated with central sensitization, hyperalgesia, and allo- operative immobility are associated with an increased risk
dynia. Measures to attenuate or prevent pain sensitization for postoperative deep vein thrombosis and pulmonary
may reduce the likelihood of development of chronic embolism. The risk for venous thromboembolism is
postoperative pain. Studies have shown that the use of 6-fold higher in pregnant women and 10-fold higher in
perioperative neuraxial blockade may prevent central puerperal women than in nonpregnant women of similar
sensitization and chronic pain.33,45,46 De Kock et al.45 age.61 In theory, early ambulation and avoidance of pro-
found that intrathecal clonidine, administered before longed immobility may reduce the risk for postpartum
colonic surgery, had antihyperalgesic effects and resulted deep vein thrombosis and pulmonary embolism. Effec-
in less residual pain 6 months after surgery than did tive postoperative analgesia can reduce pain on move-
placebo. Lavand’homme et al.46 reported that the admin- ment, thereby facilitating deep breathing, coughing, and
istration of a multimodal antihyperalgesic regimen (intra- early ambulation. These beneficial effects may lead to a
operative intravenous ketamine and epidural analgesia reduction in the incidence of pulmonary complications
with bupivacaine, sufentanil, and clonidine) was associ- (i.e., atelectasis, pneumonia) after cesarean delivery.
ated with a lower incidence of residual pain 1 year after Neuraxial analgesic techniques may be more likely to
colonic surgery compared with intravenous analgesia reduce perioperative morbidity in high-risk obstetric
administered during and after surgery. A study investigat- patients. Women with severe preeclampsia, cardiovascu-
ing risk factors for chronic pain after hysterectomy found lar disease, and morbid obesity may benefit from the
that spinal anesthesia was associated with a lower fre- reduction in cardiovascular stress and improved pulmo-
quency of chronic postoperative pain compared with nary function associated with effective postcesarean
general anesthesia.47 In another study, persistent postop- analgesia.62,63 Rawal et al.63 compared the efficacy of
erative pain was more frequent after cesarean delivery intramuscular versus epidural morphine in 30 nonpreg-
performed with general anesthesia compared with neur- nant, morbidly obese patients after abdominal surgery.
axial anesthesia.34 Additional mechanistic and clinical Patients in the epidural morphine group were more alert,
research is needed to improve our understanding of per- ambulated more quickly, recovered bowel function
sistent pain after cesarean delivery and to improve current earlier, and had fewer pulmonary complications.
treatment regimens for managing patients with Investigators have found that CEI of an opioid with a
postcesarean-related pain syndromes. dilute solution of local anesthetic attenuates coagulation
Although neuraxial opioids provide postcesarean anal- abnormalities, hemodynamic fluctuation, and stress
gesia that is superior to that provided by systemic opioids, hormone responses in nonpregnant patients.64-66 Some
some opioid-related side effects (e.g., pruritus) com- studies have suggested that opioid-based PCEA may
monly occur after neuraxial opioid administration.18,48,49 improve postoperative outcome.67-69 Patients treated with
Both higher49,50 and lower21,51 maternal satisfaction scores PCEA meperidine after cesarean delivery ambulated
have been reported with neuraxial opioid administration more quickly and experienced an earlier return of gastro-
for postcesarean analgesia. This variability in reported intestinal function compared with similar patients who
maternal satisfaction scores may be influenced by how received intravenous meperidine PCA.67
patients judge analgesic quality against the presence and
severity of opioid-related side effects (e.g., pruritus,
nausea and vomiting). PHARMACOLOGY OF NEURAXIAL
Neuraxial anesthetic and analgesic techniques may OPIOIDS
also confer important physiologic benefits that decrease
perioperative complications and improve postoperative Prior to 1974, investigators speculated that the analgesic
outcomes.52-54 The potential benefits include a lower effect of opioids was due to pain modulation at supra-
incidence of pulmonary infection and pulmonary embo- spinal centers or increased activation of descending
lism, an earlier return of gastrointestinal function, fewer inhibitory pathways, without a direct effect at the spinal
cardiovascular and coagulation disturbances, and a cord. The identification of endogenous opioid peptides,
reduction in inflammatory and stress-induced responses specific opioid binding sites, and opioid receptor sub-
to surgery.52-54 In contrast to the wealth of data from types has helped to clarify the site and mechanism of
clinical studies and meta-analyses that have shown a action of opioids within the central nervous system
624 PART VII Cesarean Delivery
(CNS).70-73 The discovery that opioid receptors are local- After the administration of an epidural bolus of sufentanil
ized within discrete areas in the CNS (laminae I, II, 50 µg,* CSF concentrations of sufentanil were 140 times
and V of the dorsal horn) suggested that exogenous greater than those found in plasma; however, the amount
opioids could be administered neuraxially to produce detected in cisternal CSF was only 5% of that measured
antinociception. Opioids administered to superficial in lumbar CSF.91
layers of the dorsal horn produced selective analgesia Hydrophilic morphine has a higher CSF bioavailabil-
of prolonged duration without affecting motor function, ity, with better penetration into the CSF and less systemic
sympathetic tone, or proprioception.74 In addition, the absorption. A bolus dose of epidural morphine 6 mg
analgesia provided by intraspinal opioids suggested that results in peak plasma concentration of 34 ng/mL at 15
many of the unwanted side effects of intraspinal local minutes after administration and a peak CSF concentra-
anesthetic administration could be avoided.75 In 1979, tion of approximately 1000 ng/mL at 1 hour.92 A poor
Wang et al.76 published the first report of intraspinal correlation between the analgesic effect and plasma levels
opioid administration in humans. Intrathecal morphine of morphine has been observed after epidural administra-
(0.5 to 1 mg) produced complete pain relief for 12 to tion, indicating a predominantly spinal location of
24 hours in six of eight patients suffering from intrac- action.93,94
table cancer pain, with no evidence of sedation, respira- Intrathecal administration allows for injection of the
tory depression, or impairment of motor function. drug directly into the CSF. This is a more efficient
Subsequently, researchers and clinicians have validated method of delivering opioid to spinal cord receptors than
the analgesic efficacy of neuraxial opioids. epidural or parenteral administration. A bolus dose of
intrathecal morphine 0.5 mg results in a CSF concentra-
tion higher than 10,000 ng/mL, with barely detectable
Central Nervous System Penetration plasma concentrations.95
Opioids administered epidurally must penetrate the dura,
pia, and arachnoid membranes to reach the dorsal horn Distribution and Movement of Opioids
and activate the spinal opioid receptors. The arachnoid
layer is the primary barrier to drug transfer into the spinal
within the Central Nervous System
cord.77 Movement through this layer is passive and The movement and distribution of opioids within the
depends on the physicochemical properties of the opioid. CNS has been described as follows (Figure 28-2):
Drugs penetrating this arachnoid layer must first move 1. Movement in the spinal cord (white and gray
into a lipid bilayer membrane, then traverse the hydro- matter). Lipophilic agents (e.g., fentanyl) are taken
philic cell itself, and finally partition into the other cell up by the white matter with much greater affinity
membrane before entering the cerebrospinal fluid (CSF). than hydrophilic agents (e.g., morphine), and less
Opioid penetration of spinal tissue is proportional to the drug will reach the dorsal horn in the gray
drug’s lipid solubility. Opioids that are highly lipid soluble matter.77,78,96
(e.g., sufentanil, fentanyl) are unable to cross the hydro- 2. Movement within the epidural space (and sub-
philic cell, whereas those that are hydrophilic have dif- sequently epidural fat or veins). Lipophilic agents
ficulty crossing the lipid membrane.78 Highly lipid-soluble are more likely to be absorbed and transported
drugs have poor CSF bioavailability because of (1) poor from the epidural space to the systemic
penetration through the arachnoid layer, (2) rapid absorp- circulation.
tion and sequestration by epidural fat, and (3) high vas- 3. Rostral spread in the CSF to the brainstem.
cular uptake by epidural veins. Rostral spread is determined by CSF drug bioavail-
Some investigators have questioned the neuraxial ability and the drug concentration gradient; hydro-
specificity of lipophilic opioids given epidurally and have philic opioids (e.g., morphine) are associated with
suggested that the primary analgesic effect occurs via more rostral spread.91,97
vascular uptake, systemic absorption, and redistribution Although opioid dose, volume of injectate, and degree of
of the drug to supraspinal sites.79-84 Earlier studies sug- ionization are important variables, lipid solubility plays
gested that parenteral fentanyl provides analgesia equiva- the key role in determining the onset of analgesia, the
lent to that provided by epidural fentanyl.84,85 Investigators
postulated that systemic absorption of fentanyl from the
epidural space resulted in the subsequent analgesic
*The Institute of Safe Medicine Practices (ISMP) has recommended
effect.84,85 Ionescu et al.86 reported that plasma levels of that health care providers never use µg as an abbreviation for micro-
sufentanil were comparable throughout a 3-hour sam- grams, but rather they should use mcg (http://www.ismp.org/tools/
pling interval after epidural or intravenous injection. In errorproneabbreviations.pdf, Accessed February 2013). The use of
contrast, more recent evidence suggests that epidural fen- the symbol µg is frequently misinterpreted and involved in harmful
medication errors. The abbreviation may be mistaken for mg (mil-
tanyl provides analgesia via a spinal mechanism.87-89 ligrams), which would result in a 1000-fold overdose. The symbol µg
Cohen et al.,90 comparing a continuous infusion of intra- should never be used when communicating medical information,
venous fentanyl with epidural fentanyl after cesarean including pharmacy and prescriber computer order entry screens,
delivery, reported improved analgesia and less supple- computer-generated labels, labels for drug storage bins, and medica-
mental analgesic consumption despite lower plasma tion administration records. However, most scholarly publications
have continued to use the abbreviation µg. The editors have chosen
fentanyl levels with epidural administration. There is evi- to retain the use of the abbreviation µg throughout this text. However,
dence that bolus administration of lipophilic opioids has the editors recommend the use of the abbreviation mcg in clinical
both spinal and supraspinal effects in obstetric patients.87-89 practice.
28 Postoperative Analgesia: Epidural and Spinal Techniques 625
(Rostral
spread
via CSF)
FIGURE 28-2 ■ Factors that influence dural penetration, cerebrospinal fluid (CSF) sequestration, and vascular clearance of epidurally
administered opioids. The major portion of epidurally administered opioids (EO) is absorbed by epidural and spinal blood vessels
or dissolved into epidural fat. Molecules taken up by the epidural plexus and azygos system may recirculate to supraspinal centers
and mediate central opioid effects. A smaller percentage of uncharged opioid molecules (EO0) traverse the dura and enter the CSF.
Lipophilic opioids rapidly exit the CSF and penetrate into spinal tissue. As with intrathecal dosing, the majority of these molecules
either are trapped within lipid membranes (nonspecific binding sites [NS]) or are rapidly removed by the spinal vasculature. A small
fraction of molecules bind to and activate opioid receptors (R). Hydrophilic opioids penetrate pia-arachnoid membranes and spinal
tissue slowly. A larger proportion of these molecules remain sequestered in CSF and are slowly transported rostrally. This CSF
depot permits gradual spinal uptake, greater dermatomal spread, and a prolonged duration of activity. CNS, central nervous system;
EO+, charged epidurally administered opioid molecules. (From Sinatra RS. Pharmacokinetics and pharmacodynamics of spinal opioids.
In Sinatra RS, Hord AH, Ginsberg B, Preble LM, editors. Acute Pain: Mechanisms and Management. St. Louis, Mosby, 1992:106.)
dermatomal spread, and the duration of activity (Table greater µ-opioid receptor affinity, resulting in a compara-
28-2).80,98 Highly lipid-soluble opioids penetrate the tively longer duration of analgesia after neuraxial
spinal cord more rapidly and have a quicker onset of administration.
action than more ionized water-soluble agents. The Intrathecal and epidural opioids often produce analge-
duration of activity is affected by the rate of clearance sia of greater intensity than similar doses administered
of the drug from the sites of activity. Lipid-soluble opioids parenterally. The gain in potency is inversely propor-
are rapidly absorbed from the epidural space, whereas tional to the lipid solubility of the agent used. Hydro-
hydrophilic agents remain in the CSF and spinal tissues philic opioids exhibit the greatest gain in potency; the
for a longer time (see Figure 28-2).80,98 Sufentanil is more potency ratio for intrathecal to systemic morphine is
lipid soluble than fentanyl; however, sufentanil has a approximately 1 : 100.98,99
626 PART VII Cesarean Delivery
Single-Dose Regimens to Optimize Postcesarean received two doses of epidural morphine 5 mg (at the
Analgesia and Minimize Opioid-Related time of delivery and at 24 hours postoperatively) required
Side Effects supplemental analgesics, compared with 76% of patients
who received one dose of 5 mg at the time of delivery.
In a prospective dose-response study, Palmer et al.104
observed that postcesarean analgesia (assessed by need Epidural versus Intrathecal Administration
for supplemental intravenous morphine PCA) improved
as the dose of epidural morphine increased from 0 to A number of studies have compared the postcesarean
3.75 mg. A further increase in dose (to 5 mg) did not analgesic efficacy of epidural and intrathecal administra-
significantly improve analgesia or reduce the amount of tion of opioids.14,111,112 Equipotent doses have been evalu-
supplemental intravenous morphine used in the first ated, with use of a conversion ratio of 20 : 1 to 30 : 1
24 postoperative hours (Figure 28-3).104 Chumpathong between epidural and intrathecal administration. Sarvela
et al.101 did not observe any difference in pain relief, et al.112 compared epidural morphine 3 mg with intrathe-
patient satisfaction, or side effects in women receiving cal morphine 0.1 mg and 0.2 mg; they found that the two
epidural morphine 2.5 mg, 3 mg, or 4 mg for postcesar- routes of administration provided postcesarean analgesia
ean analgesia. Rosen et al.102 found that epidural mor- with similar efficacy and equal duration (Figure 28-4).
phine 5 mg and 7.5 mg provided similar analgesic efficacy, Duale et al.111 observed modest improvements in pain
as opposed to a 2-mg dose, which provided ineffective scores and less morphine consumption with epidural
analgesia. Epidural morphine 3 mg was recommended by morphine 2 mg than with intrathecal morphine 0.075 mg.
Fuller et al.103 after a large retrospective study of epidural In both studies, the incidence of side effects (e.g., seda-
morphine in doses ranging from 2 to 5 mg for postcesar- tion, pruritus, nausea and vomiting) was not significantly
ean analgesia. different between the epidural and intrathecal routes of
In contemporary clinical practice, doses of epidural administration.111,112 No differences in postoperative pain
morphine 2 to 4 mg are most commonly used. Lower scores, analgesic consumption, or treatment of side effects
doses may not provide effective analgesia, and women (e.g., nausea, vomiting, pruritus) were reported in a
may require additional supplemental analgesia,102,104 cohort of women who underwent scheduled cesarean
whereas higher doses may increase opioid-related side delivery and received intrathecal morphine 0.2 mg, com-
effects without improving analgesia. pared with a cohort who underwent intrapartum cesarean
The long duration of epidural morphine analgesia delivery and received epidural morphine 4 mg.113 A meta-
prompts many clinicians to remove the epidural catheter analysis concluded that both epidural and intrathecal
after bolus administration. However, some investigators techniques provide effective postcesarean analgesia, with
have proposed that the epidural catheter should be left neither technique being superior in terms of analgesic
in situ to allow administration of additional doses.110 efficacy.14 However, intrathecal administration results in
Zakowski et al.110 reported that only 36% of patients who less systemic drug exposure and less potential fetal drug
110
*
100
90
PCA morphine use (mg)
80
70 **
60
50
40
30
20
10
0
0.0 1.25 2.50 3.75 5.0
Epidural morphine dose (mg) FIGURE 28-4 ■ Randomized trial of epidural morphine 3 mg,
intrathecal (IT) morphine 100 µg (0.1 mg), and IT morphine
FIGURE 28-3 ■ Random allocation dose-response trial of epidural 200 µg (0.2 mg). Visual analog scale (VAS) scores of postopera-
morphine 0, 1.25, 2.5, 3.75, and 5.0 mg for postcesarean deliv- tive pain during the first 24 hours at 3-hour intervals, as well
ery analgesia. Breakthrough pain as assessed by total 24-hour as the maximal pain score at rest for each patient during the
patient-controlled analgesia (PCA) morphine use. Data are first 24 hours (Max 3-24) and the maximal pain score when
mean ± 95% confidence interval. Groups were significantly dif- moving (Pop max), expressed as means and 95% error bars in
ferent (P < .001). *Group 0.0 mg was significantly different from the three groups. *P < .05, epidural compared with both IT
groups 2.5, 3.75, and 5.0 mg. **Group 1.25 mg was significantly groups at 24 hours. (From Sarvela J, Halonen P, Soikkeli A, Korttila
different from groups 3.75 and 5.0 mg. (From Palmer CM, Nogami K. A double-blinded, randomized comparison of intrathecal and epi-
WM, Van Maren G, Alves DM. Postcesarean epidural morphine: a dural morphine for elective cesarean delivery. Anesth Analg 2002;
dose-response study. Anesth Analg 2000; 90:887-91.) 95:436-40.)
628 PART VII Cesarean Delivery
Fentanyl
100
Fentanyl is not approved by the FDA for neuraxial
administration, but it is very commonly administered “off
label” for postcesarean analgesia. Commercial prepara-
tions of fentanyl contain no preservatives, are suitable for
epidural or intrathecal administration, and have an excel-
lent safety record. Grass et al.115 reported that the 50% 0
and 95% effective doses (ED50 and ED95, respectively) of 1 2 5 10 15 20
epidural fentanyl to reduce postcesarean pain scores to Volume of injectate (mL)
less than 10 mm (using a 100-mm visual analog scale)
FIGURE 28-5 ■ Duration of postcesarean analgesia provided by
were 33 µg and 92 µg, respectively. Epidural fentanyl epidural fentanyl 50 µg administered in different volumes of
doses of 1 µg/kg have also been suggested to optimize normal saline. P < .001, each group compared with the control
intraoperative analgesia.116 In clinical practice, doses of group (1 mL). (Data from Birnbach DJ, Johnson MD, Arcario T,
50 to 100 µg are given alone or in combination with et al. Effect of diluent volume on analgesia produced by epidural
fentanyl. Anesth Analg 1989; 68:808-10.)
epidural morphine. Adverse neonatal effects should be
considered if fentanyl is administered before delivery. It
may be prudent to delay fentanyl administration until the duration of analgesia provided by epidural fentanyl 50 µg
umbilical cord has been clamped if high doses (> 100 µg) could be improved by increasing the volume of normal
are planned. Epidural fentanyl doses less than 50 µg do saline in the epidural injectate (Figure 28-5); this finding
not provide optimal analgesia.117 contrasts to observations of epidural morphine (see
The slow onset of action of morphine limits its ability earlier discussion).
to provide optimal intraoperative analgesia, and more Local anesthetics may have a synergistic effect with
lipophilic opioids (e.g., fentanyl) with a faster onset of epidurally administered opioids. The concurrent admin-
analgesia are more appropriate for supplementation of istration of local anesthetic reduces epidural fentanyl
intraoperative analgesia (see Table 28-2).98,118,119 Although dose requirements after cesarean delivery.126 Epidural
single-dose epidural fentanyl improves intraoperative fentanyl, administered either as a single dose or as a
analgesia, no meaningful postoperative pain relief occurs continuous or patient-controlled infusion, generally has
beyond 4 hours.120 Naulty et al.121 reported that epidural fewer side effects than epidural morphine.83,121,122 Some
fentanyl 50 to 100 µg provided 4 to 5 hours of pain relief investigators have suggested that the administration of
and significantly reduced 24-hour analgesic requirements epidural fentanyl before incision may provide preemptive
after cesarean delivery. However, Sevarino et al.122 analgesia that improves postoperative analgesia.116
reported an analgesic duration of only 90 minutes and no
reduction in 24-hour opioid requirements in patients
who received epidural fentanyl 100 µg with epidural lido-
Sufentanil
caine anesthesia for cesarean delivery. A dose-response Epidural sufentanil is a lipid-soluble opioid that provides
study of epidural fentanyl 25, 50, 100, and 200 µg (with a rapid onset of effective postcesarean analgesia. In
lidocaine and epinephrine) found that the duration of patients recovering from cesarean delivery, the potency
analgesia ranged from 1 to 2 hours.115 These discrepan- ratio of epidural sufentanil to epidural fentanyl is approx-
cies in the duration of analgesia can likely be attributed imately 5 : 1.115 No differences in onset, quality, or dura-
to the use of different local anesthetics in these studies. tion of analgesia were found after epidural administration
Bupivacaine has a long duration of action and may poten- of equi-analgesic doses of sufentanil and fentanyl.115 Like
tiate spinal opioid analgesia by altering opioid receptor fentanyl, epidural sufentanil does not provide postopera-
conformation and facilitating opioid receptor binding.123,124 tive analgesia of significant duration. Rosen et al.127 com-
Prior epidural administration of 2-chloroprocaine may pared postcesarean epidural morphine 5 mg with epidural
be associated with a short duration of epidural fentanyl sufentanil 30, 45, or 60 µg. Although most patients who
analgesia. This effect does not appear to be a pH-dependent received sufentanil reported pain relief within 15 minutes,
phenomenon; it may reflect µ-opioid receptor antago- the duration of analgesia was 4 to 5 hours, in contrast to
nism caused by 2-chloroprocaine.109 the 26 hours of analgesia with epidural morphine.127 The
Lipophilic opioids do not spread rostrally in CSF to duration of analgesia is dose dependent; an epidural bolus
any great extent and tend to have limited dermatomal of sufentanil 25 µg produced less than 2 hours of analge-
spread.80, 98 Birnbach et al.125 found that the onset and sia, whereas 60 µg provided 5 hours of pain relief.115,127
28 Postoperative Analgesia: Epidural and Spinal Techniques 629
The rapid onset and short duration of action of sufen- studies.138,139 Halpern et al.141 found no overall differences
tanil are desirable characteristics for continuous epidural in quality of postcesarean analgesia or severity of side
infusion. The vascular uptake of epidural sufentanil is effects between patients who received either epidural
significant, and plasma concentrations increase progres- hydromorphone 0.6 mg or epidural morphine 3 mg.
sively after epidural administration. However, no data Pruritus was more pronounced in the hydromorphone
exist to establish dose limits for epidural sufentanil group in the first 6 hours; however, the incidence was
administration in this setting. higher in the morphine group at 18 hours. A Cochrane
review suggests that epidural morphine and hydromor-
phone provide analgesia with similar efficacy and side
Meperidine effects when given for the treatment of acute or chronic
Epidural meperidine has been used for postcesarean anal- pain.142
gesia and has local anesthetic properties. Two clinical
trials compared the safety and efficacy of epidural meper- Diamorphine
idine 50 mg and intramuscular meperidine 100 mg
administered to patients after cesarean delivery.128,129 Epi- Diamorphine is a lipid-soluble derivative of morphine
dural meperidine provided a faster onset of analgesia with that is commonly administered neuraxially in the United
a duration (2 to 4 hours) similar to that provided by Kingdom.143 The lipid solubility of diamorphine provides
intramuscular meperidine. Paech130 evaluated the quality rapid-onset analgesia, and its principal metabolite (mor-
of analgesia and side effects produced by a single epidural phine) facilitates a prolonged duration of analgesia. Epi-
bolus of meperidine 50 mg or fentanyl 100 µg. The onset dural diamorphine 5 mg provides rapid onset and effective
of pain relief was slightly faster with fentanyl; however, postcesarean analgesia.144,145 Roulson et al.146 found that
the duration of analgesia was longer with meperidine. epidural diamorphine 2.5 mg provided postcesarean
Ngan Kee et al.131,132 compared different doses of epidu- analgesia for 16 hours. Other investigators have found
ral meperidine (12.5, 25, 50, 75, and 100 mg) as well as the duration of postcesarean analgesia provided by epi-
varying volumes of diluent. The investigators concluded dural diamorphine to be 6 to 12 hours.144,145,147 In the
that meperidine 25 mg diluted in 5 mL of saline was United Kingdom, the National Institute of Clinical
superior to 12.5 mg and that doses greater than 50 mg Excellence (NICE) suggests a dose of epidural diamor-
offered no improvement in the quality or duration of phine of 2.5 to 5 mg for postcesarean analgesia.148
analgesia. Epidural meperidine is not associated with
marked hemodynamic effects, which are more commonly Butorphanol
observed after intrathecal administration.133 Studies that
have compared a single bolus dose of epidural or intra- The mixed agonist-antagonist opioid butorphanol offers
thecal morphine with PCEA meperidine have reported two theoretical advantages when administered epidurally:
superior analgesia with morphine, but with a higher inci- (1) modulation of visceral nociception due to selective
dence of opioid-related side effects such as nausea, pru- κ-opioid receptor activity, and (2) a ceiling effect for
ritus, and sedation.134,135 The potential for accumulation respiratory depression even if opioid molecules spread
of the active metabolite normeperidine limits meperidine rostrally to the brainstem.71 Unfortunately, significant
doses and duration of treatment in this setting.136 sedation often occurs as a result of vascular uptake and
activation of supraspinal κ-opioid receptors. Although
epidural butorphanol 2 to 4 mg provides up to 8 hours
Other Epidural Opioids of postcesarean analgesia,149,150 a dose-dependent increase
in sedation occurs. Low doses (0.5 and 0.75 mg) of epi-
Hydromorphone
dural butorphanol are not associated with significant
Hydromorphone is a hydroxylated derivative of mor- sedation but provide modest analgesia after cesarean
phine with a lipid solubility intermediate between that delivery compared with epidural bupivacaine alone.151
of morphine and meperidine.137 The quality of epidural Camann et al.152 found that epidural butorphanol 2 mg
hydromorphone analgesia after cesarean delivery appears offered few advantages over a similar dose given intrave-
to be similar to that observed with epidural morphine; nously. In addition to excessive maternal somnolence,
however, its onset is faster and its duration is slightly there is concern about the neurologic safety of epidural
shorter.138-140 Evidence suggests a potency ratio of 3 : 1 butorphanol, which is based on observations after
to 5 : 1 between epidural morphine and epidural repeated intrathecal injections in animals.153,154 Epidural
hydromorphone.137 butorphanol is not recommended for postcesarean anal-
Chestnut et al.140 evaluated postcesarean analgesia gesia because of its potential neurotoxicity, and it is not
with epidural hydromorphone 1 mg. Most patients approved by the FDA for neuraxial use.
reported good or excellent pain relief, and the mean time
to first request for supplemental analgesia was 13 hours. Nalbuphine
Dougherty et al.138 reported that epidural hydromor-
phone 1.5 mg provided 18 hours of postcesarean analge- Nalbuphine is a semisynthetic opioid with higher lipid
sia and could be prolonged to 24 hours with the addition solubility than morphine. In vitro studies have shown that
of epinephrine. Henderson et al.139 observed 19 hours of moderate agonist activity occurs at κ-opioid receptors,
postcesarean analgesia with epidural hydromorphone and antagonist activity occurs at µ-opioid receptors. In
1 mg. The incidence of pruritus was high in the two latter animal models, neuraxial nalbuphine provides effective
630 PART VII Cesarean Delivery
B, bolus; BI, background infusion; IM, intramuscular injection; LO, lockout interval; NA, data not available; PCA, intravenous patient-
controlled analgesia; PCEA, patient-controlled epidural analgesia; VAS, visual analog scale.
*Superscript numbers indicate chapter references.
†Both groups received 0.01% bupivacaine + epinephrine 0.5 µg/mL.
