Manual of Ultrasound in Obstetrics and Gynaecology, 2nd Edition - Jaypee Brothers Medical Publishers (P) Ltd. (2009)

Current Practice
in
Obstetrics and Gynecology—1
Current Practice
in
Obstetrics and Gynecology—1
Editor
Pankaj Desai
Associate Professor and Unit Chief
Department of Obstetrics and Gynecology
Medical College and SSG Hospital
Baroda-390001, India
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Current Practice in Obstetrics and Gynecology—1

© 2005, Pankaj Desai
All rights reserved. No part of this publication should be reproduced, stored in a retrieval
system, or transmitted in any form or by any means: electronic, mechanical, photocopying,
recording, or otherwise, without the prior written permission of the editor and the publisher.
This book has been published in good faith that the material provided by contributors is
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legal matters to be settled under Delhi jurisdiction only.
First Edition: 2005

ISBN 81-8061-486-7
Typeset at JPBMP typesetting unit

Printed at Gopsons Papers Ltd, Sector 60, Noida
to
pursuit of academic excellence,
at the service of humanity and mankind,
at the feet of the Almighty!
Editorial
Science today is advancing too fast that one has to run to be at the same
pace. It is, therefore, all the more necessary to keep us completely abreast
of the nuances in our subject. For teachers, students and practitioners of
the subject, this task becomes daunting. Not only because of the rapid
pace of the change, but also because of the innumerable conduits through
which knowledge comes to us these days. Traveling throughout the
country and abroad on lecture and teaching assignments, I was always
asked by specialists and students in our subject to start publishing a
series of publication like this which covers the most recent developments
in our subject, relevant to the current practice.
Ideally, neural tube defects should no more be a surprise finding in
the fetus at term. But it still does surprise us. There is a special inclusion
on this in this current book. Antibiotics in preterm labor: yes or no?
Arresting preterm labor: How and when? These are some of the dilemmas
that we face in our current practice. The chapter on preterm labor
covers these aspects succinctly. In India, Manual Vacuum Aspiration has
been revived in a big way. Many practitioners have been asking me
about the same. We have a special chapter on this aspect in the pages to
follow. Entire hoopla around HRT seemed to be falling apart since the
time that startling revelations on the long-term effects of these came in.
This aspect is covered very informatively here so as to enable clear stand
to be taken in current practice. Markets are swarmed with ovulogens.
In clinical practice we continuously require to update our knowledge
about them. It is with this aim that this chapter has been written. In this
way all topics have been carefully selected to suit the needs of current
practice.
The contributors of all the chapters too have been carefully selected.
A delicate balance is continuously preserved between the young and
the experienced, the very well known and the upcoming, from India
and abroad, well read and knowledgeable. I am extremely thankful to
them for accepting my invitation and willingly contributing to this
volume. They all had one line common running through them “They all
love their subject”.
vi Current Practice in Obstetrics and Gynecology—1
I would like to specially mention with a deep sense of my gratitude

for Dr Shonali Agarwal, who has actively helped me with the editorial
work. Without her help it would have been well nigh impossible to
bring about this publication in time.
Baroda Pankaj Desai

Contributors
Shonali Agarwal Rupinder Kaur (Ruprai)
Assistant Professor Consultant
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology
Medical College Kasturba Hospital and Medical College
Baroda Manipal
Ashish Kumar Bhattacharjee Sarbjeet Kaur

Associate Professor KJ Somaiya Medical College & Hospital,
Department of Obstetrics and Gynecology Mumbai
Gauhati Medical College
Guwahati Usha Krishna
(Retd.) Hon. Professor
Deepika Deka Department of Obstetrics and Gynecology
Additional Professor KEM Hospital, Parel
Department of Obstetrics and Gynecology Mumbai
All India Institute of Medical Sciences
Ansari Nagar Pratap Kumar
New Delhi Professor and Head of Department,
Monali Desai Kasturba Hospital and Medical College
Con. Gyne-Oncologist Manipal
Baroda
AP Manjunath
Hema Divakar Associate Professor
Consultant Obstetrician and Gynecologist Department of Obstetrics and Gynecology
Divakar’s Hospital Kasturba Medical College, Manipal
Bangalore
PS Mittal
Vandana Gaikwad Assistant Professor
Lecturer Department of Obstetrics and Gynecology
Department of Obstetrics and Gynecology Medical College
KJ Somaiya Medical College and Hospital Baroda
Mumbai
S Mittal
Sanjay Gupte Professor and Head
Hon Associate Professor Department of Obstetrics and Gynecology
Department of Obstetrics and Gynecology All India Institute of Medical Sciences
BJ Medical College Ansari Nagar
Pune New Delhi
Rajat Gyaneshwar Arun H Nayak

Con. Gynecologist Consultant Obstetrician and Gynecologist
Department of Obstetrics and Gynecology Associate Professor
Liverpool Hospital BYL Nair Hospital
Syndey, Australia Mumbai
viii Current Practice in Obstetrics and Gynecology—1
Mandakini Parihar Girija S
Hon Associate Professor Specialty Medical Officer
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology
KJ Somaiya Medical College and Hospital Kasturba Medical College
Mumbai Manipal
Ankita Pasi Ashish N Shah

Con. Gynecologist Assistant Professor
Baroda Department of Obstetrics and Gynecology
Medical College
Purvi Patel Baroda
Assistant Professor
Department of Obstetrics and Gynecology JB Sharma
Medical College Assistant Professor
Baroda Department of Obstetrics and Gynecology
All India Institute of Medical Sciences
Madhuri Patil Ansari Nagar
Consultant Infertility Specialist New Delhi
Obstetrician and Gynecologist
Bangalore Neema Sharma
Research Associate
Amol P Pawar Department of Obstetrics and Gynecology
Senior Resident All India Institute of Medical Sciences
Department of Obstetrics and Gynecology Ansari Nagar
KEM Hospital, Parel New Delhi
Mumbai
Uday Thanawalla
Prakash V Pawar Consultant Obstetrician and Gynecologist
Consultant in Medicolegal Matters and Navi Mumbai
Consultant Gynecologists
Thane, Mumbai Uma Wankhede
Associate Professor
C Rawat Department of Obstetrics and Gynecology
Assistant Professor, BJ Medical College, Pune
Medical College
Baroda
Contents
Section 1: Obstetrics
1. Current Concepts in the Prenatal Diagnosis of Neural
Tube Defects ......................................................................................... 3
Ashish Kumar Bhattacharjee
2. Preterm Labor: Evidence-Based Management ............................ 30
Ashish N Shah
3. What is Manual Vacuum Aspiration ............................................ 52
PS Mittal, C Rawat
4. Decision Making for the Intrapartum Management of
Twins ................................................................................................... 70
Deepika Deka, Neema Sharma
5. The Enigma of Hyperemesis Gravidarum ................................... 83
Shonali Agarwal
6. Episiotomy: Controversies and Current Thinking .................... 95
Ankita Pasi
7. Management of Refractory Anemia during Pregnancy ........... 106
JB Sharma, S Mittal
Section 2: Gynecology
8. Current Concepts in Screening for Ovarian Cancer ................ 115
Monali Desai
9. Sacrospinous Ligament Fixation for the Treatment of
Uterovaginal Prolapse .................................................................... 122
Purvi Patel
10. The Challenge of Posthysterectomy Hemorrhage .................... 128
Uma Wankhede, Sanjay Gupte
11. Ovulogens Revisited ...................................................................... 136
Pratap Kumar, Rupinder Kaur (Ruprai)
x Current Practice in Obstetrics and Gynecology—1
12. Current Approach to Abnormal Uterine Bleeding

in Adolescents .................................................................................. 195
Hema Divakar, Uday Thanawalla, Madhuri Patil
13. Hormone Replacement Therapy: Current Controversies
and Evidences .................................................................................. 210
Usha Krishna
14. The Enigma called Endometriosis: Current Choices
in Treatment ..................................................................................... 219
Mandakini Parihar, Vandana Gaikwad, Sarbjeet Kaur
15. Understanding Endometrial Hyperplasia ................................. 243
AP Manjunath, Girija S
16. Current Status of Endometrial Ablation in
Gynecology Practice ....................................................................... 283
Arun H Nayak
Section 3: Allied
17. Death after Female Tubal Sterilization Procedure .................. 301
Prakash V Pawar, Amol P Pawar
18. Improving the Quality of Clinical Care ..................................... 320
Rajat Gyaneshwar
Index .................................................................................................... 335
Section 1
Obstetrics
1
Ashish Kumar Bhattacharjee
Current Concepts in the

Prenatal Diagnosis of
Neural Tube Defects
INTRODUCTION
A neural tube defect (NTD) is a birth defect, which involves the brain or
spinal cord. The neural tube is the part of the fetus that becomes the
spinal cord and brain. Neural tube defects (NTDs) including spinal
malformations are the single most common congenital malformation
encountered.1 The exact cause of this is unknown although it is said to
be of multifactorial in origin. Several genetic, chromosomal and
environmental factors are said to be responsible for this condition. The
defect may be cranial involving the fetal skull and the brain or spinal
involving the vertebrae and the spinal cord. Both cranial and spinal
malformations may co-exist and hence these are also known as
craniospinal defects. Primary spinal defects often lead to secondary
cranial abnormalities. A child born with isolated spinal defect may
eventually develop hydrocephalus thereby altering the prognosis as
determined prenatally for the isolated spinal defect. While the cranial
defects show uniformly poor prognosis, there is variation in the outcome
of spinal defects. This depends on the type and the size of the defect
and also on the facilities, resource and expertise available.2 Therefore,
majority opts for termination of pregnancy after prenatal diagnosis
considering the overall poor prognosis. The few who prefer to continue
with the pregnancy end up having a severely handicapped child either
physically or mentally or both, which unfortunately becomes a burden
for the family in particular and society in general.
4 Current Obstetrics and Gynecology Practice
INCIDENCE
The incidence of NTD varies from place to place and population to
population. While it is very high in the UK, it is lowest in Japan. Currently,
the highest reported incidence is in North China (3.7/1000 live births).2
The prevalence in the UK is 4 to 5/1000 births and that in the USA is
about 1 to 2/1000 births.3,5,6 In general, it occurs in 1 in 500 to 600 births.1
The incidence of NTD in the UK increased 10-fold in mothers who had
one previous affected child, 20-fold in mothers who had two previous
affected children and 40-fold in mothers who had three previous affected
children. Even though about 95% NTD babies are born to mothers who
had not delivered an affected child before.3-5,7
The incidence of NTD from different parts of India has been reported
to vary from 0.5 to 11 per 1000 births.8-10 In general, the incidence in
northern states of Punjab, Haryana, Delhi, Rajasthan, UP and Bihar has
been much higher (3.9-9.0/1000) compared to eastern, western and
southern parts of the country (0.5-2.64/1000). However, Davangere in
Karnataka showed high incidence of NTD.10,11 The reason for high
prevalence of NTD in Punjab has been attributed to high incidences in
Sikhs, which had remained high even in migrant Sikhs.12,13 However, it
is not clear whether the high incidence of NTD in Sikhs is due to their
sociocultural practices or genetic makeup. On the other hand, the high
incidence of NTD in Davangere has been attributed to consanguinity.
The prevalence of NTD in consanguineous couples was found to be 16.3-
20.6/1000 compared to 5.9-8.4/1000 in couples without consanguinity.11
But this was not reported from Mysore14 and Madras (now Chennai).15
It would, therefore, be useful to collect prospective data from different
areas of the country on a regular basis particularly since temporal
variation in the prevalence of NTD has been reported from other parts
of the world.16,17 The informative population could be of value in looking
for genes responsible for NTD.
Anencephaly and encephalocele are associated with early spontaneous
abortions. About 3% of all early spontaneous abortions show evidence
of NTD. It has been shown that of all embryos with NTD at about 8
weeks, half aborts spontaneously, a quarter ends in stillbirths and only
the remaining quarter is born alive.18 The actual incidence, therefore, in
a population is expected to be higher than the quoted figures of this
birth defect.
The birth prevalence of NTD has declined substantially over the past
60 years in the USA and the incidence reported is 3.6-4.6/10,000 live
Current Concepts in the Prenatal Diagnosis of NTDs 5
births.19 But population-based active surveillance programs that include

prenatal diagnoses have reported NTD rates of 7.2-15.6/10,000 births
(live born and stillbirths).20 In the UK, where MSAFP and ultrasound
screening are more widespread, has recorded a 49-59% decline in the
birth prevalence of anencephaly and a 32-38% decline in the birth
prevalence of spina bifida attributable to elective termination of
pregnancy following the diagnosis of the conditions.16
ANOMALIES
The three major NTD are anencephaly, encephalocele and spina bifida.
The less common are iniencephaly and exencephaly. The lesion may be
open or closed. While anencephaly is an open lesion, encephalocele is a
close one. Spinal lesions may be both open (skin cover absent) and close
(covered with skin). About 80% lesions were found to be open21,22
reported, 85% of the infants born with NTD who survived for 5 years
had severe handicap, 10% were moderately handicapped and only 5%
had no handicap. On an average, these children spent over six months
in the hospital and had to undergo six operations during the first 5
years of their lives. Considering the scenario although most NTD are
non-lethal anomalies (excepting for anencephaly where there is either
stillbirth or the baby dies immediately after birth) are considered as
lethal for all practical purpose.23
PATHOGENESIS
The pathogenesis of NTD remains unclear. However, the theory put
forward is the failure of the rostral (directed towards the front end of
the body) and caudal neuropores to close. This might explain the
increased incidence of the defect to the cranial and caudal ends of the
neural axis. The other theory proposes that the neural tube gets disrupted
after its formation.24 The isolated NTD is considered to be polygenic
multifactorial disorder.25 This means that several genes are involved
for NTD. The role of genes in causation of NTD is supported by its
increased risk of recurrence amongst first-degree relatives compared to
the population. However, the genes responsible for NTD in humans
have not yet been identified. Environmental factors also play an
important role in causation of NTD.25 Other risk factors responsible for
NTD are, family history of NTD, maternal hyperglycemia, hyperthermia,
medications (like valproic acid, carbamazepine) and certain ethnic groups
living in certain high-risk geographical areas.
Maternal diabetes significantly increases the risk of congenital

malformations in humans. Diabetic mothers have higher risk of NTD
than the population in general.1 Even with good control of diabetes, the
risk for neural tube and other birth defects is two to five times higher
than normal if a mother has the disease. The risk could increase as
diabetes and obesity, both of which can cause high blood sugar, make
inroads into younger populations.26-29 These malformations arise at the
beginning of organogenesis, during the first 8 weeks of gestation in
human embryos. Diabetic embryopathy can affect any developing organ
system, although defects of the neural tube and heart are among the
most common. In studying neural tube defects (NTD) in a mouse model
of diabetic embryopathy, it has been shown that expression of Pax-3, a
gene that regulates neural tube closure, is significantly reduced in
embryos of diabetic mice before the manifestation of morphological
defects. The loss-of-function Pax-3 mutation causes the same kind of
NTD as those caused by maternal diabetes (open NTD) in 100% of mutant
embryos. This suggests that impaired expression of Pax-3 is sufficient to
prevent normal formation of the neural tube. It has also been shown
that the excess glucose surrounding the embryo, which is a consequence
of maternal diabetes, is responsible for the adverse effects of diabetic
pregnancy. Therefore, the mechanism which possibly explains the
spectrum of malformations associated with diabetic embryopathy is that
the embryo is exposed to excess glucose at critical times during induction
of developmental control genes.30
A research report (Death Protein may cause NTD in babies of diabetic
mothers, in FOCUS, 3/22/2002) which appeared in the March 15, 2002
issue of the journal Genes and Development provides a possible explanation
for the increased incidence of NTD in diabetic mothers. A protein
normally involved in programmed cell death may, as a consequence
of high blood sugar, mistakenly tell cells of the nascent neural tube to
die.
EMBRYOLOGY
The nervous system develops from the dorsal ectoderm. The lateral
edges of the neural plate fold to form the neural groove. Fusion of the
edges of the neural groove forms the neural tube. Fusion starts
progressing both cranially and caudally. Both caudal and cranial ends
of the tube remain temporarily open. The anterior neuropore closes by
25 days (20 somite stage) and the posterior neuropore closes at about 27
days (25 somite stage). Open NTDs have been suggested to result from
defective primary neurulation (formation of neural plate), while defective
secondary neurulation (closure and development of neural tube) gives
rise to closed NTD. Neural tube is formed usually within 6 weeks from
the last menstrual period (LMP).31-34
The neural tube defects occur because of a defect in the neurulation
(formation of neural plate followed by its closure and development)
process. Based on the presence or absence of exposed neural tissue NTD
can be open or closed. While open NTD is probably as a result of primary
neurulation, the closed ones are the results of secondary neurulation
(canalization). Another possible explanation is that open NTD (spina
bifida in particular) results from defects in either primary or secondary
neurulation, depending on their site being cranial or caudal to the
posterior neuropore (i.e., upper and lower spina bifida, respectively).33
PREVENTION
The exact etiology of NTD is not known. Several studies by individual
workers and multicentric studies have shown the beneficial effect of
folic acid in primary prevention of this defect. Folic acid supplementation
during prepregnancy and early weeks of pregnancy (during organo-
genesis) has been shown to reduce the incidence of the condition in a
given population. Women who have had a baby with a neural tube defect
have a two to three percent chance of having another NTD affected
pregnancy. Folic acid has been found to reduce greatly the risk of another
NTD affected pregnancy in these women. The double blind randomized
trial of Medical Research Council, Great Britain has shown that
supplementation of 4 mg folic acid per day for at least one month prior
to conception to 3 months postconception reduces the risk of recurrence
of NTD by 70%.35 Its efficacy in the Indian population has also been
demonstrated (unpublished ICMR Multicentric trial results). In 1992, a
randomized controlled trial in Hungary reported the protective effect
of folic acid-containing multivitamins against first occurrences of NTDs.36
However, a major study revealed that about 25 percent of NTD
recurrences would not be helped with folic acid supplementation.37-39
Hence, more research is needed to better understand the biological
mechanism by which folic acid prevents NTD and the causes of those
cases that are not connected with folic acid consumption.
The mechanism of action of folic acid in preventing the occurrence of
NTD has not been fully understood. Women who have given birth to an
NTD child show marginally lower serum and red cell foliated levels,
but the difference is not statistically significant.39 Many of these women
have been found to have higher levels of serum homocysteine (and
methionin) indicating a metabolic block in the folic acid pathway.40 It
has been proposed that considerably larger amount of folic acid (ten
times of daily requirement) is needed to overcome this metabolic block
although no dose response data are available on the efficacy of folic
acid. Folic acid found in foods is called folate and is present in a wide
variety of foods like—peas, corn, dried beans, dark green leafy
vegetables, white and whole wheat breads, beef liver and lean beef,
bananas, fortified breakfast cereals and orange juice.
Joslin Study, a research focused on neural tube defects has shown
that antioxidants may be critical in preventing birth defects in babies of
women with diabetes.41
The secondary prevention is, probably, the only way to lower the
incidence of this birth defect and lies in its antenatal detection and
subsequent termination of pregnancy. However, the role of folic acid
supplement has also been suggested in the prevention of both occurrence
and recurrence of NTD.42 Fortunately, of all embryos with NTD detected
at 8 weeks, only a quarter would be born alive.18
DIAGNOSTIC METHODS
The two modalities currently in use for screening and detection of NTD
are ultrasonography (the biophysical method) and the biochemical
method. Workers in this field have shown that a combination of the two
methods ensures maximum detection rate and minimum false-positive
rate. For the purpose of prenatal diagnosis, it is necessary to consider
whether a defect is open or close as only the former can be diagnosed
using biochemical tests. The latter group is best diagnosed using
ultrasography by an expert in this field.
About 20% of fetuses with NTD have other congenital anomalies as
reported by California Birth Defect Program.
Prenatal Diagnosis of NTD by Biochemical Tests

The secondary prevention of NTD is done by antenatal detection of the
condition in the population and subsequent selective termination of
pregnancy in diagnosed cases. This has become an important part of
antenatal care in several countries. This would reduce the incidence of
the birth defect. The aim of the antenatal screening by biochemical tests
for open NTDs is to identify the group of patients who are at increased
risk of having an affected child. Measurement of maternal serum
alphafetoprotein (MSAFP) and measurement of AFP and acetyl-
cholinesterase (AChE gel) in the amniotic fluid (AFAFP and AChE gel)
are the available biochemical screening tests.
Maternal Serum Alphafetoprotein (MSAFP)

The alphafetoprotein (AFP) is a fetospecific glycoproterin of similar
molecular weight of albumin (70,000 Daltons). The yolk sac and the fetal
liver synthesize it. At about 17 weeks, AFP concentration in fetal serum
is 30,000 times higher than in maternal serum and 150 times higher than
that in amniotic fluid. The MSAFP increases during the second trimester
by about 19% per week and reaches 50 times higher level of nonpregnant
state at 30 weeks of gestation. Wald7 et al 1984 suggested that a gestational
age of 16-18 weeks should be regarded as the best time for screening
MSAFP for open NTDs. At this stage, about 3/4th of open NTDs have
AFP levels of more than 97th percentile of normal.
The unit of expression of AFP is usually nanogram/ml (ng/ml) or
IU/ml. However, much of the interlaboratory variations can be reduced
by first finding a median value of that laboratory for that particular
period of gestation and then expressing the AFP value as a multiple of
the median obtained for normal singleton pregnancies for the period of
gestation. A sample of minimum 50 normal singleton pregnancies should
be studied and their AFP values at a particular period of gestation
arranged in ascending order. The middle value or the average of two
values gives the median. The AFP result, thereafter, is expressed as
multiple of median (MoM).
There is no definite cut-off level between normal and abnormal
MSAFP levels. The UK collaborative study (1977)21 has shown that using
a cut off of 2.5 MoM at 16-18 weeks, 88% anecephalic pregnancies and
79% open NTD (69% of total NTD, including the close ones) were picked
up. This also picked up 3.3% of normal pregnancies.
The MSAFP levels decrease with increasing maternal body weight.
This may be due to more plasma volume of the heavier mothers diluting
the quantity of AFP entering maternal circulation from the fetus.43
Although the benefits of weight adjustment for MSAFP values are small,
but it is worth trying to reduce false-positive cases.
Women with insulin-dependent diabetes mellitus show low MSAFP
levels (about 2/3 of that of normal pregnancies.6 This group of patients
show increased incidence of NTD; and hence, a lower cut-off level for
this group has been suggested by some workers.
Women carrying male fetuses tend to show significantly higher
MSAFP levels than the ones carrying female fetuses. A study by Wald
and Cuckle 19844 confirmed this.
the MSAFP levels in twin pregnancies are almost double that of
singleton pregnancies. Monozygous twin pregnancies show even higher
values than dizygous.44
Raised MSAFP levels were also detected amongst 6.8% of mothers
who had high MSAFP values in their previous pregnancies. It is also
important to note that about 90-95% of cases with confirmed elevated
MSAFP are caused by conditions other than NTD. These may be
underestimated gestational age, other congenital anomalies like ventral
wall defects, intrauterine growth retardation, multiple gestation or fetal
demise. A raised MSAFP is also considered a risk factor for preterm
labor, pre-eclampsia, abruption placentae and low birth weight.
Amniotic Fluid AFP (AFAFP)