632 PART VII Cesarean Delivery
5 DepoDur
system composed of multivesicular lipid particles con-
taining nonconcentric aqueous chambers that encapsu-
late the active drug.181,182 These naturally occurring lipids 4
are broken down by erosion and reorganization, resulting
in a sustained release of morphine for up to 48 hours after 3
epidural administration of a single dose.182-184
Two studies have evaluated the analgesic efficacy of
2
EREM for postcesarean analgesia.57, 58 Both studies con-
cluded that patients receiving EREM report lower pain
scores and have lower requirements for supplemental 1
analgesia over 48 hours than patients receiving standard
epidural morphine.57,58 In the first study, overall supple-
0
mental opioid use was approximately 50% less in the 10 20 30 40 50
EREM 10-mg and 15-mg groups than in the standard Time (h)
epidural morphine 5-mg group (Figure 28-8).57 A
follow-up study, which allowed concurrent administra- FIGURE 28-9 ■ Randomized trial of single-shot epidural mor-
tion of an NSAID in both groups, compared a single dose phine 4 mg and extended-release epidural morphine (EREM)
10 mg for postcesarean analgesia. Pain intensity over time
of EREM 10 mg with standard epidural morphine 4 mg (verbal rating scale for pain [VRSP] 0-10) during activity (sitting
after cesarean delivery. The investigators found that anal- up 90 degrees) plotted as means with standard deviations. P =
gesic consumption was 60% less in women in the EREM .003 for EREM (DepoDur) group versus the conventional mor-
group than in women in the standard epidural morphine phine group. (From Carvalho B, Roland LM, Chu LF, et al. Single-
dose, extended-release epidural morphine (DepoDur) compared to
group.58 Patients who received EREM also had better conventional epidural morphine for postcesarean pain. Anesth Analg
and more prolonged pain control both at rest and with 2007; 105:176-83.)
movement (Figure 28-9). A retrospective study of patients
undergoing knee and hip arthroplasty found that EREM
resulted in similar levels of pain control, improved ambu- epidural morphine groups, and no respiratory depression
lation, but more respiratory depression and nausea, com- or hypoxic events were observed.57,58 However, it is likely
pared with a CEI of 0.1% bupivacaine with morphine that the study groups were too small for accurate evalu-
40 µg/mL.185 In the two postcesarean studies, there was ation of side-effect profiles. Pooled data from EREM
no significant difference in the incidence of nausea, pru- studies for nonobstetric surgery suggest that EREM is
ritus, or sedation between the EREM and standard associated with more side effects than standard epidural
634 PART VII Cesarean Delivery
morphine, especially with higher doses.182,186 A meta- increased the incidence of vomiting, use of supplemental
analysis found that EREM was associated with a signifi- oxygen, and hypotension, compared with a control group
cantly higher risk for respiratory depression compared who did not receive epidural lidocaine.191 However,
with intravenous opioid PCA (odds ratio [OR], 5.8; 95% Gambling et al.192 demonstrated no differences in the
CI, 1.1 to 31.9; P = .04).187 Further research is needed to pharmacokinetic and pharmacodynamic profiles of
assess the side-effect and safety profile of EREM in EREM when administered 15, 30, and 60 minutes after
obstetric patients. epidural bupivacaine 0.25%. The package insert advises:
When EREM is given correctly in the epidural space, “Local anesthetics other than a 3-mL test dose of lido-
monitoring for respiratory depression should be contin- caine are not permitted. If the 3-mL test dose is used,
ued for 48 hours (compared with 24 hours with standard wait 15 minutes and then flush the epidural catheter with
epidural morphine).188 Unintentional intrathecal EREM 1 mL of saline before administration of EREM.”193
administration has the potential to result in profound and In summary, EREM provides effective postoperative
prolonged opioid-related side effects; however, a case pain relief and reduces the need for supplemental anal-
report of unintentional intrathecal administration of a gesics in comparison with standard epidural morphine for
standard dose of EREM did not result in profound side up to 48 hours after cesarean delivery.57,58 This analgesic
effects or respiratory depression.189 Although single-dose advantage must be weighed against potential disadvan-
EREM may reduce the need for additional doses of tages associated with EREM administration. The role of
opioid, more prolonged monitoring is necessary, which EREM for postcesarean analgesia remains unclear186;
may increase the required level of nursing care in the however, selective use may be beneficial in a subset of
postoperative period.190 patients with significant analgesic needs. In such cases, a
Currently, there is insufficient clinical evidence to single dose of EREM 6 to 10 mg is recommended after
advocate a change in the planned anesthetic technique the infant is delivered (and the umbilical cord is clamped),
(from a spinal to an epidural or CSE technique) solely for as an alternative to standard epidural morphine.
the purpose of EREM administration in patients under-
going cesarean delivery. However, many clinicians already
use CSE techniques for elective cesarean delivery in INTRATHECAL OPIOIDS
selected patients (when the duration of the cesarean
delivery is expected to extend beyond that provided by Spinal anesthesia has become the preferred anesthetic
spinal anesthesia). In addition, many cesarean deliveries technique for patients undergoing elective cesarean deliv-
are performed in women in whom an epidural catheter ery in the United States and the United Kingdom.11-13
has been placed previously during labor. Therefore, it is Intrathecal opioids are commonly administered with a
possible that EREM may be an attractive option for clini- local anesthetic to improve intraoperative and postopera-
cians who plan to use or insert an epidural catheter for tive analgesia (Table 28-5).
cesarean delivery. However, caution should be exercised
when the administration of EREM follows the use of any
epidural local anesthetic. Early pharmacokinetic studies
Morphine
suggested a potential physicochemical interaction The potency differences between intrathecal and epidu-
between EREM and epidural local anesthetics, which ral opioids account for the smaller doses of intrathecal
could negate the sustained-release effect derived from the opioid used for cesarean delivery. Intrathecal morphine
DepoFoam. A 2011 study found that epidural lidocaine 0.075 to 0.2 mg has been found to be equivalent to epi-
administration (20 to 35 mL) for cesarean delivery, dural morphine 2 to 3 mg.111,112 Initial reports of increased
administered 1 hour before EREM administration, side effects with intrathecal administration likely resulted
increased peak venous blood morphine levels and from the use of very high doses (2 to 10 mg). The
analgesic efficacy, duration of action, and side-effect intrathecal morphine (0.05 to 2 mg) provided postopera-
profile of intrathecal morphine are similar to that of epi- tive analgesia with a mean duration of 503 minutes (95%
dural morphine in patients undergoing cesarean delivery CI, 315 to 641).198 The duration of analgesia may be dose
(see earlier discussion).111,112,194 dependent.51,195Abboud et al.195 observed that postcesar-
ean analgesia increased from 19 hours to 28 hours with
intrathecal morphine 0.1 mg and 0.25 mg, respectively.
Onset and Duration
Intrathecal morphine administration may result in a Optimal Dosage
faster onset of analgesia than epidural morphine, but 45
to 60 minutes are still required for the drug to achieve a Several studies have attempted to determine the optimal
peak effect. The duration of analgesia is similar to the dose of intrathecal morphine for postcesarean analgesia.
duration after epidural administration (14 to 36 hours).* Palmer et al.199 compared postcesarean intravenous PCA
A systematic review and meta-analysis found that the morphine use after doses of intrathecal morphine ranging
median time to first analgesic request was 27 hours from 0.025 to 0.5 mg. The investigators found no sig-
(range, 11 to 29 hours) after intrathecal morphine admin- nificant difference in PCA morphine use with morphine
istration for postcesarean analgesia (Figure 28-10).51 A doses greater than 0.075 mg.199 They concluded that
meta-analysis of studies of intrathecal opioid administra- there was little justification for using a dose of intrathe-
tion in adults undergoing orthopedic, urologic, gyneco- cal morphine higher than 0.1 mg for postcesarean anal-
logic, or general surgical procedures reported that gesia. Milner et al.200 noted that intrathecal morphine
0.1 mg and 0.2 mg produced comparable analgesia but
that the lower dose led to less nausea and vomiting.
*References 50, 51, 98, 111, 112, 194-197. Yang et al.201 showed that intrathecal morphine 0.1 mg
30
28
26
24
22
20
NS
18
Hours
16
14
12
10
8
6
NS
NS
4
2
0
+ buprenorphine 0.03 mg
+ buprenorphine 0.045 mg
bupivacaine 12.5 mg
+ sufentanil 2.5 µg
bupivacaine 10.5 mg
+ sufentanil 10 µg
+ sufentanil 15 µg
+ sufentanil 20 µg
bupivacaine 0.75%
+ fentanyl 6.25 µg
bupivacaine 12.5 mg
+ fentanyl 10 µg
bupivacaine 12.5 mg
+ fentanyl 10 µg
bupivacaine 12.5 mg
+ fentanyl 15 µg
bupivacaine 15 mg
+ fentanyl 20 µg
+ fentanyl 40 µg
+ fentanyl 60 µg
bupivacaine 12-14 mg
+ fentanyl 25 µg
tetracaine 10 mg
+ morphine 0.05 mg
+ morphine 0.1 mg
+ morphine 0.2 mg
bupivacaine 12-14 mg
+ morphine 0.1 mg
bupivacaine 9.3 mg
+ morphine 0.2 mg
bupivacaine 9.3 mg
+ morphine 0.2 mg
bupivacaine 22.5 mg
+ sufentanil 5 µg
lidocaine 80 mg
+ fentanyl 15 µg
FIGURE 28-10 ■ Systematic review of intrathecal opioid analgesia for post–cesarean delivery analgesia. Time to first administration
(in hours) of postoperative supplemental analgesics in patients receiving spinal anesthesia with local anesthetic alone (dark blue
bars) or local anesthetic combined with buprenorphine, sufentanil, fentanyl, or morphine in varying doses (various bars). NS, no
significant difference from control. (From Dahl JB, Jeppesen IS, Jorgensen H, et al. Intraoperative and postoperative analgesic efficacy
and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia. Anesthesiology 1999;
91:1919-27.)
636 PART VII Cesarean Delivery
provided similar postcesarean analgesia with fewer side provided better and longer postoperative analgesia after
effects in comparison with 0.25 mg. Uchiyama et al.202 cesarean delivery.210
performed a dose-response study with intrathecal mor- The analgesic effects, duration of analgesia, and side
phine 0, 0.05, 0.1, and 0.2 mg. They observed that effects after intrathecal fentanyl are dose related.51,206,207
0.1 mg and 0.2 mg provided comparable and effective Belzarena et al.206 found that intrathecal fentanyl pro-
postcesarean analgesia for 28 hours. The 0.05-mg dose vided analgesia for a duration of 305 to 787 minutes (with
was less effective, and the incidence of side effects was 0.25 µg/kg and 0.75 µg/kg, respectively). However,
greater with the 0.2-mg dose; therefore, the investiga- patients who received the higher dose experienced
tors concluded that intrathecal morphine 0.1 mg is the decreased respiratory rates and a high incidence of side
optimal dose for postcesarean analgesia.202 A recent ret- effects (e.g., pruritus, nausea). Dahlgren et al.207 reported
rospective study reported that intrathecal morphine that intrathecal fentanyl 10 µg added to bupivacaine
0.2 mg provided better analgesia than 0.1 mg but with increased the mean time of effective analgesia from 121
the “trade-off” of increased nausea.203 Girgin et al.204 minutes to 181 minutes. Hunt et al.211 compared a range
reported no differences in analgesia with intrathecal of intrathecal fentanyl doses (2.5 to 50 µg) in combina-
morphine doses ranging from 0.1 to 0.4 mg; however, tion with intrathecal bupivacaine for cesarean delivery.
pruritus was increased with higher morphine doses. A Intrathecal fentanyl doses larger than 6.25 µg were asso-
systematic review recommended 0.1 mg as the intrathe- ciated with better intraoperative analgesia and a longer
cal morphine dose of choice.51 time to first request for additional analgesia than admin-
Several studies have compared the analgesic efficacy istration of bupivacaine alone (72 minutes versus 192
and side-effect profile of intrathecal morphine with those minutes, respectively).211 Chu et al.212 found that fentanyl
of PCEA after cesarean delivery. A study comparing doses of 12.5 to 15 µg were required to increase the dura-
intrathecal morphine 0.15 mg with PCEA with 0.06% tion of effective analgesia.
bupivacaine and sufentanil 1 µg/mL found superior anal- In summary, intrathecal fentanyl optimizes intraop-
gesia and fewer side effects with the PCEA regimen.180 erative analgesia and provides immediate postoperative
Paech et al.135 compared intrathecal morphine 0.2 mg analgesia. However, intrathecal fentanyl (10 to 25 µg)
with PCEA meperidine for postcesarean analgesia. provides a limited duration of postcesarean analgesia (2
Patients in the morphine group reported lower pain to 4 hours) and does not decrease subsequent postopera-
scores but also had a higher incidence of pruritus, nausea, tive analgesic requirements.
and drowsiness. In a study of intrathecal morphine
(0, 0.05 and 0.1 mg) followed by a CEI (0.2% ropivacaine
at 6 mL/h), intrathecal morphine improved postcesarean
Sufentanil
analgesia compared with placebo.205 Sufentanil has a fast onset of action, which may improve
In summary, the intrathecal administration of a small intraoperative analgesia and reduce the dose of local
dose of morphine (0.075 to 0.2 mg) provides effective anesthetic required for cesarean anesthesia.213 However,
analgesia for 14 to 36 hours after cesarean delivery. its pharmacokinetic properties limit the duration of effec-
Larger doses may increase side effects without conferring tive postcesarean analgesia after intrathecal administra-
additional analgesic benefit. Because of the variability in tion.51 Courtney et al.214 found that intrathecal sufentanil
patient response to intrathecal morphine, some patients 10, 15, or 20 µg resulted in a mean duration of postcesar-
may experience inadequate postoperative analgesia and/ ean analgesia of approximately 3 hours. More than 90%
or opioid-related side effects. Thus, the use of low-dose of patients reported pruritus, but only one patient
intrathecal morphine as a component of multimodal required treatment. Dahlgren et al.207 compared the
analgesia may provide optimal analgesia with a low risk safety and efficacy of the co-administration of sufentanil
for side effects (see Chapter 27). 2.5 or 5 µg, fentanyl 10 µg, or placebo with hyperbaric
bupivacaine 12.5 mg for cesarean delivery. The duration
of effective analgesia was longer with the opioids, par-
Fentanyl ticularly in the sufentanil groups; sufentanil 5 µg pro-
Intrathecal fentanyl improves intraoperative analgesia vided the longest duration of analgesia but also had the
(especially during uterine exteriorization), reduces intra- highest incidence of pruritus. Patients receiving intrathe-
operative nausea and vomiting, decreases local anesthetic cal sufentanil had lower requirements for intraoperative
dose requirement, and provides a better postoperative antiemetics and postoperative intravenous morphine.207
transition to other pain medications during recovery A study that compared intrathecal sufentanil 2.5, 5.0, and
from spinal anesthesia for cesarean delivery.206-209 7.5 µg found that 5.0 and 7.5 µg provided more effective
However, intrathecal fentanyl provides a limited duration postcesarean analgesia than was observed in a control
of postcesarean analgesia, with a median time to first group (no intrathecal opioids); however, the incidence of
request for additional analgesia of 4 hours (range, 2 to 13 pruritus was higher with sufentanil, especially with the
hours) (see Figure 28-10).51 The aforementioned meta- 7.5-µg dose.215 Karaman et al.216 found that intrathecal
analysis of studies of intrathecal opioid administration in sufentanil 5 µg delayed the time to first analgesic request
adults undergoing nonobstetric surgery reported that to 6 hours, compared with 20 hours for intrathecal mor-
intrathecal fentanyl (10 to 50 µg) provided postoperative phine 0.2 mg. A study that compared intrathecal ropiva-
analgesia with a mean duration of 114 minutes (95% CI, caine 15 mg to ropivacaine 10 mg with sufentanil 5 µg
60 to 168).198 A study that compared intrathecal mor- showed that sufentanil provided effective analgesia with
phine 0.1 mg with fentanyl 25 µg found that morphine a mean duration of only 260 minutes. However, women
28 Postoperative Analgesia: Epidural and Spinal Techniques 637
in the sufentanil group had less intraoperative hypoten- reported that intrathecal diamorphine 0.25 mg produced
sion, shivering, and vomiting, as well as a shorter dura- the same duration and quality of postcesarean analgesia
tion of motor blockade.217 A study that compared as did epidural diamorphine 5 mg, with less nausea and
intrathecal fentanyl 20 µg and sufentanil 2.5 µg added to vomiting.
bupivacaine for cesarean delivery found no difference in Diamorphine has been commonly used in the United
the quality of intraoperative and postoperative analgesia, Kingdom, but it is not available for clinical use in the
as well as no difference in the frequency of nausea and United States. In the United Kingdom, the National
pruritus between the two opioid groups.218 Institute of Clinical Excellence suggests an intrathecal
diamorphine dose of 0.3 to 0.4 mg for postcesarean
analgesia.148
Other Intrathecal Opioids
Meperidine Nalbuphine
Intrathecal meperidine reduces the intensity of pain asso- Culebras et al.230 compared intrathecal morphine 0.2 mg
ciated with the regression of spinal anesthesia and pro- with intrathecal nalbuphine (0.2, 0.8, or 1.6 mg) for
vides postoperative analgesia of intermediate duration postcesarean analgesia. Intrathecal nalbuphine 0.8 mg
(4 to 5 hours).219,220 Yu et al.221 found that the addition of provided good intraoperative and early postoperative
meperidine 10 mg to hyperbaric bupivacaine 10 mg pro- analgesia without side effects. However, intrathecal mor-
longed the mean duration of postcesarean analgesia (234 phine provided significantly longer postoperative analge-
minutes in the meperidine group versus 125 minutes in sia. In an accompanying editorial, the study was criticized
a placebo group). However, the incidence of intraopera- because the safety and neurotoxicity of nalbuphine had
tive nausea and vomiting was greater in the meperidine not been adequately assessed.155
group. A dose of 7.5 mg added to bupivacaine 10 mg
provided postoperative analgesia for 257 ± 112 minutes
(mean ± SD) compared with a saline group (161 ±
Intrathecal Opioid Combinations
65 min).222 Intrathecal administration of morphine in combination
Unlike other opioids, meperidine possesses local anes- with a lipophilic opioid (e.g., fentanyl, sufentanil) may
thetic qualities. Some anesthesia providers have adminis- offer some advantages. Intrathecal morphine has a
tered intrathecal 5% meperidine (1 mg/kg) as the sole delayed onset, and therefore lipophilic opioids with a
anesthetic agent for cesarean delivery under spinal anes- rapid onset may improve intraoperative analgesia and
thesia. However, surgical anesthesia was unreliable, with reduce the intensity of pain associated with the regression
a mean anesthetic duration of 41 ± 15 minutes.219,220 of spinal anesthesia in the postanesthesia care unit after
surgery. Chung et al.231 found that the combination of
intrathecal meperidine 10 mg and morphine 0.15 mg
Diamorphine
provided better intraoperative analgesia, less need for
Diamorphine has physicochemical properties that are of supplemental analgesia, and higher satisfaction than
value in providing intrathecal analgesia. A high lipophi- intrathecal morphine alone for cesarean delivery. Intra-
licity (octanol-water coefficient = 280) results in a rapid thecal sufentanil 5 µg co-administrated with morphine
onset of analgesia, and diamorphine’s active metabolite 0.15 mg provided better and longer pain relief than intra-
(morphine) provides a prolonged duration of analgesia. thecal sufentanil plus a single injection of subcutaneous
Kelly et al.223 compared intrathecal diamorphine morphine; however, a higher incidence of side effects,
0.125, 0.25, and 0.375 mg for cesarean delivery. The such as nausea and vomiting, was observed with intrathe-
0.25-mg and 0.375-mg doses provided effective postce- cal morphine.232
sarean analgesia; the incidence of both vomiting and pru- Some investigators have suggested that intrathecal
ritus was dose related. Stacey et al.224 reported that the morphine may be less effective when concurrently admin-
duration of analgesia was dose dependent and found that istered with intrathecal fentanyl.233 Cooper et al.233
intrathecal diamorphine 1 mg provided 10 hours of post- reported that patients who received intrathecal fentanyl
cesarean analgesia, compared with 7 hours for 0.5 mg. 25 µg with bupivacaine had higher postoperative intrave-
The rapid onset of diamorphine is a potential advantage nous morphine PCA requirements than patients who
in the provision of intraoperative as well as postoperative received bupivacaine alone. The investigators postulated
analgesia.225,226 Saravanan et al.227 concluded that the that this phenomenon was due to acute spinal opioid
ED95 for intrathecal diamorphine to prevent intraopera- tolerance. Carvalho et al.234 found no difference in post-
tive discomfort was 0.4 mg. A dose-response study using operative analgesia requirement but small differences in
intrathecal diamorphine 0.1, 0.2, or 0.3 mg reported a pain scores with the addition of increasing doses of intra-
dose-dependent enhancement of analgesia and an increase thecal fentanyl (5, 10, or 25 µg) to intrathecal morphine
in pruritus.9 0.2 mg for cesarean delivery. The authors suggested that
Husaini et al.228 observed that intrathecal diamorphine intrathecal fentanyl may induce subtle acute tolerance to
0.2 mg and intrathecal morphine 0.2 mg provided similar intrathecal morphine. However, the clinical significance
postcesarean analgesia as measured by postoperative of this finding is unclear, especially in light of the intra-
intravenous PCA morphine requirements. However, the operative benefit of using intrathecal fentanyl. Sibilla
patients who received intrathecal morphine had a higher et al.197 found that the intrathecal combination of fen-
incidence of pruritus and drowsiness. Hallworth et al.229 tanyl 25 µg with morphine 0.1 mg provided similar
638 PART VII Cesarean Delivery
postoperative analgesia to that provided by intrathecal Preservatives that are added to many commercial
morphine alone. Many anesthesia providers currently preparations may be hazardous if administered neuraxi-
administer both intrathecal morphine and fentanyl when ally. Examples are sodium (meta)bisulfite and disodium
giving spinal anesthesia for cesarean delivery.13 The ethylenediaminetetraacetic acid (EDTA), which are
co-administration of intrathecal fentanyl does not appear known to incite inflammatory and fibrotic changes in
to significantly compromise the postoperative analgesia pia-arachnoid and spinal tissue after intrathecal adminis-
provided by intrathecal morphine. tration. Dezocine has been shown to cause neuropatho-
logic changes in the dog spinal cord.243 Similarly, glycine,
a preservative added to remifentanil preparations, is con-
Multimodal Analgesia traindicated for neuraxial injection.
Despite the appropriate administration of neuraxial tech-
niques, the quality and duration of analgesia after cesar- Neonatal Effects
ean delivery is often incomplete. Thus, neuraxial opioids
are rarely the sole analgesic technique used for postcesar- All opioids have the potential for placental transfer and
ean analgesia. Rather, neuraxial opioids should be con- neonatal effects. Minimal neonatal effects have been
sidered as part of a multimodal analgesic approach for the found after the administration of epidural morphine 2 to
treatment of postcesarean pain.25,26,59 Multimodal strate- 7.5 mg for cesarean delivery.244 However, it may be pref-
gies (with neuraxial opioid and postoperative NSAID and erable to administer neuraxial opioids after umbilical
acetaminophen administration) optimize analgesia and cord clamping to avoid placental transfer. Lipophilic
reduce analgesic requirements and side effects (see opioids are associated with greater systemic uptake; if
Chapter 27). indicated (e.g., intraoperative pain during cesarean deliv-
ery), the smallest necessary dose should be administered.
Courtney et al.214 found that intrathecal sufentanil (10,
Maternal Safety and Neonatal Effects 15, or 20 µg) did not affect neonatal outcome as assessed
Careful evaluation of the potential adverse effects of by umbilical cord blood gas measurements and Apgar and
neuraxial pharmacologic agents is necessary before clini- neurobehavioral scores. Intrathecal opioids are associated
cal administration of these agents.235 In obstetric patients, with less neonatal drug transfer than epidural or intrave-
adverse maternal effects (e.g., neurotoxicity, altered nous opioid administration, given that smaller doses are
uteroplacental perfusion) as well as potential adverse neo- used for intrathecal administration.245
natal effects should be assessed. Although many agents
are used routinely and safely in clinical practice, not all
are licensed for neuraxial administration in the United SIDE EFFECTS OF NEURAXIAL OPIOIDS
States.
Respiratory Depression
Maternal Safety Pharmacokinetics and Pharmacodynamics
Neurotoxicity (safety) studies that have been conducted Neuraxial opioids can depress the respiratory centers in
for morphine, fentanyl, sufentanil, meperidine, cloni- the brainstem via direct and/or indirect mechanisms
dine, and neostigmine suggest that these agents are safe (Table 28-6).80,82,97,98,246-248 Respiratory depression after
for neuraxial administration.236-239 Morphine is approved neuraxial morphine administration is biphasic.249 Early
by the FDA for neuraxial administration. Although unli- respiratory depression can occur 30 to 90 minutes after
censed for neuraxial administration, fentanyl and sufent- epidural morphine administration (owing to systemic
anil have been used for many years without evidence of vascular absorption),98 whereas delayed respiratory
neurotoxicity. Studies in sheep have reported potential depression can occur 6 to 18 hours after epidural or
neurotoxicity with intrathecal butorphanol.153 Culebras intrathecal morphine administration (owing to rostral
et al.230 demonstrated potential toxic interactions with spread in CSF and slow penetration into the brain-
the co-administration of nalbuphine and local anesthetic. stem).118 In contrast, lipophilic opioids (e.g., fentanyl,
However, Rawal et al.153 evaluated the behavioral and sufentanil) do not cause delayed respiratory depression
histopathologic effects of butorphanol, sufentanil, and but may cause early-onset respiratory depression, typi-
nalbuphine after intrathecal administration in sheep and cally within 30 minutes, because of significant vascular
found that nalbuphine caused the least evidence of neural uptake and rostral spread in CSF and, potentially, direct
tissue damage. transit in epidural veins.246,247
Clinicians should avoid neuraxial administration of
any agent before adequate evaluation for potential neu- Incidence
rotoxicity has been completed.240-242 Drugs and diluents
that are proven safe for parenteral use may have adverse Although rare, perioperative opioid-induced respiratory
effects when administered intrathecally. Despite these depression represents a significant concern that can lead
valid concerns, a number of opioid analgesics, including to death or permanent brain damage.250,251 The reported
fentanyl and sufentanil, have been administered intrathe- incidence of respiratory depression after neuraxial opioid
cally to healthy obstetric patients without adequate inves- administration ranges from 0% to 3.4%.252 Differences
tigation of their safety profile in animal and clinical in the observed incidence of respiratory depression may
volunteer studies.242 reflect differences in patient population, opioid dose,
28 Postoperative Analgesia: Epidural and Spinal Techniques 639
TABLE 28-7 Recommendations to Reduce the Risk for Respiratory Depression after Neuraxial
Administration of Opioids
Principle Recommendation(s) Clinical Example(s)
Prevention Identify high-risk patients Patients with obesity or sleep apnea or who are receiving
magnesium or sedatives
Limit neuraxial morphine dose Intrathecal morphine 0.075 to 0.2 mg
Epidural morphine 2 to 4 mg
Detection Appropriate monitoring of:
Level of consciousness Clinical signs, sedation scores
Adequacy of ventilation Respiratory rate, end-tidal CO2 level
Adequacy of oxygenation Pulse oximetry, arterial blood PO2
Monitoring continued for duration of effect Fentanyl/sufentanil: 4 h
Morphine: 24 h
Extended-release epidural morphine: 48 h
Treatment Implementation of clinical protocols for detecting
and treating respiratory depression
Nursing and physician education
and mechanisms to ensure a rapid response to respiratory nausea and vomiting (PONV) if these symptoms occur
events are recommended. The patient who displays an intraoperatively. Neuraxial opioids may increase the risk
altered level of consciousness, bradypnea, or hypoxemia for PONV after cesarean delivery. Nausea results either
should receive continuous supplemental oxygen until she from the rostral spread of opioid in the CSF to the brain-
is alert with no evidence of respiratory depression or stem or from vascular uptake and delivery to the vomiting
hypoxemia. The routine use of supplemental oxygen is center and chemoreceptor trigger zone.118, 274 Palmer
not advised because of the associated risk for prolonged et al.199 found no difference in PONV between intrathe-
apnea as well as limitations in the sensitivity of pulse cal morphine (0.025 to 0.5 mg) and placebo, nor a rela-
oximetry to detect hypoventilation.251 An intravenous tionship between PONV and morphine dose. A similar
bolus dose of naloxone is indicated in patients with pro- study by the same group found no difference in the sever-
found somnolence and respiratory depression who do not ity of PONV in patients receiving increasing doses of
respond to arousal. Continued observation is advised epidural morphine (1.25 to 5 mg).104 Importantly, neither
after naloxone administration, because its half-life (43 to study was adequately powered to investigate PONV as a
90 minutes) may be shorter than the duration of effect primary outcome measure.
for long-acting opioids. If naloxone fails to reverse severe Many studies have investigated different regimens to
respiratory depression or arrest, prompt mask ventilation reduce PONV in patients receiving neuraxial opioids for
and/or tracheal intubation should be performed. An cesarean delivery; however, these studies did not stan-
intravenous infusion of naloxone should be maintained dardize PONV outcome measures and did not stratify
for as long as the patient remains symptomatic. It may be patients according to risk for PONV. Information about
feasible to titrate an intravenous infusion of naloxone to the use of prophylactic antiemetic agents in actual clinical
treat respiratory depression without significantly reduc- practice is lacking. A survey in Germany indicated that
ing the quality of neuraxial analgesia.270-272 Although nal- 82% of anesthesia departments did not provide any anti-
oxone is a viable therapeutic option for reversing the emetic prophylaxis for patients undergoing cesarean
opioid-induced respiratory depression, the routine delivery.275
administration of prophylactic naloxone is not recom-
mended.269 Patients who require continuous positive Individual Antiemetic Agents
airway pressure devices should be advised to continue
using these devices during the postpartum period. Older-generation antiemetics, such as metoclopramide
and droperidol, have been commonly used to prevent or
treat neuraxial opioid-induced emesis in the obstetric
Nausea and Vomiting setting. Metoclopramide 10 mg has been shown to
Nausea and vomiting are common complaints after decrease early PONV after intraoperative intravenous
cesarean delivery, and the etiology of these symptoms is fentanyl and epidural morphine administration.276 In a
presumed to be multifactorial. A 2005 review highlighted meta-analysis of studies that assessed efficacy of anti-
the anesthetic and nonanesthetic causes of intraoperative emetic prophylaxis, metoclopramide was associated with
nausea and vomiting (IONV) (Table 28-8).273 It is unclear a reduced incidence of IONV and early PONV com-
whether patients are at increased risk for postoperative pared with placebo (Figure 28-11).277 Metoclopramide
antagonizes dopamine receptors in the chemoreceptor
trigger zone. It is often administered preoperatively
TABLE 28-8 Causes, Preventive Measures, owing to its favorable prokinetic properties, and it is
and Treatment Measures for associated with a reduction in rates of IONV and PONV
Intraoperative Nausea and in patients receiving spinal anesthesia.278
Vomiting during Cesarean Droperidol is a butyrophenone that antagonizes
Delivery dopaminergic (D2) receptors in the chemoreceptor
trigger zone. Prophylactic administration of droperidol
Causes Prevention/Treatment
(0.625 to 2.5 mg) has been shown to decrease PONV
Anesthetic Causes after epidural anesthesia with epidural fentanyl279 and
Hypotension Left uterine displacement, epidural morphine.280 Sedation and drowsiness may occur
adequate preload, with droperidol, although their appearance does not
vasopressors
appear to be a dose-related phenomenon. Droperidol has
Neuraxial opioids Use optimal doses
been less widely used by anesthesia providers since the
Parenteral opioids Avoid or use minimum effective
doses
FDA issued a “black box” warning in 2001, which high-
Increased vagal activity Use vagolytics
lighted concern related to conduction abnormalities (QT
interval prolongation and an increased risk for develop-
Nonanesthetic Causes ment of torsades de pointes).
Surgical manipulation Avoid excessive manipulation The use of a transdermal scopolamine patch may also
Motion Avoid vigorous movements lower the incidence of PONV after cesarean delivery.
Uterotonic agents Titrate to clinical effect with Early work by Kotelko et al.281 indicated that scopol-
adequate doses amine is effective at reducing PONV during the first 10
Modified from Balki M, Carvalho JC. Intraoperative nausea and hours after cesarean delivery. A transdermal scopolamine
vomiting during cesarean section under regional anesthesia. Int patch (1.5 mg) provided efficacy similar to that provided
J Obstet Anesth 2005; 14:230-41. by ondansetron 4 mg in reducing postcesarean emesis
642 PART VII Cesarean Delivery
FIGURE 28-11 ■ Meta-analysis of metoclopramide for nausea and vomiting prophylaxis during and after cesarean delivery. A, Forest
plots for intraoperative nausea in patients undergoing cesarean delivery with neuraxial anesthesia. B, Forest plots for intraoperative
vomiting in patients undergoing cesarean delivery with neuraxial anesthesia. In each series, separate analyses were performed
according to whether metoclopramide was administered before block placement (overall incidence) or after umbilical cord clamping
(postdelivery incidence). CI, confidence interval. (Forest plots from Ashraf Habib, Duke University, Durham, NC. See Mishriky BM, Habib
AS. Impact of data by Fujii and colleagues on the meta-analysis of metoclopramide for antiemetic prophylaxis in women undergoing Cae-
sarean delivery under neuraxial anaesthesia. Br J Anaesth 2012; 109:826.)
among patients receiving spinal anesthesia (incidence of Serotonin (5-HT3) receptor antagonists have been
40% and 42% respectively, versus 59% in a control used for both prophylaxis and treatment of PONV. These
group).282 However, transdermal scopolamine has a drugs specifically bind to 5-HT3 receptors in the chemo-
latency period of 3 to 4 hours, which limits its ability to receptor trigger zone and at vagal afferents in the
treat early PONV. It also has a number of commonly gastrointestinal tract. Prophylactic administration of
reported side effects, including dry mouth, visual distur- ondansetron 4 to 8 mg has been shown to have a better
bances, dizziness, and agitation. antiemetic profile in the first 24 hours after intrathecal
28 Postoperative Analgesia: Epidural and Spinal Techniques 643
opioid-induced histamine release from mast cells is well intrathecal morphine compared with a saline-control
described, this does not appear to be the causative mecha- group.
nism for pruritus after neuraxial opioid administration. Pretreatment with opioid antagonists has also been
Plasma opioid and histamine levels are clinically insignifi- investigated as a method of reducing the incidence of
cant at the time of symptom presentation (3 to 6 hours opioid-induced pruritus. Morgan et al.309 reported that
after intraspinal morphine administration).98,118,302 In pretreatment with intravenous nalbuphine (20 mg, at
addition, sufentanil and fentanyl can produce pruritus but skin closure) with subsequent postoperative administra-
do not stimulate histamine release. At present, the mech- tion (40 mg, in divided doses) was ineffective in reducing
anisms of spinal and epidural opioid–induced pruritus pruritus in patients receiving epidural morphine. Simi-
remain unclear. Postulated theories of causation include larly, pretreatment with subcutaneous naloxone (0.4 mg)
(1) direct or indirect excitatory effects on central µ-opioid did not significantly reduce the incidence of pruritus in
receptors; (2) cephalad migration of the opioid within the patients receiving intrathecal fentanyl and morphine for
CSF to the trigeminal nucleus (which contains the sub- elective cesarean delivery.310 Naloxone may be more effi-
nucleus caudalis, integrates facial sensory input, and cacious as an infusion, and Luthman et al.311 reported
exhibits high opioid receptor density); (3) excitatory reductions in the severity and incidence of pruritus using
effects on dorsal or ventral horn neurons; and (4) other a naloxone infusion (0.1 mg/h) after cesarean delivery.
mechanisms (e.g., effects on dopamine-2 [D2] receptors, Naloxone and nalbuphine in patient-controlled bolus
prostaglandin system, serotonin 5-HT3 receptors, and doses, combined with a background infusion, have also
central nervous system gamma-aminobutyric acid been found to reduce the incidence of pruritus after
[GABA] and glycine receptors).302 Pregnant patients may cesarean delivery in patients who received epidural mor-
be more susceptible as a result of possible estrogenic phine 5 mg.299 Abboud et al.312 observed that the use of
interactions with opioid receptors.303 Pharmacogenetics the long-acting opioid antagonist naltrexone (9 mg,
may also play a role. Polymorphisms at the human administered orally) was associated with a lower inci-
µ-opioid receptor gene have been implicated as a poten- dence of pruritus compared with placebo after cesarean
tial explanatory factor because central-type pruritus delivery in patients who received epidural morphine
induced by neuraxial opioids may be influenced by tonic 4 mg. However, these investigators also noted a signifi-
inhibitory control of pain signaling.304 The incidence of cant increase in the incidence of unsatisfactory analgesia.
moderate-to-severe pruritus with epidural morphine A similar trend was reported with a 6-mg dose of oral
given for postcesarean analgesia has been reported to be naltrexone after administration of intrathecal morphine
lower in patients homozygous for the G118G polymor- 0.25 mg.313 A cautious approach is needed when consid-
phism in the µ-opioid receptor gene (OPRM1) than in ering high-dose naloxone therapy for treating pruritus to
patients with the A118G or A118A genotypes (incidence avoid reversing the analgesic effect of neuraxial opioids.300
5%, 42%, and 53%, respectively).305 The effects of neuraxially administered opioid antago-
nists have also been investigated. Jeon et al.314 reported
less pruritus in patients receiving epidural naloxone
Drug Therapy
(1.2 mg over 48 hours) with epidural 0.1% bupivacaine
There is little consensus regarding treatment of neuraxial and morphine (6 mg over 48 hours) than in a control
opioid-induced pruritus after cesarean delivery.306 group not receiving naloxone. Similarly, Culebras et al.230
Further, there are currently no validated or consistent investigated the effects of three different doses of intra-
methods for assessing pruritus, which limits the analysis thecal nalbuphine (0.2, 0.8, and 1.6 mg) and found a
of data from studies investigating the efficacy of antipru- significantly lower incidence of pruritus in all of the
ritic regimens. nalbuphine groups compared with a control group
Opioid antagonists are commonly employed to treat that received intrathecal morphine without nalbuphine.
opioid-related pruritus. The efficacy of opioid antago- However, the duration of analgesia was significantly
nists depends, in part, on the drug-opioid receptor inter- shorter among patients in the nalbuphine groups.230
action (antagonist versus mixed agonist-antagonist). Studies in animals and nonobstetric patients have sug-
Studies comparing opioid antagonists for the treatment gested no adverse neurologic effects after neuraxial
of pruritus have demonstrated mixed results. Cohen administration of opioid antagonists. Of note, the use of
et al.300 compared naloxone (0.2 mg, with a maximum experimental drugs and drugs not approved for neuraxial
of three doses) with nalbuphine (5 mg, with a maximum administration continues to raise concerns regarding the
of three doses) after administration of epidural morphine potential for adverse neurotoxic effects. These concerns
5 mg for postcesarean analgesia. Nalbuphine signifi- have limited the clinical assessment of neuraxially admin-
cantly reduced the severity of pruritus after 30 minutes, istered drugs for the prevention and treatment of opioid-
and fewer patients in the nalbuphine group required induced pruritus and other side effects. To avoid reversal
additional doses for treatment of persistent pruritus. of opioid-induced analgesia, further work is necessary to
Somrat et al.307 suggested that smaller doses of nalbu- identify the optimal dose of each opioid antagonist for
phine (2 to 3 mg) could adequately treat moderate-to- the prevention and treatment of pruritus.
severe pruritus after intrathecal morphine administration. NSAIDs are often incorporated into multimodal anal-
Butorphanol has attracted interest as an antipruritic gesic regimens for patients undergoing cesarean delivery.
agent. Wu et al.308 found that butorphanol 1 mg fol- Some investigators have postulated that prostaglandins
lowed by an infusion of 0.2 mg/h was associated with are involved in the etiology of pruritus after neuraxial
reduced postcesarean pruritus in patients who received opioid administration, owing to their ability to enhance
28 Postoperative Analgesia: Epidural and Spinal Techniques 645
C-fiber transmission to the CNS and release histamine. A meta-analysis of studies (published up to 2008) in
However, there is limited evidence that NSAIDs reduce women receiving spinal anesthesia for cesarean delivery
the occurrence of opioid-induced pruritus. A study evalu- indicated that prophylactic administration of a 5-HT3
ating the effect of oral celecoxib 200 mg after intrathecal antagonist did not reduce the risk for pruritus compared
morphine 0.3 mg reported no significant difference in with a control group; however, administration of a 5-HT3
the severity of pruritus or the need for rescue medications antagonist reduced the severity of pruritus and the need
between the treatment and placebo groups.315 for rescue treatment compared with placebo.286 Hetero-
Propofol has been reported to relieve pruritus caused geneity and small sample sizes in the studies included in
by neuraxial opioids in nonobstetric patients after a this systematic review limited detailed analysis of the
10-mg bolus dose without an infusion316 and after a efficacy of prophylactic administration of a 5-HT3 antag-
10-mg bolus dose followed by a 30 mg/24 h infusion.317 onist. Large-scale prospective studies are needed to better
The antipruritic effect of propofol has been proposed to investigate the prophylactic antipruritic efficacy of neur-
occur as a result of inhibitory effects on posterior horn axial 5-HT3 antagonists. Few studies have assessed the
transmission rather than specific antagonism of the opioid therapeutic effect of 5-HT3 antagonists for managing
receptors.316 However, this effect has not been observed postcesarean pruritus induced by neuraxial opioids. In
in obstetric patients who received subhypnotic doses of one study, ondansetron 4 mg had a high rate of success
propofol (10 to 20 mg) for treatment of intrathecal for the treatment of moderate-to-severe pruritus com-
morphine–induced pruritus.318,319 A comparative study pared with placebo (80% and 36%, respectively).329
demonstrated that intravenous nalbuphine 3 mg is supe- Pentazocine, a κ-opioid receptor agonist and partial
rior to propofol 20 mg for treating pruritus after admin- µ-opioid receptor agonist, may be a potentially useful
istration of intrathecal morphine.320 drug for treating opioid-induced pruritus.330 Tamdee
The use of 5-HT3 receptor antagonists for prophy- et al.331 found that pentazocine 15 mg was more effective
laxis of neuraxial opioid–induced pruritus after cesarean than ondansetron 4 mg for the treatment of moderate-
delivery has attracted interest. A meta-analysis of studies to-severe pruritus in patients who received intrathecal
of surgical patients receiving neuraxial opioids concluded morphine for postcesarean analgesia.
that prophylaxis with a 5-HT3 antagonist results in a Historically, antihistamines have been a popular first
reduced risk for postoperative pruritus, compared with choice for treatment of pruritus. However, the efficacy of
placebo (OR, 0.44; 95% CI, 0.29 to 0.68).321 Direct these agents has been questioned in patients receiving
stimulation of 5-HT3 receptors found in the dorsal horn neuraxial opioids that do not cause histamine release
of the spinal cord and in the nucleus of the spinal tract (e.g., fentanyl, sufentanil). Using a tailored treatment
of the trigeminal nerve in the medulla may occur after algorithm, Alhashemi et al.332 demonstrated that diphen-
subarachnoid opioid administration. Intravenous ondan- hydramine was less effective than nalbuphine (higher
setron 4 to 8 mg has been shown to be more effective itching scores and more treatment failures) after admin-
than placebo in reducing the incidence of postcesarean istration of intrathecal morphine 0.2 mg. Yeh et al.323
pruritus after intrathecal administration of morphine found that the incidence of pruritus was comparable
0.15 to 0.2 mg.322,323 However, other studies that com- among patients receiving diphenhydramine 30 mg and a
pared ondansetron 8 mg with placebo found no signifi- placebo (80% and 85%, respectively); however, both
cant reduction in pruritus after intrathecal administration groups had a higher incidence of pruritus than did a
of morphine (0.1 to 0.2 mg) alone324 or in combination group that received ondansetron 0.1 mg/kg (25%). In
with a lipophilic opioid (sufentanil or fentanyl).283,325 The contrast, Siddik-Sayyid et al.333 found that the therapeu-
lack of antipruritic effect may be due to the peak effect tic success rates for ondansetron 4 mg and diphenhy
of ondansetron occurring much sooner (at 15 minutes) dramine 25 mg were identical (70% for each drug), with
than that of intrathecal morphine. The antipruritic similar recurrence rates in successfully treated patients
effects associated with ondansetron may depend on the (28% versus 35%, respectively). Differences in study
dose, lipophilicity, and duration of action of the intrathe- methodology and drug-dosing regimens may explain
cal opioid.326 A study of epidurally administered ondan- the inconsistent antipruritic effect of diphenhydramine
setron (8 mg over 2 days) in patients who received observed in these studies.
epidural ropivacaine and morphine after cesarean deliv-
ery demonstrated a reduction in the incidence of pruri-
tus.327 The investigators found no histologic evidence of
Urinary Retention
neurotoxic sequelae after intrathecal ondansetron admin- The mechanisms by which neuraxial opioids affect spe-
istration in rats.327 There are conflicting data on the cific components of micturition (urge sensation, detrusor
antipruritic effect of granisetron in patients receiving and sphincter function) are not fully understood, although
intrathecal morphine for postcesarean analgesia. Siddik- spinal and supraspinal sites of action are likely to be
Sayyid et al.324 found no significant differences in the involved. Kuipers et al.334 performed urodynamic studies
incidence or severity of pruritus among patients who of healthy male volunteers receiving intrathecal sufen
received granisetron 3 mg or ondansetron 8 mg and tanil and morphine. Both opioids caused dose-dependent
those in a control group. In contrast, Tan et al.328 decreases in detrusor contractility and the “urgency to
observed that the severity of pruritus was reduced at 8 void.” Patients receiving intrathecal sufentanil had earlier
and 24 hours after cesarean delivery in patients who recovery of lower urinary tract function than those
received granisetron 3 mg compared with those who receiving intrathecal morphine.334 Intrathecal local anes-
received ondansetron 8 mg. thetics (bupivacaine and lidocaine) have been shown to
646 PART VII Cesarean Delivery
cause complete absence of detrusor contractility and urge epidural anesthesia during cesarean delivery. Interest-
sensation until the dermatomal block regresses to S2 to ingly, there was no difference in the incidence of shiver-
S3, with no partial recovery until this regression has ing between groups, but the severity of shivering was
occurred.335 significantly less in the group receiving spinal anesthesia.
Although neuraxial opioids may increase the risk for The more intense sensory block observed with spinal
postpartum urinary retention after cesarean delivery, anesthesia inhibits central thermoregulatory control
there is a lack of consensus on the definition of postpar- more than epidural anesthesia, which can affect shivering
tum urinary retention in this setting. Postpartum urinary thresholds and intensity.351
retention has been previously described as “no spontane- The effect of neuraxial opioids on thermoregulation
ous voiding within 6 hours of removal of an indwelling and shivering in patients undergoing cesarean delivery is
catheter (more than 24 hours after cesarean delivery).”336 not fully understood. One study demonstrated that
Some authorities advocate a diagnosis based on clinical patients who received intrathecal morphine 0.15 mg had a
diagnostic features (e.g., “the sudden inability to void”) greater degree of hypothermia than patients who received
or postvoid residual bladder volume (PVRV). However, no intrathecal opioid.352 However, intrathecal administra-
there is marked variability in defining “significant” PVRV tion of both fentanyl and morphine is associated with a
values (40 to 500 mL) associated with postpartum urinary lower incidence of shivering than single-dose intrathecal
retention.337 morphine alone.353 Hong and Lee354 reported that intra-
Few studies have investigated the incidence of urinary thecal meperidine 10 mg produced fewer and less intense
retention in patients who have received a neuraxial opioid shivering episodes than intrathecal morphine (0.1 and
for postcesarean analgesia. Evron et al.338 performed an 0.2 mg). Core hypothermia occurred to a similar extent in
observational study investigating the effects of epidural all study groups. In a different study, intrathecal meperi-
morphine and methadone in 120 women undergoing dine (12.5 or 25 mg) was independently associated with
cesarean delivery. Difficulty in micturition and need for a lower incidence of shivering compared with a no-
bladder catheterization were greater in the morphine meperidine control group; however, rates of PONV were
group (58%) compared with the methadone group significantly higher in the meperidine groups.355 The
(3%).338 A similar study by Liang et al.339 reported a effect of epidural opioids on thermoregulation may be
higher incidence of postcesarean urinary retention and more consistent, with a number of studies reporting a
urinary catheterization (22%) among patients receiving reduction in the incidence and severity of shivering
epidural morphine compared with other analgesia modal- after epidural meperidine, butorphanol, fentanyl, and
ities (PCEA with ropivacaine-fentanyl [7%]; intramuscu- sufentanil.356-359
lar meperidine [3%]). In a study of male volunteers, Preoperative patient warming with forced air has been
naloxone reversed the impact of neuraxial morphine on shown to reduce the incidence of perioperative and post-
urodynamic function.340 To avoid impairment of bladder/ operative core hypothermia and shivering in patients
detrusor function, urinary catheterization should be con- undergoing cesarean delivery with epidural anesthesia.360
sidered if voiding has not occurred within 6 hours.341 Risk However, a subsequent study found that perioperative
factors for postcesarean urinary retention include low forced-air warming does not prevent maternal hypother-
body mass index and multiparity.342 mia after cesarean delivery with spinal anesthesia that
includes fentanyl and morphine.343 It is likely that forced-
air warming cannot compensate for the initial rapid drop
Hypothermia and Shivering in core temperature (from heat redistribution) after
Perioperative and postoperative hypothermia and shiver- administration of spinal anesthesia.
ing are commonly observed in patients who receive neur-
axial anesthesia for cesarean delivery and are caused by a
number of interrelated processes. The true incidence of NEURAXIAL NONOPIOID ANALGESIC
core hypothermia and shivering in this setting is unclear; ADJUVANTS
however, results from earlier studies suggest that these
complications may occur in up to 66% and 85% of patients, The addition of neuraxial nonopioid adjuvants to local
respectively.343,344 Core-to-periphery heat redistribution anesthetic agents may improve the quality of both intra-
is the major cause of core hypothermia after spinal or operative and postcesarean analgesia. Nonopioid neur-
epidural anesthesia and is due to the effects of sympathetic axial adjuvants have different sites and mechanisms of
and motor nerve blockade.345 A study of healthy volunteers actions, and interactions between neuraxial opioids and
reported that core temperature can decrease by a mean nonopioid adjuvants may be additive or synergistic.
(± SD) of 0.8° ± 0.3° C in the first hour of anesthesia.346 Potential advantages of neuraxial drug combinations
Neuraxial anesthesia also impairs centrally mediated ther- include a reduction in dose of individual drugs (with
moregulatory control, lowers the vasoconstriction and subsequent reductions in dose-dependent side effects), in
shivering thresholds, and promotes greater environmental particular a reduction in postoperative opioid require-
heat loss than metabolic heat production.347-349 ments and opioid-related side effects.361
The onset and the severity of hypothermia and shiver-
ing vary according to the anesthetic technique, the anes-
thetic agents administered, and baseline thermal status of
Alpha-Adrenergic Agonists
the patient. Saito et al.350 found that spinal anesthesia α2-Adrenergic agonists bind to presynaptic and postsyn-
reduces initial core temperature more rapidly than aptic α2-adrenergic receptors at peripheral, spinal (dorsal
28 Postoperative Analgesia: Epidural and Spinal Techniques 647
design to compare different doses of intrathecal clonidine States, epidural clonidine has a “black box” warning
(150, 300, or 450 µg), the same investigators observed stating that it is not recommended for obstetric, postpar-
that both the onset and duration of analgesia and sedation tum, or perioperative pain management due to the risk
were dose dependent.376 Intrathecal clonidine was also for hemodynamic instability, especially hypotension and
associated with a significant reduction in mean arterial bradycardia. In selected cases the anesthesiologist may
pressure. Van Tuijl et al.377 assessed postcesarean analge- conclude that the potential benefits may outweigh the
sia in patients who received intrathecal clonidine 75 µg possible risks.
combined with bupivacaine before surgery versus intra- No published studies have assessed the administration
thecal bupivacaine alone. Early postoperative analgesia (1 of neuraxial dexmedetomidine in pregnant patients. A
to 2 hours) was improved with clonidine; however, no study in patients undergoing bladder surgery who
difference was found in 24-hour morphine consumption received spinal anesthesia with bupivacaine and clonidine
between the groups. 30 µg or dexmedetomidine 3 µg found similar sensory
Studies of intrathecal opioids in combination with and motor block duration, with no hemodynamic com-
clonidine have investigated the contribution of each drug promise or sedation.381 However, when dexmedetomi-
to the subsequent analgesia and side-effect profile. Ben- dine was applied to strips of pregnant human myometrium
hamou et al.378 evaluated postcesarean analgesic out- in vitro, significant increases in uterine contractility were
comes in patients who received hyperbaric bupivacaine observed.382
alone or bupivacaine and clonidine 75 µg with and
without fentanyl 12.5 µg. Patients receiving the clonidine-
fentanyl combination reported less intraoperative pain
Neostigmine
and more prolonged postcesarean analgesia (time to first By interfering with the breakdown of acetylcholine,
analgesia request 215 minutes) than those receiving neostigmine indirectly stimulates spinal nicotinic and
bupivacaine-clonidine and bupivacaine alone (183 and muscarinic receptors and the release of nitric oxide.
137 minutes, respectively). However, significantly higher The resulting analgesia is most likely due to central
rates of pruritus and sedation were reported for the and peripheral alterations in pain modulation and trans-
clonidine-fentanyl group. Paech et al.379 performed a mission. Initial studies of intrathecal neostigmine in
six-arm study assessing postcesarean analgesia after intra- animals and human volunteers have demonstrated anal-
thecal bupivacaine 12.5 mg with fentanyl 15 µg and one gesic effects without neurotoxic effects.235,383-385 However,
of the following regimens: clonidine 150 µg; morphine despite producing dose-dependent analgesia, intrathecal
0.1 mg; and morphine 0.1 mg with clonidine 30, 60, 90, neostigmine at doses greater than 25 µg also results
or 150 µg. The investigators concluded that the in nausea that is resistant to traditional antiemetic
morphine-clonidine regimens provided optimal postce- treatment (droperidol, ondansetron) and cholinergic
sarean analgesia with significantly lower pain scores at antagonists.384
rest and with coughing in the first 4 hours. The minimum Krukowski et al.386 reported that escalating doses of
effective intrathecal dose of clonidine was 30 to 60 µg intrathecal neostigmine (10 to 100 µg) improved analge-
when combined with bupivacaine, fentanyl 15 µg, and sia in a dose-independent manner when given after epi-
morphine 0.1 mg. However, a significant increase in dural anesthesia for cesarean delivery. The reduction in
intraoperative sedation was observed in all groups receiv- morphine requirements lasted up to 10 hours. The inci-
ing clonidine. Lavand’homme et al.380 compared postce- dence of nausea varied from 50% to 100%. Chung
sarean antihyperalgesic effects in patients receiving et al.387 showed that the postoperative analgesia provided
intrathecal clonidine 150 µg with bupivacaine, clonidine by intrathecal neostigmine 25 µg was similar to that
75 µg with bupivacaine-sufentanil, or bupivacaine- observed with intrathecal morphine 0.1 mg. The inves-
sufentanil. The bupivacaine-clonidine group had a sig- tigators observed that the combination of neostigmine
nificantly reduced area of peri-incisional hyperalgesia and 12.5 µg with morphine 0.05 mg prolonged the analgesia
a lower incidence of hyperalgesia compared with the in an additive (rather than a synergistic) manner, was
other study groups. However, no between-group differ- associated with less need for supplemental analgesia, and
ences were observed in postoperative morphine con- had fewer side effects than observed with either drug
sumption or in pain scores before and after discharge. administered alone in higher doses (Figure 28-14). Pan
The relationship between postoperative wound hyperal- et al.388 compared analgesic outcomes after intrathecal
gesia and chronic wound pain after cesarean delivery bupivacaine given either alone or in combination with
remains unclear (see Chapter 27). three different admixtures: intrathecal neostigmine
In summary, neuraxial clonidine does not appear to 50 µg, intrathecal clonidine 150 µg, or a neostigmine-
offer substantial improvement in analgesia over that pro- clonidine combination (same doses of each). Although
vided by neuraxial opioids. Epidural clonidine (150 to patients in the clonidine-neostigmine group had lower
800 µg) may improve postcesarean analgesia when given pain scores in the first 10 postoperative hours, they expe-
in combination with epidural opioids. Intrathecal cloni- rienced more significant side effects, including a prolon-
dine (75 to 450 µg) has modest efficacy and a relatively gation of motor block, a higher incidence of hypotension,
short duration of action. Ongoing concern about the and a higher incidence (with greater severity) of nausea
adverse side-effect profile of epidural or intrathecal and vomiting.
clonidine—notably sedation and hypotension—limit the Kaya et al.389 assessed the analgesic efficacy of epi-
neuraxial administration of this agent in patients under- dural neostigmine administration after cesarean delivery.
going cesarean delivery. Additionally, in the United In this study, a CSE technique was employed with
28 Postoperative Analgesia: Epidural and Spinal Techniques 649
100
N-Methyl-D-Aspartate Antagonists
Ketamine
80 Anesthetic and subanesthetic doses of ketamine have
analgesic properties as a result of noncompetitive antago-
nism of N-methyl-d-aspartate (NMDA) receptors.
Animal studies suggest that NMDA receptor blockade
can prevent opioid tolerance and reduce the progressive
Cumulative PCA use (mL)
60
increase in action potential discharge known as the
“wind-up phenomenon.”391-393 Research in dogs has indi-
cated that no clinical or histologic disturbance in spinal
40 tissue or the meninges occurs after exposure to a single
intrathecal injection of preservative-free S(+)-ketamine at
a dose of 1 mg/kg.394
20
Limited data exist for the role of neuraxial ketamine
in the provision of postcesarean analgesia. In patients
undergoing cesarean delivery randomly assigned to
receive intrathecal bupivacaine alone or in combination
0 with S(+) ketamine 0.05 mg/kg or fentanyl 25 µg,395 sig-
nificantly prolonged and better quality analgesia was
observed in the fentanyl group. No differences in side
effects were observed between the ketamine and fentanyl
–20 groups.395 It is unclear whether the S(+) or R(–) isomers
0 1 2 4 8 12 18 24
of ketamine have analgesic advantages over the racemate.