The AFP normally reaches amniotic fluid by excretion through fetal kidneys
and gets recirculated by fetal oral ingestion and subsequent excretion.
Conditions associated with leakage of serum or CSF from the fetus into
the amniotic fluid raises the AFAFP. Other fetal conditions like congenital
nephrosis, which increases fetal urinary excretion and conditions like
duodenal atresia which interferes with fetal ingestion and digestion also
raises AFAFP by interfering with its proper recirculation. The following
cut-off levels for AFAFP were suggested by the UK collaborative study45—
2.5 MoM at 13-15 weeks, 3.0 MoM at 16-18 weeks, 3.5 MoM at 19-21 weeks
and 4.0 MoM at 22-24 weeks gestation. Positive results detected 98% of
anencephaly and open NTDs and 0.79% unaffected pregnancies. Since the
fetal serum AFP level is significantly higher in midpregnancy, a (fetal)
blood-stained sample of amniotic fluid obtained at amniocentesis will
abnormally raise the AFAFP level.16,46
Amniotic Fluid Acetylcholinesterase (AChE) Test

Cerebrospinal fluid (CSF) contains a high concentration of AchE. This
substance, normally present in synapses, facilitates impulse transmission.
Hence, the fetal conditions, which expose the CSF to the amniotic fluid,
would raise the AChE level in the amniotic fluid. Smith et al 197947
confirmed this in Oxford. A positive AChE gel test in amniotic fluid

further reduces the false-positive rate of AFAFP test for detection of
open NTD. It has also been shown that careful interpretation of AChE
test (from the intensity of AChE band in the gel) can further distinguish
fetal ventral wall defect from open NTD.48
Ultrasonography plays an important role in the biochemical screening
process by precisely determining the gestational age at the time of
screening for MSAFP (when accuracy of gestational age is doubtful) and
by excluding multiple pregnancies where the MSAFP values are expected
to be higher than the singleton ones. However, it has been shown that
fetuses with spina bifida have smaller biparietal diameters for their
gestational age.7 Therefore, a given concentration of AFP would mean a
higher MoM when gestational age is adjusted at a lower level by the
BPD finding. This would increase the detection rate of NTD but might
influence the false-positive rate. However, a single dating scan prior to
MSAFP test will sort out several fallacies in the interpretation of the
result and detect some gross defects. A combination of both methods
for screening should detect over 90% of NTD with no concomitant
increase in the false-positive rate.49
Ultrasonography in Detection of NTD

Antenatal diagnosis of several fetal structural malformations is possible
using ultrasonography. Since the days of Professor Ian Donald in late
1950s, the technology and expertise in this field have shown a tremendous
improvement so much so that 3D or 4D ultrasound machines are now
available. The improved quality of the image on the screen has enabled
us to see more and more details of the structure and observe several
normal variations of the same. The detection rates of even the minor
and subtle defects have considerably increased. However, we must not,
at any point of time, unnecessarily increase the anxiety of the mother by
our overenthusiasm.
The incidence of NTD varies in different parts of the world. So
depending on the prevalence of the condition on that locality,
ultrasonography is either used alone as a screening tool or is used only
in high-risk cases or in combination with the biochemical test for
detection of NTD. Ultrasonography can detect both open and close
NTDs. When used by experienced operators, prenatal sonography is
sensitive and specific for the diagnoses of neural tube and ventral wall
defects in a targeted at-risk population.50 The usual recommended time
for doing this scan is around 18-20 weeks. However, early transvaginal
scan at 12-14 weeks also detects several gross defects. A review of the
multicentric data on ultrasongraphic diagnosis of NTD from 11 countries
across Europe found 98% sensitivity for anencephaly and 75% sensitivity
for spina bifida. A high prenatal detection rate for anencephaly was
reported by all registers. There was a large variation in prenatal detection
and termination rates for spina bifida between centers, reflecting
differences both in policy and culture.51 The study revealed that, prenatal
sonography is sensitive and specific for the diagnoses of neural tube
defects.
Abdominal vs Transvaginal Probes

Many of the earliest studies of diagnostic ultrasound in Ob-Gyn involved
transabdominal scanning with a 1.6 to 3.5 MHz transducer. While
relatively comfortable for the patient and useful for imaging large fetuses,
transabdominal transducer’s low frequency had and continues to have
a major limitation of decreased resolution. To address this concern, high-
frequency transvaginal transducers, which operate at 5 or 7.5 MHz, were
introduced during the late 1970s.
Modern transvaginal sonography represents a significant advance in
diagnostic capability precisely because of the probe’s proximity to the
pelvic organs. Placement of the transducer in the vagina allows use of
higher-frequency sound waves, which produce more precise images of
smaller structures and permit diagnosis of many pathological conditions
that previously could not be visualized.52-56
Three-dimensional (3D) Ultrasonography

Multiplanar views are generally more informative than rendered views
for localizing boney defects of fetal spine. Prenatal diagnosis using 3D
ultrasonography has been described. Both 2D and 3D were used
separately to determine the extent of the vertebral defects in cases of
spina bifida. Prenatal diagnosis was compared with postnatal analysis
using radiograph and MRI. The accuracy of 3D ultrasonography in
localizing the defects was found to be slightly better.57 Three-dimensional
ultrasonography may improve characterization of spina bifida by adding
diagnostic information that is complimentary to the initial 2D
ultrasonography.
Magnetic Resonance Imaging (MRI)

The MRI has been found to be useful in detecting very small spinal
defects though it is not routinely used for prenatal diagnosis. In a
reported case from Japan, where ultrasonography failed to comment
whether the spinal defect was open or closed, MRI could detect a skin
defect, which permitted prenatal diagnosis of open spina bifida.58 In
prenatal intrauterine evaluation, combined use of multiple diagnostic
tools is expected to have advantage over a single method.
FETAL SURVEY FOR NTD

For detection of any fetal structural abnormality, a thorough survey of
the fetus is necessary. This might take only a few minutes for an expert;
but at times, may not be possible due to an unfavourable position of the
fetus, which restricts the view of certain parts of the fetus. Fortunately,
fetus at this early stage of gestation keeps on moving and given some
time might allow visualization of all parts of the fetus. If this does not
happen, then asking the patient to come after some time or may be on
another day will be the only option. The sonologist should have a checklist
of the different structures to be observed during the procedure.
For the detection of NTD in particular, the survey starts at fetal skull.
Whether it is present or not? The shape of the skull is observed and any
defect looked for. The normal shape of a fetal skull is like an egg in the
transverse plane. But this shape is lost in spina bifida and the anterior
part of the frontal bone gets pinched up producing a typical lemon-
shaped skull—the famous “lemon sign” well known in the ultrasound
literature (Fig. 1.1). The contour of the skull is then carefully examined
for any defect or any herniation of meninges or brain tissue.
Next, the intracranial structures are examined thoroughly. This is
very important as it might give a clue to look for a small spinal defect,
which might have been missed otherwise. For this purpose, the fetal
brain is imaged in three different transverse planes. First, the
transthalamic plane, the level at which fetal biparietal diameter (BPD)
and head circumference (HC) are taken, moving slightly above (cranially)
gives the transventricular view; and then moving further below
(caudally) the first plane, the trancerebellar view is obtained. Examination
of the cerebellum and the ventricles are most important in this regard.
Cerebellum should maintain a right angle relation with the midline echo.
Abnormalities in these structures (ventricles and cerebellum) usually
suggest spinal defects.59-64
Fig. 1.1: Lemon sign
This should be followed by the examination of the spine throughout

its length, starting at the level of neck till the end, both in longitudinal
and transverse planes. The normal lumbosacral curve in the longitudinal
section is looked for. Examination of the spine is not complete without
having a transverse view throughout its entire length. The covering
skin over the entire length of spine is carefully examined for any defect
or herniation. Once a craniospianl abnormality is detected, special
attention should be given to look for any other structural anomaly.62
Cranial Defects
Anencephaly
The CNS was the first to be investigated by ultrasound on a fetus in
utero and anencephaly was the first congenital anomaly to be diagnosed
by this technique.65 This is the commonest form of NTD characterized
by absence of cranium and cerebral hemisphere. Anencephaly is
considered to be the final stage of acrania, as a consequence of disruption
of abnormal brain tissue unprotected by the skull. 66 The reported
incidence is 1 in 1000 births. Female fetuses are 4 times more affected
than males. Family history of NTD and twins are considered risk factors.
Sonographic findings of anencephaly are obvious and the pick-up rate
in experienced hand is up to 100%. The defect is reliably diagnosed by
10-14 weeks of gestation.55 Absence of cranial vault and the cerebral
hemispheres are typical of anencephaly. The spine ends at the base of

the skull and the vault is not seen. The orbits appear to protrude out
from the base of the skull when the vault is absent. Polyhydramnios is
usually associated with this condition due to the defective fetal
swallowing. Other reported associated anomalies with this condition
include renal anomalies, omphalocele, cleft lip-palate, diaphragmatic
hernia, cardiovascular anomaly and gastrointestinal anomaly. Prognosis
is uniformly fatal and termination of pregnancy should be advised
whenever diagnosis is confirmed (Figs 1.2A to C).
Fig. 1.2A
Fig. 1.2B
Fig. 1.2C
Figs 1.2A to C: Anencephaly
Encephalocele
This is a cranial defect (boney defect of the skull) through which meninges
and CSF (meningocele) or meninges, CSF and brain tissue herniates
(encephalocele).1 The incidence is relatively low and the reported figure
is 1 in 2,000 to 1 in 10,000 births. It arises most often from the midline at
the level of the occipital bone and less commonly from frontal and parietal
bones (Figs 1.3A and B).
Fig. 1.3A: Encephalocele with cervical meningomyelocele

Fig. 1.3B: Encephalocele
The usual sonographic finding includes a mass (cystic or solid) usually

at the back of the head. The mass when solid (containing brain tissue)
covered by herniated meninges is easy to diagnose. The cystic mass
(which is the herniated meninges alone without brain tissue) often needs
to be differentiated from a cystic hygroma, which shows internal
septations and a thick wall. Recognition of the boney defect is not always
possible due to its small size. Encephalocele can also occur at the base of
the skull protruding into the orbits, nasopharynx or oropharynx, but
prenatal diagnosis of these conditions by ultrasonography is not possible.
Ventriculomegaly and distortion of intracranial anatomy may be
observed. Most encephaloceles are usually large enough to be diagnosed
prenatally. Frontal encephaloceles are relatively difficult for ultrasound
prenatal diagnosis.
Associated hydrocephalus has been reported in up to 80% of occipital
meningocele, 65% of occipital encephalocele and 15% of frontal
encephalocele.66 Spina bifida is presented in 7 to 15% of cases.68 The
Meckel-Gruber syndrome, an autosomal recessive condition, is
characterized by occipital encephalocele, cystic renal dysplasia and
polydactyly of both feet and hands. It is also occasionally associated
with Dandy-Walker malformation (cyst in the posterior cranial fossa),

holoprocencephaly and agenesis of corpus callosum.69
Prognosis depends on the herniation of brain tissue and associated
findings. Infants with pure meningocele (herniation of only meninges)
develop a normal intelligence in 60% cases following treatment. But a
true encephalocele (containing brain tissue) carry a mortality rate of
40% and a high incidence of intelligence impairment.12,67,68 For all practical
purpose, termination of pregnancy should be offered when diagnosed
prenatally excepting for a small isolated defect of meningecele.
Iniencephaly
This is a rare malformation in which the defect of inion (occiput) is usually
combined with a dysraphic defect of the cervical spine.68 The fetus adopts
the “star gazing” position and the fixed hyperextension of the neck (a
constant feature) is easily noted. The defect may be associated with an
encephalocele or a closed spina bifida.
Foderaro et al (1987)69 reported a fetus with iniencephaly at 22 weeks
of gestation with marked hyperextension of the head and a posterior
fossa cyst.
Eighty-four percent of the infants with iniencephaly have been
reported to have associated structural anomalies. These include various
CNS and extra CNS defects (e.g. arthrogryposis, diaphragmatic hernia,
omphalocele, facial cleft, cyclopia, clubfoot, CVS anomalies, etc).
Polyhydramnios is often associated with this condition.70 Ramakrishnan
1991 reported a case report of iniencephaly with cyclopia, which is one
of the rare cases in the literature.
The fetal head may be occasionally flattened and elongated
(dolichocephaly). The cephalic index (CI), which is the ratio of biparietal
to occipitofrontal diameter should be obtained. This normally ranges
from 0.75 to 0.85. A low CI may be found in these cases due to
hyperextended head. The prognosis is universally fatal and termination
of pregnancy should be offered when prenatally diagnosed.
Exencephaly
This is characterized by complete or partial absence of the superior
portion of the cranium with complete but abnormal development of the
brain. It is also known as acrania. The incidence is much less than
anencephaly. The pathogenesis of this condition may be similar to
anencephaly and it could be just a precursor of the latter.66,71,72 The
exposed brain tissue in the amniotic fluid undergoes trauma to produce

abnormality.
Sonographic findings include absence of cranial vault with floating
brain tissue in the amniotic fluid. Associated anomalies include spinal
defects, facial cleft and talipes.
Prognosis is universally fatal and termination of pregnancy is the
only option.73
Spinal Defects
Spina Bifida
The spina bifida covers a range of vertebral and neural tube defects and
results from the failure of the posterior vertebral arch to close (fuse).
Fusion of the neural tube starts in the middle and precedes both cranially
and caudally; and for some time, the tube remains open at both the
ends. Mineralization of the spine starts at 8 weeks from three ossification
centers for each vertebra. The ventral center forms the vertebral body
and the dorsal-paired centers form the lateral and posterior parts of the
vertebra. The dorsal centers appear first in the cervical spine and proceed
toward the sacrum.32,74 This finding has been histologically confirmed.
Filly et al (1987)75 described the morphology and maturation of the spine
during the second trimester.
The defect can occur anywhere in the spine but is commonly noticed
at the lumbosacral region. The primary defect is a dysraphic spine; and
through this defect, the meninges, the CSF and the spinal cord protrude.
If only the meninges protrude out, it is called meningocele; and when
spinal tissue is also displaced out, the term is referred to as
myelomeningocele or meningomyelocele. These two are also known as
spina bifida aperta. The other type is spina bifida oculta where the
defective vertebra is covered by normal soft tissue (including skin). This
variety is difficult to diagnose prenatally; but, fortunately, it has a better
prognosis particularly when a single vertebra is involved (Fig 1.4A).
The accuracy and sensitivity of detection of spina bifida by
ultrasonography has continued to improve with the improvement of
the technology of the ultrasound machines. Experience of sonologists
and inclusion of biochemical tests into this field of prenatal diagnosis
have been able to show the maximum sensitivity and specificity in the
diagnosis of spina bifida. Roberts et al (1983)76 showed the improvement
in the sensitivity and specificity to increase from 33% and 96 to 80% and
99% within a period of 3 years. Higher accuracy of diagnosis is observed
Fig. 1.4A: Spinal defects
in high-risk cases. The accuracy of referral centers (level III ultrasound)

is close to 100%. However, in a retrospective multicentric study
employing cranial signs, the sensitivity of ultrasound for diagnosis of
spina bifida was 85%.53
For the ultrasound diagnosis of spina bifida, the examination should
start at the fetal head. The sensitivity of the cranial signs in identifying
spina bifida exceeds 99%.49,62 The pinched up-front part of the head
gives it a typical lemon shape—the “lemon sign”. 53,61-63 This sign appears
even before a small spinal defect is seen. Resolution of this sign occurs
after 34 weeks.63 A low intraspinal pressure as observed in neonates,
probably, gets transmitted to the fetal cranium deforming its shape when
the cranial bones are soft in the early weeks. But as the fetal cranium
becomes stronger with the progress of pregnancy, the sign disappears
(Figs 1.4B, Plate 1 and Figs 1.5A and B).63
The cerebral ventriculomegaly is often observed particularly of lateral
ventricles. About 1/3rd of the fetuses with hydrocephalus have spina
bifida and 3/4th of the spina bifida cases do have ventricular dilatation.63
In one study, the sensitivity of picking up spina bifida when hydrcephalus
was present, was 100%.64
The curved cerebellum associated with spina bifida has been described
as “banana sign” (Fig. 1.6).60 This is actually due to the closure of the
cisterna magna compressing the posterior fossa. Benacerraf et al noted
obliteration of cisterna magna in 22 out of 23 cases between 16 to 27
weeks.60
The BPD measurement tends to be smaller compared to the abdominal
circumference (AC) and femur length (FL) before 24 weeks.7 The cranial
and intracranial findings are indirect findings to suggest a spina bifida.60,61
Fig. 1.5A: Lemon sign
Fig. 1.5B: Spina bifida
The usual spinal defects are found in lumbosacral region, the other
common location being thoracolumbar. The sonographic appearance of
spina bifida varies with the location, size and the type of spinal defect.
Fig. 1.6: Hydrocephalus with banana sign
First, a defective dysraphic vertebra or vertebrae are noted. This can be

seen in both longitudinal and transverse view, but it is seen best in a
transverse view particularly to pick up sigle vertebral involvement. In a
normal spine the ventral and dorsal ossification centers (one ventral
and two dorsal) form a “V”shaped acute angle throughout the entire
length of the spine. The dysraphic vertebra shows wider angle forming
a “U”or a saucer-shaped deformity, which becomes obvious when
followed through its entire length. The longitudinal view is most useful
in assessing the severity of the lesion.
The soft tissue finding associated with the dysraphic vertebra
diagnoses the condition as meningocele (bulging meninges and CSF) or
myelomeningocele (bulging meninges, CSF and spinal tissue). The prone
position of the fetus favors easy diagnosis. Diagnosis is difficult if
associated with oligohydramnios or when the defective part is close to
the uterine wall or the placenta. Recently, 3 cases of spina bifida have
been diagnosed using transvaginal scan (with 7.5 MHz annular array)
using 2D and 3D techniques between 9 and 10 weeks.56 Early diagnosis
of the condition is certainly helpful in the management.
It is important to describe the type and the size (extent and location)
of the defect including any associated finding in order to discuss the
prognosis with the concerned specialist and to counsel the parents.
Multiple anomalies associated with NTD suggest chromosomal anomalies,
although isolated NTD may also show abnormal karyotype.77 Hence,

chromosome analysis of the fetus by amniocentesis should be done in
suspected or high-risk cases. This is particularly important if the parents
decide to continue with the pregnancy.
PROGNOSIS
The prognosis is best in spina bifida occulta. But this is mostly diagnosed
after birth. About 20% infants with spina bifida die. The remaining 80%
show substantial morbidity. Prognosis depends on: (i) location and extent
of the spinal defect, (ii) open or closed defect, and (iii) presence or absence
of hydrocephalus.60,78 It is also dependent on the expertise, the resources
and the facilities available. Even with timely and best treatment, the
physical and mental handicap of this group of children are very high.23
Various support groups are now available across the world to take care
of this group of handicapped children. Based on 1988 cross-sectional
data, the estimated lifetime cost of spina bifida is $ 258,000 per case.79
But the best option would be to reduce the incidence of these birth
defects where the prognosis in general is poor. Therefore, early diagnosis
and termination of pregnancy where needed is the option.
The study of changing prevalence of NTD in the North England
during 1984-96 observed a significant reduction in birth prevalence with
time. The proportion of NTD pregnancies terminated increased from
60.3% during 1984-90 to 78.6% during 1991-96, whereas the proportion
of live births declined from 31.7 to 15%. The sensitivity of antenatal
diagnosis was consistently high for anencephaly (98%) and increased
significantly for spina bifida from 60% during 1984-90 to 85% during
1991-96 (p < 0.05). Ascertainment of all cases of NTD in the Northern
Region revealed a two-fold reduction in birth prevalence between 1984-
90 and 1991-96. This has resulted from improvements in the accuracy of
antenatal detection of NTD-affected pregnancies with an increase in
terminations of pregnancy.17,80
MANAGEMENT
Early detection of NTD may help parents to prepare emotionally. It
may also help clinicians to offer intensive obstetric care and better prepare
for the delivery and the care of the newborn. In a series of 208 patients
aged 2-18 years with meningomyeloceles, no statistically significant
difference was observed in motor or sensory level, or in the ambulatory
function, between those delivered vaginally compared to those delivered