Time (h) Currently, the use of intrathecal ketamine does not appear
to offer an analgesic benefit for postcesarean analgesia;
FIGURE 28-14 ■ Randomized trial of postcesarean analgesia with
intrathecal saline (□), neostigmine 25 µg (○), morphine 0.1 mg
moreover, the potential for neurotoxicity for both
(△), or the combination of neostigmine 12.5 µg and morphine preservative-containing and preservative-free ketamine
0.05 mg (⋄) with hyperbaric bupivacaine 12 mg. Cumulative has not been adequately studied.396
patient-controlled analgesia (PCA) consumption. Intravenous Two systematic reviews have evaluated postoperative
PCA was started with fentanyl 500 µg and ketorolac 150 mg in analgesia with perioperative epidural ketamine adminis-
a total volume of 100 mL. The PCA device was set to deliver a
bolus of 5 mL (i.e., fentanyl 25 µg and ketorolac 7.5 mg), with a tration in patients undergoing nonobstetric surgery.397,398
lockout interval of 10 minutes and no basal infusion. Each value Subramaniam et al.397 analyzed results from eight studies
represents the mean ± SE. *P < .05 versus the other three that compared a combination of epidural ketamine with
groups; #P < .05 versus the combination group. (From Chung CJ, opioids to epidural opioids alone. Although marked het-
Kim JS, Park HS, Chin YJ. The efficacy of intrathecal neostigmine,
intrathecal morphine, and their combination for post-cesarean
erogeneity was observed among studies, the pain scores
section analgesia. Anesth Analg 1998; 87:341-6.) at rest were moderately lower in the patients who received
epidural ketamine. No overall difference between the
groups was observed in pain scores with movement. A
Cochrane review also reported marked heterogeneity and
intrathecal bupivacaine 8 mg and fentanyl 10 µg, and mixed analgesic outcomes in studies that assessed preop-
patients subsequently received epidural neostigmine erative and postoperative epidural administration of keta
doses of 75, 150, or 300 µg after delivery. The mine.398 To date, no published studies have evaluated
investigators reported modest, short-lived, and dose- perioperative epidural ketamine administration in patients
independent reductions in postoperative pain in the undergoing cesarean delivery. In a study of patients
neostigmine groups.389 No differences among groups undergoing gynecologic surgery, Kawana et al.399 noted
in 24-hour morphine consumption after surgery were that low-dose epidural ketamine (4, 6, or 8 mg) provided
observed. inferior analgesia compared with epidural morphine
In summary, dose-dependent side effects of intrathecal 3 mg.
neostigmine limit its use as a single neuraxial adjunct for In summary, epidural ketamine provides limited post-
postcesarean analgesia. Intrathecal neostigmine 12.5 to cesarean analgesia and cannot be recommended for
25 µg may be used in combination regimens to improve patients undergoing cesarean delivery. Further research
analgesia and reduce side effects. The use of epidural is needed to evaluate the role of epidural and intrathecal
neostigmine is not currently recommended until addi- ketamine as part of a multimodal regimen for postcesar-
tional studies substantiate greater postcesarean analgesic ean analgesia.
benefits with fewer side effects. Although data regarding
the maternal and fetal safety profile of epidural neostig- Magnesium
mine are reassuring,390 additional studies are needed to
substantiate whether epidural neostigmine can be consid- Magnesium is an NMDA receptor antagonist that may
ered as a viable alternative or adjunct to opioids for post- alter pain signaling by preventing central sensitization
cesarean analgesia. after nociceptive stimulation.400 The antinociceptive
650 PART VII Cesarean Delivery
properties of magnesium are due to its noncompetitive have investigated epinephrine as a spinal or epidural
NMDA receptor antagonism resulting in ion channel adjunct. Robertson et al.83 reported that epidural epi-
blockage in a voltage-dependent manner. Studies inves- nephrine 25 µg prolonged the duration of analgesia with
tigating intrathecal or epidural magnesium have shown epidural fentanyl 100 µg but increased the incidence of
variable analgesic effects after cesarean delivery. Sun pruritus. Similar improvements in duration of analgesia
et al.401 compared the postcesarean analgesic profile of have been observed when epinephrine (5 to 30 µg/mL)
four different epidural solutions administered in the peri- was combined with either epidural diamorphine or su
operative period. All patients received 0.1% bupivacaine fentanil; however, the incidence of side effects (including
10 mL with one of the following: morphine 1.5 mg, vomiting that required treatment) was increased.145,407 In
magnesium 500 mg, morphine 1.5 mg and magnesium contrast, McMorland et al.408 found that epidural epi-
500 mg, or placebo. Patients who received all three drugs nephrine did not enhance the efficacy of postcesarean
(bupivacaine, magnesium, and morphine) had signifi- analgesia provided by epidural sufentanil.
cantly lower postoperative pain scores at rest and with In a study assessing postoperative outcome measures
movement, an increased time to first analgesic request, for PCEA, patients who received 0.01% bupivacaine with
and increased satisfaction at 24 hours after surgery com- epinephrine (0.5 µg/mL) and fentanyl reported better
pared with women who received only two drugs. In analgesia than those who received either fentanyl or
women who received a CSE technique with intrathecal fentanyl-epinephrine.409 No significant differences in side
bupivacaine 10 mg and epidural bupivacaine 25 mg with effects were reported between PCEA regimens with and
fentanyl 100 µg, postoperative analgesic requirements without epinephrine. In another study, no improvement
were lower for women who received magnesium sulfate in analgesia and no reduction in opioid consumption
500 mg compared with a control (no magnesium) were found with the addition of epinephrine 5 µg/mL to
group.402 PCEA meperidine 5 mg/mL.410 Patients in the epineph-
Intrathecal magnesium sulfate 50 mg prolongs the rine group reported more nausea at 2 and 24 hours as
duration of spinal anesthesia and improves postoperative well as higher pruritus scores at 2 hours than patients in
analgesia in patients undergoing nonobstetric surgery the no-epinephrine group. The investigators attributed
with bupivacaine and fentanyl spinal anesthesia.403,404 the epinephrine-associated increase in side effects to
There are limited data regarding the analgesic effects of enhanced transfer of meperidine into the CSF. Studies of
intrathecal magnesium sulfate in women undergoing epidural 2% lidocaine or 0.5% bupivacaine with epineph-
cesarean delivery. No difference in the first request for rine (5 µg/mL) have not demonstrated any detrimental
postcesarean analgesia was found among patients who effects of epinephrine on umbilical artery blood flow-
were randomized to receive intrathecal magnesium velocity waveforms, uteroplacental or fetal vascular resis-
sulfate 50 mg compared with placebo (median time, 100 tance, fetal myocardial function, or fetal heart rate.411,412
minutes versus 105 minutes, respectively), and patients The use of intrathecal epinephrine as an adjuvant to
who received intrathecal fentanyl 25 µg had a longer time local anesthetics, with or without opioids, has been evalu-
to first request for analgesia (132 minutes) compared with ated in a number of studies. The addition of epinephrine
the magnesium group.405 200 µg to hyperbaric spinal bupivacaine improved peri-
Intravenous magnesium sulfate, given in either a “low- operative analgesia but was associated with a longer dura-
dose” regimen (25 mg/kg bolus and a 24-hour infusion tion of residual sensory and motor block.413 In a separate
at 1 g/h) or a “high-dose” regimen (50 mg/kg bolus and study, a combined intrathecal regimen of epinephrine
a 24-hour infusion at 2 g/h), was evaluated in patients 200 µg with morphine 0.2 mg did not significantly
undergoing spinal anesthesia for cesarean delivery.406 No improve postoperative analgesia compared with intrathe-
differences in sequential pain scores or cumulative opioid cal morphine 0.2 mg alone.414 Zakowski et al.415 found
consumption were found up to 48 hours postoperatively. earlier and higher peak plasma bupivacaine concentra-
Some investigators have postulated that the blood-brain tions with the addition of spinal epinephrine 200 µg to
barrier may affect the rate of transfer of magnesium into spinal bupivacaine in patients undergoing cesarean deliv-
the CSF, a possibility that may explain why CSF magne- ery. The investigators postulated that epinephrine might
sium concentrations do not directly reflect plasma have a vasodilatory or biphasic action on certain vascular
concentrations.404 beds. In contrast, plasma levels of morphine were approx-
In summary, epidural administration of magnesium, imately 66% lower in the epinephrine group than in the
co-administered with neuraxial opioids, may have a favor- control group.415
able analgesic effect in patients after cesarean delivery. In summary, the use of epidural epinephrine (2.5 to
However, more research, including dose-response studies, 30 µg/mL) seems to prolong the duration of analgesia
are needed to more formally assess the analgesic efficacy with epidural opioids but may increase opioid-related
of epidural and intrathecal magnesium in the postcesar- side effects. The use of intrathecal epinephrine 200 µg
ean period. does not seem to enhance neuraxial opioid analgesia and
is associated with prolonged sensory and motor block.
Epinephrine
Epinephrine has a direct analgesic effect by binding to
Newer Agents
alpha-adrenergic receptors and may potentiate local In the future, newer agents and adjuvants may enhance
anesthetics by inducing local vasoconstriction and de- postoperative pain management strategies in patients
creased drug clearance. A number of clinical studies receiving neuraxial anesthesia for cesarean delivery.
28 Postoperative Analgesia: Epidural and Spinal Techniques 651
Adenosine (and adenosine analogues) may have antino- been shown to have analgesic effects after intrathe-
ciceptive effects that involve spinal adenosine A1 recep- cal administration.431
tors.416 Intrathecal adenosine may enhance the effect of Before recommendations can be made about the
intrathecal clonidine, ketamine, and morphine. However, potential use of new adjuncts, neurotoxicity studies are
studies have not demonstrated improved analgesia with necessary to ensure these agents’ safety for neuraxial
intrathecal adenosine administration in patients undergo- administration. In addition, studies assessing analgesic
ing hysterectomy.417,418 Among pregnant women, no ben- efficacy, side effects, and toxicity must demonstrate that
eficial effects in the quality or duration of analgesia have these agents result in significant improvement over the
been observed in patients who received both intrathecal neuraxial local anesthetic and opioid regimens currently
adenosine 500 µg and sufentanil compared with intrathe- used in clinical practice.
cal sufentanil alone.419
A direct relationship may exist between central potas-
sium channels and antinociception. Several animal KEY POINTS
studies have investigated potassium channel openers
(nicorandil, sildenafil) administered by the intrathecal420 • Epidural or intrathecal administration of opioids
or epidural421 route. These drugs may also enhance the provides better postoperative pain relief than
analgesic effects of neuraxial opioids and α2-adrenergic systemic administration.
agonists. • Effective postoperative analgesia provided by
Intrathecal midazolam produces analgesia by acting neuraxial techniques confers many physiologic
on GABAA receptors and reducing dorsal (sensory) and benefits and may improve postoperative maternal
motor horn excitability. Midazolam’s solubility in water and neonatal outcomes after cesarean delivery.
is pH dependent, and the likelihood of drug precipitation • Neuraxial administration of a hydrophilic opioid
is high at physiologic pH and concentrations greater than (e.g., morphine) has a delayed onset of analgesia
1 mg/mL.422,423 There has been growing interest in the owing to slow penetration of drug into the spinal
use of midazolam as an intrathecal agent for treating cord but results in a prolonged duration of action
acute postoperative pain. A meta-analysis of studies that (14 to 36 hours) because of high bioavailability in
assessed the clinical benefit and side effects of intrathecal the cerebrospinal fluid and minimal absorption
midazolam in obstetric and nonobstetric patients indi- into the systemic circulation.
cated that it has a favorable pharmacologic profile.424
Intrathecal midazolam was associated with significantly • Neuraxial administration of a lipophilic opioid
improved analgesia and a reduced risk for PONV. Impor- (e.g., fentanyl, sufentanil) has a rapid onset of
tant side effects (including respiratory depression, pro- analgesia owing to rapid spinal tissue penetration
longed motor block, and neurotoxicity) were reported as of drug. Neuraxial administration of lipophilic
rare and were not significantly increased in patients who opioids may improve intraoperative analgesia.
received intrathecal midazolam, compared with those However, these agents are also rapidly absorbed
who received placebo. Tucker et al.425 performed a cohort systemically and consequently have a limited
study to investigate potential neurotoxic effects of intra- duration of activity (2 to 4 hours) after cesarean
thecal midazolam 2 mg in 1100 patients receiving spinal delivery.
anesthesia; they reported no increased risk for neurologic • In clinical practice, single-dose epidural (2 to
or urologic symptoms up to 1 month after neuraxial 4 mg) or intrathecal (0.075 to 0.2 mg) morphine
block. In the obstetric setting, one study demonstrated administration is most commonly used. Higher
that the combination of intrathecal midazolam 2 mg and doses may increase opioid-related side effects
intrathecal fentanyl 10 µg reduced labor pain to a greater without improving analgesia.
degree than was observed with either drug given alone.426 • Epidural and intrathecal administration of
No adverse maternal or fetal events and no clinical evi- morphine provide similar analgesic efficacy and
dence of neurologic impairment were reported among result in comparable incidence and severity of
subjects in this study. After cesarean delivery, patients opioid-related side effects.
who received intrathecal midazolam 2 mg (without neur- • Patient-controlled epidural analgesia (PCEA)
axial opioids) had more prolonged postoperative analge- regimens with lipophilic opioids (e.g., fentanyl,
sia and lower pain scores for 6 hours after surgery sufentanil) may improve postcesarean analgesia
compared with patients who received either intrathecal and maternal satisfaction and may be worthwhile
midazolam 1 mg or no midazolam.427 The impact of mul- for patients with high postoperative analgesic
timodal regimens that include intrathecal midazolam on requirements. No consensus currently exists
postcesarean analgesia remains unclear. regarding optimal PCEA regimens (e.g., opioid
Several neuraxially administered drugs have been with or without local anesthetic; demand bolus
shown to produce antinociceptive effects by altering with or without a background infusion). The
calcium channel conductance at the spinal level. disadvantages associated with PCEA (reduced
Intrathecal gabapentin reduced incision-induced allo- maternal mobility, higher cost, additional nursing
dynia in rats,428,429 and epidural verapamil lowered workload, and potential catheter-related
postoperative opioid consumption after lower abdomi- complications) may limit the use of this approach
nal surgery.430 Ziconotide, a neuronal N-type-selective for provision of postcesarean analgesia.
voltage-sensitive calcium entry–blocking agent, has
652 PART VII Cesarean Delivery
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660 PART VII Cesarean Delivery
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384. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of trial. Am J Obstet Gynecol 2006; 194:1596-602.
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1995; 82:331-43. tion of postoperative epidural sufentanil analgesia with epineph-
385. Hood DD, Eisenach JC, Tong C, et al. Cardiorespiratory and rine. Anesth Analg 1990; 70:323-5.
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386. Krukowski JA, Hood DD, Eisenach JC, et al. Intrathecal neostig- 409. Cohen S, Lowenwirt I, Pantuck CB, et al. Bupivacaine 0.01% and/
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adrenaline to pethidine for patient-controlled epidural analgesia K+(ATP) channel openers via interaction with morphine and an
after caesarean section. Anaesthesia 1998; 53:1012-16. alpha2-adrenergic agonist in rats. Anesth Analg 2000; 90:
411. McLintic AJ, Danskin FH, Reid JA, Thorburn J. Effect of adrena- 1146-51.
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412. Alahuhta S, Rasanen J, Jouppila R, et al. Effects of extradural of intrathecal midazolam: a cautionary tale. Anesth Analg 2004;
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413. Abouleish EI. Epinephrine improves the quality of spinal hyper- perioperative analgesia: a meta-analysis. Anaesth Intensive Care
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66:395-400. 425. Tucker A, Lai C, Nadeson R, Goodchild C. Intrathecal mid-
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417. Rane K, Sollevi A, Segerdahl M. Intrathecal adenosine adminis- nels or N-methyl-d-aspartic acid receptors? Anesth Analg 2006;
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418. Sharma M, Mohta M, Chawla R. Efficacy of intrathecal adenosine ruthenium red attenuate the antiallodynic effect of intrathecal
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PA RT V I I I
ANESTHETIC
COMPLICATIONS
Donald Caton, MD
James Young Simpson introduced anesthesia to obstetrics biochemistry were not very well developed. There was
when the practice of medicine was in a period of great no tradition for drug testing that Simpson and Meigs
flux. As late as 1820, most Western medical schools were could model. Their inexperience with medical science
still practicing a form of medicine derived from the was reflected in their response to obstetric anesthesia.
teachings of Galen, a second-century Greek physician. For example, seeking a better agent to replace ether,
According to Galenic principles, all disease originated Simpson simply tried a series of compounds on himself
from an imbalance among the four elements (earth, air, and his friends until he stumbled upon one that worked—
fire, and water), hydraulic pressures, or electrical forces. chloroform. Within a month he had administered chlo-
Treatment consisted of the time-honored measures of roform to a patient and had published a paper. He
purging, bleeding, cupping, or the administration of conducted no animal studies or clinical trials, collected
stimulants or depressants. Simpson, Meigs, Channing, no data, and performed no statistical analyses of his
and all the others involved in the early debate about results. His claims were reviewed by no clinical board or
obstetric anesthesia learned this style of practice as governmental agency, and he had no reason to fear a
students. malpractice suit. Such an approach led to a rapid dis-
Within a few years of their graduation, Galenic forms semination of new ideas, but it took years before anyone
of medicine had been discredited and had disappeared. identified the problems associated with the new remedy,
In its place Laennec, Louis, and other French physicians much less sorted them out. Accordingly, after the intro-
developed principles of medical theory and practice that duction of obstetric anesthesia, more than half a century
we use today—physical diagnosis, statistical analysis, passed before physicians began to develop the tools that
physiology, pathology, and chemistry.1 they needed to understand the problems associated with
Thus the introduction of anesthesia represented a sig- the use of ether and chloroform.3
nificant challenge. Physicians who had once been taught REFERENCES
to treat the pain of childbirth with bloodletting could 1. Temkin O: Galenism: Rise and Decline of a Medical Philosophy.
now use ether or chloroform. They recognized the thera- Ithaca, NY: Cornell University Press, 1973.
peutic potential of the drugs, but they also recognized 2. Rosenberg CE. The therapeutic revolution: medicine, meaning, and
their dangers and questioned their safety and effects on social change in nineteenth-century America. In Vogel MJ, Rosen-
labor and the newborn.2 berg CE, editors. The Therapeutic Revolution: Essays in the Social
History of American Medicine. Philadelphia: University of Pennsyl-
Evaluating the risks of anesthesia was quite different vania Press, 1979:3-26.
from recognizing the problems. In 1850, pharmacology 3. Newman C. The Evolution of Medical Education in the Nineteenth
was in its infancy, and medical physiology, pathology, and Century. New York: Oxford University Press, 1957.
C H A P T E R 2 9
CHAPTER OUTLINE
HISTORY PROPHYLAXIS
INCIDENCE, MORBIDITY, AND MORTALITY Preoperative Oral Fluid Administration
Choice of Anesthesia
GASTROESOPHAGEAL ANATOMY AND
Antacids
PHYSIOLOGY
Histamine-2 Receptor Antagonists
Esophagus
Proton-Pump Inhibitors
Gastrointestinal Motility
Metoclopramide
Gastric Secretion
Sellick Maneuver and Induction of
Ingestion of Food Anesthesia
Effects of Pregnancy on Gastric Function
RECOMMENDATIONS FOR CESAREAN DELIVERY
RISK FACTORS FOR ASPIRATION PNEUMONITIS
ORAL INTAKE DURING LABOR
PATHOPHYSIOLOGY
CLINICAL COURSE
TREATMENT
Management of Aspiration
Management of Respiratory Failure
40
Number of deaths
35
30
25
20
15
10
5
0 FIGURE 29-1 ■ Maternal mortality from anesthe-
53 56 59 62 65 68 71 74 77 80 83 86 89 92 95 98 01 04 07 sia and pulmonary aspiration in the United
Middle year of triennium Kingdom, 1952-2008. (Compiled from data from
references 4 through 6.)
use of neuraxial analgesic/anesthetic techniques, both period from 1994 to 2008, there were three maternal
during labor and for cesarean delivery, is the single most deaths from aspiration; one was an obese parturient, the
important factor in this remarkable decline in maternal second was a mother anesthetized 3 days after delivery,
mortality from pulmonary aspiration. and the third was a women with a placenta previa who
The reported incidence of aspiration pneumonitis required an emergency cesarean delivery after eating a
depends on the criteria used for making the diagnosis. full meal and aspirated on emergence from general anes-
The relative risk for aspiration in pregnant versus non- thesia. Although the number of anesthetics, particularly
pregnant women can best be estimated from comparisons general anesthetics, administered to parturients during
within single-study populations. Olsson et al.7 reported this 15-year period is unknown, there were approximately
an overall incidence of aspiration of 1 in 2131 in the 10.5 million deliveries, indicating that the mortality rate
general population undergoing anesthesia and 1 in 661 from aspiration was less than 1 in 3.5 million deliveries.
in women undergoing cesarean delivery (i.e., a threefold Data on pulmonary aspiration in obstetrics in the
higher aspiration risk). In two other surveys related to United States are more difficult to evaluate. Despite the
aspiration (one a retrospective review of 172,334 con- establishment of an ongoing National Pregnancy Mortal-
secutive patients undergoing general anesthesia and the ity Surveillance System by the Centers for Disease
other a review of 133 cases of aspiration from the Aus- Control and Prevention (CDC), it is often difficult to
tralian Anaesthetic Incident Monitoring Study [AIMS]), obtain adequate and detailed information about every
there were no cases of pulmonary aspiration in women maternal death. Prior to 1990, aspiration was the most
undergoing either elective or emergency cesarean deliv- common cause of anesthesia-related maternal death in
ery.8,9 However, in the latter two studies, emergency the United States; it has been calculated that at that time
surgery was a significant predisposing factor for aspira- there were 17 deaths related to general anesthesia for
tion; this finding may be relevant for the practice of every one death related to regional anesthesia.10 By the
obstetric anesthesia, given that many obstetric surgical early 1990s, this ratio had improved to 6 to 1. By 2002,
procedures are performed on an urgent or emergency death rates for both general and regional anesthesia were
basis. The AIMS study also implicated obesity as a sig- similar.11 However, mortality statistics are generally a
nificant risk factor for aspiration; others have noted that poor predictor of maternal morbidity; several studies
obesity is associated with an increased risk for maternal have indicated that perioperative aspiration can be associ-
mortality.4,5 ated with important morbidity in obstetric patients,12,13
Morbidity and mortality associated with aspiration and thus all possible measures still must be taken to
vary according to (1) the physical status of the patient, prevent pulmonary aspiration in obstetric patients.
(2) the type and volume of aspirate, (3) the therapy
administered, and (4) the criteria used for making the
diagnosis. Since 1952, the Department of Health in the GASTROESOPHAGEAL ANATOMY
United Kingdom has published detailed triennial reports
on all maternal deaths. Data from these reports, now
AND PHYSIOLOGY
administered by the body Mothers and Babies—Reducing Esophagus
Risk through Audits and Confidential Enquiries across the UK
(MBRRACE-UK), indicate that death from pulmonary In adults, the esophagus is approximately 25 cm long and
aspiration in obstetrics is vanishingly rare (see Figure the esophagogastric junction is approximately 40 cm
29-1).4-6 In the last five reports, which cover the 15-year from the incisor teeth. In humans, the proximal one third
29 Aspiration: Risk, Prophylaxis, and Treatment 667
of the esophagus is composed of striated muscle but the activity, and phase IV is a brief period of intermittent
distal end contains only smooth muscle. Muscular sphinc- activity leading back to phase I. The MMC first appears
ters at both ends are normally closed. The cricopharyn- in the lower esophageal sphincter and stomach, followed
geal or upper esophageal sphincter prevents the entry of by the duodenum, and finally the terminal ileum, at
air into the esophagus during respiration, and the gastro- which time a new cycle begins in the lower esophageal
esophageal or lower esophageal sphincter prevents the sphincter and stomach. The phase of the MMC at the
reflux of gastric contents. The lower esophageal sphinc- time of administration of certain drugs can affect absorp-
ter is characterized anatomically and manometrically as a tion and thereby the onset of therapeutic effect.16 Eating
3-cm zone of specialized muscle that maintains tonic abolishes the MMC and induces a pattern of intermittent
activity. The end-expiratory pressure in the sphincter is spike activity that appears similar to that in phase II. The
8 to 20 mm Hg above the end-expiratory gastric pres- duration of the fed pattern is determined both by the
sure. The lower esophageal sphincter is kept in place by calorie content and the type of nutrients in the meal.
the phrenoesophageal ligament, which inserts into the The stomach, through the processes of receptive
esophagus approximately 3 cm above the diaphragmatic relaxation and gastric accommodation, can accept 1.0 to
opening (Figure 29-2). The lower esophageal sphincter 1.5 L of food before intragastric pressure begins to
is not always closed; transient relaxations occur that increase. The contraction waves that propel food into the
account for the gastroesophageal reflux that healthy sub- small intestine begin in the antrum. The pylorus closes
jects experience.14 midway through the contraction wave, allowing some
fluid to exit into the duodenum but causing the remaining
fluid to move retrograde toward the body of the stomach.17
Gastrointestinal Motility The jet of fluid that exits the pylorus contains primarily
Differences in fasting and fed patterns of gut motility are liquid and fine particles. Large particles that lag behind
now firmly established. During fasting, the main compo- are caught in the retrograde flow of fluid, which assists
nent of peristalsis is the migrating motor complex in their disintegration. Therefore, the manner by which
(MMC).15 Each MMC cycle lasts 90 to 120 minutes and individual components of a meal pass through the stomach
comprises four phases: phase I has little or no electrical depends on the particle size and the viscosity of the sus-
spike activity and thus no measurable contractions, phase pension. Small particles and fluids exit the stomach faster
II has intermittent spike activity, phase III has spikes of than larger particles.17 The outlet of the stomach—the
large amplitude and is associated with strong contractile pylorus—limits outflow by means of both its chronic tone
Esophagus
Diaphragm
Esophageal hiatus
Stomach
Fundus
Body
Pylorus
Antrum
Uterus
FIGURE 29-2 ■ The stomach and its relationship to the diaphragm in nonpregnancy (left) and pregnancy (right). The stomach con-
sists of a fundus, body, antrum, and pylorus. The function of the lower esophageal sphincter depends on the chronic contraction
of circular muscle fibers, the wrapping of the esophagus by the crus of the diaphragm at the esophageal hiatus, and the length of
the esophagus exposed to intra-abdominal pressure. The gravid uterus may encroach on the stomach and alter the effectiveness
of the lower esophageal sphincter. (Drawing by Naveen Nathan, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
668 PART VIII Anesthetic Complications
Gastric Secretion
In one day, the stomach produces as much as 1500 mL
of highly acidic fluid containing the proteolytic enzyme
pepsin.18 Normal individuals can produce a peak acid
output of 38 mmol/h.19 Acid is secreted at a low basal rate
of approximately 10% of maximal output, even when the
stomach is empty.19,20 There is diurnal variation in this
basal rate of gastric acid secretion, with the lowest and
highest outputs occurring in the morning and evening,
respectively.
The stomach lining has two types of glands: pyloric FIGURE 29-3 ■ The oxyntic cell produces hydrogen ions that
and oxyntic. The pyloric glands contain chief cells, are secreted into the gastric lumen and bicarbonate ions that
which secrete pepsinogen, the precursor for pepsin. The are secreted into the bloodstream. H2-receptor antagonists (e.g.,
ranitidine, famotidine) and proton-pump inhibitors (e.g.,
oxyntic glands contain the oxyntic cells, which secrete omeprazole) act on the oxyntic cell to reduce gastric acid secre-
hydrochloric acid. Water molecules and carbon dioxide tion. H2-receptor antagonists block the histamine receptor on
in the oxyntic cells combine to form carbonic acid, which the basal membrane to decrease hydrogen ion production in
dissociates into hydrogen ions and bicarbonate. The the oxyntic cell. Omeprazole blocks the active transport of the
bicarbonate leaves the cell for the bloodstream, and the hydrogen ions into the gastric lumen. ACh, acetylcholine; ATP,
adenosine triphosphate; cAMP, cyclic adenosine monophos-
hydrogen ions are actively exchanged for potassium ions phate; CO2, carbon dioxide; H+, hydrogen ion; HCO3−, bicarbon-
in the canaliculi connecting with the lumen of the oxyntic ate; H2O, water; K+, potassium.
gland. The secretions of the oxyntic cell can contain a
hydrochloric acid concentration as great as 160 mmol/L
(pH 0.8).18 Proton pump inhibitors (PPIs) block the the meal.20,22,23 Gastric acid secretion during a mixed-
hydrogen ion pump on the canaliculi to decrease acid composition meal increases to approximately 80% of
production.21 peak acid output.19 The intestinal phase begins with the
The pylorus contains G cells, which secrete gastrin movement of food into the small intestine and is largely
into the bloodstream when stimulated by the vagus nerve, inhibitory. Hormones (e.g., gastrin, cholecystokinin,
stomach distention, tactile stimuli, or chemical stimuli secretin) and an enterogastric reflex further modulate
(e.g., amino acids, certain peptides). Gastrin binds to gastric acid secretion and motility depending on the com-
gastrin receptors on the oxyntic cell to stimulate the position and volume of the food in the duodenum.18,24
secretion of hydrochloric acid. Acetylcholine binds to This inhibition of gastric emptying by food in the duo-
muscarinic (M1) receptors on the oxyntic cell to cause an denum enables the duodenal contents to be processed
increase in intracellular calcium ion concentration, which before more material is delivered from the stomach.
results in hydrochloric acid secretion. Histamine poten- After the ingestion of a meal, gastric emptying depends
tiates the effects of both acetylcholine and gastrin by on (1) the pre-meal volume, (2) the volume ingested, (3)
combining with H2 receptors on the oxyntic cell to the composition of the meal, (4) the size of the solids, (5)
increase the intracellular cyclic adenosine monophos- the amount of gastric secretion, (6) the physical charac-
phate concentration, leading to a dramatic increase in the teristics of the stomach contents entering the duodenum,
production of acid.18 H2-receptor antagonists (e.g., and (7) patient position.20,24-26 A mixture of liquids and
ranitidine, famotidine) prevent histamine’s potentiation solids passes through the stomach much more slowly
of acid production (Figure 29-3). than liquids alone. Gastric emptying is slowed by high
lipid content, high caloric load, and large particle
size.20,27,28 Thus, predicting an exact time for the passage
Ingestion of Food of liquids and solids through the stomach is very difficult.