by cesarean section (CS).81 In another retrospective population-based
study of 160 fetuses with uncomplicated meningomyelocele, prelabor
cesarean delivery resulted better motor function at 2 years age than
vaginal delivery or CS after a period of labor.82 Follow-up to the age of
4 years in 85% of these cases continued to show a significantly better
outcome compared to those delivered vaginally.
Management of infants born with NTD, where the pregnancies were
decided to continue, is complicated and involves multidisciplinary team
of experts. The team includes pediatrician, orthopedic surgeon,
neurologist, physiotherapist, etc. Aggressive surgical and medical care
is often necessary for severely affected cases. The treatment depends
on the level and the severity of the defect. Infants with high defects
with gross neurological deficits are not suitable for surgery. If good
prognosis is expected, skin should be closed within 48 hours. Early
physiotherapy is done for orthopedic abnormalities. Osteotomies, if
required, are usually done within first few years of life. Shunting for
hydrocephalus has been performed for a long time with varied results.
Immediate complications like meningitis occur at times. Mortality of
these infants is around 10-15%. Another 10-15% suffer severe mental
retardation. About 60% show normal IQ but have learning and attention
deficit. Paralysis and incontinence of bladder are observed as late
complications.31,78,83-85 Special schooling facilities and rehabilitative
services are necessary for children with permanent disabilities.
CONCLUSION
Neural tube defects occur very early in pregnancy, probably, before the
mother recognizes that she is pregnant. Therefore, the preventive aspect
of NTD should be emphasized and the message should be sent to the
general population since very little can be done to a handicapped child
born with the defect. A fortified foodstuff with folic acid for the pregnant
mothers is a good option towards prevention. Pregnant women should
be offered both MSAFP and ultrasonographic tests for early detection
of NTD. A repeat test may be performed in cases of doubt before
embarking on amniocentesis because of the procedure-related risk
(around 0.2-0.5%). There is no need for amniocentesis in patients with
elevated MSAFP and normal ultrasonographic examinations. 86
Amniocentesis, however, is useful particularly where fetal chromosomal
abnormality is suspected. The biochemical tests are not to be considered
as a substitute for fetal survey by ultrasound. The latter has the added
advantage of diagnosing closed spinal defects as well as associated
anomalies of other organ systems. This gives a total picture of the fetus
to be able to draw a prognosis before counseling the parents. The high-
resolution ultrasound particularly with 3D and 4D facilities should
identify most detectable defects. The high recurrence risk of the condition
and the increased incidence amongst the first-degree relatives establish
the genetic origin of the condition. Hence, there is a need for setting up
preconception clinics where the affected and anxious parents are
counseled by experts for planning a future pregnancy. The potential
benefits of early detection of NTD must, however, be weighed against
the potential hazards of screening. The hazards include procedure-linked
complications of amniocentesis (causing fetal damage or miscarriage) or
the risks of elective termination of pregnancy. These also include the
risk of elective abortion of normal pregnancies due to false-positive test
results. But above all, the harmful psychological effect on parents with a
positive test result is to be considered seriously. This is particularly
important because a large majority of positive screening on low-risk
pregnancies are false-positives and the expectant parents carrying normal
fetuses, unnecessarily face mental trauma.
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47. Smith CJ, Kelleher PC, Belanger L, Dallaire L. Reactivity of amniotic fluid alpha
fetoprotein with concanavalin A in diagnosis of NTD. BMJ 1979;I: 920-921.
48. Collaborative acetylcholinesterase study report 1881. Amniotic fluid
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49. Watson WJ, Cheschier NC, Katz VL et al. The role of ultrasound in the evaluation
of patients with elevated MSAFP: A review. Obstet Gynecol 1991; 78: 123-128.
50. Lennon CA, Gray DL. Sensitivity and specificity of ultrasound for the detection
of NTD and ventral wall defects in high risk population. Obstet Gynecol 1999
Oct; 94(4): 562-566.
51. Boyd PA, Wellwsley DG, De Walle HE et al. Evaluation of the prenatal diagnosis
of NTD by fetal ultrasonographic examination in different centres across Europe.
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52. Timor Tritsch IE, Monteagudo A. Transvaginal neurosonography:
Standardization of the planes and sections by anatomic landmarks. Ultrasound
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53. Sebire NJ, Nobel PL, Thorpe-Beeston JG et al. Presence of the lemon sign in
fetuses with spina bifida at the 10-14 weeks scan. Ultrasound Obstet Gynecol.
1997; 10: 403-407.
54. Monteagudo A, Timor Tritsch I, Moomjy M. Nomogram of the lateral ventricles
using transvaginal sonography. J Ultrasound Med 1993; 12:265-269.
55. Johnson SP, Sebire NJ, Snijders RJM et al. Ultrasound screening for anencephaly
at 10-14 weeks. Ultrasound Obstet Gynecol 1997; 9: 14-18.
56. Blaas gestational week HGK, Eik-Nes SH, Isaksen CV. Detection of spina bifida
before 10 gestational weeks using two and three D ultrasound. Ultrasound in
Obstetrics and Gynaecology 2000;16(1): 25.
57. Williams MA, Hickok DE, Zingheim RW et al. Elevated MSAFP levels and
midtrimester placental abnormalities in relation to subsequent adverse pregnancy
outcome. Am J Obstet Gynecol 1992; 167: 1032-103.
58. Nakahara T, Uozumi T, Monden S et al. Prenatal diagnosis of open spina bifida
by MRI. Brain Dev 1993 Jan-Feb; 15(1): 75-78.
59. Babcock CJ, Chong BW, Salamat MS et al. Sonographic anatomy of developing
cerebellum: Normal embryology can resemble pathology. AJR 1996; 166: 427-
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60. Benacerraf BR et al. Abnormal US appearance of the cerebellum (banana sign):
Indirect sign of spina bifida. Radiology 1989; 171: 151-153.
61. Furness ME, Barbary JE, Verco PW. Fetal head shape in spina bifida in the
second trimester. JCU 1987; 15: 451-453.
62. Nicholaides KH, Campbell S, Gabbe SG. Ultrasound screening for spina bifida:
Cranial and cerebellar signs. Lancet 1986; 2:72-74.
63. Nyberg DA, Mack LA, Hirsch J et al. Abnormalities of fetal cranial contour in
sonographic detection of spina bifida: Evaluation of “lemon sign”. Radiology
1988; 167: 387-392.
64. Nyberg DA, Mack LA, Hirsch J et al. Fetal hydrocephalus: Sonographic detection
and clinical significance of associated anomalies. Radiology 1987; 163: 187-191.
65. Campbell S, Johnstone FD, Holt EM. Anencephaly: Early ultrasonic diagnosis
and active management. Lancet 1972; 2:1226.
66. Timor Tritsch IE, Greencbaum E, Monteagudo A et al. Exencephaly-anencephaly
sequence: Proof by ultrasound imaging and amniotic fluid cytology. J Mater
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67. Guthkelch AN. Occipital cranium bifidum. Arch Dis Child 1970; 45: 104-109.
68. Chervenak FA, Blakemore KJ, Mahoney MJ et al: Diagnosis and management
of fetal cephalocele. Obstet Gynecol 1984; 64:86-90.
69. Foderaro AE, Abu-Yousef MM, Benda JA et al. Antenatal diagnosis of
iniencephaly. J Clin Ultrasound 1987; 15: 550-554.
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iniencephaly. J Med Genet 1976; 13: 263-265.
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72. Hendricks SK, Cyr DR, Nyberg DA et al. Exencephaly- Clinical and ultrasonic
correlation to anencephaly. Obstet Gynecol 1988; 72: 898-901.
73. Campbell S. Early prenatal diagnosis of NTD by ultrasound. Clin Obstet Gynecol
1977; 20:351-359.
74. Cochlin DL. Ultrasound of fetal spine. Clin Radiol 1982; 33: 641-650.
75. Filly RA, Simpson GF, Linkowski G: Fetal spine morphology and maturation
during the second trimester. J Ultrasound Med 1987; 6: 631-636.
76. Roberts CJ, Hibbard BM, Roberts EE et al. Diagnostic effectiveness of ultrasound
in detection of neural tube defects. Lancet 1983; ii: 1068-1068.
77. O’Reilly GC, Shields LE. Karyotyping for isolated NTD. Jr Rep Med 2000; 45: 950-
952.
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1539-1578.
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in children with myelomeningocele: A retrospective analysis. Child’s Brain 1984;
11: 112-118.
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Engl J Med 1990; 323: 557-561.
2
Ashish N Shah
Preterm Labor: Evidence-

Based Management
INTRODUCTION
Evidence-based medicine has been defined by the Evidence-based
Medicine Working Group as: “...an approach to practicing medicine in
which the clinician is aware of the evidence in support of clinical practice,
and the strength of that evidence.”
Evidence-based medicine is a process of life-long, problem-based
learning. The process involves:
1. Converting information needs into focused questions.
2. Efficiently tracking down the best evidence with which to answer
the question.
3. Critically appraising the evidence for validity and clinical usefulness.
4. Applying the results in clinical practice.
5. Evaluating performance of the evidence in clinical application.
The practice and teaching of evidence-based medicine has outcome
products which help the health care providers and consumers keep up
with the medical literature and assess the evidence. These products
synthesize/filter/evaluate the primary research literature. Dissemination
and incorporation of valid clinical research findings into medical practice
is the ultimate goal. So, the evidence can be obtained from:
• Systematic Reviews/Meta-analyses
• Critically Appraised Topics (e.g., ACP Journal Club)
• Practice Guidelines
• Evaluated Bibliographic Databases (e.g., Cochrane Library)
• Consensus Development Reports
• Decision Analyses
• Patient Education/Decisions Tools
Preterm Labor: Evidence-Based Management 31
Knowing the importance of the evidence-based medicine and practice,

the next question is why is it needed in obstetrics? There are very few
conditions in obstetrics where the obstetrician can be completely sure
beyond doubt! Preterm labor falls on the extreme where there can hardly
be anything to be sure about. And that is why evidence-based practice
gains more importance than anything else in the subject of preterm
labor. There are two major key issues involved in the management of
preterm labor: the first one is prevention of preterm labor and the second
care of preterm baby after birth. With advances in the understanding of
physiology of quiescence and initiation of labor, pathophysiology of
various factors affecting the quiet uterine milieu, physiology of fetal
maturity and advances in management of preterm baby, today we are
at the verge of decreasing perinatal morbidity and mortality in preterm
to a significant extent.
The main issues where the controversy revolves around related to
preterm labor can be summed up as follows:
1. The appropriate criteria for diagnosing preterm labor.
2. The predictors of preterm labor and their effectiveness in judging
the preterm labor
3. The efficacy and effectiveness of antibiotics with respect to covert
infections that might prompt preterm labor.
4. The role of cervical cerclage.
5. The efficacy and effectiveness of tocolytic agents, the type of tocolytic
agent and the duration of tocolysis.
6. The role of prophylactic corticosteroids for better neonatal outcome.
7. The efficacy of home uterine activity monitoring in decreasing adverse
outcomes in women who are experiencing preterm labor.
DEFINITION
The definition itself is lacking consensus amongst various authors. As
per the WHO recommendation, “Preterm labor is defined as the initiation
of regular painful uterine contractions that occur usually with increasing
frequency and intensity associated with progressive cervical changes of
effacement and dilatation culminating in the delivery of preterm infant
prior to 37 completed weeks or <259 days from the first day of last
menstrual cycle.”1
The issue of lower limit of this duration, differentiating abortion
from preterm labor is more controversial. It should be that gestational
age thought to correlate with fetal viability, i.e. the gestation at which
the fetus is thought to be capable of born alive and to sustain life without
undue morbidity and mortality. The RCOG recommends it to be 24
weeks, FIGO defines it to be 22 weeks; and in the USA, it is accepted as
20 weeks.2
But the most accepted definition of ‘preterm labor’ as given by the
Philippine Society of Maternal and Fetal Medicine goes as follows:
Uterine contractions occurring
• between 20 and 36 weeks of gestation and
• at a rate of four in 20 minutes or eight in 1 hour and
• with ruptured membranes or
• with intact membranes with at least one of the following:
— documented change in cervical status over time or
— dilatation of at least 2.0 cm or
— effacement of at least 80%.
PREDICTION OF PRETERM LABOR

Prediction of preterm labor is obviously more important than the
diagnosis of it. There are a number of factors that can be used as possibly
good markers to predict preterm labor. However, none of these can
accurately predict preterm labor.
High-Risk Factors from History

As regards the evidence, there are certain predictors kept under the
level IV and recommendation Grade C for prediction of preterm labor.
These are the high-risk factors from the detailed history and examination.
There are many risk factors mentioned, but the single most important
amongst all is the history of previous preterm birth.
• Young age of mother—less than 16 years of age or more than 35
years of age
• Lower socioeconomic class
• Reduced body mass index (BMI)—BMI less than 19.0
• Cigarette smoking, cocaine abuse
• High psychological stress
• Previous preterm delivery—the strongest association
• Multiple pregnancy
• Cervical incompetence
• Uterine abnormalities
• Premature rupture of membranes obstetric complications, including
hypertension in pregnancy, antepartum hemorrhage, infection,
polyhydramnios, fetal congenital abnormalities, IUFD.
• Systemic infections of the mother like pneumonia, acute pyelobep-

hritis, appendicitis, etc.
More than 50% of women who deliver prematurely, however, have
no known antecedent risk factors.
Ultrasound Markers
Vaginal examinations to assess the cervical status and ultrasound
visualization of cervical length and dilatation have been suggested to be
useful in the prediction of preterm labor. Vaginal examination actually
is palpation of only vaginal portion of cervix and so cannot give very
good idea of the status of internal os which is one of the very important
points to be evaluated. There are three important parameters to be
examined on vaginal ultrasound.
• Shape of the cervix at internal os
• Length of cervical canal
• Funneling in response to fundal pressure
As regards shape of the cervix at the level of internal os, the mnemonic
‘Thank Your Vaginal Ultrasound’ is frequently suggested by many
authors. The normal shape of the cervix is T-shaped with internal os
represented by the place where the horizontal and vertical bar of the T
meets. A T-shaped configuration of the internal os area with diameter
< 4 mm denotes cervical competence. This throws out the older concept
of deciding the cervical competence by using Hegar’s dilator no. 8. The
loss of normal T-shape to Y, V or U demonstrated on vaginal ultrasound,
denotes varying degrees of cervical incompetence.
Goldenberg et al have suggested cervical length to be a good
parameter to predict preterm labor. According to them, cervical length
< 25 mm at 24-28 weeks is quite predictive of preterm labor. Shortened
cervical length in the midtrimester preferentially predicts early, i.e. < 26
weeks, as opposed to later, i.e. 26-36 weeks, spontaneous preterm birth
in high-risk women.3
Funneling technique is described by Gomez et al as one of the
predictors of preterm labor. The transvaginal probe of ultrasound is
introduced and the area of internal os is located. Then gentle pressure is
applied over the area of fundus of the uterus; while, at the same time,
observing any ‘funneling’ changes at the area of internal os. According
to Iams et al (1996), this technique has similar value in predicting preterm
birth as cervical length measurements. Whereas according to Gomez et
al (1994), this technique is more accurate than clinical measurements in
predicting the risk of preterm delivery in symptomatic patients.
Biological Markers
There are certain other markers that fall under the Grade B of
recommendation of evidence. These are the biological markers of
preterm labor.
Overall, fetal fibronectin presents strong evidence of effectiveness
as a diagnostic tool for assessing the risk of preterm birth in women
with symptoms of preterm labor. It is only moderately successful in
predicting which women with a positive test would deliver before term,
but they consistently exhibited strong NPVs, thereby identifying women
at low risk of preterm birth. It can be concluded that these biologic
markers offer valuable information that could allow women to avoid
unnecessary treatments. These tests can usefully supplement clinical
judgment, especially in terms of identifying women who are not likely
to experience a preterm birth.
Fetal fibronectin is a protein present at the chorionic decidual interface
which is released into the cervicovaginal secretions in response to an
increase in chorionic decidual protease activity which generally precedes
preterm labor. Immunohistochemical studies have shown that fetal
fibronectin is found in the placenta and membranes at points of contact
with the uterine wall. Thus, it reflects the separation of the chorion
from the decidual layer then releasing chorionic components of the
extracellular matrix which contain fetal fibronectin into the cervical and
vaginal secretions. As regards the evidence, fetal fibronectin level > 50
ng/ml is found only in 3-4% of women with term uncomplicated
pregnancies, whereas the same level is present in 93.8% of women with
preterm premature rupture of membranes and in 50.4% in women with
preterm labor and intact membranes. On an average, the presence of
fetal fibronectin precedes preterm labor by > 3 weeks. The negative
predictive value of fetal fibronectin is more important in clinical practice.4
The negative predictive value of fetal fibronectin for delivery within 7
days, within 14 days and <37 weeks of pregnancy is respectively 99.5%,
99.2% and 84.5%.5
Not only just one testing of fetal fibronectin, but subsequent testing
has also some significance. The greater the percentage of fetal fibronectin
positivity amongst repetitive tests, the higher is the risk of spontaneous
preterm births. Further, after one positive fetal fibronectin test, two
negative tests are required before the risk of spontaneous preterm
delivery returns to normal.6
Overall, the short cervical length, with positive fetal fibronectin levels
with prior preterm birth together can be a very good predictor of
preterm labor. Cervical length and fetal fibronectin levels have
independent, distinct and significant effects on recurrence risk of preterm
labor. Predicted recurrence risk is increased to 2 to 4 times in women
with positive fetal fibronectin compared to negative fetal fibronectin
and risk increases as cervical length shortens in both fetal fibronectin
positive and negative women.7
Women who are symptomatic for preterm labor should be considered
for fetal fibronectin and bacterial vaginosis testing.8
There are now a few genetic factors as well, at least having association
with the preterm labor. The rarer of 2 alleles of a polymorphism in the
promoter of the tumor necrosis factor (TNF) alpha gene has been
associated with spontaneous preterm birth following preterm premature
rupture of the fetal membranes in some populations. Maternal carriers
of the TNF-2 are at a significantly increased risk of spontaneous preterm
birth. The association between TNF-2 and preterm birth is further
modified by the presence of bacterial vaginosis, such that those with a
“susceptible” genotype and bacterial vaginosis are having increased odds
of preterm birth. There is preliminary evidence that an interaction
between genetic susceptibilities (i.e. TNF-2 carriers) and environmental
factors (i.e. bacterial vaginosis) is associated with an increased risk of
spontaneous preterm birth.9
The interleukin-10 (IL-10) is regarded predominantly as an inhibitor
of cell-mediated inflammatory reactions. As such, it has been suggested
that IL-10 could have therapeutic potential, including the treatment of
preterm labor. It is found that IL-10 does indeed exert anti-inflammatory
properties in choriodecidua; but that, in the adjacent amnion, it has
remarkable pro-inflammatory actions. Amnion prostaglandin PGE2
production is significantly increased following 24-hr treatment with IL-
10. In contrast, choriodecidual production of IL-8 and tumor necrosis
factor (TNF)-alpha is dramatically inhibited by IL-10, confirming the
ability of this tissue to exhibit a classical IL-10 response. The IL-10 has
its stimulatory actions on amnion in the presence of IL-1 beta and TNF-
alpha stimulation. These findings suggest that the fetal membranes can
exhibit opposing responses to IL-10, depending on whether the
inflammatory insult occurs at the maternal or fetal face. While inflam-
matory reactions are negatively regulated by IL-10 in choriodecidua, if
the pathogen reaches the amnion and threatens the fetus,
proinflammatory reactions may predominate to ensure successful labor
to spare and protect the fetus.10
The maternal salivary estriol has also been suggested as a useful

indicator of preterm labor. However, there is no meta-analysis carried
out for this test so far. It is suggested that fetal placental signal increases
the mother’s salivary estriol and this surge, prior to 36 weeks, indicates
risk of spontaneous preterm labor. This maternal salivary estriol surge
occurs 3 weeks before onset of preterm labor with quantitative values
> 2.3 ng/ml. Thus, detection of an early maternal salivary estriol surge
or an increased estriol level > 2.3 ng/ml may help identify the women at
increased risk for preterm labor.
PREVENTION OF PRETERM LABOR

After knowing the various predictive factors for preterm labor, the most
vital step in the management of preterm labor should be the prevention
of preterm labor whenever possible. But this is easier said than actually
done. In around half of all the cases of preterm labor, as mentioned
earlier, there are no high-risk factors preceding the onset of preterm
labor. With whatever possible modalities we have, all the evidences
suggest that all these measures fall under the level IV and grade C of
reported evidence. The main management revolves around the following
points:
• Good antenatal care is important in the prevention of preterm
delivery. Advice on bedrest and abstinence from sexual intercourse
should be explained to the high-risk patient.
• Role of prophylactic cervical cerclage.
• Antibiotic treatment of women with bacterial vaginosis or in women
with rupture of membranes may be associated with a reduction in
preterm delivery.
• Role of prophylactic progesterones is controversial.
Antenatal Advice
Good antenatal care is important and can help to detect some of the
maternal and fetal factors that could lead to preterm delivery. A patient
with risk factors may be advised on the early warning symptoms and
signs of preterm labor, the importance of bedrest and abstinence from
sexual intercourse.
There is no evidence, either supporting or refuting the use of bedrest
at home or in hospital, to prevent preterm birth. Although bedrest in
hospital or at home is widely used as the first step of treatment, there is
no evidence that this practice could be beneficial. Due to the potential
adverse effects that bedrest could have on women and their families,
and the increased costs for the healthcare system, clinicians should not
routinely advise women to rest in bed to prevent preterm birth. Potential
benefits and harms should be discussed with women facing an increased
risk of preterm birth. Appropriate research is mandatory. Future trials
should evaluate both the effectiveness of bedrest, and the effectiveness
of the prescription of bedrest, to prevent preterm birth.11
Cervical Cerclage
The role of prophylactic cervical cerclage in women at high-risk of preterm
labor is controversial. In one of the systemic reviews on this subject, the
reported number of cases to be treated to prevent one additional preterm
birth before 34 weeks was 24 women.12 The effectiveness of prophylactic
cerclage in preventing preterm delivery in women at low or medium
risk for second-trimester pregnancy loss has not been proven. The role
of cerclage in women whose ultrasound reveals short cervix remains
uncertain.13 The available evidence from a meta-analysis does not support
cerclage for a sonographically detected short cervix.14
Antibiotics
At the beginning of the 21st century, preterm delivery remains the major
perinatal challenge. Even mild and moderate preterm birth infants are
at high relative risk for death. Widespread uncertainty exists about the
benefits and risks of antibiotic use for women in spontaneous labor with
intact membranes and for those with preterm premature rupture of
membranes.
Preterm Labor with Intact Membranes

The findings of ORACLE Collaborative Group of randomized, blinded,
placebo-controlled trial involving 161 centers and 15 countries of ORACLE
I and II are highly relevant as regards use of antibiotics in preterm labor.
The main conclusion of the study states that for women with established
preterm labor with intact fetal membranes, erythromycin, amoxycillin-
clavunic acid or combined treatments are not better than placebo for
preventing the composite outcome measure of neonatal death, chronic
lung disease, or major cerebral abnormality.15 The Cochrane database
review fails to demonstrate a clear overall benefit from prophylactic
antibiotic treatment for preterm labor with intact membranes on neonatal
outcomes and raises concerns about increased neonatal mortality for
those who received antibiotics. This treatment can not therefore be

currently recommended for routine practice. Further research may be
justified in order to determine if there is a subgroup of women who
could experience benefit from antibiotic treatment for preterm labor
prior to membrane rupture, and to identify which antibiotic or
combination of antibiotics is most effective.16
Preterm Labor with Ruptured Membranes

When no other cause is found, infection is generally been implicated in
the cause of preterm labor, but it is of special concern when the
membranes are ruptured. Clinicians have been ambivalent about the
effectiveness of antibiotics among women with ruptured membranes
who do not have other signs of infection. Cochrane-based data supports
the routine use of antibiotics in preterm premature rupture of membranes
with a delay in delivery and a reduction in major markers of neonatal
morbidity. The choice as to which antibiotic would be preferred is less
clear. Secondary analyses in women with preterm premature rupture of
membranes suggested that given the growing body of evidence that
intrauterine infection is linked to long-term adverse outcome and the
absence of findings to show harm associated with erythromycin
treatment, it is highly likely that prophylactic treatment in this situation
with erythromycin will become standard. Similarly, it would be wise to
avoid the use of amoxicillin-clavunic acid (augmentin) in these situations,
as yet, there are no evidences to support its usefulness.17 The ORACLE
trial, aggregated high quality evidence and from its meta-analyses, it is
now established that antibiotics are associated with reduced maternal
and neonatal morbidity in preterm wtih rupture of membranes. However,
this message comes with a warning about β-lactam antibiotics. Macrolide
antibiotics are associated with improved outcomes. β-lactam antibiotics
are associated with increased neonatal necrotizing enterocolitis.
Preterm Labor with an Established Infection

Bacterial Vaginosis
Patients with bacterial vaginosis may be at an increased risk of preterm
delivery. Antibiotic treatment with ampicillin, erythromycin or
metronidazole can eradicate bacterial vaginosis in pregnancy. However,
the current evidence does not support screening and treating all pregnant
women with asymptomatic bacterial vaginosis to prevent preterm birth
and its consequences. For women with a previous preterm birth, there
is very little evidence that detection and treatment of bacterial vaginosis

will prevent a further preterm birth, but it may reduce the risk of low
birth weight and preterm premature rupture of membranes.18
Asymptomatic bacteriuria
Asymptomatic bacteriuria, if untreated, will lead to acute pyelonephritis
in up to 30% of mothers. Asymptomatic bacteriuria may have a role in
preterm birth or it may be a marker for low socioeconomic status which
is associated with low birth weight. The routine use of urine cultures in
the assessment of preterm labor is costly and adds little value to obtaining
a diagnosis except in the presence of specific complaints.19 Antibiotic
treatment is effective in reducing the risk of pyelonephritis in pregnancy
but probably not preterm. An apparent reduction in preterm delivery is
consistent with current theories about the role of infection in preterm
birth, but this association should be interpreted with caution.20
Ureaplasma urealyticum
Amongst all other infections, detection of ureaplasma in vagina is also
considered as one of the possible causative factors for preterm labor.
However, there is insufficient evidence to show whether giving antibiotics
to women with ureaplasma in the vagina will prevent preterm birth.21
Prophylactic Progesterones
Particularly, after the advent of natural and micronised progesterones
in the last few years, the role of progesterones as regards preterm labor
has fallen into great controversy.
There are studies that suggest prophylactic vaginal progesterone does
reduce the frequency of uterine contractions and the rate of preterm
delivery in women at high-risk for preterm.22 But most of these are not
large studies with proper randomization. And so, before establishing
the definite role of progesterones in preterm labor, the meta-analysis is
required to begin its prophylactic use in high-risk cases of preterm.
ROLE OF MATERNAL CORTICOSTEROID ADMINISTRATION

Antenatal corticosteroids for promoting fetal maturity in utero have now
been used for decades together. Respiratory distress syndrome (RDS)
affects 40 to 50% of babies born before 32 weeks of gestation. The role
of corticosteroids has now been proven to reduce the incidence of the
morbidity associated with respiratory distress syndrome in preterm
births with the evidence level IA and grade A.
It is very important to remember that the primary aim of using beta-

agonists should be only to delay delivery for 24 to 48 hours in order to
administer corticosteroids to promote fetal lung maturity. All women
between 24 and 36 weeks of pregnancy at risk for preterm delivery may
benefit from antenatal corticosteroid therapy. Patients eligible for
therapy with tocolytic agents are also eligible for treatment with
antenatal corticosteroids.
There was some controversy regarding the dosing schedule of
corticosteroids which also has now been solved beyond doubt. The
dosage schedule for corticosteroids is also now established with evidence
grade A, level IA. Maternal corticosteroid administration should be given
using two doses of 12 mg of betamethasone intramuscularly 24 hours
apart. The other alternative is the dexamethasone 4 mg intramuscularly
every 6 hours for total of 4 doses. The effect of treatment is optimal if
the baby is delivered more than 24 hours and less than 7 days after the
start of treatment. As treatment for less than 24 hours is still associated
with significant reduction in neonatal mortality, antenatal corticosteroids
may still be given unless immediate delivery is anticipated. There was a
confusion regarding the repeat or the booster dose of the same drug to
be administered after 7 days if the patient has not delivered by then.
But now it is established that any type of repeat or booster dose is not
useful; and, in fact, can prove to be of some harm if given repeatedly.
So, once administered in its complete regime, repetition of the dose is
not recommended any time thereafter. There is now evidence that the
fetal blood glucorticoid bioactivity increases shortly after the
administration of maternal corticosteroids. Thus, the antenatal exposure
of preterm fetuses to betamethasone causes a sizeable, but brief, peak of
supraphysiological glucorticoid bioactivity.23
There are certain facts established with evidence grade A that can be
remembered as precautions while administering corticosteroids to
mother.
Corticosteroid therapy does not appear to increase the risk of
maternal or fetal infection regardless of whether the membranes are
ruptured or not at the time of treatment. The following points must also
be considered when administering corticosteroids:
• Corticosteroids may be used with caution in patients with severe
pre-eclampsia/hypertension.
• Impaired glucose tolerance may occur if repeated doses of
corticosteroids are given, especially in conjunction with beta-agonist
therapy.
• Extremely rare complication of adrenal insufficiency should be

considered if there is an unexplained collapse of either the mother or
baby who is exposed to repeated courses of neonatal corticosteroids.
INHIBITION OF PRETERM LABOR

Aims of Inhibition of Preterm Labor
• Achieve quiescence of uterine irritability, when arrangements are
made for in utero transfer to an obstetric unit with tertiary perinatal
facilities.
• Postpone the preterm delivery by at least 48 hours of beginning
treatment so as to allow the effects of administered corticosteroids
to enhance fetal pulmonary maturity.
Contraindications to Inhibition of Preterm Labor

In spite of aiming at the best outcome with available options of treatment,
it is not possible to achieve desirable goals in all clinical conditions.
Clinically, preterm labor presents with a wide variety of clinical scenario.
And so, it is important to understand the conditions where the preterm
labor should not be inhibited. These usually are the cases where delivery
is in the best interest of the mother and/or the baby. There is level IV,
grade C evidence for these conditions. These situations are as narrated
below:
• In the situations where delivery is imminent or when other obstetric
factors dictate that delivery should not be delayed, inhibition of
preterm labor may be withheld:
– Fulminating pre-eclampsia
– Severe abruptio placenta
– Fetal distress
– Severe chorioamnionitis in the presence of rupture of membranes
– Fetal demise or lethal fetal anomaly
– Development of serious side effects during the use of beta agonists
• Therapy should be discontinued if labor progresses despite treatment.
Modalities of Treatment
Any woman presenting with preterm labor requires due attention and
careful evaluation. When a patient with suspected preterm labor is
examined, a full history must be obtained and a clinical examination
must be performed. The clinical examination should include a speculum
examination of the cervix to exclude rupture of membranes, digital

examination to assess the cervical status, assessment of fetal presentation
and estimated fetal weight. Vaginal and cervical microbiological cultures
and a midstream specimen of urine culture may be considered to exclude
an infective etiology. The aims of treatment and the potential side effects
of such treatment should be explained to the patient. A dialogue with a
neonatologist at this stage will also be helpful in the management of the
patient.
The treatment to be tried in case of established preterm labor is to inhibit
the labor, if not for a long duration, then at least until the effect of the
corticosteroids for fetal maturity is achieved or the patient is transferred
to a better center for presumably required neonatal care. Along with the
drugs, various supportive measures have also been suggested.
Various drugs claimed to provide uterine quiescence or tocolysis are
as follows:
• Beta-agonists/ sympathomimetics: Ritodrine, terbutaline, salbutamol,
isoxsuprine.
• Magnesium sulphate
• Calcium-channel blockers: Nifedipine, nicardipine
• Prostaglandin synthatase inhibitors: Indomethacin
• Nitric oxide donors: Nitroglycerine
• Oxytocin antagonist: Atosiban, barusiban.
First-Line Tocolytic Therapy

As the above-mentioned list suggests, there are a number of options
available to be used for tocolysis. The important decision to make is the
choice of the tocolytic agent as a first line of treatment.
Literature comparing an intervention group of women receiving first-
line treatment with tocolytics relative to a control group is available
only for beta-mimetics and magnesium sulfate. Results across studies
are mixed: for beta-mimetics, there is an evidence of efficacy in terms of
estimated gestational age at birth, prolongation of pregnancy for 1 day
or more, and improved infant outcomes (birth weight greater than 2,500
gm). Significant differences are not found between magnesium sulfate
and placebo. With respect to comparisons among different classes of
tocolytics (chiefly in relation to beta-mimetics), results again are mixed.
Meta-analyses suggest that all tocolytics, with the exception of ethanol,
are effective in extending pregnancies at or beyond 36-38 weeks of
gestation compared with a no-treatment group. Beta-mimetics, calcium
channel blockers, and magnesium sulfate nearly doubled the odds of

term births, relative to control, with potentially small differences in effect
sizes between classes. Overall, the evidence supports the notion that
first-line treatment with beta-mimetics, calcium channel blockers,
magnesium sulfate, or NSAIDs offers small improvements in prolonging
pregnancy. Data concerning relative efficacy are mixed, but they clearly
support the conclusion that ethanol is less efficacious than other tocolytic
options and support the generally held clinical belief that ethanol is an
inappropriate treatment for women with preterm labor symptoms.
Concerns that other treatments offer greater efficacy with less risk seem
to be warranted in regard to treatment with beta-mimetics as well. The
benefits of beta-mimetics never are found to exceed other options, and
the maternal harms are shown to be potentially more severe.
Maintenance Tocolytics
For improving the gestational age at birth or for prolongation of
pregnancy, or for achieving good birth weight, maintenance treatment
confers no benefits.
Beta agonists (sympathomimetics)
The uterine smooth muscles are abundant in α2-receptors. So, a drug
that can act specifically on these receptors would be more useful with
fewer side effects. Epinephrine was tried initially as a tocolytic but it
proved to be a weak tocolytic.
Several meta-analyses of parenteral beta-mimetics to inhibit preterm
labor have consistently confirmed that these drugs delay labor for no
more than 48 hours.24 Additionally, oral beta agonists are shown to be
ineffective and have no benefits.25
Ritodrine hydrochloride is the prototype amongst all the tocolytics
available and it is the only approved beta mimetic by Food and Drug
Administration (FDA) so far. Ritodrine can be given either as an
intravenous loading dose infusion till tocolysis is reached followed by a
decrease in infusion rate. The other way of administration is the
conventional schedule of increasing doses until uterine quiescence is
achieved. Despite the small differences, the loading model is easier to
apply, requires fewer dose adjustments, is better tolerated with fewer
side effects, and reduces the likelihood of clinical error.26
Women with preterm labor that is arrested with tocolytic therapy
are at increased risk of recurrent preterm labor. Terbutaline pump
maintenance therapy has been given to such women to decrease the risk
of recurrent preterm labor, preterm birth, and its consequences.

Terbutaline pump maintenance therapy has not been shown to decrease
the risk of preterm birth by prolonging pregnancy. Furthermore, the
lack of information on the safety of the therapy, as well as its substantial
expense, argues against its role in the management of arrested preterm
labor. Future use should only be in the context of well-conducted,
adequately powered randomized controlled trials.27
The dose and the route of the administration of one or the other beta
mimetics have remained equally controversial. As per the available
evidence level IV and grade C of recommendation, the following facts
are derived:
• To reduce the risk of pulmonary edema, beta agonists should be
administered intravenously with the minimum volume of fluid.
• Beta agonists should also be used with caution in a woman with
multiple pregnancy.
• Beta agonists should be administered via a controlled infusion device.
• The infusion rate should be increased at regular intervals until
contractions have ceased or until the maternal pulse reaches 130-140
per minute.
• The maximum recommended dose is 350 micrograms per minute for
ritodrine infusion.
• The dose may be reduced slowly if uterine contractions have ceased.
• Many studies include the use of oral maintenance treatment after the
contractions have stopped. However, the use of oral maintenance
therapy remains controversial.
Because of its various side effects, the beta mimetics have fallen into
disfavor of many clinicians. Again, with the level IV evidence, following
have been reported as side effects of beta mimetics when used in the
inhibition of preterm labor:
• Palpitations, tremors, nausea, vomiting and headaches are commonly
reported symptoms.
• Maternal tachycardia: A frequent dose-related effect is maternal
tachycardia. Heart rate should not be allowed to exceed 130-140 beats
per minute due to the associated risk of pulmonary congestion.
• Pulmonary edema: Pulmonary edema is commonly associated with
aggressive intravenous hydration. Fluid balance should be carefully
monitored. If pulmonary edema occurs, the treatment should be
discontinued and diuretic treatment be considered.
• Myocardial ischemia: Myocardial ischemia is an uncommon but serious
side effect due to increased maternal cardiac output with beta-agonist
administration.
• Hyperglycemia: Diabetic patients will need additional monitoring and

adjustment of glucose levels as beta agonists influence carbohydrate
metabolism, especially when combined with maternal corticosteroid
administration. Hyperinsulinemia and hypokalemia are also
associated sometimes.
Magnesium sulfate for tocolysis
Magnesium sulfate is used infrequently as it is associated with significant
maternal and fetal side effects. The loading dose is 6 gm over 15 min
and the maintenance dose is 2 gm/hr. The dose may be increased by 1
gm/hr if contractions persist up to a maximum of 4-5 gm/hr. Tocolysis
is achieved more rapidly in patients treated with a higher maintenance
dose of magnesium sulfate, i.e. 5 gm/hr have and they required shorter
admissions to the labor and delivery unit without increased maternal or
neonatal morbidity.28 The tocolysis should be maintained for 12-24 hours
if successful. The intravenous fluids should be limited to 125 ml/hr.
And careful monitoring should be done for magnesium sulfate toxicity.
Calcium channel blockers for inhibiting preterm labor
The calcium channel blockers most commonly used as tocolytics are
nifedipine and nicardipine. These agents act to inhibit calcium influx
across cell membranes, thereby decreasing tone in the smooth muscle of
the vasculature. They act as profound vasodilator agents and have
minimal effect on the cardiac conduction system. Numerous randomized
clinical trials have shown them to be as effective as beta mimetics and
magnesium in achieving tocolysis. When used for tocolysis, calcium
antagonists have a fewer maternal side effects than other tocolytics and
have no adverse effect on fetal outcome.29 Nifedipine in comparison
with ritodrine in the management of preterm labor is significantly
associated with a longer postponement of delivery, fewer maternal side
effects, and fewer admissions to the NICU.30 Further research should
address the effects of different dosage regimens and formulations of
calcium channel blockers on maternal and neonatal outcomes.31
Nifedipine has also been suggested to be used as a maintenance
tocolysis in some cases. The gestational age and time gained from
initiation of maintenance therapy to delivery are longer in women
receiving oral maintenance tocolysis with nifedipine. However,
maintenance therapy did not decrease the recurrence of preterm labor
episodes or improve perinatal outcomes.32,33
Indomethacin for tocolysis

The use of this drug should be limited to women with preterm labor at
< 32 weeks and without having any oligohydramnios. The recommended
loading dose is 100 mg rectally or 50 mg orally and may be repeated in
1 hour if no decrease is noted in contraction frequency. The maintenance
dose is 25-50 mg 4 times a day for maximum of 2-3 days. The amniotic
fluid level must be checked before initiation of therapy and after 48
hours. If oligohydramnios is found, the dosage of the drug should be
decreased or discontinued. The Doppler echocardiography should be
done to check ductus arteriosus flow and triscuspid regurgitation.
Another drug tried from the similar group is celecoxib, selective cyclo-
oxygenase II inhibitor. In the initial evaluation, the safety of short-term
celecoxib in women with preterm labor was superior to that of
indomethacin as regards ductal velocity, but not the amniotic fluid
volume.34
Nitric oxide donors
Nitric oxide donors, such as nitroglycerin, have been used to relax the
uterus. Transdermal nitroglycerin appears to be a safe therapy for the
mother and fetus and is a promising new option for the treatment of
preterm labor.35 Nitric oxide donors neither delay delivery nor improve
neonatal outcome when compared with placebo, no treatment or
alternative tocolytics such as ritodrine, albuterol and magnesium sulfate.
There is, however, a reduction in numbers of deliveries less than 37
weeks when compared with alternative tocolytics, but the numbers of
deliveries before 32 and 34 weeks are not influenced. Side effects (other
than headache) are reduced in women who receive nitric oxide donors
rather than other tocolytics. However, women are significantly more
likely to experience headache when NO donors have been used. There
is currently insufficient evidence to support the routine administration
of nitric oxide donors in the treatment of threatened preterm labor.36
Oxytocin antagonists for tocolysis
Atosiban is a protein derivative of oxytocin and vasopressin which is a
competitive inhibitor of oxytocin and its receptor sites in the deciduas,
fetal membranes and myometrial cell membranes. Initial phase I and II
trials with this drug suggest encouraging results for inhibiting preterm
labor. Currently, this drug is undergoing phase III trial. Though it is to
be administered intravenously, no titration is required with atosiban as
it is administered as a fixed dose. Initial trials of the treatment of patients
in preterm labor with atosiban resulted in prolongation of pregnancy
for up to 7 days for those at a gestational age > 28 weeks, and this
occurred with a low rate of maternal-fetal adverse effects. Efficacy and
infant outcome data at <28 weeks are inconclusive.37 Patients admitted
with an acute episode of preterm labor who respond to early
intravenously administered tocolysis remain at risk of having subsequent
episodes of preterm labor and preterm delivery. Several pharmacologic
agents have been used in an attempt to reduce subsequent episodes of
preterm labor, and all are associated with significant side effects.
Atosiban is effective in the treatment of an acute episode of preterm
labor and maintenance therapy to prolong uterine quiescence after
successful treatment of an acute episode of preterm labor. As per the
evidence grade A, level IB, oxytocin antagonists are useful in inhibiting
preterm labor with potentially fewer maternal side effects than beta
agonists. This treatment is usually well tolerated by the patient.38
Another drug in the same group is barusiban. It is a synthetic oxytocin
analogue and is shown to potently inhibit oxytocin-induced activity of
myometrium. The responsiveness to vasopressin is not influenced by
this compound. Barusiban depending upon concentration inhibits
oxytocin-induced myometrial contractions of myometrium at least as
potently as atosiban. It remains to be determined if the selectivity of
barusiban for the oxytocin receptor confers any advantage over atosiban
as a tocolytic in preterm labor.39
Hydration Therapy for Inhibition of Preterm Labor

The data are too few to support the use of hydration as a specific
treatment for women presenting with preterm labor. The two small
studies available do not show any advantage of hydration compared to
bedrest alone. Intravenous hydration does not seem to be beneficial,
even during the period of evaluation soon after admission, in women
with preterm labor. Women with evidence of dehydration may,
however, benefit from the intervention.40
Supportive Measures
In a patient at increased risk of recurrent preterm contractions, the role
of bedrest, reduced physical activity, avoidance of nipple stimulation
and abstinence from sexual intercourse may be explained to the patient,
especially if the preterm labor is related to antepartum hemorrhage.
However, none of these can be of any proven role by the available
evidence.
HOME UTERINE ACTIVITY MONITORING

Many authorities have repeatedly concluded that home uterine activity
monitoring is only investigational, several pharmaceutical companies
continue to market this technology to health providers. The controversy
evolving around this topic was at its peak about a decade back. Of the
four randomized controlled trials reviewed, none of these found a
significant effect from home uterine activity monitoring. Meta-analysis
has confirmed this “no-effect” conclusion in relation to gestational age
at birth and birth weight. Almost all major obstetric organizations have
accepted the fact that home uterine activity monitoring is expensive and
burdensome and actually does not affect the rate of preterm delivery
and it should not be used clinically.41,42
PHENOBARBITAL PRIOR TO PRETERM BIRTH

There were reports suggesting the role of prophylactic role of
phenobarbital for periventricular hemorrhage. But the available evidence
does not support the use of prophylactic maternal phenobarbital
administration to prevent periventricular hemorrhage or to protect from
neurological disability in preterm infants. If any future trials are carried
out, they should measure neurodevelopmental status at follow-up.
DELIVERY OF THE PRETERM FETUS

With the evidence level IV and grade C, the following points can be
emphasized for the delivery of the preterm infant.
• It should be conducted in an obstetric unit with neonatal intensive
care facilities.
• Fetal monitoring during labor is important to ensure fetal well-being
and should be interpreted more rigidly as the preterm fetus is likely
to tolerate hypoxia more poorly.
• As regards mode of delivery, preterm labor per se is not an indication
of cesarean section irrespective of expected birth weight. And the
notion of carrying out abdominal delivery for preventing insult of
vaginal delivery to the fetus is no more supported by the available
evidence.
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of Obstetricians and Gynecologists. London: RCOG, 1977.
2. Beard RW, Sharp F. Proceedings of the Thirteenth Study Group of the Royal
College of Obstetricians and Gynecologists. RCOG, 1985.
3. Owen J, Yost N, Berghella V. Can shortened midtrimester cervical length predict
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4. Lockwood CJ et al. N Eng J Med 1991, 325:669.
5. Peaceman AM et al. Am J Obstet Gynecol. 1997, 177:13.
6. Goldenberg RL. For the NICHHD-MFM Units Network. Am J Obstet Gynecol
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7. Iams J D. For the NICHHD-MFM Units Network. Am J Obstet Gynecol 1998;178:
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8. Stevens AO, Chauhan SP, Magann EF et al. Fetal fibronectin and bacterial
vaginosis are associated with preterm birth in women who are symptomatic for
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9. Macones GA, Parry S, Elkousy M et al. A polymorphism in the promoter region
of TNF and bacterial vaginosis: Preliminary evidence of gene-environment
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10. Mitchell MD, Simpson KL, Keelan JA. Paradoxical proinflammatory actions of
interleukin-10 in human amnion: potential roles in term and preterm labour.
J Clin Endocrinol Metab 2004 Aug;89(8):4149-52.
11. Sosa C, Althabe F, Belizán J, Bergel E. Bedrest in singleton pregnancies for
preventing preterm birth (Cochrane Review). In: The Cochrane Library, Issue
3, 2004.
12. Bachmann LM, Coomarasamy A, Honest H, Khan KS. Elective cervical cerclage
for prevention of preterm birth: A systematic review. Acta Obstet Gynecol
Scand 2003 May;82(5):398-404.
13. Drakeley AJ, Roberts D, Alfirevic Z. Cervical cerclage for prevention of preterm
delivery: Meta-analysis of randomized trials. Obstet Gynecol 2003 Sep;102(3):621-
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14. Belej-Rak T, Okun N, Windrim R, Ross S, Hannah ME. Effectiveness of cervical
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15. Kenyon SL, Taylor DJ, Tarnow-Mordi W. For the ORACLE Collaborative Group.
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16. King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with
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17. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm premature rupture of
membranes. Cochrane Database Syst Rev 2002;(1).
18. McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating
bacterial vaginosis in pregnancy (Cochrane Review). In: The Cochrane Library,
Issue 3, 2004.
19. Hundley AF, Onderdonk AB, Greenberg JA. Value of routine urine culture in
the assessment of preterm labor. J Reprod Med 2003 Nov;48(11):853-7.
20. Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy (Cochrane
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21. Raynes-Greenow CH, Roberts CL, Bell JC, Peat B, Gilbert GL. Antibiotics for
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22. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Role of vaginal progesterone
in preterm labor. Am J Obstet Gynecol 2003 Feb;188(2):419-24
23. Kajantie E et al. Circulating glucocorticoid bioactivity in the preterm newborn
after antenatal betamethasone treatment. J Clin Endocrinol Metab 2004
Aug;89(8):3999-4003.
24. Lamont RF. The contemporary use of beta agonists. Br J Obstet Gynecol
1993;100:890.
25. Macones GA, Berlin M, Berlin JA. Efficacy of oral beta agonists maintenance
therapy in preterm labor: A meta-analysis. Obstet Gynecol 1995;85:313
26. Holleboom CA, Merkus JM, van Elferen LW, Keirse MJ. Randomised comparison
between a loading and incremental dose model for ritodrine administration in
preterm labour. Br J Obstet Gynaecol. 1996 Jul;103(7):695-701.
27. Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance
therapy after threatened preterm labor for preventing preterm birth (Cochrane
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28. Terrone DA, Rinehart BK, Kimmel ES, May WL, Larmon JE, Morrison JC. A
prospective, randomized, controlled trial of high and low maintenance doses of
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29. Economy KE, Abuhamad AZ. Calcium channel blockers as tocolytics. Semin
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30. Papatsonis DN, Van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA.
Nifedipine and ritodrine in the management of preterm labor: A randomized
multicenter trial. Obstet Gynecol 1997 Aug;90(2):230-4.
31. King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel
blockers for inhibiting preterm labor (Cochrane Review). In: The Cochrane
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32. Sayin NC, Varol FG, Balkanli-Kaplan P, Sayin M. Oral nifedipine maintenance
therapy after acute intravenous tocolysis in preterm labor. J Perinat Med
2004;32(3):220-4.
33. Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for
preterm labor: A randomized clinical trial. Am J Obstet Gynecol 1999
Oct;181(4):822-7.
34. Stika CS, Gross GA, Leguizamon G, Gerber S, Levy R, Mathur A, Bernhard LM,
Nelson DM, Sadovsky Y. A prospective randomized safety trial of celecoxib for
treatment of preterm labor. Am J Obstet Gynecol 2002 Sep;187(3):653-60.
35. Schleussner E, Moller A, Gross W, Kahler C, Moller U, Richter S, Seewald HJ.
Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or
intravenous fenoterol combined with magnesium sulfate. Eur J Obstet Gynecol
Reprod Biol 2003 Jan 10;106(1):14-9.
36. K Duckitt, S Thornton. Nitric oxide donors for the treatment of preterm labour
(Cochrane Review). In: The Cochrane Library, Issue 3, 2004.
37. Romero R, Sibai BM, Sanchez-Ramos L et al. An oxytocin receptor antagonist
(atosiban) in the treatment of preterm labor: A randomized, double-blind,
placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000
May;182(5):1173-83.
38. Valenzuela GJ, Sanchez-Ramos L, Romero R, Silver HM, Koltun WD, Millar L,
Hobbins J, Rayburn W, Shangold G, Wang J, Smith J, Creasy GW. Maintenance
treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban
PTL-098 Study Group. Am J Obstet Gynecol 2000 May;182(5):1184-90.
39. Pierzynski P et al. Inhibitory effect of barusiban and atosiban on oxytocin-

induced contractions of myometrium from preterm and term pregnant women.
J Soc Gynecol Investig 2004 Sep;11(6):384-7.
40. Stan C, Boulvain M, Hirsbrunner-Amagbaly P, Pfister R. Hydration for treatment
of preterm labor (Cochrane Review). In: The Cochrane Library, Issue 3, 2004.
41. American College of Obstetrician and Gynecologists. Preterm Labor. Technical
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42. US Preventive Services Task Force. Home Uterine Activity Monitoring: Review
Article. JAMA 1993;270:371.
3
PS Mittal, C Rawat
What is Manual Vacuum