When a meal is eaten, the mechanisms that control the For non-nutrient liquids (e.g., normal saline), the gastric
secretion of gastric juice and the motility and emptying volume decreases exponentially with respect to time.26 In
of the stomach interact in a complex manner to coordi- one study, 90% of a 150-mL saline meal given to fasting
nate the functions of the stomach. The response to eating adults in the sitting position passed through the stomach
is divided into three phases: cephalic, gastric, and intes- in a median time of 14 minutes; however, in adults in the
tinal. Chewing, tasting, and smelling cause an increase in left lateral position, the median time for gastric emptying
the vagal stimulation of the stomach, which in turn was 28 minutes.25 In another study, 100% of a 500-mL
increases gastric acid production. This represents the saline meal given to fasting adults passed through the
cephalic phase of digestion.18 In this phase, gastric acid stomach within 2 hours, as determined by a polyethylene
output increases to approximately 55% of peak output.22 glycol marker.20 However, despite complete emptying of
The gastric phase begins with the release of gastrin. the saline test meal, the mean residual gastric volume at
Gastric acid secretion depends on antral distention, vagal the end of 2 hours was 46 mL; this was because of greater
activity, gastrin concentration, and the composition of secretion of gastric acid. Progressively less complete
29 Aspiration: Risk, Prophylaxis, and Treatment 669
gastric emptying and higher mean residual gastric con- be regarded as having an incompetent lower esophageal
tents were observed with meals containing amino acids, sphincter. These physiologic changes return to their pre-
glucose, and glucose with fat.20 These studies indicate pregnancy levels by 48 hours after delivery.33
that the volume and composition of the test meal, as well Serial studies assessing gastric acidity during preg-
as the resulting gastric secretions, strongly affect gastric nancy have proved difficult to perform because pregnant
emptying and residual gastric content. For example, the women do not usually wish to swallow nasogastric tubes
subject described in Figure 29-4 responded to the test repeatedly for research purposes. However, in the most
meal by secreting 800 mL of gastric juice and conse- comprehensive study of gastric acid secretion during
quently the volume in the stomach remained high for pregnancy, basal and histamine-augmented gastric acid
almost 2 hours despite early, rapid emptying.29 secretion was measured in 10 controls and 30 pregnant
women equally distributed throughout the three trimes-
Effects of Pregnancy on ters of pregnancy.35 No significant differences in basal
gastric acid secretion were seen between the pregnant
Gastric Function and nonpregnant women. However, when the women
Gastroesophageal reflux, resulting in heartburn, is a were divided into groups according to gestational age, the
common complication of late pregnancy. Pregnancy mean rate of gastric acid secretion was found to be
compromises the integrity of the lower esophageal reduced during the second trimester. The maximal
sphincter; it alters the anatomic relationship of the response to histamine was significantly lower in women
esophagus to the diaphragm and stomach, raises intragas- in the first and second trimesters than in women who
tric pressure, and in some women limits the ability of were either not pregnant or in the third trimester of
the lower esophageal sphincter to increase its tone.30-33 pregnancy.35
Progesterone, which relaxes smooth muscle, probably Assessment of gastric emptying during pregnancy
accounts for the inability of the lower esophageal sphinc- and labor presents technical and ethical challenges, and
ter to increase its tone.34 Lower esophageal pH monitor- a variety of techniques have been used (Table 29-1).36-60
ing has shown a higher incidence of reflux in pregnant Pregnancy does not significantly alter the rate of gastric
women at term, even in those who are asymptomatic, emptying.39 In addition, gastric emptying was not found
than in nonpregnant controls. Therefore, at term gesta- to be delayed in either obese or nonobese term pregnant
tion the pregnant woman who requires anesthesia should women who ingested 300 mL of water after an overnight
fast.56,57 However, management of obese parturients
should take into account the possible presence of other
associated problems in this group of patients (e.g., hiatal
500 hernia or difficult airway). Gastric emptying appears to
400 mL MEAL
be normal in early labor but becomes delayed as labor
400 advances49; the cause is uncertain. Pain is known to delay
Volume in stomach (mL)
PATHOPHYSIOLOGY
FIGURE 29-5 ■ Relationship between acidity and PaO2. In this
study, 4 mL/kg of fluid of varying pH was instilled into the tra- Aspiration pneumonitis (Mendelson’s syndrome)
cheas of dogs. The severity of the hypoxemia correlated with
the pH of the aspirate. A maximal decrease in PaO2 occurred
describes a chemical injury to the tracheobronchial tree
with aspirates with a pH of less than 2.5. B, baseline. (From Awe and alveoli caused by the inhalation of sterile acidic
WC, Fletcher WS, Jacob SW. The pathophysiology of aspiration gastric contents, whereas aspiration pneumonia may be
pneumonitis. Surgery 1966; 60:232-9.) regarded as an infectious process of the respiratory tract
caused by the inhalation of oropharyngeal secretions that
are colonized by pathogenic bacteria. Aspiration of gastric
contents could therefore result in acid injury to the lung
with or without bacterial and particulate matter–related
than 2.5 cause a granulocytic reaction that continues effects.
beyond the acute phase.72 Aspiration of particulate mate- Aspiration of acidic liquid injures the alveolar epithe-
rial can engender a clinical picture with severity equal to lium and results in an alveolar exudate composed of
or greater than that caused by the aspiration of acidic edema, albumin, fibrin, cellular debris, and red blood
liquid.71 Aspiration of small volumes of neutral liquid cells,3,69,71,72 whereas the aspiration of neutral, nonparticu-
results in a very low rate of mortality. However, aspira- late liquid leads to an alveolar exudate with minimal
tion of large volumes of neutral liquid results in a high damage to the alveoli. The phospholipid and apoprotein
mortality rate, presumably as a result of the disruption of composition of surfactant changes, exerting a negative
surfactant by the large volume of liquid or from a mecha- effect on its surface-active properties.77 This effect leads
nism similar to that seen in “near drowning.”67 to an increase in intraalveolar water and protein content
Historically, anesthesia providers have considered a and a loss of lung volume, resulting in a decrease in pul-
nonparticulate gastric fluid with a pH less than 2.5 and a monary compliance and intrapulmonary shunting of
gastric volume greater than 25 mL (i.e., 0.4 mL/kg) as blood. The cellular debris and bronchial denuding cause
risk factors for aspiration pneumonitis.64,69,70 No human bronchial obstruction. The exudative pulmonary edema,
study has directly addressed the relationship between bronchial obstruction, reduced lung compliance, and
preoperative fasting, gastric acidity and volume, and the shunting result in hypoxemia, increased pulmonary vas-
risk for pulmonary aspiration during anesthesia.73,74 cular resistance, and increased work of breathing. After
There appears to be a reasonable scientific basis using a the direct acid-mediated injury of the respiratory tract,
gastric pH cut-off value of less than 2.5 as a risk factor. an intense inflammatory response ensues from macro-
In animal experiments, the risk for aspiration pneumoni- phage activation and secretion of cytokines, interleukins
tis clearly increased with decreasing pH of the tracheal (IL) IL-1, IL-6, IL-8, and IL-10, and tumor necrosis
aspirate.64,67 Awe et al.64 illustrated this concept in a graph factor-alpha (TNF-α).78 These inflammatory mediators
of Pao2 versus time for aspirates of varying pH (see Figure lead to the chemotaxis, accumulation, and activation of
29-5). neutrophils in the alveolar exudate, up-regulation of
Animal studies have also demonstrated that an adhesion molecules within the pulmonary vasculature,
increase in the volume of tracheal aspirate is associated and activation of the complement pathways. The neutro-
with a higher risk for aspiration pneumonitis.67 However, phils subsequently release oxidants, proteases, leukotri-
the volume of aspirated material associated with risk enes, and other proinflammatory molecules.78
has been disputed. The commonly accepted volume of Amplification of these inflammatory processes may result
0.4 mL/kg (approximately 25 mL in a 70-kg adult) in the development of acute lung injury or acute respira-
originated from an experiment in a single rhesus monkey tory distress syndrome (ARDS) (Figure 29-6).77-79
in which 0.4 mL/kg of an acidic liquid was adminis- The acidic contents of the stomach prevent the growth
tered into the right mainstem bronchus and resulted of bacteria under normal conditions. However, gastric
in the animal’s death.70 The investigators made the contents may become colonized with pathogenic gram-
assumption that this entire volume, if contained in the negative bacteria in patients receiving antacid therapy or
stomach, could be aspirated. However, Raidoo et al.75 with enteral feeding tubes, gastroparesis, or intestinal
672 PART VIII Anesthetic Complications
Normal alveolus
A
8
1 Interstitium
2 Red cell
7
3 Endothelial cell
4 Type II cell
6 5 Fibroblast
1 6 Surfactant layer
4 7 Alveolar macrophage
Capillary 3
IL-8 8 12 Fibroblast
13 Cellular debris
Cap 14 Activated neutrophil
illar
y IL-8
10 15 Alveolar macrophage
12
16 Inactivated surfactant
11
FIGURE 29-6 ■ Illustration showing the normal alveolus (A) and the injured alveolus (B) during acute lung injury. In the acute phase
of acute lung injury there is formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are
marginating through the interstitium into the air space. Alveolar macrophages secrete interleukin (IL)-1, 6, 8, and 10, as well as
tumor necrosis factor-alpha (TNF-α), that stimulate and activate neutrophils. Neutrophils release proinflammatory molecules (oxi-
dants, proteases, leukotrienes, platelet-activating factor [PAF ]). The influx of protein-rich edema fluid into the alveolus has led to
the inactivation of surfactant and, together with unresolved fibrin depositions, fibrin-rich hyaline membranes are formed. MIF, mül-
lerian inhibiting factor. (From Dahlem P, van Aalderen WMC, Bos AP. Pediatric acute lung injury. Paediatr Respir Rev 2007; 8:348-62.)
obstruction. The bacterial content adds to the inflamma- lobes, whereas aspiration in the semirecumbent or
tory response to acid aspiration.80 upright position typically leads to injury to the lower
Aspiration of particulate matter in the supine position lobes. The right lower lobe is the most common site
most commonly involves injury to the posterior segments of aspiration injury because the right mainstem bronchus
of the upper lobes and the apical segments of the lower has larger and more vertical architecture compared with
29 Aspiration: Risk, Prophylaxis, and Treatment 673
In most cases of aspiration during anesthesia, the anes- Rigid Bronchoscopy and Lavage
thesia provider witnesses regurgitation of gastric contents
into the hypopharynx.3 Patients who aspirate while Suction of the upper airway followed by tracheal intuba-
breathing spontaneously have a brief period of breath- tion and suction of the primary bronchi commonly pre-
holding followed by tachypnea, tachycardia, and a slight cedes rigid bronchoscopy. Rigid bronchoscopy is useful
respiratory acidosis. Significant aspiration always results for removing large food particles that cause airway
in some hypoxemia caused by greater shunting and fre- obstruction. Lung lavage with saline or bicarbonate does
quent bronchospasm. not reduce the parenchymal damage caused by acid aspi-
An abnormality on a chest radiograph can be seen in ration and can worsen preexisting hypoxemia.80
85% to 90% of patients who aspirate gastric contents.68,81
Because these chest radiographic findings may lag behind Antibiotics
clinical signs by as much as 12 to 24 hours, the initial
radiograph may appear normal.81 In mild cases, alveolar Prophylactic antibiotics are not efficacious for aspiration
infiltrates are seen in the dependent portions of the lungs. and may lead to the development of infection with resis-
Severe aspiration results in diffuse bilateral infiltrates tant organisms. Infection is not a component of acute
without signs of heart failure (i.e., engorged pulmonary pulmonary aspiration of sterile gastric contents.80 Antibi-
vasculature and/or enlarged cardiac silhouette) (Figure otics should be administered only in the presence of clini-
29-7). cal findings that suggest infection (e.g., fever, worsening
These symptoms and signs may progress to satisfy infiltrates on chest radiographs, leukocytosis, positive
the Berlin Definition for ARDS; the criteria are as result of Gram stain of sputum, clinical deterioration).
follows82: In patients who are intubated, a nonbronchoscopic
• Clinical: within a week of known clinical insult bronchoalveolar lavage sample can be sent for laboratory
• Chest imaging: bilateral opacities not explained by analysis. Tracheal sputum samples may be insufficient to
effusions identify a bacterial pathogen, and some authorities rec-
• Biochemical: Pao2/Fio2 ratio less than 300 with con- ommend sampling of the lower respiratory tract with a
tinuous positive airway pressure (CPAP) or positive protected specimen brush.80
end-expiratory pressure (PEEP) greater than 5 cm Empirical antibiotic therapy is appropriate in patients
H2O with suspected bacterial colonization of gastric contents.
• Origin of pulmonary edema: not explained by cardiac The “at risk” group (see earlier discussion) includes
failure or fluid overload patients who have gastroparesis or bowel obstruction and
674 PART VIII Anesthetic Complications
those who are receiving enteral feeding or antacid therapy. to 30 cm H2O and providing the lowest effective
Empirical antibiotic therapy is also appropriate in patients tidal volume to prevent alveolar overdistention and
with aspiration pneumonitis that fails to resolve tidal (cyclic) recruitment-derecruitment. Such “lung-
within 48 hours. The choice of antibiotic depends on protective” strategies correlated with improved outcomes
the observed local patterns of antibiotic resistance. The in a prospective multicenter trial of the management of
target pathogens are gram-positive organisms (e.g., “early” ARDS; the use of initial tidal volumes and plateau
Streptococcus pneumoniae, Staphylococcus aureus) and some pressures of 6 mL/kg and 30 cm H2O or less was com-
gram-negative organisms (e.g., Haemophilus influenzae, pared with the use of 12 mL/kg and 50 cm H2O or less.87
Escherichia coli, Enterobacteriaceae) when the diagnosis is
made less than 48 hours after hospital admission (i.e., Positive End-Expiratory Pressure
community-acquired pneumonia). Pseudomonas aerugi-
nosa is a common pathogen in cases of nosocomial PEEP is a recommended component of the initial venti-
(hospital-acquired) aspiration pneumonia. Anaerobes are lator settings for ventilatory support in the setting of
no longer believed to be present in the majority of ARDS. A randomized clinical trial of ARDS (n = 549)
cases.80 Pharmacologic therapy should be altered when funded by the National Institutes of Health (NIH) com-
specific pathogens and their antibiotic sensitivities are pared the effects of low and intermediate PEEP levels set
determined. according to predetermined combinations of PEEP and
Fio2 in the setting of a lung-protective mechanical ven-
tilation strategy.88 There were no significant differences
Treatment of Hypoxemia
in hospital mortality (24.9% versus 27.5%, respectively)
Exudation of fluid into the alveoli, decreased surface or days to unassisted breathing (14.5 days versus 13.8
activity of surfactant, and atelectasis all result in intrapul- days, respectively) between the two groups. However, the
monary shunting and hypoxemia. The administration of role of comparatively higher levels of PEEP in protective
CPAP in patients breathing spontaneously or the admin- ventilation strategies for ARDS is far from clear.89-91
istration of PEEP in patients undergoing mechanical
ventilation restores functional residual capacity, reduces Fluid Management
pulmonary shunting, and reverses hypoxemia. Supple-
mental oxygen should be given as required. In a 2 × 2 factorial trial design, the ARDS Clinical Trials
Network research group evaluated the use of conserva-
tive versus liberal fluid strategy and the value of guiding
Corticosteroids
this intervention with central venous pressure or pulmo-
Despite decades-long use of corticosteroids in the man- nary artery wedge pressure measurements.92 The group
agement of aspiration pneumonitis, animal and human that received conservative fluid management, whether
studies have failed to demonstrate a beneficial effect on guided by central venous pressure and/or pulmonary cap-
pulmonary function, lung injury, alveolar-capillary per- illary wedge pressure measurements, had much lower net
meability, or clinical outcomes after acid aspiration.80 fluid balance, better lung function, and a shorter duration
Thus, the administration of corticosteroids for aspiration of mechanical ventilation and intensive care unit stay.
pneumonitis cannot be recommended. Further, there appeared to be no increase in the incidence
or duration of shock or need for dialysis in the conserva-
tive fluid management arm of the trial. Thus, early man-
Management of Respiratory Failure agement of ARDS (after initial resuscitation) focuses on
Aspiration of gastric contents can result in activation of limiting iatrogenic insult with conservative fluid manage-
inflammatory intrapulmonary pathways80 consistent with ment strategy.
the pathophysiology observed in ARDS.79,82 The basic
tenets of management of ARDS include the use of Basic Critical Care Algorithms
“lung-protective” ventilation strategies, the judicious
management of fluids, and the application of basic critical To minimize the risk for sepsis, central venous catheters
care algorithms. The management of severe ARDS and other invasive hemodynamic monitors should be
and hypoxemia resistant to conventional management removed as early as is clinically feasible. Aseptic precau-
involves the use of rescue therapies (e.g., prone position- tions should be used during care, and infections should
ing, high-frequency oscillatory ventilation, extracorpo- be treated with antibiotics specific to the bacterial patho-
real membrane oxygenation) usually used in the critical gen for 3 to 7 days. Whether tight and rigorous glycemic
care setting83 and thus will not form part of this overview. control should be employed is controversial. Occasional
The following section outlines the basic principles in withdrawal of sedation and the use of prophylaxis for
immediate management and stabilization. Readers are gastrointestinal bleeding and thromboembolic events are
referred to extensive reviews of management of ARDS currently considered the standard of care in any critically
for further information.83-86 ill patient (see Chapter 55).93
follow one of two courses: (1) rapid improvement in lung Because the incidence of aspiration pneumonitis is
function with an uncomplicated recovery or (2) slow low, the efficacy of prophylactic regimens is measured by
improvements in lung function, oxygenation, and ventila- their ability to alter gastric pH and volume. In 30% to
tion with prolonged weaning and recovery. 43% of pregnant women the fasting gastric volume is
The corticosteroid controversy in ARDS in the context greater than 25 mL and the gastric fluid pH is less than
of aspiration is still unresolved.80 Although a recent sys- 2.5.101,102 However, the percentage of term parturients at
tematic review suggested potential benefit from cortico- risk may not differ from that of patients undergoing elec-
steroids,94 their use did not appear to improve lung tive abortion, postpartum sterilization, or gynecologic
function or recovery in patients with ARDS in two of the surgery (Table 29-2).103-105 Gastric volume and acidity at
well-conducted randomized clinical trials95,96 and may be term gestation are similar to gastric volume and acidity
associated with longer-term side effects. To further add during early pregnancy, during the postpartum period,
to the controversy, a 2007 randomized controlled trial and in nonpregnant patients.101-108 Decreased lower
reported an improvement in outcomes in patients with esophageal sphincter tone and a higher risk for difficult
ARDS randomized to receive a methylprednisolone infu- intubation are the primary factors that increase the risk
sion versus placebo.97 In our opinion, there appears to be for aspiration during pregnancy and the immediate post-
no benefit from giving corticosteroids with the aim of partum period, and these are the factors that mandate the
attenuating lung injury after aspiration. However, if cor- need for pharmacologic prophylaxis.
ticosteroids are being used for other reasons (e.g., bron-
chospasm, steroid replacement), then corticosteroid
therapy could be considered.
Preoperative Oral Fluid Administration
Multiple studies have described no increase in gastric
volume or acidity after the oral administration of 150 mL
PROPHYLAXIS of fluid (e.g., coffee, tea, water, other clear liquids, orange
juice without pulp) in nonpregnant adults 2 hours before
The risk for aspiration is extremely low when gastric elective surgery.109,110 The patients in these studies all
emptying is normal and patients, including parturients, fasted overnight and should have had a low gastric volume
are appropriately fasted. Factors predisposing to regurgi- when the test meal was given. Lewis and Crawford111
tation, particularly in obstetrics, include emergency noted that in women undergoing elective cesarean deliv-
surgery, difficult/failed tracheal intubation, light anesthe- ery, those who had been allowed to consume a meal of
sia, and gastroesophageal reflux. The risk for failed intu- both tea and toast 2 to 4 hours preoperatively had an
bation is 3 to 11 times greater in pregnant patients than increase in gastric volume and a decrease in gastric pH
in nonpregnant patients98,99 (see Chapter 30). Airway compared with a control group. Consumption of tea
edema, breast enlargement, obesity, and the high rate of without toast resulted in an increase in gastric volume but
emergency surgery can all contribute to the risk for failed it did not alter gastric pH. Particulate material was aspi-
intubation in pregnant women. Aspiration pneumonitis rated from the stomachs of 2 of the 11 patients who
is often associated with difficult or failed intubation consumed both tea and toast. The investigators did not
during the induction of general anesthesia. In a survey state the volume of tea consumed by these patients.
conducted by the Society for Obstetric Anesthesia and In addition, when gastric emptying of both 50 mL and
Perinatology, intubation was recorded as difficult in 14 300 mL of water was assessed in nonlaboring term par-
of 19 cases of aspiration in which tracheal intubation was turients, the gastric emptying half-time for 300 mL was
used.100 Moreover, Warner et al.9 reported that the risk significantly shorter than that for 50 mL.56 When a
for aspiration during emergence from anesthesia was similar study was conducted in obese nonlaboring partu-
almost as high as that during induction of anesthesia. rients term (mean [±SD] prepregnancy body mass index
Thus, prophylactic regimens must provide protection 41 ± 9 kg/m2), the gastric emptying time for 300 mL was
during both induction of, and emergence from, general not longer than that for 50 mL.57 The latter finding sug-
anesthesia. Although the risk for aspiration during elec- gests that the American Society of Anesthesiologists
tive, as opposed to emergency, surgery under general (ASA) Guidelines for Obstetric Anesthesia,73 which state
anesthesia is very low, parturients undergoing cesarean that “the uncomplicated patient undergoing elective
delivery or other surgical procedures should receive cesarean delivery may have modest amounts of clear
pharmacologic prophylaxis. liquids up to 2 h before induction of anesthesia” could
676 PART VIII Anesthetic Complications
also be applied to healthy, obese pregnant women present- their efficacy depends on the baseline gastric volume and
ing for elective surgery. However, factors other than the acidity.119,120 A total of 30 mL of sodium citrate neutral-
rate of gastric emptying can influence the rate of pulmo- izes 255 mL of hydrochloric acid with a pH of 1.0. The
nary aspiration, particularly in obese subjects. Obesity is effective duration of action of sodium citrate is variable
associated with a higher incidence of gastroesophageal and depends on the rate of gastric emptying.121,122
reflux and difficulty with airway management (both intra- O’Sullivan and Bullingham121,122 used radiotelemetry pH
operatively and postoperatively) (see Chapter 50). More- pills to perform noninvasive assessments of the efficacy
over, the cesarean delivery rate is higher and the success of sodium citrate in pregnant women. After the adminis-
rate of trial of labor after cesarean delivery is lower in tration of 15 mL of sodium citrate to women in the third
obese parturients.112,113 trimester of pregnancy, the time that the pH remained
greater than 3.0 was less than 30 minutes.121 When the
same study was repeated in laboring women,122 the mean
Choice of Anesthesia time that the pH remained greater than 3.0 was 57
The Obstetric Anesthesia Work Force Survey demon- minutes in subjects who had received no analgesia and
strated that the use of neuraxial anesthesia for cesarean 166 minutes in those who had received meperidine. Non-
delivery rose dramatically from 1981 to 2001, with the particulate antacids should be administered within 20
use of general anesthesia accounting for less than 5% of minutes of the induction of general anesthesia, particu-
elective procedures.114 A review of procedures performed larly if the procedure is an emergency and there is insuf-
at a large tertiary care obstetric facility showed that from ficient time for a co-administered H2-receptor antagonist
1990 to 1995 the use of general anesthesia for cesarean to be effective.
delivery decreased from 7.2% to 3.6%. The yearly inci-
dence of difficult intubation ranged from 1.3% to 16.3%,
with one maternal death resulting from a failed intuba-
Histamine-2 Receptor Antagonists
tion.115 Hawkins et al.10 reported 67 maternal deaths The ASA Task Force on Obstetric Anesthesia concluded
resulting from complications of general anesthesia and 33 that H2-receptor antagonists are efficacious in reducing
maternal deaths resulting from complications of neur- gastric acidity and volume.73 H2-receptor antagonists
axial anesthesia in the United States during the years block histamine receptors on the oxyntic cell and thus
1979 to 1990. Approximately 73% of general anesthesia– diminish gastric acid production, leading to a slight
related maternal deaths were due to airway problems, reduction in gastric volume in the fasting patient. When
primarily failed intubation and/or aspiration. However, given intravenously, an H2-receptor antagonist begins to
data collected by Hawkins et al. for the more recent take effect in as little as 30 minutes, but 60 to 90 minutes
period spanning the years 1997 to 2002 indicate that the are required for maximal effect.102 After oral administra-
mortality rates for cesarean delivery are similar for tion, gastric pH is higher than 2.5 in approximately 60%
general and regional anesthesia.11 Studies reviewing failed of patients at 60 minutes and in 90% at 90 minutes.123
intubation during the periods 1993 to 1998 and 1999 to The duration of action is sufficiently long to cover emer-
2003 in the United Kingdom showed that whereas the gence from general anesthesia for a cesarean delivery.
rate of failed intubation during this period had not Cimetidine (given in doses of 200 to 400 mg intrave-
declined there were no deaths from this potentially nously or orally) reduces gastric acidity within 60 to
fatal complication.116,117 Although this relative change in 90 minutes.102,123 Therapeutic plasma concentrations are
maternal mortality from the complications of general sustained for approximately 4 hours. Cimetidine may
anesthesia is very encouraging, other factors such as the decrease the rate of plasma clearance of certain drugs,
worldwide obesity epidemic have increased the chal- including some local anesthetics (e.g., lidocaine), by
lenges presented to anesthesia providers, particularly binding to the cytochrome P450 system in the hepatocyte
with respect to emergency operative deliveries. There- and by reducing hepatic blood flow.124 Cimetidine crosses
fore, techniques for preventing pulmonary aspiration of the placenta, but this does not appear to have harmful
gastric contents will remain or even become increasingly effects.125 Because arrhythmias and cardiac arrest have
pertinent to clinical practice. been reported with the rapid intravenous administration
of cimetidine,126 a slow rate of intravenous administration
or the oral route of administration is recommended. The
Antacids use of cimetidine in obstetric anesthesia has largely been
The ASA Practice Guidelines for Obstetric Anesthesia replaced by the use of other H2-receptor antagonists.
state, “Before surgical procedures (i.e., cesarean delivery, Ranitidine, a chemically substituted amino-alkyl
postpartum tubal ligation) practitioners should consider furan, has been evaluated after the administration of an
the timely administration of nonparticulate antacids, H2- intravenous or intramuscular dose of 50 to 100 mg or an
receptor antagonists, and/or metoclopramide for aspira- oral dose of 150 mg.127-129 These studies have noted that
tion prophylaxis.”73 Particulate antacids should not be the administration of ranitidine results in a gastric pH
used as prophylaxis because when aspirated they cause greater than 2.5 within 1 hour and sustained therapeutic
pulmonary shunting and hypoxemia of magnitude similar concentrations for approximately 8 hours.127-129 Raniti-
to that caused by acid aspiration and greater than that dine does not have any major interaction with the
caused by saline, alkalinized saline, or sodium citrate.118 cytochrome P450 system130 and does not alter plasma
Therefore, nonparticulate antacids (e.g., 0.3 M sodium concentrations of lidocaine or bupivacaine after their epi-
citrate, Bicitra, Alka-Seltzer effervescent) should be used; dural administration.131
29 Aspiration: Risk, Prophylaxis, and Treatment 677
Nizatidine (given in doses of 150 to 300 mg orally) of pulmonary aspiration of gastric contents and the
and famotidine (given in doses of 20 to 40 mg orally absence of high-quality studies of antacid prophylaxis,
or intravenously) are alternative H2-receptor antago- rather than the presence of studies demonstrating nega-
nists.132,133 Both have a duration of action greater than 10 tive results; the Cochrane review cited only three studies,
hours and do not interfere with the metabolism of other published in 1971, 1980, and 1984. One study assessed
drugs by the cytochrome P450 system.132,133 the use of metoclopramide and perphenazine in women
Tramadol, a synthetic 4-phenyl-piperidine analogue receiving meperidine in labor, and the other two studies
of codeine with a low affinity for µ-opioid receptors, has focused on the use of particulate antacids. An audit of
the additional property of inhibiting type 3 muscarinic acid aspiration prophylaxis during labor in the United
receptors that mediate gastric gland secretion and smooth Kingdom showed a decreasing number of institutions
muscle contraction. In one study, 60 healthy parturients with policies to administer routine antacid prophylaxis to
undergoing elective cesarean delivery under general all laboring women. However, many institutions
anesthesia were randomly assigned to receive either attempted to identify women at high risk for an emer-
intramuscular tramadol 100 mg or famotidine 20 mg 1 gency cesarean delivery, to whom they gave oral raniti-
hour before surgery.134 The median (range) gastric fluid dine 150 mg at 6-hour intervals throughout labor.141
pH after induction of anesthesia was 6.4 (1.7 to 7.2) in
the tramadol group and 6.3 (1.9 to 8.1) in the famotidine Sellick Maneuver and Induction
group. Two patients in each group had a gastric volume
greater than 0.4 mL/kg with a pH less than 2.5. Parturi-
of Anesthesia
ents in the tramadol group had better pain scores and Sellick demonstrated that the occlusion of the esophagus
used less analgesia during the first 24 hours after delivery. by cricoid pressure in cadavers prevented the flow of
Neonatal well-being was similar in the two groups. barium from the stomach to the pharynx.142 He also
Further investigation is required before such a novel reported the successful use of this maneuver in 26 cases
method of antacid prophylaxis is adopted into everyday to prevent the passive regurgitation of gastric contents
clinical practice. into the airway. For proper application of cricoid pres-
sure, the head should be fully extended; it may help to
have a trained assistant place a hand behind the patient’s
Proton-Pump Inhibitors neck, so that the cervical vertebrae and esophagus are
Omeprazole (20 to 40 mg orally) and lansoprazole (15 brought forward, making it easier to occlude the latter.