Aspiration
INTRODUCTION
Millions of women every year have an unwanted pregnancy. Some
unwanted pregnancies are carried to term; others end in an induced
abortion. Studies show that many married women in developing
countries often do not have access to the contraception they require to
space their children or limit family size. 1 Where contraception is
unavailable, inaccessible or fails, there will inevitably be a large number
of unwanted pregnancies. Women may resort to terminate such
pregnancies. An estimated 26 to 31 million legal abortions are performed
every year;2 millions of abortions, however, are performed outside the
legal system as unsafe abortions.
Unsafe abortions are characterized by the lack or inadequacy of skills
of the provider, hazardous techniques and unsanitary facilities. 3
Complications from unsafely induced abortions pose a serious global
threat to women’s health and lives. The WHO estimates that 10-50% of
women who have an unsafe abortion need medical care4 and account
for an estimated 13% of pregnancy related deaths.5 The tragedy of unsafe
abortion is that it is the most easily prevented cause of maternal death.
To perform safe abortions, MTP Act was passed by the Indian
Parliament in 1971 and came into force from 1st April 1972. The aim of
this Act was to reduce maternal morbidity and mortality due to
abortions.
Although the Act was implemented almost 30 years ago, the
complications of abortions continue to be a major contributor to maternal
death. This is an indication of the unmet need for safe abortion services.
The National Population Policy 2000 includes provision of safe abortion
services as one of the operational strategies. It includes the expansion of
What is Manual Vacuum Aspiration 53
access to safe abortion services through introduction of simple and safe

techniques such as Manual Vacuum Aspiration.
MANUAL VACUUM ASPIRATION

Manual vacuum aspiration (MVA) is a procedure for fertility control. It
is used for artificial removal of contents of the uterus within 8 weeks
from last menstrual period. It is a miniature suction curettage or Minivac.6
It was developed in 1960’s and underwent many changes in the last 30
years and has now come with a new design. It produces a negative
pressure of 60-70 cm of Hg. Pressure less than 60 cm is associated with
higher incidence of incomplete abortion and higher pressure is prone to
produce myometrial injury. Merik et al observed that uterine aspiration
removes 100% of fetal parts and 93% of villi.7 The aspirated material
contains almost no basal endometrium or myometrium thus indicating
minimal uterine damage. Greenslade et al reviewed more than 5000
women undergoing early abortion by MVA and found 98% success rate
which matches the success rate achieved by electric suction.8 Same results
were achieved by International Projects Assistance Services (IPAS)
multicentric study in India with success rate of 98.6%.9
OBJECTIVE OF INTRODUCING MVA TECHNIQUE

After studies and trials it was shown that MVA is a safe and simple
technique for termination of early pregnancy and it can be used in those
places where facilities are suboptimal like in PHC’s. Thus, helping to
increase the access to safe abortion services and also to offer another
safe method for termination of pregnancy.
INDICATIONS FOR USE OF MVA

1. Termination of pregnancies up to 8 weeks of gestation by medical
officers and up to 12 weeks by specialists.10
2. It can also be used for evacuation of uterus in incomplete abortion11
or molar pregnancy.12
3. Endometrial biopsy and endometrial aspiration cytology are the other
uses of MVA.9
• After studies in John Hopkins University, use of MVA was
suggested in second trimester abortion procedure with equal safety
and efficacy as in first trimester.13 But this suggestion faced many
controversies and requires to be investigated more widely.
CONTRAINDICATIONS
As such there is no absolute contraindication for MVA, however, MVA
should not be used in the following conditions at PHC’s and in facilities
without emergency backup.
1. Septic conditions.
2. Suspicion of ectopic pregnancy.
3. Pregnancy with fibroid uterus.
4. History of cesarean section or uterine surgery.
5. Severe cervical stenosis.
6. Medical disorders such as anemia (hemoglobin < 8 gm%), bleeding
disorders, hypertension, heart diseases, renal diseases, diabetes
mellitus.
MVA should be used carefully in the following conditions only after
ensuring arrangements for immediate referral: (i) Young adolescent and
(ii) Nulliparous women.
In case of vaginal discharge, infection must be treated before
considering for the procedure.
COUNSELING OF A CLIENT
As a thumb rule, every client who seeks MTP services must be counseled.
Counseling is an integral part of the safe abortion services. Along with
the explanation of type of procedure performed it helps the client to
decide about using a contraceptive method to avoid another unwanted
pregnancy leading to repeat termination of pregnancy. The process of
decision-making may be difficult for her and she may need help so
wherever possible spouse should be counseled.
Counseling ensures that the consent for the procedure is based on
information and client understands the implications. If even after
counseling, a client refuses for family planning method, MTP should not
be refused.
Counseling can be done at pre-abortion or post-abortion time and at
the time of follow up visit. All the three situations have their importance
but pre-abortion time is most favorable as client willingly listens to the
counseling.
Critical steps in counseling are:
1. Privacy and confidentiality.
2. Establish rapport with the client and gain confidence of the client.
3. Make the client feel comfortable psychologically as well as
physically.
4. Identify the reason for termination of the pregnancy.

5. Use simple language and discuss the potential problems associated
with termination.
6. Allow the client to clarify doubts.
7. Counseling specifically related to procedure performed i.e. MVA
• Type of sensation the client may feel.
• Likely risks associated with the procedure.
• General instructions to the client related to preparation.
• Idea about care after procedure.
8. Discuss various contraceptive methods available using cafeteria
approach including mechanism of action, advantages and
disadvantages, when and where to go for care.
9. Help the client to chose a method and assess whether the method
chosen is appropriate or not. If inappropriate, explain the reason
and help to choose another.
10. If the method is appropriate, provide method-specific information.
11. Record the refusal or acceptance of any point covered in counseling.
CLIENT ASSESSMENT
Eligibility to undergo MVA for termination of pregnancy is critical, to
avoid complications which would result in significant maternal morbidity
and mortality.
Assessment provides the following information—
1. Confirmation of pregnancy.
2. Assessment of period of gestation.
3. Assessment of the client’s general health condition.
4. Associated gynecological disorders and infections.
5. Associated medical problems.
Lab investigations required are: blood grouping, hemoglobin, urine
albumin and sugar.
All findings should be documented.
CARE BEFORE PERFORMING MVA

General instructions to the client: The client
• Should be accompanied by a responsible person, preferably the
spouse.
• Have a light breakfast early morning.10
• Must bathe and wear clean and loose clothing.
• Must not wear any jewelry.
Instruction to the Staff

• Shaving of the perineum and vulva is not required.
• Obtain informed consent for the procedure.
• Immunization against tetanus and pre-procedure antibiotic should
be provided.
• Give a dose of analgesic and anti-spasmodic an hour before the
procedure.
Take all aseptic and antiseptic precautions prior to, during and after
the procedure.
The procedure can be done under para-cervical block by 1% lignocaine
so there is no need for sedation or general anesthesia.14 Indications for
G.A are extremely young client, very anxious client and in cases of cervical
stenosis.
REQUIREMENT FOR PROCEDURE

In any of the centers recognized under the MTP Act, MVA should be
performed only in the labor room or the minor Operation Theater. The
facility of clean running water, a toilet and a separate place with privacy
for counseling must be available.
EQUIPMENT AND INSTRUMENTS NEEDED

1. MVA set:
a. MVA syringe: It is a 60 c.c syringe (usually made with polyethylene/
high density polypropylene) with a capacity to hold vacuum of
25-26 inch of Hg or 60 to 70 cm of Hg or 600 to 700 mm of Hg
which is almost equivalent to the vacuum created in an electric
suction pump. It has a water displacement capacity of 80% (i.e. 50
ml) of the syringe capacity in less than 1 second.9 The parts of
syringe are (Figs 3.1 and 3.2):
• A Barrel with calibration.
• Double/single valve set that fits to the tip of the barrel.
• The tip of the syringe is fashioned to hold the cannula tight.
• Plunger with arms that snap out when the plunger is pulled
back.
• Collar-stop that holds and locks the plunger inside the syringe
when fully pulled back out of the barrel.
• Plunger O-ring.
• Silicone for lubricating the O-ring.
Fig. 3.1: MVA syringe
Fig. 3.2: MVA double valve syringe and cannulae

b. Flexible plastic cannulae of sizes 4 to 8 mm (outside diameter)

corresponding to the period of gestation. Each cannula has a closed
rounded tip with two opposing openings with an overhanging
convex hood that acts as a curette. There are dots over the cannula
to know the uterocervical length. The dot nearest to the tip of the
cannula is 6 cms from the tip and each dot is at 1 cm interval.
2. Other instruments: required as per routine suction and evacuation set,
e.g. Sim’s speculum, anterior vaginal wall retractor, vulsellum, etc.
3. Equipment for resuscitation must be available like Ambu bag, oral
airway, oxygen cylinders.
4. Drugs for sedation, local anesthesia, antibiotics and for emergency
must be available.
TECHNIQUE OF MVA
• Ensure that all the equipment, instruments and drugs to be used
during the procedure are sterilized and ready to use.
• Ask the client to empty the bladder.
• Preparation of Vacuum Syringe and Cannulae: After scrubbing, wear
sterile gown and gloves. Inspect the syringe and cannulae for any
visible cracks and defects and ensure that the syringe can hold vacuum
to its maximum capacity and throw out cracked cannulae as broken
cannula causes tissue injury. Close the pinch valve by pushing the
buttons down and forward towards the syringe tip—one can feel
the valve lock. Pull back on the plunger until the arms of the plunger
snap outwards at the end of the syringe barrel holding the plunger
in place. Check the stable positioning of the plunger arms (the plunger
arms must be fully extended to the sides and secured over the edge
of the barrel). With the arms in this position, the plunger will not
move forward and vacuum is maintained (Figs 3.3 and 3.4).
• Preparation of the client: Give lithotomy position and clean the
perineum and suprapubic area with antiseptic solution with the help
of sponges using a sponge holding forceps. Clean the vagina with
antiseptic solution and use clean perineal sheet as a drape. Do pelvic
examination before starting the procedure. Communication must be
maintained with the client throughout the procedure and the client
should be told each step.
• Steps of procedure: Insert the speculum gently to visualize the cervix.
Hold the anterior lip of cervix using vulsellum and hold steady while
gently applying traction. Insert the cannula through the cervix into the
uterine cavity just past the internal os by rotating the cannula while
Fig. 3.3: Preparation of vacuum in syringe-1
Fig. 3.4: Preparation of vacuum in syringe-2
gently applying pressure. Start with cannula of size 4 and gradually

increase to the size that corresponds with the period of gestation. Push
the appropriate cannula slowly beyond the os until it touches the fundus
(Figs 3.5 and 3.6).
Note the uterine depth by the dots visible on the cannula and now
withdraw the cannula slightly. Attach the prepared syringe to the
cannula, ensuring that the cannula does not move forward. Release
the pinch valve on the syringe to release the vacuum into the uterine
cavity (Figs 3.7 and 3.9).
Fig. 3.5: Cannula insertion—1
Fig. 3.6: Cannula insertion—2
Fig. 3.7: Vacuum release

Fig. 3.8: Releasing pinch valve
Bloody tissue and bubbles should begin to flow through the cannula
into the syringe. Evacuate any remaining contents of the uterine cavity
by gently rotating the syringe and then moving the cannula gently and
slowly, back and forth within the uterine cavity (Figs 3.9 and 3.10).
Fig. 3.9: Evacuation of uterine contents
Check for the Signs of Complete Evacuation

The procedure is complete when red or pink foam and no more tissue
are seen, a gritty sensation is felt known as ‘uterine cry’,15 and the uterus
contracts around the cannula or cervix grips the cannula.
Withdraw the cannula and detach the syringe. Remove the vulsellum
and speculum and clean the vagina with antiseptic solution. Place all the
instruments including syringe in the disinfection tray. Inspect the tissue
Fig. 3.10: Evacuation
removed from the uterus for its volume and nature to see villi. Clean
the cannula in water, villi/sac will be seen floating.
Precautions
Do not rotate the cannula more than 180 degree (half turn).
Care should be taken to insert, remove or pull instruments slowly in
order to avoid inflicting pain.
Ensure that no opening of cannula is outside the os as this will cause
vacuum to be lost.
Ensure that the cannula is not pushed in too much, to avoid
perforation.
While the vacuum is well established and the cannula is in the uterus,
ensure that the syringe is not grasped by the plunger, as it may cause
the plunger arms to be unlocked and slide back into the syringe, pushing
the contents back into the uterus.
MANAGEMENT OF PROBLEMS DURING THE PROCEDURE

1. Technical problems with the MVA:
a. The syringe is full: Close the valve of the syringe and disconnect
the syringe. Empty the contents by opening the pinch valve and
pushing the plunger in. Re-establish the vacuum, connect the
syringe to the cannula and continue the procedure.
b. The opening of the cannula is outside the uterus with the valve
open: In these cases vacuum will lost, so remove the syringe and
cannula, close the valve of the syringe, detach the syringe and
empty its contents. Re-establish the vacuum and reinsert the

cannula, reconnect the syringe and continue the procedure.
c. The cannula is clogged: This is evidenced by the absence of tissue or
bubbles flowing into the syringe. In such a situation, close the
valve of the syringe and remove the syringe and cannula. Remove
the material blocking the cannula using sterile forceps or flush the
cannula and the syringe with sterile solution or water. Disconnect
the syringe from the cannula, re- prepare the syringe as described
earlier or change the cannula.
d. The syringe does not hold vacuum: Try lubricating the plunger and
barrel with the lubricant. If the lubrication does not work, replace
the O-ring. Even then if the vacuum does not build up, discard
syringe.
2. Clinical problem during the procedure: In case of suspected perforation,
fat or omentum is seen in the cannula, excessive bleeding or no
products of conception are seen. Manage the condition accordingly
by taking second opinion if specialist is doing or refer the client to
higher center if medical officer is doing the procedure or if procedure
is being performed in the periphery.
CLIENT CARE AFTER PROCEDURE

After procedure is over, check the vital signs and make her rest
comfortably at a place where she can be observed. Before discharging
her, check vital signs, bleeding per vaginum, ask for abdominal cramps,
ask to pass urine, have some light diet and discharge her at least after
two hours when she is stable and able to walk without assistance.
ADVICE ON DISCHARGE
• Prescribe antibiotics.
• Tell about uterine cramps and spotting per vaginum, which usually
occur during normal recovery.
• Inform about return of normal menses within 4 to 6 weeks.
• Counsel regarding contraceptive, as fertility returns in 2 weeks.
• To avoid intercourse until a week after bleeding stops.
• Ask to report immediately if no menstrual period within 4 to 6 weeks,
bleeding more than normal menstrual flow or prolonged bleeding.
Also warn about severe or increased pain during menses, foul
smelling discharge per vaginum and fever.
• Never forget to give date for follow up i.e when, where and whom
to visit.
• As per guidelines, after any suction procedure patient’s uterus must
be checked after 3 weeks for evidence of continuation of pregnancy.10
FOLLOW UP
If possible, one home visit by Female Health Worker or Female Health
Assistant should be done within a week to ensure the client’s well being.
During the visit, the worker should do the following:
a. Inquire about problems.
b. Look for any signs and symptoms requiring treatment or refer.
c. Clear doubts if any.
d. Counseling for contraceptive.
e. Record visit and advice given.
Client must come for follow up at least after two weeks to hospital
and doctor should do the following:
a. Inquire about problems.
b. Look for any signs and symptoms of complications if any.
c. Contraceptive counseling.
d. Record visit and advice given.
COMPLICATIONS
No surgical procedure is devoid of complications and this is also
applicable to MVA. Complications can occur during or after the
procedure. However the rate of complications is lower compared to
other surgical methods of termination of pregnancy.
Complications during the procedure occur as a complication of local
anesthesia and also due to procedure itself as excessive bleeding per
vaginum, uterine perforation or fainting. Fainting usually occurs due to
vasovagal attack when the cervix is forcefully dilated. This may last
only for a few seconds to minutes, provided the pain is controlled.
Delayed complications include incomplete evacuation (commonest),
infection and continuation of pregnancy. Failure rate is 1 in 500
pregnancies.16
Causes of Failure of Uterine Evacuation by MVA

a. Failure to assess size (size is more).
b. Failure to detect extra-uterine pregnancy.
c. Pregnancy in a rudimentary horn of uterus.

d. Anatomically abnormal uterus.
e. Failure to assess direction of the uterine cavity.
f. Small size cannulae.
g. Difficult dilatation.
h. Uncooperative client.
i. Surgeon’s limited experience
j. Faulty instruments and technique.
Remote complications may occur during future pregnancies, e.g.:
adherent placenta, uterine rupture due to previous undiagnosed
perforation during MVA, recurrent mid pregnancy abortions due to
cervical incompetence as a result of injury to the cervix, ectopic pregnancy,
infertility and amenorrhea due to Asherman’s syndrome.
STERILIZATION AND MAINTENANCE OF EQUIPMENT
Decontamination
Immediately after use soak all the instruments including cannulae and
syringes for 10 minutes in 5% chlorine solution and for the MVA syringe
draw the solution through the cannulae which should then be soaked in
the solution. As chlorine solution can corrode the metal in metallic articles,
exposure should be limited to 10 minutes and items should be washed
immediately after removing them. Change the chlorine solution daily
or more frequently if grossly contaminated.
After decontamination, wash the items thoroughly in lukewarm water
with detergent to remove all organic material. Detergent must be used,
as water alone will not remove proteins or oils. Soap is not recommended
as it can leave a residue, which is difficult to remove. Hot water should
not be used because it can coagulate protein such as blood, making it
hard to remove.
Do not use brushes or other small objects to remove matter as they
can scratch the inside of cannulae and syringes creating crevices where
organic material can get trapped. Use soft cloth for scrubbing.
Disassemble the syringe. Ensure that the collar, O-ring and valve set
and cannula are carefully removed.
After washing, equipment should be dried. Wet instruments should
not be placed into chemical disinfectants because water may dilute the
chemicals.
Sterilization/High Level Disinfection (HLD)

For HLD submerge the decontaminated and cleaned MVA syringe and
cannulae in 2% activated glutaraldehyde (Cidex) or 5% chlorine for 20
minutes. For sterilizing the equipment, submerge the syringe and
cannulae overnight (for 10 hours).
After HLD or sterilization, rinse with sterile water or boiled cool
water and make air dry before storing. Do not use iodine or formaline
and also do not boil or autoclave.
STORAGE/REASSURANCE
The MVA syringe should be lubricated and reassembled and also checked
for vacuum tightness before storing. Stored in covered trays, which are
sterilized or disinfected under HLD. Use these within one week. If not
used within a week, items should be re-cleaned and HLD should be
done.
ADVANTAGES OF MVA TECHNIQUE

• It is a simple, safe and effective technique.
• Equipment is cheap and portable.
• Also used for incomplete abortion.
• Not dependent on electricity so better in rural areas. Also if electricity
fails in urban areas it can be used as a backup method.17
• No need for any anesthesia. In selected cases only, local infiltration
is needed.
• Can be done upto 8 weeks of pregnancy by trained medical officers
and upto 12 weeks by specialists.
• Its complication rate is low. If uterus gets perforated, sucking of the
bowels is avoided since the vacuum very quickly drops, unlike in
electric machine where vacuum creation continues till the system is
switched off.
• It is easy to inspect the aspirate for products of conception, as tissue
remains more or less intact.
• Can be used by less qualified persons.
• Needs less cervical dilatation.
• Less discomfort to the client.
• No noise at all.
Women treated with MVA were significantly more likely than those
treated with sharp curettage to receive a contraceptive method before
leaving the hospital and also these clients receive better information
regarding uterine evacuation procedure and feel more at ease during
the procedure as they understand the pain management more. Reason
being, better communication between health care provider and client,
as woman remains conscious through out the entire process.17
Menstrual Regulation (MR) versus MVA18

• MR can be performed only up to 6 weeks after last period.
• Menstrual regulation is not included under the MTP Act.
• Can be done by 4, 5 or 6 mm cannulae only.
• Consists of single valve syringe only
MVA versus Electric Vacuum Aspiration (Table 13.1)

Table 13.1
Manual vacuum aspiration Electric vacuum aspiration
• Portable and economical. • Heavy, expensive and noisy apparatus.
• Not dependent on electricity. • Electricity dependent.
• More suited for rural settings. • More suited for urban settings.
• Takes one second to create 26" • Takes 1 to 1.5 minutes to create 26" of
of Hg vacuum. Hg vacuum.
• Rotation possible to 360 degree • Rotation does not occur easily because
because of easy maneuverability. of kinking of tube.
• Precreated vacuum gets transferred • Vacuum is created gradually within the
to uterine cavity. uterine cavity.
• Precreated transfer of vacuum • Since vacuum takes time to reach 26 “
helps to find cleavage between the of Hg not possible to create cleavage
sac and endometrial lining, allowing easily, therefore, material comes out in
sac to get sucked into the aperture of pieces causing more bleeding.
the cannula en mass causing minimal
bleeding.
• In case of uterine perforation, the • In case of perforation, vacuum continues
vacuum drops to less than 10 mmHg endangering pulling out of mesentery
and therefore, prevents sucking in and intestines.
of mesentery and intestines.
• Cannula acts as a dilator causing • Metal dilator to be used, which causes
minimal discomfort and pain. pain and damage to the cervix.
• Relatively newer technique, hence • Established technique for nearly two
not many are conversant. decades and most are conversant.
Advantages of MVA over D&C

• Shorter time is required for the procedure.
• More complete removal of uterine contents.
• Risk of perforation is less.
• Less blood loss.