to 30 mg orally) are substituted benzimidazoles that The trained assistant should place the thumb and middle
inhibit the hydrogen ion pump on the gastric surface of finger on either side of the cricoid cartilage; no more than
the oxyntic cell. Purported advantages of proton pump light pressure should be applied while the patient is
inhibitors (PPIs) are a long duration of action, low toxic- awake, to prevent coughing, straining, retching, and
ity, and the potential for low maternal and fetal blood esophageal rupture. After denitrogenation (preoxygen-
concentrations at the time of delivery.21,135,136 For emer- ation) and administration of induction drugs, an increas-
gency cesarean delivery, studies have suggested that H2- ingly firm downward pressure is applied to the cricoid
receptor antagonists and PPIs administered intravenously cartilage as loss of consciousness occurs. Full application
are equally effective adjuncts to sodium citrate for reduc- of cricoid pressure requires a force of 30 Newtons (N),
ing gastric acidity and volume.136 However, a meta- 1 N being the force required to accelerate a mass of 1 kg
analysis has indicated that premedication with ranitidine by 1 m/s2. (As a practical clinical guide to the amount of
is more effective than PPIs in reducing the volume of force to apply, 10 N is approximately equivalent to the
gastric secretion and increasing gastric pH.137 downward force exerted by a mass of 1 kg.) Vanner and
Pryle143 demonstrated that 30 N of cricoid force pre-
vented regurgitation of saline in cadavers with esophageal
Metoclopramide pressures as high as 40 mm Hg. They recommended a
Metoclopramide is a procainamide derivative that is a modest cricoid force (10 N) before loss of consciousness,
peripheral cholinergic agonist and a central dopamine increasing to 30 N after loss of consciousness; their data
receptor antagonist. An intravenous dose of metoclo- suggested that such pressure should be sufficient to
pramide 10 mg increases lower esophageal sphincter tone prevent passive regurgitation of esophageal contents
and reduces gastric volume by increasing gastric peristal- during induction of general anesthesia in most
sis. Metoclopramide can have a significant effect on patients.144,145 Cricoid pressure is maintained until the
gastric volume in as little as 15 minutes.101 Unfortunately, endotracheal tube cuff is inflated and correct endotra-
prior administration of an opioid or atropine antagonizes cheal tube position is confirmed.
the effect of metoclopramide.138 Extrapyramidal effects The value of cricoid pressure has been questioned. A
are a major potential side effect of metoclopramide. study employing magnetic resonance imaging of 22
Metoclopramide crosses the placenta, but studies have healthy volunteers of mixed sex noted that the resting
reported no significant effects on the fetus or neonate.139 position of the esophagus was lateral relative to the
A Cochrane review of antacid prophylaxis concluded cricoid cartilage in 53% of the subjects without cricoid
that there was no evidence to support the routine admin- pressure and in 91% with cricoid pressure.146 In addition,
istration of drugs to women in normal labor to reduce cricoid pressure displaced the esophagus relative to its
the incidence of pulmonary aspiration or Mendelson’s initial resting position to the left and right in 68% and
syndrome.140 This conclusion reflects the low incidence 21% of the subjects, respectively. The authors suggested
678 PART VIII Anesthetic Complications
that cricoid pressure may lead to airway displacement and degrees to prevent reflux and aspiration.148 Over subse-
an inability to reliably produce midline esophageal com- quent years, others argued the advantages of both the
pression; these factors could limit the protective effect of supine and head-down positions for induction of anes-
the maneuver against passive reflux and make the intuba- thesia. Hignett et al.149 demonstrated that the functional
tion process more difficult. However, Rice at al.147 chal- residual capacity of healthy term parturients was increased
lenged these conclusions in a subsequent magnetic in the 30-degree head-up position compared with the
resonance imaging study investigating the efficacy of supine position. Moreover, in the 30-degree head-up
cricoid pressure. They demonstrated that the hypophar- position, the esophageal pressure is lower and thus the
ynx, rather than the esophagus, lies behind the cricoid force applied to the cricoid could be reduced to 20 N143;
cartilage (Figure 29-8). The relationship of the cricoid this reduction in force may reduce the incidence of airway
and laryngeal cartilages is constant and is maintained by problems, because these problems are often proportional
their connecting ligaments and muscles. Because the to the force applied.150 Further work is required to deter-
cricoid cartilage and postcricoid hypopharynx are con- mine whether the increase in functional residual capacity
stantly related, they will behave as a unit when com- in the 30-degree head-up position prolongs the time to
pressed against the cervical spine. They contended oxyhemoglobin desaturation during the apnea phase
that the sealing of the hypopharynx is therefore indepen- of rapid-sequence induction and whether this position
dent of the position of the esophagus and the actual should be routinely adopted for induction of general
position of the esophagus is irrelevant to the successful anesthesia in obstetric patients.
application of cricoid pressure. Should the incorrect application of cricoid pressure
When the technique of rapid-sequence induction of distort the laryngeal inlet and cause difficulty with laryn-
anesthesia with tracheal intubation was first described in goscopy and/or intubation, the cricoid pressure should
detail, it was recommended that the trunk be elevated 30 be promptly released.
A B
C D
FIGURE 29-8 ■ Axial magnetic resonance images in the sniffing position, without (A) and with (B) cricoid pressure. A, Postcricoid
hypopharynx (arrow) and the vitamin E marker (arrowhead) placed by the anesthesiologist before imaging. C, Example of postcricoid
hypopharynx compression (arrow) lateral to the vertebral body with cricoid pressure. In this image, the postcricoid hypopharynx is
compressed against the longus colli muscle group (arrowhead). D, Image 2 cm inferior to the cricoid ring distinctly shows the cervi-
cal esophagus (arrow) lateral to the vertebral body. In B and C, the anesthesiologist’s thumb and index finger can be seen pushing
on the cricoid cartilage. The axial image chosen for each study (A-C) was the image at the most inferior level of the cricoid cartilage.
(From Rice MJ, Mancuso AA, Gibbs C, et al. Cricoid pressure results in compression of the postcricoid hypopharynx: the esophageal position
is irrelevant. Anesth Analg 2009; 109:1546-52.)
29 Aspiration: Risk, Prophylaxis, and Treatment 679
400
of “accelerated starvation” if denied food and drink.151
Fasting results in the production of ketones, primarily 300
beta-hydroxybutyrate and acetoacetic acid, and the non-
esterified fatty acids from which they are derived. These 200
changes are exacerbated by the metabolic demands of
labor and delivery. Consequently, some obstetricians and
100
nurse-midwives have suggested that maternal oral intake
policies should be liberalized during labor.152 It is argued
0
that allowing mothers to eat and drink during labor pre- NVD IVD CD Vomited
vents ketosis and dehydration and subsequently improves
obstetric outcome. The widespread use of neuraxial anal- FIGURE 29-9 ■ The effect of eating during labor on maternal
gesia has resulted in a reduction in the use of systemic obstetric outcome. CD, cesarean delivery; IVD, instrumental
vaginal delivery; NVD, normal vaginal delivery. (Based on data
opioids for labor analgesia114; thus, fewer women may be from O’Sullivan G, Liu B, Hart D, et al. Effect of food intake during
at risk for opioid-induced delays in gastric emptying labour on obstetric outcome: randomised controlled trial. BMJ 2009;
(with its inherent potential for aspiration). This trend has 338:b784.)
680 PART VIII Anesthetic Complications
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ranitidine for prophylaxis against aspiration pneumonitis in emer- a supine position on the functional residual capacity of term par-
gency caesarean section. Anaesthesia 1992; 47:101-4. turients. Anesth Analg 2011; 113:1098-102.
137. Clark K, Lam LT, Gibson S, Currow D. The effect of ranitidine 150. Hartsilver EL, Vanner RG. Airway obstruction with cricoid pres-
versus proton pump inhibitors on gastric secretions: a meta- sure. Anaesthesia 2000; 55:208-11.
analysis of randomised control trials. Anaesthesia 2009; 64: 151. Metzger BE, Ravnikar V, Vileisis RA, Freinkel N. “Accelerated
652-7. starvation” and the skipped breakfast in late normal pregnancy.
138. Hey VM, Ostick DG, Mazumder JK, Lord WD. Pethidine, meto- Lancet 1982; 1:588-92.
clopramide and the gastro-oesophageal sphincter: a study in 152. O’Sullivan G, Shennan A. Labour—a gastronomic experience! Int
healthy volunteers. Anaesthesia 1981; 36:173-6. J Obstet Anesth 2002; 11:1-3.
139. Bylsma-Howell M, Riggs KW, McMorland GH, et al. Placental 153. Scrutton MJ, Metcalfe GA, Lowy C, et al. Eating in labour: a
transport of metoclopramide: assessment of maternal and neonatal randomised controlled trial assessing the risks and benefits. Anaes-
effects. Can Anaesth Soc J 1983; 30:487-92. thesia 1999; 54:329-34.
140. Gyte GM, Richens Y. Routine prophylactic drugs in normal 154. Kubli M, Scrutton MJ, Seed PT, O’Sullivan G. An evaluation of
labour for reducing gastric aspiration and its effects. Cochrane isotonic “sport drinks” during labor. Anesth Analg 2002; 94:
Database Syst Rev 2006; (3):CD005298. 404-8.
141. Calthorpe N, Lewis M. Acid aspiration prophylaxis in labour: 155. O’Sullivan G, Liu B, Hart D, et al. Effect of food intake during
a survey of UK obstetric units. Int J Obstet Anesth 2005; labour on obstetric outcome: randomised controlled trial. BMJ
14:300-4. 2009; 338:b784.
142. Sellick BA. Cricoid pressure to control regurgitation of stomach 156. American College of Obstetricians and Gynecologist. Oral intake
contents during induction of anaesthesia. Lancet 1961; 2:404-6. during labor. ACOG Committee Opinion No. 441. Washington,
143. Vanner RG, Pryle BJ. Regurgitation and oesophageal rupture with DC, September 2009 (Reaffirmed 2011). (Obstet Gynecol 2009;
cricoid pressure: a cadaver study. Anaesthesia 1992; 47:732-5. 114:714.)
144. Vanner RG, O’Dwyer JP, Pryle BJ, Reynolds F. Upper oesopha- 157. Smith I, Kranke P, Murat I, et al. Perioperative fasting in adults
geal sphincter pressure and the effect of cricoid pressure. Anaes- and children: guidelines from the European Society of Anaesthe-
thesia 1992; 47:95-100. siology. Eur J Anaesthesiol 2011; 28:556-69.
C H A P T E R 3 0
CHAPTER OUTLINE
RISK MANAGEMENT
Definitions Planning
Incidence and Epidemiology Neuraxial Anesthesia
Maternal Morbidity and Mortality Awake Intubation before General Anesthesia
Physiologic and Anatomic Changes Indirect Optical/Video Laryngoscopy
of Pregnancy Awake Tracheostomy or Surgery Standby
AIRWAY ASSESSMENT Local Anesthesia for Cesarean Delivery
Cormack and Lehane Grade THE UNANTICIPATED DIFFICULT AIRWAY
Mallampati Class Features of the Obstetric Patient
Thyromental Distance Cannot Intubate but Can Ventilate
Atlanto-occipital Joint Extension Cannot Intubate and Cannot Ventilate
Mandibular Protrusion Laryngeal Mask Airway
Other Assessments Laryngeal Tube and Esophageal-Tracheal
Multivariable Assessments Combitube
Recommendations Cannula and Surgical Cricothyrotomy
PROPHYLAXIS EXTUBATION OF THE PATIENT WITH
Neuraxial Labor Analgesia A DIFFICULT AIRWAY
Fasting and Antacid Prophylaxis General Principles
Patient Positioning Airway Exchange Catheters
Denitrogenation (Preoxygenation)
Rapid-Sequence Induction and
Cricoid Pressure
anesthetic procedures.4 Independent predictors of impos- difficulty with obstetric airway management. There are
sible mask ventilation were previous neck irradiation, significant physiologic and anatomic changes of preg-
male gender, diagnosis of sleep apnea, and a Mallampati nancy (see later discussion) affecting the airway, oxygen-
class III or IV (see later discussion).4 Difficult laryngeal ation, and metabolism. The majority of obstetric general
mask ventilation may be defined as the inability within anesthetics are administered for emergency deliveries,
three attempts of device insertion to produce expired often during off hours16; these anesthetic procedures may
tidal volumes more than 7 mL/kg (leak pressure > 15 to be conducted by inexperienced anesthesia providers with
20 cm H2O).1 In a study of 11,910 nonobstetric patients,5 less proficiency in difficult airway management. Indeed,
the incidence of difficult laryngeal mask ventilation was in one U.K. study,12 the relative risk of failed intubation
0.19%. at emergency compared with elective cesarean delivery
Although failed tracheal intubation is a tangible end- was 1.79 (95% confidence interval [CI], 0.61 to 5.26).
point, defining difficult intubation is more complex. Excessive cricoid pressure applied by a poorly trained
Difficulty may be encountered because of failure to visu- assistant can worsen the glottic view at laryngoscopy,17 as
alize the glottis (difficult laryngoscopy) or due to an ana- can positioning the parturient with left lateral tilt. Marfin
tomic laryngeal or tracheal abnormality. Difficulty has et al.18 proposed that the introduction of disposable
been variously defined by (1) the time taken to intubate, airway equipment may adversely affect airway manage-
(2) the number of attempts, (3) the view at laryngoscopy, ment; single-use, disposable gum elastic bougies are less
and (4) the requirement for special equipment. reliable than reusable devices.
Although a dramatic decrease in the number of An increase in the incidence of airway-related compli-
anesthesia-related deaths has been reported in the Con- cations in obstetric patients has been predicted.19,20 The
fidential Enquiries into Maternal Deaths in the United change in maternal demographics, most notably an
Kingdom over the past 40 years, complications from increase in the prevalence of maternal obesity, may
general anesthesia, primarily complications of airway increase the risk for complications from general anesthe-
management, continue to be the leading cause of sia, especially when performed for emergency proce-
anesthesia-related maternal mortality.6 Similarly, data dures. With a decrease in the number of cesarean
from the United States have demonstrated a higher case- deliveries performed under general anesthesia, trainees
fatality rate with general anesthesia compared with neur- have fewer opportunities to become familiar with chal-
axial anesthesia.7 Although the development of national lenges of the obstetric difficult airway.21-23 Changes in
guidelines2,8,9 has resulted in a more systematic approach anesthesia training, notably the reduction in trainee
to the management of the difficult airway, deaths directly working hours and the advent of supraglottic airway
resulting from anesthesia still occur owing to failures in (SGA) devices mean that, overall, laryngoscopy and
ventilation, tracheal intubation, or airway management intubation are now less commonly performed than previ-
following extubation. Despite widespread use of neur- ously. Therefore, the skills required to manage a chal-
axial anesthesia for operative delivery, general anesthesia lenging tracheal intubation are less likely to have been
may still be required in emergency situations, if neuraxial gained before working on the labor and delivery unit
anesthesia is contraindicated or patients refuse it, or if without direct supervision. In an editorial, Russell19 sug-
neuraxial anesthesia has failed to provide adequate gested that failure to intubate during emergency cesarean
anesthesia. delivery may be a self-fulfilling prophecy as practitioners
draw on less experience with intubating the trachea
during general anesthesia for an emergency cesarean
Incidence and Epidemiology delivery.
The incidence of failed intubation in obstetrics has long The increasing prevalence of maternal obesity is of
been considered to be approximately 1 in 250 to 300,10-14 significant concern. Obese women are at increased risk
which is approximately eight times greater than that in for obstetric interventions requiring anesthesia24 and are
the general population (Table 30-1).15 A number of more likely to have unsuccessful neuraxial anesthesia,
reasons have been proposed to explain the increased necessitating the use of general anesthesia for emergency
delivery (see Chapter 50). Difficulty with intubation has
been reported to occur in 15.5% of the nonobstetric
TABLE 30-1 The Incidence of Failed Intubation obese population.25 A large Danish cohort study of more
in Obstetrics than 90,000 nonobstetric patients found that BMI of
greater than 35 kg/m2 was a significant risk factor for
Study Year Country No. Incidence difficult intubation (odds ratio, 1.34)26; BMI was a more
Lyons10
1985 UK 2331 1 : 291 accurate predictor of difficult intubation than weight
Rocke28 1992 South Africa 1500 1 : 750 alone. Data collected from one U.K. region from 1993
Hawthorne11 1996 UK 5802 1 : 250 to 1998 identified 26 parturients with failed intubation at
Tsen21 1998 US 536 1 : 536 cesarean delivery; the mean BMI was 33.1 kg/m2.12 Poor
Barnardo12 2000 UK 8970 1 : 249 head and neck positioning at induction of anesthesia,
Rahman13 2005 UK 4768 1 : 238 inappropriate cricoid pressure, and operator anxiety may
McDonnell14 2008 Australia 1095 1 : 274 be responsible for a higher incidence of difficult airway
Djabatey29 2009 UK 3430 0 management in obese patients.27
McKeen30 2011 Canada 2633 1 : 1300 In contrast to some experts, others have questioned
whether the rate of difficult and failed intubation is
686 PART VIII Anesthetic Complications
increasing in obstetric anesthesia practice.28-30 A more TABLE 30-2 Case-Fatality Rates and Risk
liberal attitude toward the use of general anesthesia has Ratios of Anesthesia-Related
been suggested to lead to greater familiarity with mater- Mortality during Cesarean
nal airway management and subsequent reduced rates of Delivery in the United States:
difficulty.29 The ethics of using a technique potentially 1979 to 2002
associated with greater risk for individual harm to reduce
the overall incidence of anesthesia-related mortality asso- Case-Fatality Rates*
ciated with the technique presents an interesting dilemma. GENERAL NEURAXIAL
Certainly the presence of experienced anesthesia staff Year Range ANESTHESIA ANESTHESIA Risk Ratio
during induction of general anesthesia is recommended
1979-1984 20.0 8.6 2.3 (95% CI,
and should reduce the morbidity and mortality, and 1.9-2.9)
perhaps the frequency, of difficulty with airway manage- 1985-1990 32.3 1.9 16.7 (95% CI,
ment.16 It is hoped that the introduction and widespread 12.9-21.8)
acceptance of simulation training in obstetrics31 will lead 1991-1996 16.8 2.5 6.7 (95% CI,
to improvement in staff performance during critical 3.0-14.9)
events such as difficult airway management. 1997-2002 6.5 3.8 1.7 (95% CI,
0.6-4.6)
SaO2 (%)
during pregnancy, more acute changes may be observed 80 Normal
during labor. Mallampati class scores deteriorate during 10-kg
Mean time
labor.39-41 Decreases in upper airway volume during labor Obese
child to recovery of
have been demonstrated by acoustic reflectometry.39 The 70 127-kg twitch height
from 1 mg/kg
volume of both the oral component of the airway (from adult
succinylcholine i.v.
the incisors to the oropharyngeal junction) and the pha-
60 10% 50% 90%
ryngeal component (from the oropharyngeal junction to 0
the glottis) are decreased, presumably as a result of 0 1 2 3 4 5 6 6.8 7 8 8.5 9 10 10.2
increasing soft tissue edema. Airway narrowing may be Time of VE = 0 (minutes)
more significant in women with preeclampsia. The airway
edema that has been observed during labor may be exac- FIGURE 30-1 ■ Time to hemoglobin desaturation (initial SaO2 =
erbated by expulsive efforts during the second stage of 0.87). SaO2 versus time of apnea for various types of patients.
(From Benumof JL, Dagg R, Benumof R. Critical hemoglobin
labor42 or after extubation after cesarean delivery.28 It is desaturation will occur before return to an unparalyzed state follow-
therefore prudent to reevaluate the airway before induc- ing 1 mg/kg intravenous succinylcholine. Anesthesiology 1997;
tion of general anesthesia rather than rely solely on a 87:979-82.)
prelabor assessment.39
Nasal capillary engorgement during pregnancy
increases the risk for epistaxis after nasal instrumentation
and has led many practitioners to believe that nasal intu- significantly shorter than that for recovery from paralysis
bation is relatively contraindicated in pregnancy. In a from succinylcholine.46 Therefore, should ventilation be
2011 review, Arendt et al.43 challenged this opinion, sug- impossible, it cannot be assumed that the patient will
gesting that nasal fiberoptic intubation is acceptable after recommence breathing before dangerously low levels of
careful and appropriate preparation of the nasal mucosa oxygen saturation have been reached.
with topical vasoconstrictors. However, the effects of
topical agents on both the prevention of epistaxis and Weight Gain
maternal hemodynamic parameters and uteroplacental
perfusion must be evaluated and the relative risk of this During pregnancy, most women gain 10 to 15 kg (22 to
procedure should be assessed on an individual basis. 33 lb) or more. This weight gain is composed of increases
in fat deposition, blood and interstitial fluid volume, and
uterine and fetal mass. High BMI is associated with dif-
Respiratory and Metabolic Changes
ficulty in mask ventilation and tracheal intubation4,27 and
As pregnancy progresses, the gravid uterus increasingly with a greater risk for requiring emergency cesarean
encroaches on the diaphragm and lung volumes are delivery.24 BMI is directly associated with more rapid
reduced. By term, expiratory reserve volume decreases by oxygen desaturation during apnea during the induction
25% and residual volume decreases by 15%, resulting in of general anesthesia.
a 20% reduction in functional residual capacity (FRC).
This decrease is more marked in the supine than upright Breast Enlargement
position, and in the obese than lean patient. Closing
volume is unchanged in pregnancy, but the decrease Breast enlargement during pregnancy may impede intu-
in FRC results in airway closure in 50% of women if bation by interfering with correct placement of the
they are supine.44 Metabolic requirements for oxygen laryngoscope blade and laryngoscopic manipulation to
increase by nearly 60% during pregnancy, predominantly improve visualization of the larynx. Various strategies
because of fetal demands. Oxygen requirement is further can minimize this problem, the most important of which
increased during labor (see Chapter 2). These changes is optimizing the patient’s position. With both arms
make pregnant women more likely to become hypoxemic abducted, breast tissue falls away from the chest. Ensur-
during periods of apnea such as during the induction of ing that the patient is in the ideal intubating position
general anesthesia.45 Therefore, adequate denitrogena- (discussed later) further helps with laryngoscope blade
tion (so-called preoxygenation—replacing nitrogen in insertion; a short-handled laryngoscope is recommended.
the FRC with oxygen) is vital to delay the onset of hypox- The handle can be directed toward the shoulder on inser-
emia during periods of apnea (see later discussion). tion of the blade and then redirected once the blade is in
Preoxygenation and the rate of hemoglobin desatura- the oropharynx.
tion have been investigated by computer modeling.46-48 In
these models, labor, morbid obesity, and sepsis all hasten Full Dentition
preoxygenation; however, desaturation also occurs more
rapidly in the moderately ill and the obese (Figure 30-1). Full dentition is typically present in young pregnant
Significantly, the time to life-threatening hypoxemia is women and can interfere with direct laryngoscopy,
688 PART VIII Anesthetic Complications
AIRWAY ASSESSMENT
Preanesthetic assessment of the airway is necessary before
both general or neuraxial anesthesia, so that plans for
airway management can be made in advance. A variety of Grade III Grade IV
bedside tests have been used, either singularly or in com-
bination, to predict the airway difficulty. The validity of FIGURE 30-2 ■ Cormack and Lehane laryngoscopic view grades.
many tests has been questioned, and it is useful to con- Grade I is visualization of the entire laryngeal aperture. Grade
II is visualization of only the posterior portion of the laryngeal
sider how these assessments have been investigated.49 aperture. Grade III is visualization of only the epiglottis. Grade
First, airway difficulty, the outcome, must be defined. A IV is visualization of only the soft palate. (From Cormack RS,
number of definitions have been used (see earlier discus- Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia
sion), including difficulty or failure with ventilation (with 1984; 39:1105-11.)
or without a supraglottic airway) or intubation. Second,
various predictive factors that are associated with difficult
airway management have been tested on different sample
populations of patients.
For an assessment to be useful it must be both sensitive means of training for general anesthesia in the obstetric
(i.e., correctly identify those whose tracheas are difficult patient. Therefore, the Cormack and Lehane grade is not
to intubate) and specific (i.e., correctly identify those a preoperative assessment tool but rather a classification
whose tracheas are easy to intubate). Despite having method to describe the relative difficulty with subsequent
both reasonably high sensitivity and specificity, many tracheal intubation. The original description includes
predictive tests have limited use in the clinical environ- four grades of laryngoscopy (Figure 30-2):
ment because failed intubation is rare; the number of • Grade 1: Full view of glottis
false-positive tests (those predicted to be difficult that • Grade 2: Partial view of glottis or arytenoids
are not) will always be significantly higher than the • Grade 3: Only epiglottis visible
number of true-positive tests (those predicted to be dif- • Grade 4: Neither glottis nor epiglottis visible
ficult that are).49 The positive predictive value (ratio of Subsequent modifications have been proposed. Grade
true-positive tests to the total number of positive tests) 2 may be divided into 2A (part of vocal cords visible) and
for individual difficult airway tests is typically less than 2B (only arytenoids or very posterior origin of vocal cords
50%, that is, fewer than half of the procedures predicted visible).51,52 Further, Grade 3 may be divided into those
to be difficult will actually be difficult.49 However, com- in which the epiglottis is visible and lifted, such as with
bining difficult airway tests can raise the index of suspi- a gum elastic bougie (Grade 3A), and those in which the
cion for difficulty with airway management. Despite epiglottis is visible but not able to be lifted (Grade 3B).52,53
these shortcomings in difficult airway prediction, airway Increasing difficulty with intubation is to be expected
assessment is a vital part of anesthetic management. Pre- with each progressive grade of the Cormack and Lehane
anesthetic assessment allows the consideration of poten- classification.
tial airway problems and the creation of a stepwise plan Because of the widespread acceptance of the Cormack
for dealing with difficulties should they arise. Common and Lehane grading system, some useful information can
methods of airway assessment used in clinical practice are be gained by reviewing the anesthetic records of patients
discussed next. who have a previous history of direct laryngoscopy; the
Cormack and Lehane glottic view grade is often docu-
mented. However, prior reports should be treated with
Cormack and Lehane Grade caution because grades given in the nonpregnant state
Cormack and Lehane50 devised a glottic view grading will likely differ from those determined during preg-
system in 1984. The purpose of the system was to grade nancy, and the potential for inter-observer and intra-
the glottic view obtained with direct laryngoscopy as a observer variability exists.
30 The Difficult Airway: Risk, Assessment, Prophylaxis, and Management 689
Tongue
Mandibular space
Trachea
A B
FIGURE 30-4 ■ The mandibular space viewed by the laryngoscopist inserting a curved laryngoscope blade into the airway in a supine
patient. The mandibular space is the area bounded by the plane of the line of vision and the part of the mandibular arch in front of
this plane (lower and upper extent of brackets, respectively). A, Normal-size mandibular space with room for the tongue. The laryn-
goscopist has an unimpeded view of the glottis. B, Small mandibular space—the tongue impedes the view of the glottis. (Drawing
by Naveen Nathan, MD, Northwestern University Feinberg School of Medicine, Chicago, IL.)