• Fewer major complications.
• Well suited for local anesthesia only.
• Appropriate for performance by well-trained para-professionals.
• Easily adapted to be an out patient procedure.
Disadvantages
• Main disadvantages related to the equipment are that the MVA
syringes need to be replaced after 60 procedures and cannulae after
12 procedures.9
• Complications are those which may be encountered with any of the
surgical methods used for termination of pregnancy, namely:
— Hemorrhage
— Infection
— Perforation
Yet the complication rate is low and with careful selection of clients
and care during the procedure above can be avoided.
• MVA can be misused to perform illegal abortions.
CONCLUSION
In conclusion we must say that all couples and individuals have the
basic human right to decide freely and responsibly the number and
spacing of their children and every child should be a wanted child. It is,
therefore, important that government, inter-government and non-
government organizations deal openly and forthrightly with unwanted
pregnancies as a major health concern.
Prevention of unwanted pregnancies must always be given the highest
priority and if not possible, government should provide safe abortion
facilities. Manual Vacuum Aspiration technique is a safe effective procedure
for uterine evacuation by various cadres of health care providers being
trained in the provision of post abortion care services.19 It is meant to
assist with the expansion of the existing safe abortion services and not to
replace the existing techniques of medical termination of pregnancy,
since it provides an additional method with many advantages.20
REFERENCES
1. Westoff CF, Ochoa LH. Demographic and Health Surveys. Unmet need and the
demand for Family Planning Comparative Studies 5. Columbia M D Institute
for Resource Development/Macro International Inc, 1991.
2. Henshaw SK, Morrow E. Induced abortions: A world review. 1990 Supplement

New York (AGI).
3. The prevention and management of unsafe abortion- Report of a Technical
Working Group, Geneva; 12-15 April 1992.
4. Starrs A. Proceedings of the SMH Technical Consultation, 18-23 Oct 1997,
Colombo, Sri Lanka.
5. WHO Unsafe Abortion. Global and regional estimates of incidence and mortality
due to unsafe abortion with a listing of available country data. Geneva WHO
1998.
6. Seanfine: “Abortion obtained soon after conception.” The Globe and mail.
Toronto On 1997, Dec 23.
7. Mataliya MV, Jassawala MJ. Manual on MTP : An update, 3rd edn, New Delhi:
Jaypee Brothers 1999;9:48.
8. Greenslade FC, Benson J, Winklers et al. Summary of clinical and programmatic
experience with MVA. Adv Abortion care, 1993;3: 1-4.
9. Parikh MN. MVA. The Journal of Obst Gynecol of India 2003;53: 437-438.
10. Guidelines for Medical Officers for MTP up to 8 weeks- Maternal Health Division
from Department of Family Welfare Govt. of India, New Delhi 2001;1:4.
11. Fawcus S, Mc Intyre J, Jewlers RK et al. Management of incomplete abortion at
South African public hospitals. S Afr Med J 1998;87: 438-42.
12. WHO: Integrated Management of Pregnancy and Childbirth (IMPAC)—
Management of complications of pregnancy and childbirth: A guide for midwives
and doctors, 2000;65.
13. Todd CS, Soler ME, Castleman L, Rogers MK, Blumenthal PD. MVA for second
trimester pregnancy termination. Int J Gynecol Obstet 2003;83: 5-9.
14. Gomez PI, Gaitan H, Nova C, Parodar A. Paracervical block in MVA. Obstet
Gynecol 2004;103: 943-51.
15. Chaudhri SK. Pregnancy Termination. In Chaudhri SK (Ed): Practice of Fertility
Control, 4th edn. New Delhi: BI Churchill Livingstone, 1997;13:228.
16. http: // www.google.co.in/ search.www.ppin.org/observices.cfm
17. Billings DL, Velasquez JF, Cueras RP. Comparing the quality of three models of
post abortion care in public hospitals in Mexico City. International Family Planning
Perspective 2003;29(3):112-120.
18. Shah S. Technical nuances. MVA: Making Abortion Safer, FOGSI Focus 2002;6:
9-11.
19. Uterine evacuation using MVA. Niger Med J 2001;44(1):17-20.
20. Forna F, Gulmozogly AM. Surgical procedures to evacuate incomplete abortion
(Cochrane review). In: The Cochrane Library, Issue 4, Oxford: Update Software
2001.
4
Deepika Deka, Neema Sharma
Decision Making for the

Intrapartum Management
of Twins
INTRODUCTION
There is enough evidence that multifetal gestations are at increased risk
of maternal and fetal complications. In experienced hands, close clinical
attention to the course of the pregnancy, combined with serial ultrasonic
and biophysical studies and supportive psychological counseling produce
good results. The increased incidence of fetal malpresentation, preterm
and dysfunctional labor, intrauterine growth restriction and discordant
growth, placental abnormalities, cord prolapse, post partum hemorrhage
requires skilled obstetrical maneuvers and care. Appropriate intrapartum
management is as important as intensive antenatal care to improve
perinatal outcome.1
It was demonstrated in the early 1960s that the overall duration of
labor is the same with twins as is the case with singleton pregnancies,
and longer in nulliparous women than multiparous women.2 However,
Friedman showed that, although the latent phase was shortened (2.7 hr
for twins versus 5.6 hr for singletons), the active phase and the second
stage of labor were prolonged.3
INITIAL INTRAPARTUM EVALUATION OF TWIN GESTATIONS

Because of the advent of routine sonographic examinations during
pregnancy, most twin gestations are diagnosed in the antepartum period.
Upon admission to the labor and delivery suite, a pertinent obstetric
history should be meticulously reviewed for potential complicating
factors, which might alter intrapartum management. The history should
Decision Making for the Intrapartum Management of Twins 71
also include verification of pregnancy dating and determination of

accurate gestational age. The following antepartum features should be
checked, and evaluation should be performed, ultrasonically if necessary:
1. Presentation of each fetus (first cephalic/non cephalic, second non-
cephalic)
2. Estimated fetal weights of each twin (<1.5 kg/>3.5 kg), any growth
restriction or discordance
3. Amniotic fluid assessment, polyhydramnios
4. Fetal congenital malformations of any twin
5. Placental locations, whether in the lower segment
6. Chorionicity and amnionicity, especially whether monochorionic -
monoamniotic
7. Viability of each fetus
8. Biophysical assessment of each twin
Ultrasonographic assessment is useful in evaluation of these
parameters to make critical decision in route of delivery.
ROUTE OF DELIVERY
There is no general consensus regarding the optimal route of delivery
in multiple gestations. Cesarean section rate in twins are 2-3 times higher
than for singleton pregnancy.4 Table 4.1 shows obstetric indications for
cesarean section in twin gestation.1
Table 4.1: Obstetric indications for cesarean section in twin gestation
• Non cephalic presentation of twin A
• Intrauterine growth restriction in dichorionic twins
• Placenta previa
• Fetal abnormality precluding safe vaginal delivery, e.g. conjoined twins
• Chronic TTTS in monochorionic twins
• Monoamniotic twins
(Houlihan C, Knuppel RA: Clin Perinatol 1996)
The preferred delivery route for women with twins is dependent on

several factors—(i) presentation and position of the twins, (ii) maternal
and/or fetal complications, (iii) estimated fetal weights, besides,
(iv) experience and skill of the obstetrician in intrauterine fetal
manipulations, and (v) availability of resources for specialized monitoring
and emergency care in labor and delivery. Patricks et al have given
certain recommendations for intrapartum management at vaginal
delivery in twins4 as given in Table 4.2.
Table 4.2: Recommendations for intrapartum management at vaginal delivery in twins
• No obstetrical contraindication to vaginal delivery as in singleton pregnancy
• Appropriate fetal presentation and position
• Fetal monitoring feasible for both fetuses
• Experienced Obstetric attendant present throughout labor
• Availability of additional trained Obstetric personnel for delivery
• Availability of an adequate number of skilled personnel for newborn resuscitation
• Immediate availability of Anesthesiologist
• Immediate access to emergency cesarean delivery
• Availability of obstetric ultrasound in labor ward
• Immediate availability of blood products
• Adequate intravenous access
(Patricks S Ramsey, John T Repha: Seminars in Perinatology 2003)
PRESENTATIONS AND POSITION OF TWINS

Each of twin fetuses may have several types of presentation, lie and
position—cephalic, breech, transverse, oblique, face, brow, etc. The
commonest presentations are shown in Table 4.3.
Table 4.3: Type and incidence of twin presentations in labor

Twin A Twin B Incidence %
Vertex Vertex 42.5
Vertex Non Vertex 38.4
Non vertex Other 19.2
(Chervenak FA, Johnson RE, Berkowitz RL et al. Am J Obstet Gynecol 1984).
Vertex-vertex is the most common presentation of twins at term.

Over 40% of twin pregnancies are in a Vx/Vx presentation at the time of
labor and delivery.5 The route of success for vaginal delivery in vertex-
vertex twins is 70 to 80%.6 Currently, no data supports the notion that
vertex-vertex preterm gestation should be electively delivered
abdominally. Data from several large studies indicate no increase in
perinatal morbidity or mortality in vertex-vertex infants delivered
vaginally or by cesarean section, regardless of gestational age or birth
weight.7
Major area of controversy in the obstetric literature is the optimal
management of the vertex-nonvertex twin gestation. Issues contributing
to this area of controversy include gestational age of the fetuses,
difference in birth weight among the inter twin pairs, safety and efficacy
of external cephalic version, and risk of performing total breech
extractions.
ESTIMATED FETAL WEIGHTS

If the Twin-A is too large so as to cause problems for the after coming
head, or if it is too small so as to cause entrapment of head in an
inadequately dilated cervix, cesarean section is a better alternative. Adam
et al advised cesarean section of the non-vertex second twin less than
1500 gm because of a poorer outcome if delivered by internal podalic
version and breech extraction.8 However in non-vertex second twin
weighing more than 1500 gm and less than 3500 gm vaginal delivery
may be a safe option.5 ACOG recommends external cephalic version for
second twin less than 1500 gm.
FETAL COMPLICATIONS
Cesarean Section is recommended for fetal complications such as
monoamniotic twins, which will avoid problems of twin entanglement
during parturition, conjoined twins if the fetuses are mature as vaginal
delivery may be traumatic. Vaginal delivery of conjoined twins for the
purpose of pregnancy termination is possible because the union is most
often pliable, although dystocia is common. Discordant twins may be a
sign of pathological growth restriction in one fetus, which predicts an
adverse neonatal outcome. The incidence of respiratory distress,
intraventricular hemorrhage, periventricular leukomalacia, sepsis and
necrotizing enterocolitis all increase with the degree of discordance.
Maternal request is an important indication for cesarean section as it
is related to a high proportion of twins as a consequence of infertility
treatment in older couples.
INDUCTION OF LABOR
The American College of Obstetricians and Gynecologists (1995) has
stated that multifetal gestation is not a contraindication to labor
induction, but is a condition that warrants special attention. Satin and
Co-workers compared outcomes in 55 women with twins who were
given oxytocin for augmentation or induction of labor with 55 matched
singleton pregnancies. 9 Women with twin pregnancies responded
similarly to women with singleton. Standard protocols for cervical
ripening and labor induction appear to be appropriate for twin
pregnancies. Use of amniotomy on the presenting fetus’s sac, once
adequate cervical dilation and engagement of fetal head is achieved,
can promote progression of labor.
ANALGESIA/ANESTHESIA DURING LABOR

Epidural anesthesia is recommended for twin pregnancy. It offers
superior pain relief when compared to narcotic alternatives. It facilitates
either external or internal manipulation of twin 2 into a longitudinal lie
and/or perform breech extraction where indicated. Where epidural
anesthesia is contraindicated or declined by the woman, or she presents
in advanced labor, anesthetist should be available during the second
and third stages of labor, since any indication for general anesthesia is
likely to be emergency. Continuous epidural analgesia should be preceded
by adequate hydration, and the block should be allowed to come up
slowly to avoid a hypotensive episode. Because women pregnant with
multiple fetuses are even more vulnerable to supine hypotension during
labor and delivery, they must be placed in full lateral position during
and after induction of epidural analgesia. Crawford evaluated labor
progression in a series of 200 women with twin gestations.10 Women
who received epidural anesthesia had a significantly longer second stage
of labor compared to those who did not (90 min vs 30 min, respectively).
The mean delivery interval between the first and second twins was not
altered by epidural analgesia.
INTRAPARTUM FETAL MONITORING

When it is apparent that labor has been established, intravenous access
is obtained with a wide bore needle; hemoglobin, blood for grouping
and cross matching is done, lactated Ringer with aqueous dextrose
solution is infused at a rate of 60-120 ml/min. Nursing, pediatric/
neonatology, and anesthesia personnel are informed.
Routine continuous electronic fetal heart rate monitoring is
recommended for all twin pregnancies where facilities exist. Intrapartum
intermittent auscultation for fetal heart rate monitoring is not recom-
mended for pregnancies with twins.10 With twin gestation, two external
fetal heart rate monitors that allow for simultaneous monitoring of both
fetuses may be used. If satisfactory external monitoring of fetuses is not
possible during labor, an attempt should be made to apply a fetal scalp
electrode on the vertex of the presenting fetus where available, thus
allowing for the first twin to be monitored internally and second twin
to be monitored externally. Divergent fetal heart rate patterns should
be noted to assure that both the fetuses are being adequately monitored.
Fetal pulse oximetry is increasingly being used for monitoring these
fetuses.11 The ability to measure fetal oxygen saturation especially during
the second stage of twin labor adds critical information about fetal status
and aids the interpretation of abnormal FHR patterns.12
However, in most centers in India where continuous electronic fetal
heart rate monitoring is not available, intermittent auscultation of fetal
heart is recommended every 30 min during first stage of labor and 15
min during second stage of labor. Auscultation should be performed
after a contraction and for 60 seconds. Two fetal heart rate with difference
of 15 beats/min should be documented.
MANAGEMENT OF VAGINAL DELIVERY OF FIRST TWIN

Cephalic Presentation
Vaginal delivery of the first twin is conducted in a manner similar to
that for a singleton gestation. Immediately after delivery of the first
twin, the umbilical cord should be tightly clamped at both fetal and
placental ends. This practice prevents acute intrapartum fetoplacental
transfusion, which can be disastrous to the second twin in monochorionic
gestations. After twin A is delivered, blood should not be collected
until after delivery of the second twin. There are two reasons for this:
(i) there may be vascular connections between the placentas such that
blood from Twin B escapes through the cord of Twin A and (ii) removal
of blood from the placenta may hasten its separation from the uterine
wall, leading to placental abruption.
Non-Vertex Twin A
The ACOG 1998, has recommended cesarean section when the first twin
is non cephalic except in those instances in which the fetuses are so
immature that they will not survive.11 It is done because of following
reasons—
a. The presence of twin B could potentially interfere with the flexing of
the non-vertex twin A during descent.
b. If the fetus is quite small, the extremities and trunk may be delivered
through a cervix, which is inadequately effaced and dilated for the
head, which gets stuck.
c. Risk of umbilical cord prolapse.
d. Concern regarding a breech vaginal delivery through a non-distended
birth canal and untested pelvis.
e. There is the risk of disastrous complication of interlocking of the
fetal heads
Interlocking of the twins is rare and according to Cohen and

coworkers (1965) occurred once in 817 twin gestation.13 However, it
should be suspected if there is a delay during labor, in which the first
twin is in breech and the second twin is in a cephalic presentation. If a
vaginal delivery of a breech-vertex twin pregnancy is contemplated, an
abdominal X-ray or ultrasonogram at the beginning of labor should be
considered looking for evidence of inter locking twins. In addition, a
delay in descent of the breech presentation in a breech-vertex twin pair
should be an indication for cesarean delivery. If interlocking twins are
unexpectantly encountered in second stage, the Zavanelli maneuver
where breech baby is reposited into the vagina followed by cesarean
section may be an option to resolve this complication.
A recent study has shown that the perinatal mortality rate for breech
first twin delivered vaginally was not statistically different from vertex
presentation.14 There was no perinatal loss among babies delivered
vaginally by the breech. There was no difference in perinatal outcome
for the breech first twin born abdominally or vaginally. They concluded
that in the absence of a uterine scar or a footling presentation, there is
no valid reason to prohibit vaginal delivery when either twin presents
by the breech.
MANAGEMENT OF VAGINAL DELIVERY OF SECOND TWIN (Fig. 4.1)

The abdomen is palpated immediately following delivery of twin A.
Ultrasound can be used to confirm presentation, position, attitude and
fetal heart activity of twin B.
Intravenous oxytocin infusion is started at the rate of 4 mIU/min if
not previously running, or dose is doubled if used prior to delivery of
the twin A. Immediate augmentation shortens the inter-twin delivery
interval by preventing the commonly observed quiescence in uterine
activity following delivery of twin A. Efficient descent of the presenting
part, surrounded by intact fore waters, is achieved, thereby preventing
the cervix from closing, and ensuring that it remains fully dilated. Once
the presenting part is felt below the ischial spine, the woman should be
encouraged to push with each contraction. The membranes should not
be ruptured routinely, particularly with a breech presentation to avoid
the pitfalls of either a ‘high head’ or an unnecessary breech extraction.
Oxytocin should not be started until the obstetrician is absolutely
confident that the lie of twin 2 is longitudinal, otherwise an impacted
transverse lie may result.
Vertex/Non-vertex
Vaginal delivery of twin A
Twin B, wt 1500 gm Twin B, wt 1500 gm
ECV of twin B
Vaginal breech ECV

Successful Unsuccessful delivery of twin B of twin B
Probable CS
vaginal Successful Unsuccessful
delivery
Probable Vaginal CS
vaginal breech
delivery delivery
Fig. 4.1: Management of twin pregnancies
Second Twin Cephalic

With further progress of labor, the vertex of twin B should enter the
pelvis. At this time, amniotomy can be performed and monitoring of
twin B is carried out until its delivery. Operative delivery for the cephalic
second twin is associated with malposition and a high station. For this
reason ventouse is far safer than forceps delivery. A smaller cap is
preferred, so that application at a higher station will not include maternal
soft tissue.
Chauhan and Roberts15 summarized the reported experience of 373
sets of vertex/vertex twins. Twenty percent of the women in this
combined series underwent cesarean delivery for both twins. The
incidence of vaginal delivery of both twins, when their presentations
were vertex/vertex, was 72.9%. Importantly 2.2% of the second twins
were ultimately delivered by internal podalic version or breech extraction,
and 5.1% of the pregnancies required cesarean delivery for the second
twin. The most common indications for cesarean delivery of the second
twin included abnormal fetal heart tracing, malpresentation, umbilical
cord prolapse, and failure to progress.
Second Twin Breech

It is of more concern than for breech singletons because the second twin
is usually worse off than the first. Recent data have shown that for non
vertex second twins weighing more than 1500 gm. vaginal delivery may
be a safe option. Chervenak et al retrospectively reviewed the outcome
of 135 sets of vertex-nonvertex twins delivered between 1977 and 1981.5
In 69% of patients, breech extraction was performed on twin B, whereas
in 9% of patients, twin B was delivered as vertex after successful external
cephalic version. Cesarean Section was performed on both twins in 22%
of patients. Authors found that at birth weights of more than 1500 gm
there were no cases of low 5-min Apgar score, neonatal deaths or
documented cases of intraventricular hemorrhage, whereas the incidence
of these complications were significant in infants with birth weight of
less than 1500 gm delivered by breech extraction. Chervenak et al
recommended that vaginal breech delivery of twin B may be attempted
if the following criteria are met:5
1. Adequate maternal pelvis
2. Estimated fetal weight of more than 1500 gm and less than 3500 gm
3. Flexed fetal head
4. Sonographic estimates of fetal size obtained intrapartum
5. Use of sonography to facilitate breech extraction
External Cephalic Version

The American College of Obstetrics and Gynecologists recommend
external cephalic version in non-vertex second twin version as a
reasonable alternative in the situation of nonvertex second twins. It is
recommended especially when the estimated fetal weight of the second
twin is <1500 gm or when marked inter-twin weight discordance is noted
(>500 gm). Contraindication and causes of failure of external cephalic
version includes oligohydramnios and rupture of membranes,
established labor.
Procedure
Maternal flexion at the knees and hips relaxes abdominal musculature
and lateral uterine displacement prevents supine hypotension. Some
authors use powder on the maternal abdomen to facilitate a better grip
on the fetal poles. Others have used lubricant gel, olive or mineral oil so
the hands can slide over the maternal abdomen as the fetus is turned.
The critical first step is elevation of the fetal breech from the maternal
pelvis. After elevation of the breech, a to-and-fro movement
on appropriate poles of the fetus facilitates external cephalic version.
The patient’s pain threshold dictates how much pressure can be exerted.
Anesthesia, analgesia or sedation are not recommended as they might

allow excess force to be used causing placental abruption cord accident
or uterine rupture.16 The fetal heart rate is monitored either continuously
or intermittently by Doppler or real time ultrasound throughout the
version attempt.
Tchabo and Tornao reported their experience with ECV of second
born twin.17 They found that ECV was successful in 11 of 12 transverse
and 16 of 18 breech second born twin, i.e. successful vaginal delivery in
88% of breech and 92% of transverse presentations. Other investigators,
however, have described lower success rates or a higher incidence of
complications when ECV is attempted in second-born twins. Chauhan
et al 18 reported their experience with external cephalic version of the
nonvertex second twin and reviewed the literature assembling a series
of 118 cases for study. The overall success rate for external cephalic
version was 58% (range 46-80%). Complications, including umbilical cord
prolapse, fetal distress, abruptio placenta and compound presentation,
occurred in 10% of the version attempts.
Internal Podalic Version (IPV)

The IPV of the second twin should be attempted only when there is a clear
obstetrical indication, the estimated fetal weight of the fetus is
> 1500 gm, a clinician experienced by IPV and breech extraction is present,
adequate analgesia with immediate availability of obstetric anes-
thesiologist, and when access to immediate cesarean delivery is available.
It is indicated when emergency delivery is mandated (i.e. nonreassuring
fetal heart rate pattern, excessive bleeding or prolapse of the umbilical
cord). However, the cervix should be fully dilated and adequate amount
of liquor should be present for intrauterine manipulation. It must not be
attempted in neglected obstructed labor. Following delivery of the first
twin, ultrasound assessment is made to verify fetal presentation. With
both hands, one vaginally and one transabdominally, the fetal head is
displaced from the pelvic inlet. The internal hand is introduced further
forward towards the uterine fundus and the fetal feet are identified and
grasped. Using a gentle steady traction, the feet are guided down into the
lower birth canal and the cephalic pole is pushed up using the external
hand. Membranes are ruptured and total breech extraction is performed.
Chauhan et al analyzed data from 11 series of vertex-non-vertex twins (n
= 638) delivered by internal podalic version or by an assisted or total
breech extraction.15 Almost 90% of the twins had birth weights of more
than 1500 gm. The overall complication rate associated with breech delivery
was 1.4%. These complications include one fractured clavicle, and humerus,
two isolated fractured humeri, two cases of fetal distress, two cases of
cord prolapse, and two Cesarean Section for failed extraction.
Fishman et al 19 compared the outcome of vaginally delivered vertex
and breech second born twins of the 390 live born vaginally delivered
second twins, 207 were delivered as vertex and 183 were delivered as
breech. Ninety five percent of the breech deliveries were total breech
extractions. No significant differences were noted between the two
groups with respect to incidence of low 5 minute Apgar scores, neonatal
intensive care unit admissions, or length of neonatal hospitalization.
Time Interval between Vaginal Delivery of Twins

The acceptable time interval between vaginal delivery of twins remains
actively debated. Before epidural analgesia and widespread electronic
fetal heart rate monitoring, it was common to push the presenting part
into the pelvis after 5 min and perform amniotomy, resorting to operative
vaginal delivery after a further 10 min if spontaneous delivery was not
imminent.20 This limitation was to avoid complications such as cord
prolapse, uterine inertia, placental abruptio and retraction of cervix. In
modern obstetrics with epidural analgesia and, continuous fetal heart
rate monitoring; delay in twin-twin delivery is acceptable, provided
progress is being made towards successful vaginal delivery, bleeding is
minimal, and the CTG is normal. Adam et al found no low Apgar scores
among the 17 second twins delivering beyond 30 min.8
THIRD STAGE OF LABOR

The risk of atonic primary postpartum hemorrhage is considerably
increased with twin delivery. Upon delivery of the second twin, the
oxytocin infusion should be accelerated and intramuscular syntometrine
given. The oxytocin infusion should continue for 4 hr following delivery
and the placental discs inspected for completeness before repair of any
episotomy or vaginal tears. The woman is observed for 12 hr. Placenta
is delivered gently to preserve the attachment of the amnion and chorion.
The placenta and membranes should be closely inspected to determine
zygosity. The infant is monozygotic if there is one amniotic sac or
juxtaposed amnions are not separated by chorion. If adjacent amnions
are separated by chorion, the fetus could be either dizygotic or
monozygotic, but dizygosity is more common.
CONCLUSION
Optimal intrapartum management of twins continues to be debated.
Ultrasonography is very useful in initial assessment of the fetuses in the
labor and delivery suite, observations of the second twin after the first
has delivered, and in external cephalic version. Twin deliveries should
be undertaken in fully equipped hospital, with adequate facilities and
team of obstetricians and neonatologists.
REFERENCES
1. Houlihan C, Knuppel RA. Intrapartum management of multiple gestations.
Clin Perinatol 1996; 23: 91-116.
2. Ross C, Philpott N. Five year survey of multiple pregnancies. Can Med Assoc J
1953;69:247.
3. Friedman E, Sachtebern M. The effect of uterine overdistention on labor in
Multiple pregnancy. Obstet Gynecol 1964;164:23.
4. Patricks S, Ramsey, John T Repha. Intrapartum management of multifetal
pregnancies: Seminars in Perinatology 2003; 27:54-72.
5. Chervenak FA, Johnson RE, Berkowitz RL et al. Is routine cesarean section
necessary for vertex-breech and vertex transverse twin gestation? Am J Obstet
Gynecol 1984:148:1-5.
6. Cetrulo C. The controversy of mode of delivery in twins: The intrapartum
management of twin gestation. Semin Perinatol 1986; 10(1): 44-9.
7. Greig PC, Veille JC, Morgan T et al. The effect of presentation of mode of
delivery on neonatal outcome in the second twin: Am J Obstet Gynecol 1992;
167:901-6.
8. Adam C, Allen AC, Baskett TF. Twin delivery: Influence of the presentation and
method of delivery on the second twin. Am J Obstet Gynecol 1991; 165:23-27.
9. Satin AJ, Fausett MB, Gorden MC, Barth WH. Oxytocin labor stimulation of twin
gestations: Effective and efficient. Am J Obstet Gynecol 1996;174:483.
10. Crawford JS. A prospective study of 200 consecutive twin deliveries: Anesthesia
1987; 42:33-43.
11. American College of Obstetricians and Gynaecologists Educational Bulletin #
253: Special problems of multiple gestation. American College of Obstetricians
and Gynaecologists 1998;1-17.
12. Skocrylas M, Laudanski T. Use of oxi-cardiolocography in twin delivery. Ginekol
Pol 2002 Jan; 73(1): 19-23.
13. Cohen M, Koul SG, Rosenthal AH. Fetal interlocking complicating twin gestation.
Am J Obstet Gynecol 1965:91:407.
14. Roopnarine Singh AJ, Sirjusingh A, Bassaw B. Vaginal breech delivery and
perinatal mortality in twins. J Obstet Gynaecol 2002; 2293: 291-3.
15. Chauhan SP, Roberts WE. Intrapartum management. In Gall SA (Ed): Multiple
pregnancy and Delivery. St Louis: Mosby-Year Book, 1994;243-280.
16. Bradley-Watson PJ. The decreasing value of external cephalic version in modern
obstetric practice. Am J Obstet Gynecol 1975; 123:237.
17. Tchabo JG, Tornao T. Selected intrapartum internal podalic version of the second
twin. Obstet Gynecol 1992;79:421-423.
18. Chauhan SP, Roberts WF, Mc Laren RA et al. Delivery of nonvertex second
twin: Breech extraction versus external cephalic version. Am J Obstet Gynecol
1995;173:1015-20 .
19. Fishman A, Crubb DK, Kovacs BW. Vaginal delivery of the nonvertex second
twin. Am J Obstet Gynecol 1993;168;861-4 .
20. Donald I. Practical obstetric problems. London: Loyd-Luke, 1979 .
The Enigma of Hyperemesis Gravidarum 83
5
Shonali Agarwal
The Enigma of
Hyperemesis
Gravidarum
INTRODUCTION
Vomiting is a symptom, which is commonly associated with pregnancy.
It may be simply a result of altered physiology due to pregnancy or may
be a manifestation of some medical, surgical or gynecological
complications, which can occur at any time during pregnancy.
The causes of vomiting during pregnancy can be classified as under:
a. Early Pregnancy:
1. Related to pregnancy:
— Emesis gravidarum (morning sickness)
— Hyperemesis gravidarum
2. Unrelated to pregnancy:
Medical causes:
— Intestinal infestation
— Urinary tract infection, uremia
— Diabetic ketoacidosis
— Hepatitis
Surgical causes:
— Acute appendicitis
— Intestinal obstruction
— Peptic ulcer
— Cholecystitis
Gynecological causes:
— Twisted ovarian cyst
— Red degeneration of fibroid
b. Late pregnancy:
1. Related to pregnancy:
— Continuation of above mentioned causes
— Acute fulminant pre-eclampsia
2. Not related to pregnancy: Hiatus hernia
Out of all these causes the commonest ones are emesis gravidarum
and hyperemesis gravidarum
EMESIS GRAVIDARUM
• Commonly called ‘Morning sickness’ or the simple vomiting of
pregnancy.
• Occurs in about 50% of pregnant mothers.1
• Vomiting is associated with nausea and commonly occurs after
overnight recumbency.
• Vomitus is small, clear and bile stained.
• Not associated with any deleterious effect on the mother’s health or
restriction of day-to-day activities.
• Usually disappears by 14-16 weeks of gestation.
• Treatment:
— Reassurance and knowledge regarding the physiology.
— Advice to consume some high carbohydrate diet like dry toast or
biscuit before getting up from bed.
— Antiemetics only if the above mentioned treatment fails
HYPEREMESIS GRAVIDARUM
This entity has been defined in different ways in the literature. The two
most commonly used definitions are:
• Severe type of vomiting in pregnancy that has deleterious effect on
the mother’s health.
• Persistant vomiting with ketoneuria and weight loss more than 5%
before 16 weeks of gestation.3
INCIDENCE
Different books and studies mention variable incidence with mean being
about 1 in 1000 pregnancies. The incidence is steadily declining now-a-
days owing to:
• Better family planning methods reducing the incidence of unwanted
pregnancies.
• Better availability of antenatal care.

• Availability of safe and potent antiemetics.
In the western literature a difference has been noted in the various
races2.
16/1000 live births in Whites.
07/1000 live births in colored races.
ETIOLOGY
The exact etiology is not known but certain associations are known and
few theories are proposed.
The proposed theories are:
Hormonal
These are the most widely researched ones.
1. Excess of human chorionic gonadotropin
2. Hyperthyroidism
3. Hyperprogestronism
4. Hyperestrogenism
β hCG)
1. Excess of Human Chorionic Gonadotropin (β
• Increased incidence and intensity of vomiting when βhCG is at peak
(8-12 weeks)
• More incidence in molar gestations and multiple gestations in which
hCG levels are higher than normal singleton pregnancies.
• Associated with transient and self-reversible hyperthyroidism.4
2. Hyperthyroidism
• Hyperemesis gravidarum is associated with transient hyper-
thyroidism in the first trimester which gradually declines with the
increase in the gestational age without treatment with any antithyroid
drugs.2,4,5-13,16
• Bioassays indicated that the serum of mothers with hyperemesis
during pregnancy revealed significantly greater iodine uptake in
thyroid cells culture the other control sera.
• This is possibly because of the increase nonimmunological thyroid
which stimulator activates human TSH receptors in vitro.3
3. Hyperprogestronism
• Causes relaxation of cardioesophagial sphincter.
• Decreased intestinal motility and increased gastric emptying time.
4. Hyperestrogenism15
Psychogenic
• Hyperemesis is more in unwanted pregnancies.
• It is more in uninformed mothers.
• Usually decreases when shifted from home surroundings to a
different place.
Dietary Deficiencies
Hyperemesis if associated with:
• Low carbohydrate reserves.
• Deficiency of B-complex vitamins.
• Trace element deficiency.14
Allergic Basis
• Because the condition responds to antihistaminics in some.
Others
• Infection of gastrointestinal tract with Helicobacter pylori17
• High interleukin and cytokine levels18
• Low weight: height ratio in pregnancy19
• Immunological basis as more in primigravida.
PATHOLOGY
There are no specific anatomical findings. The organic changes are
generalized manifestations of starvation and severe malnutrition which
occurs only in prolonged untreated cases.
Organic Changes
Liver: Centrilobular fatty infiltration without necrosis.
Kidneys: Fatty changes in the cells of proximal convoluted tubules.
Heart: Occasional subendocardial hemorrhages.
Brain: Small hemorrhages in the hypothalamus, which is suggestive of
‘Wernicke’s encepalopathy’.
Metabolic Changes21,22
These are a result of combined combination of dehydration and
starvation due to vomiting.
Inadequate food intake leads to glycogen depletion. For the energy
supply, the fat reserves are hence mobilized. Due to the low carbohydrate
availability, there is incomplete oxidation of fat and accumulation of
ketone bodies in the blood. There is increase in the endogenous tissue
protein metabolism leading to excessive excretion of non-protein nitrogen
in the urine. Acetone is as a result excreted in the breath and in urine.
Biochemical Changes
Following are the biochemical changes occurring in condition of
hyperemesis gravidarum:
Increase in:
• Circulating ketone bodies
• Plasma levels of sodium, potassium, chloride& bilirubin.
Decrease in:
• PH
• Plasma levels of glucose, protein, vitamin.
Circulatory changes:
• Haemoconcentration
• Hypovolemia
CLINICAL COURSE
Early
• No evidence of dehydration and/or starvation.
• Vomitus contains only food or bile stained.
• Nutrition is not affected.
• Blood biochemistry and urine analysis is normal.
Late
• Increased vomiting.
• Oliguria.
• Epigastic pain.
• Constipation.
COMPLICATIONS
Complications are usually an effect of uncontrolled vomiting leading to
starvation and ketoacidosis. Few of the complications may also result
from the mechanical effect of increased intra-abdominal pressure
secondary to continuous vomiting.
Following are some of the complications reported in the literature
till date.
• Wernicke’s encephalopathy:23 It is characterized by restlessness,
mental apathy, insomnia, convulsion and coma.
• Korsakoff’s psychosis
• Peripheral neuritis:20 It is due to vitamin B12 deficiency as a result of
prolonged loss in vomiting.
• Coagulation disorder:29 It is due vitamin K deficiency and hemo-
concentration due loss of body fluids in vomiting.
• Pneumomediastinum:25 It is due to esophageal rapture.
• Spleenic avulsion:26 It is due to sudden increase in intra-abdominal
pressure.
• Blurring of vision27
• Renal of vision
• Hepatic dysfunction
• Mallory-Weiss syndrome
CLINICAL FEATURES
General Examination
• Progressive emaciation with weight loss.
• Anxious look with sunken eyes.
• Icterus
• Dry, coated tongue.
• Teeth covered with sordes.
• Acetone smell in breath.
• Tachycardia
• Hypotension
Per Abdomen Examination

• Uterus may be less than weeks of gestation.
• Epigastric tenderness.
Respiratory System
• Signs of acidosis, ketosis.
Cardiovascular System
• Findings due anemia.
Central Nervous System

• Wernicke’s encephalopathy
• Korsakoff’s psychosis
INVESTIGATIONS
Blood
• Complete blood count
• Blood sugar—Decreased
• PCV—Increased (suggestive of hemoconcentration)
• Sodium, Potassium, Chloride—Decreased
• Urea, Uric acid—Increased
• Bilirubin—Decreased
• Free T4—Increased, TSH—Decreased
• Hepatic enzymes.
Urine
• Small quantity and concentrated.
• High specific gravity
• Decreased chloride
Ophthalmic Examination
• Retinal hemorrhage, rarely retinal detachment
ECG
• To detect serum potassium levels.
USG
• To rule out molar gestation, multiple gestations.
MANAGEMENT
Principles of Management
1. To correct fluid, electrolyte and metabolic imbalance.
2. To prevent the occurrence of serious complications.
Steps of Management of Mother with Hyperemesis Gravidarum

Hospitalization
Owing to the neurologic factors involved in the occurrence of hyperemesis
gravidarum; it is often found that shifting the patients from home
surroundings to hospital reduces the symptoms even with the same
treatment as provided earlier at home.14
Sympathetic but firm handling of the patients should be done.
Fluid Management
Oral feeding should be withheld for 24 to 48 hours.28-30
Fluid requirement per day should be calculated taking into
consideration the fluid loss in vomiting + urine output + insensible losses
for perspiration, respiration and pyrexia.
Fluid less should be compensated by 1.5 lit. 5% dextrose + 1.5 lit. Of
dextrose saline + 5% dextrose equal to vomitus and urine output in last
24 hours.31, 32
Drip rate is calculated as:
No. of lit. of fluid to be infused in 24 hours multiplied by 12.
Some recommend addition of insulin 10 units per pint to allow
intracellular shift of glucose.
Potassium supplementation should be done only if indicated and with
proper ECG monitoring to avoid complications like cardiac arrhythmias
and heart block.
Drugs 34,35
Following are the group of drugs used in the management of hyperemesis
gravidarum:
Antiemetics and Antihistaminics

Majority of the studies prove that these drugs are safe in pregnancy and
rapid clinical improvement. They should be used in order to tide over
the situation fast and prevent complications.
They consists of the following group of drugs:

Piperazine derivatives
These drugs act by blocking the middle ear vestibular cerebellar pathway
and reduce the excitability of the middle ear.
Drugs FDA grading Dose
Meclizine B a 25-50 mg orally bd
Cyclizine B 50 mg IM 6 hourly
Buclizine C a 50 mg orally bd
Dopamine agonists
Drug FDA grading Dose
Metaclopromide36 Bb 10 mg orally qds
10 mg IM 6 hourly
Amorphous antagonists
Drug FDA grade Dose
Droperidol37 Cb 2.5–5 mg IM or IV slowly
Phenothiazine derivatives
These drugs block the postsynaptic mesolimbic dopaminergic receptors
in the brainstem reticular system.
Prometazine Cb 25 mg orally qds
12.5–25 mg IM 6 hourly
Prochlorperazine C 5–10 mg orally tds
5–10 mg IM 4 hourly
Max. 40 mg/day
Chlorpromazine C 10-25 mg orally qds
25 mg IM 6 hourly
Antihistaminics
They are the selective 5-HT receptor antagonists.
Ondensetron33 B b 8 mg IV every 4 hourly
Doxylamine Bb 25 mg orally qds or 50 mg hs
Vitamins38
They are used to prevent the neuropathy and accelerate the carbohydrate
metabolism.
Intramuscular injection containing Vit.B1, Vit. B6, Vit.C are given
daily.
Corticosteroids31-33,39,40
Many studies have shown a positive effect of a short course of
corticosteroids followed by rapid taper in resistant cases.
For example, methylprednisolone 10 mg tds for 2 days with rapid
taper over 2 weeks.
Ginger and its Extracts41

Ginger and its extracts contain gingerols, which inhibit the growth of
Cag A+ strain of H.pylori, which is associated with hyperemesis
gravidarum.
Alternative Therapies42
• Medical hypnosis43
• Accupressure:44 Pressure over the point P6 on the volar aspect of
wrist helps to relieve vomiting.
• Electrostimulation of vestibular apparatus.45
Nursing Care
Sympathetic but firm handling by trained staff plays an essential role in
the management of hyperemesis.
Accurate maintenance of input/output chart, vital sign chart, weight
chart, etc. is needed for the proper management of mother with
hyperemesis gravidarum.
Diet
Usually diet is started after patient has no vomiting for 24 hours with
treatment. It is started before the intravenous fluid therapy is omitted
in the form of small and frequent meals of dry carbohydrate rich foods
like biscuit, toast, etc. Diet is normalized quickly as the stomach is more
likely to retain solids than liquids. Gradually then full diet is stared.
Role of Termination of Pregnancy

Owing to the aforementioned treatment modalities termination of
pregnancy solely due to hyperemesis is a rare event now-a-days and is
carried out only in few situations; some which are as follows:
• Hemodynamic instability due to intractable vomiting inspite of
adequate and appropriate treatment.
• Hepatic failure
• Acute renal failure

• Neurological complications.
REFERENCES
1. Usha Saraiya, Kamini Rao, Alokendu Chaterjee. Principles and practice of
obstetrics and gynecology for postgraduates. 2nd edn. New Delhi: FOGSI
Publication, Jaypee Brothers Medical Publishers (P) Ltd, 2003;107.
2. Kenneth R Niswander, Arthur T Enva. Manual of obstetrics. 5th edn. Boston:
Little Brown and Company, 1996;109-110.
3. Daniel R, Mishell, JR Thomas Kirschhaum, C Paul. Year book of obstetrics and
gynecology. Chicago: Mosby-yearbook, Inc. 1994;94-95.
4. GoodwinTM et al. Role of HCG in transient hyperthyroidism in pregnancy. J of
Clinical Endocrinology Metab 1992;75:1333-1337.
5. Goodwin TM, Montoro M, Mestman JH et al. Transient hyperthyroidism and
hyperemesis gravidarum-clinical aspects. Am J Obstet Gynecol 1992; Nov 167:
648-652.
6. Kimura et al. Transient hyperthyroidism of hyperemesis gravidarum. BJOG
2002 June; 109(6): 683-8.
7. ACOG practice bulletin. Thyroid disease in pregnancy. Int J Gynecol Obstet 2002
Nov; 79(2): 171-80.
8. Kennedy RL, Darne J, Davis R et Al. Clinical Endocrinol 1992;36:83-89.
9. Lao TT, Chin RKH, Change AMZ. The outcome of hyperemetic pregnancies
complicated by transient hyperthyroidism. Aust NZ J Obstet Gynecol May 1987;
27:99-101.
10. Chan C et al. Gestational transient thyrotoxicosis. Am J Emer Med 2003 Oct;
21(6): 506.
11. Arslan EO, Censizl, Arslan M. Thyroid function in Hyperemesis gravidarum
and correlation with serum Leptin. Int J Gynecol Obstet Nov 2003;83(2):187-8.
12. Caffery TJ. Transient hyperthyroidism in preg. J Am Board FamPract. Jan 2002;
13(1): 35-8.
13. Tan JY, Con KL, Jeo GS. Hyperthyroidism in first trimester. BJOG 2002 June;
109(6): 683-8.
14. Teksen F, Dokmai G, Kavas D et al. Copper, Zinc, and magnesium status in
hyperemesis gravidarum. J Obstet Gynecol 2001;21(1): 46-48.
15. Laginu P, Tamim R, Mucci LA. Low prolactin and high estradiol in emesis
gravidarum. Obstet Gynecol 2003 April; 104(4): 639-44.
16. Bjelica A, Zoric D, Kapamadita A. Persistant hyperemesis gravidarum as
psychosomatic dysfunction: A case report. Med Preg 2003 March-April; 56(3-4):
183-6.
17. Xia LB, Yang J, LI AB et al. Relationship between hyperemesis gravidarum and
Helicobacter seropositivity. Clin Med J (Engl) 2004 Feb; 117(2): 301-2.
18. Kuscu NK, Yilfrum, Koyuncu F et al. IL-6 levels in hyperemesis gravidarum.
Arch Gynecol Obstet 2003 Nov; 269(1): 13-5.
19. Rochelson B, Vohra H, Parvishzadch J. Loq pregnancy ideal wt: ht ratio on
females with hyperemesis gravidarum. J Reprod Med 2003 June; 48(6): 422-4.
20. Kallen B, Landberg A, Aberg A. Relationship between age, smoking and vitamins
and nausea and vomiting of pregnancy. Acta Obstet Gynecol Scand Oct 2003;
82(10): 916-20.
21. Philip B. Review of current literature on hyperemesis gravidarum. WMJ 2003;
102(3): 46-51.
22. Smell LH, Haushneg BP, Burkh L. Metabolic changes in hyperemesis gravidarum.
J Perinat Neonat Nurs Sep 1998; 12(2): 26-37.
23. Ohara N, Navita F, Kayana et al. Wernicke’s encephalopathy associated with
hyperemesis gravidarum. Hosp Med 2003 June; 64(6): 46-48.
24. Robibsib JN, Banerjee R, Thiet MO. Coagulopathy as a complication in
hyperemesis gravidarum. Obstet Gynecol 1998 Oct; 94(4.2): 637-5.
25. Liang SG, Ooka F, Santo A et al. Pneumomedistinum due to esophageal rapture
in pregnancy. Obstet Gynecol Res 2002 June: 28(3): 172-5.
26. Nguyear N, Deital N, Lacy E. Spleenic avulsion in pregnancy. Can Surg 1995 Oct;
38(5): 464-5.
27. Kanyama N, Khatun S, Beayet Hmetall. Vasospasm of cerebral artery in
hyperemesis gravidarum. Gynecol Obstet Invest 1998 Aug; 46(2): 139-41.
28. Vaisman N, Kaida R, Levin I et al. Nasojejunal feeding in hyperemesis
gravidarum—a preliminary study. Clin Nutr 2004 Feb; 23(1): 53-57.
29. Arsenaut My. Management of nausea and vomiting of pregnancy. J Obstet and
Gynecolcan 2002 Oct; 24(10): 817-31.
30. HsuJJ, Glena R, Nelson DK et al. Nasogastric entral feeding in hyperemesis
gravidarum. Obst & Gynecol 1996 Sep; 88(3): 343-6.
31. Kuscu MK, Koyunda F. Current concepts and management of hyperemesis
gravidarum. Post Grad Med J 2002 Feb; 78(96): 76-9.
32. Jewel D, Young G. Intervention of nausea and vomiting on early preg. Cochrane
Database Syst Rev 2003; (4): CD000145.
33. Spu SS, Yi SK, Cheug CW. Treatment of hyperemesis gravidarum by
Ondensetron. Gynecol Reprod Bio 2002 Oct; 105(1): 73-74.
34. Willamson C. Drugs in pregnancy-Gastrointestinal diseases. Best Pract Res
Clinical Obstet Gynecol 2001 Dec; 15(6): 937-52.
35. Nelson Piercy. Drug Saf 1998 Aug; 19(2): 155-64.
36. Schroder D, Stein J. Antihistaminics and metaclopromide are safe and effective
in vomiting of pregnancy. MMW Fort Schr Med 2002 Dec; 144(50): 32-4.
37. Nageotee M, Briggs GG, Towers CW et al. Droperidol and diphenhydramins in
management of hyperemesis gravidarum. Am J Obstet Gynecol 1996 June;
174(6): 1801-5.
38. RabendaK, Wilczynski J, Breborowicz GH. Wernicke’s encephalopathy due to
hyperemesis. Ginekol Pol 2003 Aug; 74(8):633-7.
39. Yost NP, McIntire DD, Wians FH. A randomised placebo controlled trial of
corticosteriods for hyperemesis gravidarum. Obstet Gynecol 2003 Dec; 102(6):
1250-4.
40. Chan LY, Cam MH, Lau TK et al. Successful treatment of intractable hyperemesis
gravidarum with methylprednisolone: A case report. J Reprod Med 2003 Apr;
48(4):293-5.
41. Mahady GB, Pendland SL, Yun GS et al. Ginger and gingerols inhibit growth of
Cag A strains of H. pylori. Anticancer Res 2003 Sep-Oct: 23(5A): 3699-702.
42. Hollyer T, Boon H, Georgoesis et al. Use of complimentary and alternative
medicine (CAM) in nausea and vomiting of pregnancy. BMC Complement A
Hern-Med 2000 May; 21(1): 5.
43. Sim EP, Schwartz J. Medical hypnosis in hyperemesis gravidarum. Birth 1999
Dec; 26(4): 248-54.
44. Rosen T, Vecicina M, Miller HS. RCT of low level nerve stimulation for nausea
and vomiting of pregnancy. Obstet Gynecol 2003 July; 102(1): 129-35.
45. Golazewski et al. Electrostimulation of vestibular apparatus to cure intractable
vomiting. Z Gebert Neonatal 1995 May-June; 199(3): 107-10.
Episiotomy: Controversies and Current Thinking 95
6
Ankita Pasi
Episiotomy:
Controversies and
Current Thinking
Childbirth is a natural physiological process. But as time passed health

care personnel began assisting it and in due course indulged in interfering
with it. Finally a stage reached where a nulliparous woman in labor had
to succumb to surgical cutting of her tissues—if she escaped a cesarean
section her perineum got cut. Millions of women in India are subjected
to avoidable unnecessary episiotomy. Thanks to the arrival of evidence
based medicine, obstetricians have started questioning the need and
the wisdom of routine episiotomy.
INTRODUCTION
An episiotomy is a surgical incision made to enlarge the vaginal opening
during childbirth to assist delivery of the baby. This incision can be
midline or at an angle from the posterior end of the vulva. It should be
performed under local anesthesia and should, of course, be sutured after
delivery.
EPISIOTOMY TYPES
Here are the three major types of episiotomy (Figs 6.1A to C).
According to William’s Obstetrics,1 midline episiotomies are less
painful, heal better, are less likely to cause dyspareunia, and cause less
blood loss, but they are more likely to extend into the rectum.
Mediolateral episiotomies are the opposite.
Vaginal
opening
Perineum
Midline episiotomy
Vaginal
opening
Perineum
Mediolateral episiotomy
Vaginal
opening
Perineum
Hockey stick episiotomy
Figs 6.1A to C: Types of episiotomy