MANDIBULAR
two proximal endpoints. The results were subject to
PROTRUSION TEST logistic regression analysis. Although most difficult intu-
bations could be predicted, half of those that were antici-
pated to be difficult were ultimately found to be easy,
even with the most predictive combination of tests.65
Tse et al.66 combined the angle at full head extension
(in an upright position, the angle made by a line joining
the ear tragus [apex] and the corner of the mouth to a
• Class A: Lower incisors line parallel to the floor [horizontal]), thyromental dis-
can be protruded anterior tance, and Mallampati classification in an attempt to
to the upper incisors predict difficult intubation in a general surgery popula-
tion. Although these tests were likely to identify easy
intubations, they had low sensitivity for predicting those
in whom intubation was difficult.66
In a study of 400 pregnant women scheduled for elec-
tive cesarean delivery, Honarmand and Safavi67 evaluated
Mallampati class score, ratio of height to thyromental
distance, and the ULBT, both in isolation and combina-
tion. A total of 8.75% patients had a Cormack and Lehane
grade 3 or 4 laryngoscopic view; the ratio of height to
• Class B: The lower incisors thyromental distance was the best predictor of this
can be brought edge to edge outcome.67
with the upper incisors
Recommendations
The thoroughness of the airway assessment often depends
on the urgency with which surgery needs to be per-
formed. For emergency procedures, relatively little time
is available; and so it is prudent to assess all women in
the labor and delivery suite soon after their arrival, focus-
ing on those with the greatest risk for intervention.68
However, changes in assessment during the course of
labor must be anticipated, and reevaluation before induc-
• Class C: The lower incisors ing anesthesia is vital to the safe care of these patients.
cannot be brought edge to The assessment should attempt to identify the patients
edge with the upper incisors who will be difficult to ventilate and whose tracheas will
be difficult to intubate. It should start with a history to
MC detect factors that may indicate the presence of a difficult
airway, as well as the potential risk for pulmonary aspira-
FIGURE 30-6 ■ Mandibular protrusion test. Three classifications
tion. Examination of previous anesthetic records, if
are based on the test, which is also referred to as the upper lip available, may indicate problems with ventilation or intu-
bite test. (Redrawn from Munnur U, de Boisblanc B, Suresh MS. bation. The presence of comorbidities such as obesity
Airway problems in pregnancy. Crit Care Med 2005; 33:S259-68.) and preeclampsia should be considered. The ASA Prac-
tice Guidelines for Management of the Difficult Airway2
list 11 components that can be assessed (Table 30-3),
acknowledging the absence of a single test that can reli-
Frerk64 demonstrated that a combination of the Mal- ably predict who is likely to present difficulty with airway
lampati score and thyromental distance was more predic- management. Consequently, a combination of assess-
tive than either test alone; the combined assessment had ments is generally considered preferable.
a sensitivity of 81% and a specificity of 98% in predicting Performing and documenting mouth opening, the
a difficult airway. However, owing to the rarity of difficult Mallampati class, atlanto-occipital mobility, thyromental
intubation, the positive predictive value was only 64%.64 distance, and mandibular protrusion may be performed
Realizing that there was an absence of a clear description relatively quickly and should identify most patients who
and agreement as to the method of performing individual will present difficulties with airway management. The
tests, Lewis et al.65 assessed different methods of grading preanesthesia evaluation should seek to identify risk
the oropharyngeal view and the mandibular space as pre- factors for difficulty with mask ventilation, laryngoscopy,
dictors of difficult laryngoscopy. Twenty-four different airway device insertion (including intubation), and per-
oropharyngeal assessments were considered using two formance of a surgical airway. When risk factors are iden-
body positions, three head positions, and two tongue tified, appropriate plans for airway management, such as
positions, each with and without phonation. Similarly, the ready availability of additional equipment and per-
the mandibular space was measured in 24 ways using two sonnel (e.g., individuals experienced with airway manage-
body positions, three head positions, and two distal and ment and the creation of a surgical airway) should be
692 PART VIII Anesthetic Complications
OA PA OA
LA
OA
PA
LA
PA, LA
A B C
FIGURE 30-7 ■ Head and neck position during laryngoscopy. As the head position changes from neutral, the alignment of the oral
axis (OA), pharyngeal axis (PA), and laryngeal axis (LA) changes within the upper airway. A, The head is resting on a large pad that
flexes the neck on the chest and aligns the LA with the PA (the neutral position). B, The head is resting on a pad (which flexes the
neck on the chest) and concomitant extension of the head on the neck can be seen, which brings all three axes into alignment (the
sniffing position). C, Extension of the head on the neck without concomitant elevation of the head on a pad, which results in non-
alignment of the PA and LA with the OA. (From Benumof JL. Conventional [laryngoscopic] orotracheal and nasotracheal intubation [single-
lumen type]. In Benumof JL, editor. Clinical Procedures in Anesthesia and Intensive Care. Philadelphia, JB Lippincott, 1991:115-48.)
the authors found little extra benefit from using doses provide a superior laryngoscopic view.96 However, it
above 1.5 mg/kg. should also be remembered that the two-handed cricoid
The potential disadvantage of increasing the succinyl- pressure technique does not allow the anesthetic assistant
choline dose is delayed return of spontaneous respiration; to assist with other procedures, such as holding additional
return of spontaneous ventilation is vital should intuba- equipment necessary for difficult airway management.
tion not be achieved. Reducing the succinylcholine dose
to 0.5 to 0.6 mg/kg does not appear to compromise intu-
bating conditions, at least when administered in the non-
obstetric population with propofol and fentanyl; the
MANAGEMENT
lower dose slightly shortens the recovery time.88 In preg- Planning
nancy, however, the reduced maternal FRC and greater
oxygen demands make significant desaturation likely The approach to the difficult airway in the obstetric
before the return of spontaneous respiration, no matter patient depends on the situation as well as the skill set
the succinylcholine dose. Because thiopental remains a of the anesthesia provider. In Figure 30-9 a suggested
widely used induction agent, and opioids are not com- approach is outlined for management of obstetric patients
monly administered, continued use of succinylcholine 1 with an anticipated difficult airway. After an initial assess-
to 1.5 mg/kg is recommended. ment of the patient, an airway management plan should
The side effect profile of succinylcholine has resulted be created and shared with the patient and other members
in consideration of alternative muscle relaxants for the of the multidisciplinary team. In extreme cases, the anes-
rapid-sequence technique. Rocuronium is often used thesia considerations may influence the mode and timing
when succinylcholine is contraindicated; however, its of delivery. Despite a thorough airway assessment and
prolonged duration of action is a significant concern management plan, unanticipated or unrecognized airway
when failure to ventilate or intubate occurs. Sugamma- issues and complications may arise; alternative algorithms
dex, with its ability to rapidly reverse the effects of and equipment should be readily available to ensure oxy-
rocuronium, may help resolve this controversial issue; genation and ventilation. Emergence and extubation
however, the drug is not available in the United States should also be planned in advance. Lack of forethought
and there have been no clinical trials in pregnancy. When and planning can lead to poor decision-making in crisis
used with propofol for rapid-sequence induction, a 2008 situations.
meta-analysis indicated that succinylcholine (1 mg/kg or
greater) produced superior intubating conditions com-
pared with rocuronium (0.6 to 0.7 mg/kg) (relative risk
Neuraxial Anesthesia
[RR], 0.88; 95% CI, 0.80 to 0.97).89 No significant dif- The value of establishing and confirming a functional
ference was observed between the two agents when a epidural catheter during labor in patients with an antici-
larger dose of rocuronium (1.2 mg/kg) was used.89 There- pated difficult airway has been described (see earlier dis-
fore, succinylcholine remains the preferred muscle relax- cussion). A neuraxial anesthetic technique may also be
ant for use in rapid-sequence induction. preferable in patients with an anticipated difficult airway
Cricoid pressure as a method to decrease pulmonary undergoing urgent or elective cesarean delivery. The
aspiration during induction of anesthesia was first choice of anesthetic technique (e.g., single-shot spinal,
described in 1961.90 Interest in the technique was pro- combined spinal-epidural, epidural, continuous spinal
moted by the reports of deaths due to aspiration under techniques) depends on the circumstances and prefer-
general anesthesia.91 Although the effectiveness of cricoid ences of the anesthesia provider. Neuraxial techniques do
pressure in preventing pulmonary aspiration of gastric not obviate the necessity of planning airway manage-
contents has recently been challenged,92,93 it is frequently ment. High spinal anesthesia necessitating urgent airway
used during the induction of obstetric general anesthesia intervention is a complication of all neuraxial techniques.
(see Chapters 26 and 29). However, the use of cricoid Epidural anesthesia may be complicated by unintentional
pressure can adversely affect the ease of ventilation, intravascular or intrathecal injection. Despite optimal
laryngoscopy, and intubation. In a comparison of cricoid planning and execution, a neuraxial anesthetic technique
pressure with 20 N, 30 N, and 44 N of force, increasing may fail to provide a surgical blockade of adequate density
pressure was more likely to lead to cricoid deformity and or duration.33,58,97 Therefore, plans for securing the airway
esophageal occlusion, particularly in women.94 Difficulty must always be preformulated, and standard and alterna-
with ventilation is less likely when 30 N is applied (cur- tive airway equipment should be readily available.
rently accepted practice) than with 44 N (the previously
suggested optimum value).95 When correctly applied, Awake Intubation before
with an increase in force from 10 N to 30 N with the
induction of general anesthesia, there is little evidence of
General Anesthesia
harm. However, when difficulty with intubation or ven- Performing an awake intubation may be the safest option
tilation arises, pressure may need to be reduced or for the patient with an anticipated difficult airway, par-
released (see later discussion). ticularly if very difficult or impossible mask ventilation is
Although the cricoid pressure technique originally anticipated or if neuraxial anesthesia is contraindicated
described by Sellick90 was a one-handed technique, the or fails. Even patients with an advanced upper airway
placement of a second hand behind the patient’s neck to pathologic process have the ability to breathe when
prevent excessive neck flexion has been observed to awake. However, the induction of general anesthesia with
696 PART VIII Anesthetic Complications
FIGURE 30-9 ■ Algorithm for anticipated difficult airway. This algorithm is not intended to provide comprehensive guidance
that addresses every contingency. Rather, it should help anesthesia providers consider the various options that are available.
Management should be individualized, and the anesthesia provider’s clinical skills and judgment should guide decision-making. For
additional information, the reader is referred to the American Society of Anesthesiologists practice guidelines.2 CSA, continuous
spinal anesthesia technique; CSE, combined spinal-epidural technique; LEA, lumbar epidural analgesia or anesthesia technique;
spinal, spinal anesthesia technique.
FIGURE 30-10 ■ Topical airway anesthesia. The MacKenzie technique108 uses a 20-gauge intravenous cannula with an injection port
connected to oxygen tubing via a three-way tap to produce a jetlike spray of local anesthetic administered from a syringe connected
to the cannula with the oxygen flowing at 2 L/min.
interventions are required to maintain a patent airway, application of local anesthetic is the most commonly used
and spontaneous ventilation is adequate.102 An overdose technique, owing to its ease and effectiveness. There are
of the sedative/hypnotic or analgesic drugs can result in a number of techniques. For example, the patient can be
airway obstruction, hypoxemia, and cardiorespiratory asked to gargle and slowly swallow viscous lidocaine (2%
depression; maintenance of continuous verbal contact is or 4%), or lidocaine (2%, 4%, or 10%) can be aerosolized
the optimal method for avoiding oversedation.103 and sprayed onto the tongue and oropharynx.
The choice of drugs to produce conscious sedation A number of commercially available devices, which are
depends on the preference and experience of the anes- produced in a variety of shapes and sizes, can aerosolize
thesia provider. Small boluses of intravenous midazolam and spray local anesthetic solutions in a jetlike stream.
(0.5 to 1 mg) and fentanyl (25 to 50 µg) are usually ade- The Mackenzie technique uses an intravenous cannula
quate104; the use of a propofol infusion has also been with an injection port (e.g., 20- or 18-gauge) connected
described.105 Remifentanil may confer some advantages to oxygen tubing via a three-way connector (Figure
over fentanyl in providing rapid onset, more precise titra- 30-10). Administration of local anesthetic from a syringe
tion with the ability to use an infusion, and rapid metabo- through the connector, with the oxygen flowing at 2 L/
lism and dissipation of effects; decreased respiratory rate min, creates a jetlike spray.108 An additional method uses
or apnea may be quickly reversed by stopping the infu- a nebulizer mask or mouth piece, with 4% lidocaine (4
sion. Remifentanil infusion rates between 0.05 and to 6 mL) placed in the nebulizer bowl and connected to
0.175 µg/kg/min have been used for awake fiberoptic an oxygen source at a flow rate of 8 L/min. This method
intubation in nonobstetric patients106; target-controlled is easy to administer, noninvasive, and comfortable for
infusions of remifentanil, with or without propofol, can the patient, with minimal or absent coughing. Each of
also provide ideal conditions.107 Neonatal effects of the these techniques may be insufficient as a single entity and
drugs used for sedation are usually minimal; however, the may be combined with other methods, including instilla-
neonatologist should be informed of the drugs adminis- tion of local anesthetic through the working channel of
tered to the mother before delivery. the fiberoptic bronchoscope channel.
The “spray as you go” (SAYGO) technique uses the
working channel of the fiberoptic bronchoscope to instill
Topical Anesthesia
local anesthetic onto the mucous membranes of the
Providing adequate topical anesthesia of the upper respi- airway. The working channel of an intubating fiberoptic
ratory tract is one of the most critical elements of suc- bronchoscope, such as the Olympus LF-2 (Olympus
cessful awake fiberoptic intubation. Local anesthetic America Inc. Centre Valley, PA, USA), is 600 mm long
agents can be used in two basic ways to provide topical and 1.5 mm in diameter. If a small syringe is directly
upper airway anesthesia: direct application to the mucosa attached to the working channel port and the solution is
or the injection for laryngeal nerve blocks. Topical merely injected, the local anesthetic is likely to stay in the
698 PART VIII Anesthetic Complications
channel rather than be sprayed onto the mucosa. This Suggested Airway Anesthesia
problem can be overcome by placing an epidural catheter BOX 30-3
for Awake Fiberoptic Intubation
through the working channel; using a Luer-Lok connec-
tor for the epidural catheter allows a direct and tight TOPICAL ANESTHESIA
connection with the local anesthetic syringe and avoids • Tongue and oropharynx: 2% lidocaine gargle (5 to
leakage. The local anesthetic agent is drawn up in a 2-mL 10 mL) plus 4% lidocaine (3 to 4 mL) sprayed using
syringe and “dripped” on the mucus membranes; this the Mackenzie technique*
instillation can be better targeted if the distal tip of the • Supraglottic region: SAYGO through an epidural cath-
epidural catheter is allowed to protrude approximately eter,† 4% lidocaine (1 to 2 mL)
1 cm from the tip of the fiberoptic bronchoscope. • Glottic/infraglottic: SAYGO through an epidural cath-
eter,† 4% lidocaine (1 to 2 mL)
Dhonneur et al.131 reported the successful use of a obstetrician makes a midline abdominal incision, makes
difficult airway algorithm in which the Airtraq device minimal use of retractors, and does not exteriorize the
was used in parturients as a rescue device if tracheal uterus. Alternatively, the obstetrician might begin surgery
intubation failed after 2 minutes of direct laryngoscopy. and deliver the infant with the aid of local infiltration.
During a 6-month period, 69 parturients underwent Temporary hemostasis may be achieved until the airway
emergency cesarean delivery under general anesthesia; 2 is secured and then surgery completed after the induction
morbidly obese parturients required the Airtraq device of general anesthesia.
for successful tracheal intubation. The investigators sug- Cesarean delivery performed with local infiltration, if
gested that the device might be an acceptable primary successful, has the advantages of preserving maternal
airway management tool in cases of emergency cesarean hemodynamic stability and a patent airway while allow-
delivery in parturients with an anticipated difficult ing emergency delivery of the infant. However, the tech-
airway. Aziz et al.132 retrospectively analyzed 180 tra- nique requires a skilled and patient obstetrician. Maternal
cheal intubations over a 3-year period in their obstetric anesthesia is typically incomplete and often inadequate,
unit. Traditional direct laryngoscopy resulted in 157 of a fact that subsequently presents significant management
163 successful intubations on first attempt, with one issues, given that the abdomen has been opened, posi-
failed intubation (95% CI, 92% to 99%). Video laryn- tioning options are limited, and the consequences of the
goscopy with a GlideScope resulted in 18 of 18 success- surgical procedure such as hemorrhage may require
ful intubations on the first attempt (95% CI, 81% to immediate attention.
100%) and a successful intubation in the patient with the
failed direct laryngoscopy. Of note, the patients whose
tracheas were intubated with the video laryngoscope
were more likely to require urgent or emergency surgery
THE UNANTICIPATED DIFFICULT AIRWAY
and/or have predictors of difficult direct laryngoscopy Features of the Obstetric Patient
than the patients whose tracheas were intubated using
direct laryngoscopy. Despite attempts to adequately assess parturients preop-
The GlideScope has also been used for awake eratively, cases of unanticipated difficulty with airway
intubation or to assist fiberoptic laryngoscopy management do occur (Figure 30-12).141 Therefore, the
intubation.133,134 anesthesia provider and the entire operating team should
have a plan to manage unanticipated difficulties in airway
Awake Tracheostomy or Surgery Standby management before administering general anesthesia to
obstetric patients. Although national guidelines exist for
It is possible to perform an awake tracheostomy with this scenario in the nonobstetric patient,2,8 none exist
local anesthesia, a technique that may be required in specifically for the obstetric patient. The lack of guide-
some situations in which airway management is antici- lines likely reflects the unique and often difficult conflict
pated to be extremely difficult and dangerous.103,135,136 In posed by the failure to intubate the mother’s trachea: the
some cases, particularly if there is a known airway patho- optimal and safe management of the mother may
logic process, it is prudent to request that a surgical team threaten the life of the fetus and vice versa. A classifica-
proficient in emergency surgical airway management be tion schema for the degree of urgency of cesarean deliv-
immediately available before the induction of anesthesia ery142 may help clarify the risks to the mother and fetus,
for cesarean delivery. thereby improving communication among providers,
particularly between anesthesia providers and team
members whose primary focus may be directed toward
Local Anesthesia for Cesarean Delivery the fetus (obstetricians, midwives, neonatologists). Com-
Rarely, the infiltration of local anesthesia may be used as munication between anesthesia providers and other
a primary anesthetic technique for emergency cesarean members of the multidisciplinary team is vital,73 espe-
delivery in the patient with an anticipated difficult airway. cially if the anesthesia provider(s) believes it is in the
This technique, which has been well described, is most best interest of the mother to delay delivery of the fetus
often used in developing countries, where contemporary to manage the difficult airway. The entire operating
anesthetic techniques may not be readily available.137-139 room team should be familiar with local protocols to
Few obstetricians today are familiar or proficient with manage this infrequent but life-threatening situation.
this technique, but some resident training programs Examples of failed intubation guidelines are available on
still provide instruction on its use.58 A large volume the website of the Obstetric Anaesthetists’ Association
(i.e., 75 to 100 mL) of a dilute local anesthetic solution, (OAA).143
such as 0.5% lidocaine, is often required. Administration The safest method to prevent difficulty in airway man-
of such a large volume entails a risk for systemic local agement is by making the first attempt at laryngoscopy
anesthetic toxicity. the best attempt. This is achieved by using optimal head
Mei et al.140 described four cases in which cesarean and neck position, applying cricoid pressure correctly,
delivery was performed with bilateral transversus abdom- and waiting for an adequate dose of muscle relaxant to
inis plane (TAP) block and ilioinguinal-iliohypogastric act (see earlier discussion). If an adequate view of the
(IIIH) nerve blocks using 0.5% ropivacaine 40 mL. larynx is not achieved, a second attempt should be made
In some cases it is possible to perform the entire surgi- using a gum elastic bougie and/or a different laryngos-
cal procedure with local infiltration, provided the copy blade or device. In experienced hands, laryngoscopy
30 The Difficult Airway: Risk, Assessment, Prophylaxis, and Management 701
Difficult or impossible
mask ventilation:
• Insert oral airway
Nonreassuring
• Attempt two-person fetal status
mask ventilation
• Attempt SGA (e.g., LMA)
insertion with cricoid Clinical Consider proceeding No fetal
pressure judgment with surgery compromise
FIGURE 30-12 ■ Algorithm for unanticipated difficult airway. This algorithm is not intended to provide comprehensive guidance that
addresses every contingency. Rather, it should help anesthesia providers consider the various options that are available. Manage-
ment should be individualized, and the anesthesia provider’s clinical skills and judgment should guide decision-making. For addi-
tional information, the reader is referred to the American Society of Anesthesiologists practice guidelines.2 SGA, supraglottic airway;
LMA, laryngeal mask airway.
attempts should be limited to no more than three, and difficulty is encountered, a two-person mask technique
the second or third attempt should be performed only in should be employed, with one person firmly holding the
those cases in which a portion of the laryngeal anatomy mask in place with two hands while providing a jaw lift
is visible (Cormack and Lehane grade 3A or better). If a as the second person squeezes the reservoir bag.58,141
grade 3B or 4 laryngoscopic view is identified with the Once facemask ventilation is attempted, several scenarios
initial laryngoscopy attempt, the anesthesia provider may arise, which are discussed next.
should immediately focus attention on ensuring adequate
oxygenation and ventilation of the mother.144
The fact that the trachea cannot be intubated should
Cannot Intubate but Can Ventilate
be conveyed loudly to the entire operating room team In the “cannot intubate but can ventilate” scenario,
and help should be summoned immediately. Maintenance maternal and fetal status should be rapidly assessed in
of maternal and fetal oxygenation becomes the anesthesia consultation with the obstetrician. If the mother and
provider’s first priority. Facemask ventilation should be fetus are not in immediate jeopardy, then the safest course
attempted with maintenance of cricoid pressure. Place- is to awaken the mother. Once this is accomplished, other
ment of an oropharyngeal airway may be helpful. If anesthetic options, such as an awake intubation or a
702 PART VIII Anesthetic Complications
neuraxial anesthetic technique, should be considered. tracheostomy). If these methods prove successful, the
The risk for proceeding with surgery in this scenario risks and benefits of proceeding with surgery should be
represents an elective commitment to the possibility of discussed among team members; both maternal and fetal
mask airway failure, more airway manipulation, aspira- health should be considered. A 14- or 16-gauge cannula
tion, and progression to a “cannot ventilate” scenario. placed through the cricothyroid membrane is inherently
If the situation is immediately life threatening to the unstable; thus, ideally, a more definitive airway should be
mother secondary to hemorrhage (e.g., uterine rupture, established before surgery is started.58
placental abruption), it may be necessary to proceed
with cesarean delivery to optimize outcome for both the
mother and infant. Significant angst and controversy
Laryngeal Mask Airway
often accompany decision-making in the management of The LMA is arguably the SGA with which anesthesia
a stable mother with evidence of life-threatening fetal providers are most familiar. The introduction of the
compromise, such as fetal bradycardia as a result of a LMA into anesthetic practice was a significant advance
prolapsed umbilical cord. In such cases, if mask ventila- in airway management that resulted in major alterations
tion is easy and adequate, the risk-benefit ratio of pro- to the difficult airway algorithms of the ASA and other
ceeding with an unsecured airway and an increased risk societies.2,8 The insertion of an LMA in an obstetric
for aspiration should be weighed against the benefits of patient who can easily be ventilated by facemask is con-
prompt delivery of the infant. In cases in which the troversial, because little additional ventilation benefit
maternal risk for aspiration is considered low and mask is obtained and the placement of an LMA can induce
ventilation is easy, it may be reasonable to continue mask vomiting and aspiration in this setting. However, in
ventilation and avoid further intubation attempts. It is any situation in which conventional facemask ventilation
unclear as to whether continued mask ventilation or is difficult or impossible, an SGA is the rescue device
repeated intubation attempts represent the greater risk to of choice.
the mother; even insertion of an LMA may further trau- The LMA has many advantages, most notably its
matize the airway or precipitate regurgitation. ease of use and a very high initial success rate.145 More-
The anesthesia provider should carefully consider the over, the LMA need not be perfectly positioned over
maternal risks of proceeding with cesarean delivery in a the larynx to allow adequate ventilation. When assessed
mother with an unsecured and unprotected airway, espe- by flexible fiberoptic endoscopy, radiography, and mag-
cially if no urgency exists and/or mask ventilation is netic resonance imaging, the placement of the LMA
difficult. Some obstetric anesthesiologists argue that around the larynx is variable145; however, 94% to 99% of
even a nonreassuring (but non–life-threatening) fetal patients with an LMA have little or no difficulty with
heart rate tracing does not always justify proceeding ventilation.
with cesarean delivery under general anesthesia in a In a prospective study, an LMA was inserted by expe-
patient with an unsecured airway. Alternatively, in some rienced users in 1067 healthy parturients undergoing elec-
of these cases, proceeding with cesarean delivery via tive cesarean delivery under general anesthesia.146 The
mask ventilation or with an SGA may be a better option investigators demonstrated that a clinically effective and
than awakening the patient, especially in those in whom acceptable airway was obtained on the first attempt in
neuraxial techniques are contraindicated. In these cases, 98% of the patients and on the second or third attempt
the importance of communication between the obstetric in an additional 1%. Fewer than 1% of patients required
and anesthesia teams cannot be overemphasized (see intubation for failure to obtain satisfactory LMA place-
Chapter 11). ment within 90 seconds, or for an Spo2 less than 94%, or
an end-tidal CO2 greater than 45 mm Hg. Moreover, the
airway management (which was accomplished with the
Cannot Intubate and Cannot Ventilate LMA, maintenance of cricoid pressure until delivery, and
In the “cannot intubate and cannot ventilate” scenario, mechanical tidal-volume ventilation of 8 to 12 mL/kg)
the first objective remains the maintenance of maternal was associated with no episodes of hypoxemia (Spo2
and fetal oxygenation. This scenario indicates that face- < 90%), regurgitation, aspiration, laryngospasm, bron-
mask ventilation has failed despite optimizing head and chospasm, or gastric insufflation. The investigators con-
neck position, inserting an oropharyngeal airway, and cluded that, in experienced hands, an LMA is effective
using the two-person mask technique. If partial ventila- and “probably safe” for ventilation and the administra-
tion exists and succinylcholine has been given, it may be tion of a volatile anesthetic agent for general anesthesia
possible to allow the neuromuscular blockade to resolve in selected healthy patients undergoing elective cesarean
and spontaneous ventilation to return. If ventilation is delivery.
not possible, insertion of an SGA (e.g., LMA, laryngeal A number of reports have described the use of an LMA
tube) should be considered (see next section). Initial SGA as a rescue device for obstetric patients in whom conven-
insertion should be attempted with the application of tional methods of securing the airway have failed.147-152 In
cricoid pressure144; however, pressure may need to be a national case control study performed in the United
reduced or removed to facilitate insertion. If SGA inser- Kingdom from 2007 to 2009, 39 of 57 patients with a
tion or ventilation fails, the management team should failed intubation were managed with a classic LMA.153
secure an airway using an anterior neck technique (i.e., An LMA may also act as a conduit for intubation;
jet ventilation via a cannula inserted through the crico- however, passage of an ETT without visualization has
thyroid membrane, or surgical cricothyrotomy or a low success rate.154 By contrast, fiberoptic-guided
30 The Difficult Airway: Risk, Assessment, Prophylaxis, and Management 703
1 2 3 4
Epiglottis
Arytenoid
cartilage
Thyroid
cartilage
Cricoid
cartilage
Fiberoptic bronchoscope
A LMA shaft C
Bronchoscopy
Bronchoscopy
elbow to
elbow to
nasal RAE ETT LMA shaft with
standard ETT
to LMA adapters indwelling 6.0
adapter
nasal RAE ETT
with indwelling FOB
Vocal cords
Tip of ETT
Vocal cords
LMA adapter
Cuff of Cuff of
standard ETT LMA shaft with indwelling nasal RAE
6.0 standard ETT ETT
B with indwelling FOB D
FIGURE 30-17 ■ Schematic diagram of set-up for continuous ventilation during fiberoptic bronchoscopy–guided tracheal intubation
using a laryngeal mask airway (LMA) as a conduit for both the endotracheal tube (ETT) and fiberoptic bronchoscope (FOB). In A
and B, a standard 28-cm-long ETT is shown. (A 6-mm inner diameter nasal RAE tube [Nellcor, Boulder, CO] may also be used.)
A, Components of the continuous ventilation system. B, With passage of the tip of a cuffed 6-mm internal diameter tracheal tube
to the level of the LMA grille and a 4-mm outer diameter FOB through the self-sealing diaphragm of a bronchoscope elbow adapter,
ventilation can occur around the FOB but within the ETT lumen; the deflated cuff inside the shaft of the LMA makes an airtight seal
and permits positive-pressure ventilation. C, After the fiberoptic bronchoscope is passed into the trachea, the ETT is advanced over
the FOB into the trachea until the ETT adapter is near that of the LMA (if using a nasal RAE ETT) or is flush up against the adapter
of the LMA (if using a standard ETT). The preformed curvature of the nasal RAE tube presents no problem with insertion if the
outside of the tube is adequately lubricated. D, Schematic of C, with superimposed upper airway anatomy.
When a fiberoptic bronchoscope is passed through an tracheal intubation; however, these techniques take time
LMA, the bronchoscope should be introduced through and skill and should be performed by anesthesia providers
the self-sealing diaphragm of an elbow adapter attached experienced in their use.
to the ETT and the airway circuit to allow continuous
ventilation (Figure 30-17). The space available for venti- Laryngeal Tube and Esophageal-Tracheal
lation around a 4-mm outer diameter (OD) fiberoptic
bronchoscope placed within a 6-mm ID ETT is equiva-
Combitube
lent to that available with a 4.5-mm ID tube. Alterna- The laryngeal tube (VBM Medizintechnik GmbH, Sulz,
tively, a two-stage method can be employed, in which a Germany) is another SGA device.179,180 Laryngeal tubes
fiberoptic bronchoscope is placed through the lumen of are manufactured from either silicone or polyvinylchlo-
an Aintree Intubation Catheter (Cook Critical Care, ride (PVC) and have ventilation apertures between a
Bloomington, IN, USA) and the stem of a size 3 or 4 proximal oropharyngeal cuff and a distal esophageal cuff.
LMA. With the LMA in the oropharynx, the fiberoptic The laryngeal tube is inserted into the oropharynx until
bronchoscope and Aintree Catheter are advanced through resistance is met, which should result in positioning of
the vocal cords, the fiberoptic bronchoscope withdrawn, the ventilation apertures directly above the glottic
and then an ETT is guided over the Aintree Catheter.178 opening. These devices are reported to provide seal pres-
There are no studies assessing the success rate of these sures similar to those with the ProSeal LMA (40 cm
advanced techniques that use the LMA as a conduit for H2O) and insertion times and success rates comparable
706 PART VIII Anesthetic Complications
to those of the LMA.181 The Laryngeal Tube-S (LTS) 2. Wide-bore cricothyrotomy using a purpose-
contains a second lumen that can be used for drainage of designed cannula greater than 4 mm ID (e.g.,
the stomach.182 The LTS has been used successfully after QuickTrach; VBM Medizintechnik GmbH, Sulz,
a failed intubation and ventilation in a patient undergoing Germany)
emergency cesarean delivery.183 3. Surgical cricothyrotomy using a scalpel to enable
The esophageal-tracheal Combitube (ETC) (Sheridan placement of a small (< 6 mm ID) standard tracheal
Catheter Corporation, Argyle, NY, USA) is a twin-lumen or tracheostomy tube
plastic tube with an outer diameter of 13 mm. One lumen Narrow-bore cannula cricothyrotomy requires the use
has an open distal end and thus resembles a tracheal tube of a high-pressure ventilation source (e.g., Manujet) for
(i.e. the tracheal lumen), and the other (esophageal) transtracheal jet ventilation (TTJV). The other two tech-
lumen has a closed distal end. The ETC has a 100-mL niques use standard ventilation circuits. Most TTJV
proximal pharyngeal balloon; when the ETC is correctly systems have an in-line regulator that allows the delivery
positioned, the pharyngeal balloon fills the space between pressure to be controlled to between 0 and 50 psi. A
the tongue base and soft palate. When inflated, the proxi- minimum pressure of 20 to 30 psi is required in the
mal balloon seals the oral and nasal cavities. Distal to majority of patients to inflate the chest and provide
the pharyngeal balloon, but proximal to the level of the appropriate tidal volumes and minute ventilation.188
larynx, are eight perforations in the esophageal lumen. A During TTJV, it is critical that the operator allow time
smaller 15-mL distal cuff, similar to that on an ETT, seals for exhalation of inspired gas to avoid hyperinflation of
either the esophagus or trachea when inflated. The ETC the lungs, potential air trapping, and barotrauma.189-191
is inserted, with or without the aid of a laryngoscope, but Exhalation can be facilitated by keeping the airway
its insertion does not require visualization of the larynx. patent by some means (e.g., nasal/oral airway, jaw
Indeed, in the usual clinical context, the larynx cannot be thrust, LMA). There are numerous reports of the use of
visualized. The ETC enters the esophagus 96% of the TTJV as a means to prevent hypoxemia during life-
time, allowing ventilation through the esophageal lumen threatening airway emergencies192-194 and as a temporiz-
perforations.184 If the ETC enters the trachea, the patient’s ing measure before a more definitive surgical airway can
lungs can be ventilated directly through the tracheal be established.
lumen. Therefore, regardless of whether the distal end Although cannula cricothyrotomy is faster and carries
of the ETC enters the trachea or esophagus, the anesthe- significantly fewer risks, its success rate is much lower
sia provider can ventilate the lungs, assuming correct than that of surgical cricothyrotomy.187 Skill fade associ-
identification of which lumen should be used for ated with increased length of time since training is likely
ventilation. to have a more significant impact on outcome than choice
The ETC allows adequate ventilation while prevent- of device.187 The choice of technique can therefore be
ing aspiration of gastric contents. If the distal end of the determined by local protocols. The anesthesia provider
ETC enters the esophagus, the ETC can assist in remov- should evaluate and practice various airway techniques to
ing gastric fluids through suction applied to the “tra- maximize success during an emergency.
cheal” lumen. When long-term ventilation is anticipated
or required, the ETC should be exchanged for an endo-
tracheal tube. EXTUBATION OF THE PATIENT WITH
Use of the ETC in the out-of-hospital setting has been
associated with a notable incidence of serious complica-
A DIFFICULT AIRWAY
tions, including upper airway bleeding, esophageal lac- General Principles
eration and perforation, and mediastinitis.185 Although a
lower incidence of serious complications would be Tracheal extubation is a critical step during emergence
expected in the more controlled operating room environ- from general anesthesia. Airway condition at time of tra-
ment with an anesthesiologist using a laryngoscope to cheal extubation may be less favorable than at induction
facilitate placement, the stiffness and the anterior curva- of anesthesia. The patient’s disease process (e.g., pre-
ture of the ETC, as well as the potential for balloon eclampsia) may contribute to worsening airway edema, as
overinflation, still represent potential sources of airway do the fluid and blood products that have been adminis-
and esophageal injury. tered during the procedure. Comorbidities, such as
obesity and obstructive sleep apnea, may contribute to an
increased risk for airway compromise after extubation of
Cannula and Surgical Cricothyrotomy the trachea. Although the majority of extubations occur
The anesthesia provider must diagnose the failure of without incident, a number of serious adverse events,
facemask and alternative devices to oxygenate and venti- including hypoxic brain injury, occur during emergence
late the patient and decide that direct tracheal access is from general anesthesia and tracheal extubation or in the
necessary. A delay in performing cricothyrotomy results postoperative period.35,195-198
in greater morbidity and mortality than complications After publication of the ASA guidelines for manage-
resulting from the attempt.35,186 Three techniques for cri- ment of the difficult airway,2 there was a statistically sig-
cothyrotomy are available187: nificant reduction in airway claims arising from injury at
1. Narrow-bore cricothyrotomy using a purpose- induction of anesthesia.199 However, the number of claims
designed cannula less than 2 mm ID (e.g., Ravus- arising from intraoperative events and those at extubation
sin; VBM Medizintechnik GmbH, Sulz, Germany) and during recovery has not changed. Death and brain
30 The Difficult Airway: Risk, Assessment, Prophylaxis, and Management 707
injury occur more commonly after extubation and during airway-exchange catheter (AEC) inserted through the
recovery than during induction of anesthesia.199 Not sur- ETT before extubation.205,206 There are many commer-
prisingly, extubation problems are more common in cially available AECs: the Cook AEC (Cook Critical
obese patients and in those with obstructive sleep apnea.199 Care, Bloomington, IN, USA) is a long, thin, hollow tube
In the fourth National Audit Project (NAP4) of the Royal made from semi-rigid thermostable polyurethane. It has
College of Anaesthetists and the Difficult Airway Society a blunt end with distal terminal and side holes; it is radi-
(DAS), major airway complications in patients receiving opaque and has length markings on its outer surface. The
anesthesia occurred during emergence or recovery in catheter is supplied with a removable 15-mm connector
approximately one third of the reported cases.100 that is compatible with anesthetic circuits for oxygen-
Extubation is an elective procedure that should ation and Luer-Lok connectors for use with high-pressure
always have a management strategy.200-202 The goals of source (jet) ventilation. AECs are available in various
extubation management are to ensure uninterrupted sizes; the most appropriate sizes for extubation are of
oxygen delivery, avoid airway stimulation, and allow ven- sufficient length (e.g., 83 cm) and diameter (e.g., 11- to
tilation and possibly reintubation with minimum diffi- 14-gauge) to remain between the vocal cords while
culty and delay should extubation fail. The U.K. Difficult removing and/or reinserting an ETT. These catheters
Airway Society Extubation Guidelines9 describe a four- are compatible with tracheal tubes of internal diameters
step approach to the safe management of tracheal greater than 4 and 5 mm, respectively. Successful reintu-
extubation: bation can be enhanced by the use of a smaller tracheal
Step 1: Plan extubation tube and rotation of the ETT 90 degrees during insertion
Step 2: Prepare for extubation to facilitate passage of the bevel through the vocal cords.115
Step 3: Perform extubation Mort207 evaluated 354 patients with potentially diffi-
Step 4: Postextubation care: recovery and follow-up cult airways who were extubated over an AEC; 51 required
The planning and preparation steps allow the anesthe- reintubation. The reintubation success rate was greater
sia provider to stratify risk and categorize the patient as than 90%. Complications during airway management,
either at low risk or at risk for extubation complications. including low oxygen saturation, bradycardia, hypoten-
A fasted patient with an uncomplicated airway is at low sion, esophageal intubation, and the need for accessory
risk, whereas a patient at risk for aspiration in whom the airway adjuncts, were less common when an AEC was
ability to oxygenate and reintubate is potentially difficult used to assist re-intubation. Successful outcomes have
is at risk.9 By definition, all obstetric patients fall into the been reported in other similar studies.205,208 Visualization
“at-risk” group owing to the risk for pulmonary aspira- of the larynx, either by direct or video laryngoscopy,
tion.9 A crucial decision is to determine whether it is safe during AEC use can also increase the success of reintuba-
to extubate the trachea or to postpone the extubation. tion and reduce the incidence of complications.209
Unfortunately, studies attempting to identify risk factors Morbidity associated with AEC use is predominantly
that can reliably predict difficulty with extubation, per- a result of inappropriate positioning and failure of oxy-
formed almost entirely in the critical care population, genation. The distal tip of the AEC is ideally positioned
have been inconclusive.203 The leak test, in which the in the mid trachea; oxygen insufflation and jet ventilation
ETT cuff is deflated, the proximal end of the tube is through an AEC should only be undertaken with extreme
occluded, and the patient is evaluated to determine if she caution, because barotrauma and death have been
can spontaneously ventilate around the tube, has not reported.206,210,211
been uniformly demonstrated to predict success with
extubation.204
If the surgical procedure was long, or massive bleeding
KEY POINTS
and significant fluid replacement has occurred, consider-
ation should be given to transferring the patient to the • The morbidity and mortality associated with
intensive care unit and delaying tracheal extubation. The airway management are key concerns for
decision to remove the ETT should follow a full assess- obstetric anesthesia providers.
ment of the patient (i.e., ability to follow commands,
appropriate level of consciousness, recovery from neuro- • Difficulties with airway management occur with
muscular blockade). The head of the bed can be elevated both intubation and extubation of the trachea.
or the patient positioned on her left side. Patients for • Physiologic and anatomic changes of pregnancy,
whom oxygenation and/or reintubation is predicted to be such as airway edema, respiratory and metabolic
difficult may benefit from the insertion of an airway changes, weight gain, breast enlargement, and
exchange catheter before tracheal extubation (see later the risk for gastroesophageal reflux, contribute to
discussion). difficult airway management.
• All parturients receiving either general or
neuraxial anesthesia must undergo airway
Airway Exchange Catheters assessment; plans should be devised for
In situations in which the patient appears ready for extu- airway management.
bation but concerns exist regarding potential difficulty • Airway difficulty is best predicted using a
with—and/or need for—re-intubation (e.g., difficult combination of assessments, including
intubation), establishing continuous airway access may Mallampati class, thyromental distance,
be of benefit; such access can be achieved with an
708 PART VIII Anesthetic Complications
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165. Joo HS, Rose DK. The intubating laryngeal mask airway with and barotrauma associated with transtracheal jet ventilation. Br J
without fiberoptic guidance. Anesth Analg 1999; 88:662-6. Anaesth 1990; 64:524-7.
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192. McLellan I, Gordon P, Khawaja S, Thomas A. Percutaneous 202. Dravid R, Lee G. Extubation and re-intubation strategy. In Popat
transtracheal high frequency jet ventilation as an aid to difficult M, editor. Difficult Airway Management. Oxford, Oxford Univer-
intubation. Can J Anaesth 1988; 35:404-5. sity Press, 2009:131-44.
193. Chandradeva K, Palin C, Ghosh SM, Pinches SC. Percutaneous 203. Caroleo S, Agnello F, Abdallah K, et al. Weaning from
transtracheal jet ventilation as a guide to tracheal intubation in mechanical ventilation: an open issue. Minerva Anestesiol 2007;
severe upper airway obstruction from supraglottic oedema. Br J 73:417-27.
Anaesth 2005; 94:683-6. 204. Kriner EJ, Shafazand S, Colice GL. The endotracheal tube cuff-
194. McHugh R, Kumar M, Sprung J, Bourke D. Transtracheal leak test as a predictor for postextubation stridor. Respir Care
jet ventilation in management of the difficult airway. Anaesth 2005; 50:1632-8.
Intensive Care 2007; 35:406-8. 205. Dosemeci L, Yilmaz M, Yegin A, et al. The routine use of pediatric
195. Peskett MJ. Clinical indicators and other complications in the airway exchange catheter after extubation of adult patients who
recovery room or postanaesthetic care unit. Anaesthesia 1999; have undergone maxillofacial or major neck surgery: a clinical
54:1143-9. observational study. Crit Care 2004; 8:R385-90.
196. Rose DK, Cohen MM, Wigglesworth DF, DeBoer DP. Critical 206. Benumof JL. Airway exchange catheters: simple concept, poten-
respiratory events in the postanesthesia care unit: patient, surgical, tially great danger. Anesthesiology 1999; 91:342-4.
and anesthetic factors. Anesthesiology 1994; 81:410-18. 207. Mort TC. Continuous airway access for the difficult extubation:
197. Auroy Y, Benhamou D, Pequignot F, et al. Mortality related the efficacy of the airway exchange catheter. Anesth Analg 2007;
to anaesthesia in France: analysis of deaths related to airway com- 105:1357-62.
plications. Anaesthesia 2009; 64:366-70. 208. Loudermilk EP, Hartmannsgruber M, Stoltzfus DP, Langevin PB.
198. Lewis G. Saving Mothers’ Lives: Reviewing Maternal Deaths to A prospective study of the safety of tracheal extubation using a
make Motherhood Safer—2003–2005. The Seventh Report on pediatric airway exchange catheter for patients with a known dif-
Confidential Enquiries into Maternal Deaths in the United ficult airway. Chest 1997; 111:1660-5.
Kingdom. London, CEMACH, 2007. 209. Mort TC. Tracheal tube exchange: feasibility of continuous glottic
199. Peterson GN, Domino KB, Caplan RA, et al. Management of the viewing with advanced laryngoscopy assistance. Anesth Analg
difficult airway: a closed claims analysis. Anesthesiology 2005; 2009; 108:1228-31.
103:33-9. 210. Baraka AS. Tension pneumothorax complicating jet ventilation
200. Cooper RM. Extubation and changing endotracheal tubes. In via a cook airway exchange catheter. Anesthesiology 1999;
Hagberg CA, editor. Benumof’s Airway Management: Principles 91:557-8.
and Practice. 2nd edition. Philadelphia, Mosby, 2007:1164-80. 211. Duggan LV, Law JA, Murphy MF. Brief review: Supplement-
201. Calder I, Pearce A. Basic principles of airway management. ing oxygen through an airway exchange catheter: efficacy, com-
Core Topics in Airway Management. Cambridge, Cambridge plications, and recommendations. Can J Anaesth 2011; 58:
University Press, 2011:43-52. 560-8.
C H A P T E R 3 1
Postpartum Headache
Alison Macarthur, BMSc, MD, FRCPC, MSc
CHAPTER OUTLINE
Postpartum headache is the complaint of cephalic, neck, problems may require the opinion of a
or shoulder pain occurring during the first 6 weeks after neurologist. The purpose of this chapter is to discuss
delivery. The incidence of postpartum headache through- the differential diagnosis of postpartum headache and
out the 6-week postpartum period has not been followed PDPH in particular.
in a prospective manner. However, information is avail-
able from an evaluation of women during the first week
postpartum,1 from a database that recorded symptoms
during pregnancy and in the first week after delivery,2 and DIFFERENTIAL DIAGNOSIS OF
from a survey of women at 5 months and 1 year postpar- POSTPARTUM HEADACHE
tum.3 Goldszmidt et al.1 evaluated 985 women during the
first week postpartum and found a 38.7% incidence of The classification of headaches follows the International
headache. The median time to onset of symptoms was 2 Classification of Headache Disorders (ICHD), created in
days, and the median duration of headache was 4 hours. 1988 by the Headache Classification Subcommittee of
Benhamou et al.2 examined information collected on the International Headache Society. This classification
pregnant women who delivered at their institution during system, which has been updated (ICHD-II), identifies
a 2-year period; exclusion criteria included recognized two broad categories of headaches: primary and second-
dural punctures, preterm deliveries, multiple gestation, ary (Box 31-1).4 Primary headaches are classified as
and/or elective cesarean delivery. Headache was reported migraine, tension-type headache, cluster headache and
by 12% of 1058 patients who had epidural anesthesia trigeminal autonomic cephalalgia, or other. Secondary
without dural puncture and by 15% of 140 patients who headaches are attributable to a specific underlying patho-
delivered without epidural anesthesia. Saurel-Cubizolles logic process. Primary headaches are 20 times more
et al.3 surveyed 1,286 postpartum women and found the common than secondary headaches among women in the
incidence of headache was 22% and 42% at 5 and 12 first week postpartum.1
months, respectively. After delivery, women frequently suffer from headache.
Post–dural puncture headache (PDPH) is one of Stella et al.5 retrospectively reviewed 5 years of hospital
the most common postpartum complications of neur records to identify women who had postpartum headaches
axial anesthesia. However, physicians and nurses should between 24 hours and 6 weeks after delivery. Ninety-five
be aware that a dural puncture is only one of many women met these criteria, and although the incidence of
causes of postpartum headache (Table 31-1). Most head- postpartum headache could not be calculated, the study
aches are benign or do not require immediate attention; did identify some important features of postpartum head-
however, the timely diagnosis of some headaches (e.g., ache. Most women (82%) were still in the hospital at time
cortical vein thrombosis, subdural hematoma) is critical of onset of the headache. Additionally, the demographics
to good outcomes. Knowledge of both benign and non- of the study population largely reflected the general
benign headaches is important for the anesthesiologist obstetric population; the mean age was 25 years, 87% of
who is frequently the first physician to evaluate the the women had received some type of neuraxial analgesia/
patient with postpartum headache. Difficult diagnostic anesthesia, and 29% had a cesarean delivery.
713
714 PART VIII Anesthetic Complications
CSF, cerebrospinal fluid; CT, computed tomography; FLAIR, fluid-attenuated inversion recovery; MRA, magnetic resonance angiogram;
MRI, magnetic resonance imaging.
*The International Classification of Headache Disorders-II criteria state that caffeine-withdrawal headache occurs on cessation of
≥ 200 mg daily caffeine consumption for more than 2 weeks.4 However, others have suggested that caffeine-withdrawal headache may
occur after as little as 3 days’ exposure to 300 mg/day or 7 days’ exposure to 100 mg/day.35
International Classification of can be associated with scalp tenderness, and are usually
BOX 31-1 Headache Disorders (ICHD-II) of mild to moderate severity.
Classification
Migraine
PRIMARY
• Migraine Migrainous headaches (or migraines) are defined as recur-
• Tension-type headache ring cranial pain lasting 4 to 72 hours, often with typical
• Cluster headache and other trigeminal autonomic features such as pulsating pain in a unilateral location,
cephalgias nausea, and photophobia.4 Headache with aura is a subtype
• Other primary headaches of migraine that is characterized by focal neurologic symp-
toms preceding the headache. The prevalence of migraine
SECONDARY
is approximately 17% in the female population (three
• Headache attributed to: times more common than in men) and is more common in
• Head and/or neck trauma
patients between 30 and 50 years or age.6 Pregnancy has
• Cranial or cervical vascular disorder
• Nonvascular intracranial disorder an ameliorating effect on migraine frequency in the major-
• A substance or its withdrawal ity of sufferers. However, symptoms may recur soon after
• Infection delivery, with reports of 34% within the first week post-
• Disorder of homeostasis partum and 55% within the first month.7 Generally, the
• Disorder of the cranial structures (e.g., eyes, ears, symptoms are similar to their typical pattern, although
nose, sinuses, teeth, mouth) often milder and less often unilateral. It is rare for a
• Psychiatric disorder migraine to manifest for the first time during the postpar-
• Cranial neuralgias and central causes of facial pain tum period. There appears to be an association between
• Other headache, cranial neuralgia, central or primary migraines and preeclampsia, which may reflect an under-
facial pain
lying predisposition to cerebral ischemic injury.8
Modified from Headache Classification Subcommittee of the International
Headache Society. The International Classification of Headache Disorders:
2nd edition. Cephalalgia 2004; 24(Suppl 1):9-160.
Secondary Headaches
A common secondary headache in the postpartum period
is the musculoskeletal headache, exacerbated by the
Primary Headaches maternal physical exertion of labor and associated sleep
deprivation. This headache has accompanying neck and
The postpartum patient can present with a recurrence of shoulder pain without a history of dural puncture.
her known primary disorder or with the first manifesta- Approximately 11% to 14% of postpartum headaches are
tion of a primary condition. Patients with a history of diagnosed as musculoskeletal.1 Other causes of secondary
headache disorders typically are diagnosed with one of headache are discussed in the following paragraphs.
the four major types of primary headaches. The most
common postpartum headaches are tension-type and Hypertension
migrainous headaches, which account for almost two
thirds of headaches during this period.1,2 Tension-type Hypertensive disorders of pregnancy, including pre-
headaches are often circumferential and constricting, eclampsia, are commonly associated with headaches.
716 PART VIII Anesthetic Complications
Eclampsia is a form of hypertensive encephalopathy that seizure prophylaxis). However, irreversible cytotoxic
includes headache, visual disturbances, nausea, vomiting, edema with permanent neurologic damage can occur if
seizures, stupor, and sometimes coma. Seizures may the initial disorder is not diagnosed early. This syndrome
occur in the absence of severe hypertension. Headache is often manifests in the postpartum period, frequently in
a serious premonitory sign, being present in over 50% of conjunction with preeclampsia. Distinguishing PRES
women in whom eclampsia develops.9 Other hyperten- from preeclampsia or eclampsia is complex because head-
sive disorders, with or without superimposed preeclamp- ache, seizures, and focal neurologic deficits, such as tem-
sia, are also associated with headaches both antepartum porary loss of vision, are common symptoms of both
and postpartum and may lead to encephalopathy. The disorders.13,14 Typical features that distinguish PRES
diagnosis can be complex if the parturient’s labor and from other postpartum headaches include seizures and
delivery course is complicated by a dural puncture.10 focal neurologic deficits, such as temporary loss of vision.
Definitive diagnosis is made with MRI.
Posterior Reversible
Leukoencephalopathy Syndrome Cortical Vein Thrombosis
Posterior reversible (leuko)encephalopathy syndrome The incidence of cerebral cortical vein thrombosis is
(PRES) was described in 1996 after recognition of con- increased during pregnancy and in the puerperium, and
sistent symptom presentation and brain magnetic reso- is estimated to be 10 to 20 per 100,000 deliveries in
nance imaging (MRI) findings in a diverse group of developed countries. The incidence appears higher in
patients. Conditions associated with PRES include developing countries (e.g., 450 per 100,000 deliveries
preeclampsia, uremia, hemolytic-uremic syndrome, and in India).15 Often it is difficult to distinguish cortical vein
exposure to immunosuppressant drugs.11 Approximately thrombosis from PDPH, because the headache of corti-
25% of cases of PRES occur during pregnancy or in the cal vein thrombosis may have a postural component. Pre-
immediate postpartum period. PRES symptoms include ceding dural punctures have been reported, and it has
headache, seizures, altered mental status, visual changes, been hypothesized that the reductions in cerebrospinal
and, occasionally, focal neurologic deficits.12 fluid (CSF) pressure and cerebral vasodilation that
The neuroradiologic features of PRES include sym- accompany dural puncture predispose to thrombosis
metric areas of cerebral edema, predominantly involving development.16 Associated features may include focal
the white matter regions of the posterior circula neurologic signs, seizures, and coma. Cerebral infarction
tion (occipital lobes, posterior parietal and temporal may ensue if diagnosis is delayed. Diagnosis is best con-
lobes) (Figure 31-1). The pathophysiology of PRES firmed by MRI, because computed tomography (CT)
is similar to that of hypertensive encephalopathy in appears to identify only one third of cases.17 Treatment
that altered cerebrovascular regulation causes loss of of cortical vein thrombosis largely is symptomatic, with
blood-brain barrier integrity. The accompanying vaso- the aim of preventing seizures. Anticoagulation therapy
genic edema can be reversed by prompt recognition is commonly used to treat these patients, with observa-
and supportive therapy (e.g., cessation of provocative tional and randomized trial studies indicating better
medications, aggressive treatment of hypertension, outcomes.18
FIGURE 31-1 ■ Posterior reversible (leuko)encephalopathy syndrome (PRES). Axial fluid-attenuated inversion-recovery (FLAIR) images
demonstrate foci of abnormally increased T2 signal (arrows) in the subcortical white matter and cortex of the frontal and parietal
lobes involving both anterior and posterior circulations. (From Long TR, Hein BD, Brown MJ, et al. Posterior reversible encephalopathy
syndrome during pregnancy: seizures in a previously healthy parturient. J Clin Anesth 2007; 19:145-8.)
31 Postpartum Headache 717
Cerebral Infarction/Ischemia headache onset was 9.3 days. The headaches were con-
stant in character and both unilateral and bilateral.
Cerebral arterial insufficiency is one cause of stroke in Stricken woman appeared older (mean age, 35 years)
pregnancy with an estimated incidence of 4 to 11 per than the average parturient. Diagnosis was made after
100,000 deliveries.19 Approximately half of the events carotid vessel ultrasonography or magnetic resonance
occur in the peripartum period, and the clinical presenta- angiography.
tion often comprises a sudden onset of a nonpostural
thunderclap headache, vomiting, seizures, and focal neu- Brain Tumor
rologic deficits. Postpartum cerebral angiopathy has been
detected with the aid of cerebral angiography, in which a Intracranial tumors may manifest as postpartum head-
characteristic “arterial beading” pattern indicative of ache. Headache that is dull rather than throbbing may
arterial spasm is evident.20 Initial CT and MRI findings be an early feature of a brain tumor. Nausea, vomiting,
are often normal, and intracranial Doppler or angio- seizures, and/or focal neurologic signs may be present.
graphic investigations may be necessary to diagnose the Neurologic examination may reveal evidence of increased
arterial ischemia or infarct. Treatment is supportive and ICP. Case reports suggest that atypical presentation
may include vasodilator therapy. of the headache, either with persisting headache symp-
toms in the supine position or exacerbation after epidural
Subarachnoid Hemorrhage blood patch, should prompt further neuroradiologic
investigations.24,25
Subarachnoid hemorrhage (SAH) occurs secondary to
aneurysmal or nonaneurysmal causes. The risk for SAH Idiopathic Intracranial Hypertension
due to nonaneurysmal causes appears to be increased
during pregnancy. A 2012 U.S. population–based study Parturients with idiopathic intracranial hypertension (i.e.,
estimated an overall incidence of peripartum SAH at increased ICP in the absence of a mass lesion, also known
5.8 per 100,000 deliveries.21 The classic presentation con- as pseudotumor cerebri or benign intracranial hyperten-
sists of the sudden onset of a severe headache that is sion) have headache and visual disturbances, usually in the
unlike any previous headache. Associated symptoms antepartum period. The features of the postpartum head-
may be present, such as decreased level of consciousness ache of pseudotumor cerebri mimic the usual chronic
and focal deficits. Pregnancy may increase the risk for headache symptoms experienced by the patient. The
bleeding because of increased blood volume and hor- diagnosis largely is one of exclusion (see Chapter 49).
monal changes that affect arterial integrity. Two thirds of Treatment involves reduction of CSF pressure, either
all cases in pregnancy occur in the postpartum period, with glucocorticoids, carbonic anhydrase inhibitors,
but maternal mortality appears to be less than in non- diuretics, or serial lumbar punctures. Case reports describe
pregnant patients.21 Other factors associated with SAH the use of an intrathecal catheter for labor analgesia26 and
during pregnancy include advanced maternal age, African administration of epidural blood patch for PDPH in
American race, hypertensive disorders, smoking history, patients with idiopathic intracranial hypertension.27
alcohol abuse, and intracranial venous thrombosis. Sus-
picion of SAH necessitates urgent investigation by CT Spontaneous Intracranial Hypotension
scan, because nonsurgical therapies (e.g., endovascular
ablation) are available and long-term sequelae can be Spontaneous intracranial hypotension develops because
minimized. of CSF leakage secondary to dural tears. The tears usually
occur at the thoracic spinal level and are not associated
with prior spinal intervention.28 Diagnosis requires radio-
Subdural Hematoma
isotope cisternography and CT myelography, which may
In rare instances, dural puncture is associated with the also identify the level of the leak. Presentation of this
subsequent development of a subdural hematoma (see disorder is identical to that of PDPH, because the patho-
later discussion). In several case reports, the identification physiology is the same. The only difference is the lack of
of the subdural hematoma was preceded by symptoms of a prior neuraxial procedure in spontaneous intracranial
a PDPH.22 Dural puncture results in leakage of CSF hypotension. One case report has described the develop-
and decreased intracranial pressure (ICP). Presumably, ment of a postural headache 4 days after a spontaneous
the reduction in ICP causes stress on bridging cerebral vaginal delivery without neuraxial anesthesia.29 The
vessels, which may precipitate bleeding. Neurologic signs patient was found to have a cervicothoracic dural leak.
of subdural hematoma are variable but include evidence
of increased ICP (e.g., headache, somnolence, vomiting, Pneumocephalus
confusion) and focal abnormalities.
The subdural or subarachnoid injection of air used for
identification of the epidural space may be associated
Carotid Artery Dissection
with the sudden onset of severe headache, sometimes
A rare, vascular cause of postpartum headache is sponta- accompanied by neck pain, back pain, or changes in
neous carotid artery dissection. Borelli et al.23 reviewed mental status.30 Headache symptoms can mimic PDPH
the 19 known published cases of postpartum carotid in that they are worse in the sitting position and may be
artery dissection. The mean interval from delivery to relieved by lying down. Radiologic studies confirm the
718 PART VIII Anesthetic Complications