Episiotomies are said to provide the following benefits:

• Speed up the birth
• Prevent Tearing
• Protects against incontinence
• Protects against pelvic floor relaxation
• Heals easier than tears
These all appear to be valid reasons. The fact is that medical research
has not proven any of these benefits. In fact, in many of the cases, the
opposite is actually true. Episiotomies can actually cause harm.
The following have been reported as side effects of the episiotomy:
• Infection
• Increased Pain
• Increase in 3rd and 4th degree vaginal lacerations (euphemistically
called extensions)
• Longer healing times
• Increased discomfort when intercourse is resumed
EPISIOTOMY: IS IT REALLY NECESSARY?

In recent years, the effectiveness of routine episiotomy to prevent severe
tears and neonatal asphyxia has been questioned, and evidence shows
that the procedure results in considerable maternal morbidity.
Dr JM Thorp,2 in Episiotomy: Can its routine use be defended? says, “There
is little evidence to support routine use of episiotomy. This procedure
may well increase the incidence of third- and fourth-degree lacerations.
There are few data to support the premise that this procedure prevents
pelvic relaxation.”
The American College of Obstetricians and Gynecologists say that
episiotomy “is not always necessary” and “should not be considered
routine.”
Proponents of episiotomies say it helps to lessen perineal trauma,
minimize postpartum pelvic floor dysfunction, reduce blood loss at
delivery, and protect against neonatal trauma. That episiotomy protects
the fetus from damage is an unproven assumption. That birth without
episiotomy will result in prolapse of the uterus, or in weakened support
for the bladder from excessively stretched muscles has also never been
proven.1,3 Moreover, should the woman desire enhanced sexual pleasure
for herself or her partner from increased vaginal tightness, she can achieve
the desired results by exercising the pelvic floor muscles after birth.
OBSTETRIC MYTHS VERSUS RESEARCH REALITIES

Williams Obstetrics1 states, “The reasons for episiotomy’s popularity
among obstetricians are clear. It substitutes a straight, neat surgical
incision for the ragged laceration that otherwise frequently results. It is
easier to repair and heals better than a tear.” Human Labor and Birth4
adds that it averts “brain damage” by “lessening the pounding of the
head on the perineum.” An earlier edition of William’s Obstetrics5 claims
that it reduces the incidence of cystocele, rectocele, and stress
incontinence although the 1989 edition admits this benefit is unproved.
EPISIOTOMY AND INCIDENCE OF PERINEAL LACERATIONS

Episiotomies do not prevent tears into or through the anal sphincter or
vaginal tears. In fact, deep tears almost never occur in the absence of an
episiotomy. Median episiotomy has no great advantage over a first or
second degree laceration when there are no overriding fetal indications.
In an Italian study6, episiotomies did not, in fact, reduce the incidence
of serious perineal lacerations but increased them. Having an episiotomy
may increase perineal pain in the postpartum period. This can result in
trouble defecating, much to the new mother’s despair.
Even when properly repaired, tears of the anal sphincter may cause
chronic problems with coital pain and gas or fecal incontinence later in
life. In addition, anal injury predisposes to rectovaginal fistulas. Although
mediolateral episiotomy offered some protection against severe tears
for primiparas, studies have found they have other problems, including
increased pain, poorer cosmetic results, and more dyspareunia.
If a woman does not have an episiotomy, she is likely to have a small
tear, but with rare exceptions the tear will be, at worst, no worse than
an episiotomy.
Another study of 241 first-time hospital-birthers showed7 that “the
proportion of deep perineal lacerations was lowest (0.9%) in women
without episiotomy who were not confined to the lithotomy position;
it was greatest (27.9%) in women delivered in stirrups with an
episiotomy... there was more than a twenty-fold increase in the rate of
deep laceration when episiotomy was used,” as well as a fourteen-fold
increase in the rate of deep perineal lacerations when stirrups were used.
In other words, the combination of episiotomy with the lithotomy
position and stirrups works to offer women the highest possible chance
that they will have deep perineal lacerations as they give birth.
After adjusting for these risk factors, midline episiotomy was still
associated with 4 (nulliparas) to 12 (multiparas) times as many severe
lacerations, and mediolateral episiotomy was still associated with a 2.5
times greater risk of severe laceration.
The results of the first North American randomized controlled trial
indicate that the routine use of episiotomy has no justification. Median
episiotomy fails to prevent trauma or relaxation of the pelvic floor;
furthermore, in primiparous women it appears to be causally associated
with third- and fourth-degree tears. This procedure should be limited
to specific maternal and fetal indications.8
EPISIOTOMIES DO NOT PREVENT PELVIC FLOOR

MUSCLE RELAXATION
Episiotomies do not prevent relaxation of the pelvic floor musculature.
Therefore, they do not prevent urinary incontinence or improve sexual
satisfaction.2,3,9-13 Spontaneous laceration and intact perineum were
similar, which means not doing an episiotomy does no harm and that
the major effect on pelvic floor function may be intrinsic to vaginal birth.
By preventing overstretching of the pelvic floor muscles, episiotomies
are also supposed to prevent pelvic floor relaxation. Pelvic floor relaxation
causes sexual dissatisfaction after childbirth, urinary incontinence, and
uterine prolapse. But older women currently having repair surgery for
incontinence and prolapse all had generous episiotomies. In any case,
episiotomy is not done until the head is almost ready to be born. By
then, the pelvic floor muscles are already fully distended.
ANAL INCONTINENCE
Episiotomy predisposes to rectal tears.14,15 Women with anal sphincter
injury showed reduced muscle strength compared with controls. Since
anal sphincter strength decreases with age, women with sphincter injuries
are at increased risk for incontinence later in life.
EPISIOTOMIES DO NOT HEAL BETTER THAN TEARS

Episiotomies are not easier to repair than tears.3,12,14,16-18 Episiotomies
do not heal better than tears. Like any other surgery, episiotomy has
risks, including extension of the incision, blood loss, dyspareunia, pain,
poor healing. Women without episiotomies exhibit better perineal healing
than women with episiotomies.
PAIN AND DYSPAREUNIA

Episiotomies are not less painful than tears. They may cause prolonged
problems with pain, especially pain during intercourse.19,20 Factors
associated with longer than average perineal pain or dyspareunia were
a vaginal but not perineal tear; forceps delivery (forceps may cause
vaginal tears or bruising); and mediolateral rather than midline
episiotomy.
EPISIOTOMIES DO NOT PREVENT FETAL BRAIN DAMAGE

Episiotomies do not prevent birth injuries or fetal brain damage.
Neonatal mortality rates were similar for episiotomy versus no
episiotomy among both nulliparas (6.7% versus 8.6%) and multiparas
(10.0% versus 9.3%) as were 5-minute Apgar scores.21 One of the two
postulated protective effects of episiotomy is reduced pressure on the
fetal head. However, to achieve this, episiotomy would have to be done
before the head distended the perineum. The other protective effect is
shortening second stage. However, length of second stage does not
correlate consistently with outcome. A woman’s perineum is soft, elastic
tissue, not concrete. No one has ever shown that an episiotomy protects
fetal neurologic well being, not even in the tiniest, most vulnerable
preterm infants, let alone a healthy, term newborn.22
EPISIOTOMY INCREASES BLOOD LOSS

Episiotomy unquestionably adds to the 3rd stage blood loss. According
to Thorp et al,23 episiotomy blood loss exceeds 300 ml in 10% cases. This
is substantial and could be crucial in anemic women of the developing
world contributing to hemorrhagic death. An episiotomy given too early
obviously causes greater blood loss.24
Like any other surgery, episiotomy has risks, including extension of
the incision, blood loss, dyspareunia, pain, poor healing. Women without
episiotomies exhibit better perineal healing than women with
episiotomies.
DOWNSIDE OF EPISIOTOMIES
As with any other surgical procedure, episiotomies may lead to infection,
including fatal infections. In their literature survey Thacker and Banta3
found wound infections and abscess rates ranging from 0.5 to 3%.
Moreover, there are two extremely rare gangrenous infections called
necrotizing fasciitis and clostridial myonecrosis reported in the literature.

These infections kill many of the women who contract them and maim
the survivors. William’s Obstetrics1 says of them in boldface type,
“Mortality is virtually universal without surgical treatment, and it
approaches 50% even if aggressive excision is performed.” While these
infections are rare, they make a substantial contribution to maternal
mortality. Obviously, an infection could start in a repaired tear, but
substantial numbers of women who do not have episiotomies have intact
perineums. There also appears to be an association between the extent
of the wound and these deadly infections. It bears repeating that women
with no episiotomy hardly ever suffer deep tears.
Vaginal pack used during suturing does on occasion, get forgotten
and left over causing foul discharge and infection. Such packs should
have a string attached to them to prevent them getting left over. Cases
of broken suture needle retained in the wound 25 and of scar
endometriosis26 are reported.
Epidurals increase the need for episiotomy.27,28 They also increase
the probability of instrumental delivery. Instrumental delivery increases
both the odds of episiotomy and deep tears. Epidurals associated with
episiotomy, and not having an epidural associated with intact perineum
“likely due to the well-known effect of epidural analgesia on the woman’s
ability to push.”
ASSOCIATION OF EPISIOTOMY AND DELIVERY POSITION WITH

DEEP PERINEAL LACERATION
The lithotomy position increases the need for episiotomy, probably
because the perineum is tightly stretched. 27 The birth attendant’s
philosophy, technique, skill, and experience are the major determinants
of perineal outcome.7
Some techniques for reducing perineal trauma that have been
evaluated and found effective are: prenatal perineal massage, slow
delivery of the head, supporting the perineum, keeping the head flexed,
delivering the shoulders one at a time, and doing instrumental deliveries
without episiotomy.29-31 (Others, such as perineal massage during labor
or hot compresses have yet to be studied.) Independent of specifically
contracting the pelvic floor muscles (Kegels), a regular exercise program
strengthens the pelvic floor.
CURRENT RECOMMENDATIONS
Restrictive episiotomy policies appear to have a number of benefits
compared to routine episiotomy policies. There is less posterior perineal
trauma, less suturing and fewer complications, no difference for most
pain measures and severe vaginal or perineal trauma, but there was an
increased risk of anterior perineal trauma with restrictive episiotomy.32
Routine episiotomy should be abandoned and episiotomy rates above
30% cannot be justified.33
CONCLUSION
A review of the literature on the pros and cons of episiotomy suggests
that it should be used restrictively.
Episiotomies are not always necessary, and there is much you can do
to lessen your chances of having this surgical incision. Some preventative
measures are:
• Good nutrition (Healthy skin stretches more easily)
• Kegels (exercise for your pelvic floor muscles)
• Prenatal discussion with your care provider about episiotomy
• Prenatal perineal massage
• A slowed second stage (controlled pushing)
• Warm compresses, perineal massage and support during delivery
Episiotomies, however, may be indicated if there is any sign of fetal
distress while the baby is in the birth canal or there are clinical indications
to deliver the baby quickly. Perineal massage in the period prior to
childbirth is intended to reduce the need for episiotomy, by making the
perineum more flexible.
Situations needing episiotomy are:
• Instrumental delivery.
• Malpresentation.
• Large baby.
• Imminent perineal tear.
• Severe maternal/fetal compromise.
EPISIOTOMIES SHOULD BE USED JUDICIOUSLY24

• Caution must be observed in both techniques that the rectum is not
entered inadvertently.
• If it is performed too early, excess blood loss will probably occur.
• The sutures should be placed tightly enough to ensure hemostasis,
but not so tightly as to occlude capillary perfusion. The episiotomy
should be stitched tightly enough to prevent bleeding but loosely

enough for blood flow in the tissue.
• If the knot is placed at or inside the hymenal ring, postpartum
dyspareunia can be minimized.
• Postpartum discomfort or dyspareunia can be minimized by avoiding
suture knots at the fourchette.
• A gentle rectal examination should be performed to ascertain that no
sutures were inadvertently placed through the rectal mucosa. Such
sutures could serve as a nidus of infection or fistula formation.
• A sponge and needle count should also be routinely performed at
the conclusion of the repair. Besides being embarrassing, a sponge
retained in the vagina may be the nidus for an infection. Likewise, a
needle retained or broken off in the episiotomy repair mandates
exploration of the wound.
• Perineal extensions of midline episiotomies frequently involve the
rectal sphincter or mucosa. In repairing a third-degree extension the
importance of attention to anatomic reapproximation and hemostasis
as well as the use of interrupted sutures cannot be overemphasized
for successful repair.
• Severe hemorrhage is possible with episiotomy. Excessive perineal
pain should raise the possibility of a perineal, vulvar, vaginal, or
ischiorectal haematoma.
• As with any surgical procedure, infection is a potential complication
of episiotomy. A rare but extremely serious and sometimes fatal
infectious complication of episiotomy is necrotizing fasciitis.
• Many patients receiving episiotomies require oral analgesics for
several days afterward.
• Postepisiotomy pain that is catamenial in nature may represent
endometriosis.
• Another aspect of episiotomy pain that should not be underestimated
is its psychosexual impact.
• Relative contraindications include the patient’s absolute refusal to
consent to the procedure.
REFERENCES
1. Cunningham FG, MacDonald PC, Gant NF E(ds). William’s Obstetrics. 18th edn.
Norwalk, CT: Appleton and Lange, 1989.
2. Thorp JM, Bowes WA. Episiotomy: Can its routine use be defended? Am J
Obstet Gynecol 1989; 160:1027-30.
3. Thacker SB, Banta HD. Benefits and risks of episiotomy: An interpretive review
of the English language literature, 1860-1980. Obstet Gynecol Surv 1983; 38(6):
322-338.
4. Oxorn-Foote H. Human labor and birth. 5th edn. Norwalk, CT: Appleton-
Century-Crofts, 1986.
5. Pritchard JA, MacDonald PC, Gant NF (Eds). William’s Obstetrics. 17th edn.
Norwalk: Appleton, Century, Crofts, 1985.
6. Andrea Sartore, Francesco De Seta et al. The effects of mediolateral episiotomy
on pelvic floor function after vaginal delivery. Obstet Gynecol 2000;103: 669-673.
7. Borgatta L, Piening SL, Cohen WR. Association of episiotomy and delivery
position with deep perineal laceration during spontaneous delivery in
nulliparous women. Am J Obstet Gynecol 1989; 160(2): 294-297.
8. Klein MC, Gauthier RJ et al. Relationship of episiotomy to perineal trauma and
morbidity, sexual dysfunction, and pelvic floor relaxation. Am J Obstet Gynecol
1994; 171: 591-98.
9. Bromberg MH. Presumptive maternal benefits of routine episiotomy. J Nurse
Midwifery 1986; 31(3): 121-27.
10. Hofmeyr GJ, Sonnedecker EW. Elective episiotomy in perspective. S Afr Med J
1987; 71(6): 357-59.
11. Klein M et al. Does episiotomy prevent perineal trauma and pelvic floor
relaxation? Online J Curr Clin Trials 1992; 1 (Document 10).
12. Gordon H, Logue M. Perineal muscle function after childbirth. Lancet 1985; 2:
123-125.
13. Rockner G, Jonasson A, Olund A. The effect of mediolateral episiotomy at
delivery on pelvic floor muscle strength evaluated with vaginal cones. Acta
Obstet Gynecol Scand 1991; 70(1):51-54.
14. Snooks SJ et al. Risk factors in childbirth causing damage to the pelvic floor
innervation. Br J Surg 1985; 72 (Suppl): S 15-S 17.
15. Haadem K et al. Anal sphincter function after delivery rupture. Obstet Gynecol
1987; 70(1): 53-56.
16. Reynolds JL, Yudkin PL. Changes in the management of labor: 2. Perineal
management. Can Med Assoc J 1987; 136(10): 1045-49
17. Wilcox LS et al. Episiotomy and its role in the incidence of perineal lacerations
in a maternity center and a tertiary hospital obstetric service. Am J Obstet
Gynecol 1989; 160(5 Pt 1): 1047-52.
18. Sleep J et al. West Berkshire perineal management trial. Br Med J 1987; 289:
587-90.
19. Sleep J and Grant A. West Berkshire perineal management trial: Three year
follow up. Br Med J 1987; 32(3): 181-83.
20. Abraham S et al. Recovery after childbirth: A preliminary prospective study.
Med J Aust 1990; 152(1): 9-12.
21. The TG. Is routine episiotomy beneficial in the low birth weight delivery? Int
J Gynaecol Obstet 1990; 31(2): 135-40.
22. Lobb MO, Duthie SJ, Cooke RW. The influence of episiotomy on the neonatal
survival and incidence of periventricular haemorrhage in very-low-birth-
weight infants. Eur J Obstet Gynecol Reprod Biol 1986; 22(1-2): 17-21.
23. Thorp JM et al. Selected use of midline episiotomy: Effect on perineal trauma.
Obstet Gynecol 1987; 70(2): 260-62.
24. Varner MW. Episiotomy: Techniques and indications. Clin Obstet Gynecol 1986;
29(2): 309-17.
25. Parikh MN. Complications of episiotomy. J Obstet Gynecol Ind 2002; 52: 70-71.
26. Agarwal M, Gupta D. Scar endometriosis in episiotomy. J Obstet Gynecol Ind
2004: 54: 89.
27. Nodine PM, Roberts J. Factors associated with perineal outcome during childbirth.
J Nurse Midwifery 1987 May-June; 32(3): 123-130.
28. Legino LJ et al. Third- and fourth-degree perineal tears, 50 years’ experience at
a university hospital. J Reprod Med 1988; 33(5): 423-426.
29. Avery MD, Van Arsdale L. Perineal massage: Effect on the incidence of
episiotomy and laceration in a nulliparous population. J Nurse Midwifery 1987;
32(3):181-184.
30. Thompson DJ. No episiotomy? Aust N Z J Obstet Gynaecol 1987; 27(1): 18-20.
31. Helwig JT, Thorp JM, Bowes WA. Does midline episiotomy increase the risk of
third- and fourth-degree lacerations in operative vaginal deliveries? Obstet
Gynecol 1993; 82(2): 276-79.
32. Carroli G, Belizan J, Stamp G. Episiotomy for vaginal birth (Cochrane Review).
In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software.
33. Argentine Episiotomy Trial Collaborative Group. Routine vs selective
episiotomy: A randomised controlled trial. Lancet 1993;342:1517-18.
7
JB Sharma, S Mittal
Management of
Refractory Anemia
during Pregnancy
INTRODUCTION
Anemia is the commonest medical disorder in pregnancy having varied
incidence, etiology and degree of severity in different populations with
a prevalence ranging between 35-75% in developing countries.1,2 It is
responsible for 40% maternal deaths by causing direct and indirect deaths
and also causes significant perinatal mortality and morbidity.3,4 The
standard definition of World Health Organization for the diagnosis of
anemia in pregnancy is a hemoglobin (Hb) concentration of less than 11
gm/dl (7.45 mmol/L) and a hematocrit of less than 0.33 with severe
anemia being when Hb levels fall below 7.0 gm/dl.5 In India prevalence
of anemia can be as high as 87% during pregnancy due to women with
florid anemia or with severe iron depletion going into pregnancy, poor
nutrition, dietary habits like food faddism and vegetarianism, excessive
worm load during pregnancy.6-10 Iron deficiency anemia is the commonest
cause followed by folate deficiency. In spite of routine iron supplemen-
tation to all pregnant women in India and the availability of National
Nutritional Anemia Control Programme, the problem of anemia has
continued unabated. This is partly because of non-compliance due to
side effects of oral iron treatment, which is notorious to cause gastric
upset in many women.11 Recently newer iron preparations like iron
polymaltose (Ferium) and carbonyl iron (Fefol-Z, Anofer) have been
introduced for better compliance as they are better tolerated with rare
side-effects. Even once or twice weekly oral iron has been recommended
for better compliance.12,13 Recently, two or three high doses of parenteral
Management of Refractory Anemia during Pregnancy 107
iron have been found to be effective when given at one monthly interval
during pregnancy.14,15
CAUSES OF ANEMIA
It can occur in one or more of the following ways:16
1. Anemia due to decreased red cell production
i. Nutritional anemia (lack of iron, folate, vitamin-B12 and other
nutrients)
ii. Anemia of chronic diseases like chronic inflammation
iii. Bone marrow suppression
iv. Marrow infiltration
2. Anemia due to increased red cell destruction like hemoglobinopathies
or acquired hemolytic anemias.
3. Anemia due to blood loss.
Causes of Refractory Anemia in Pregnancy6

1. Anemia of chronic diseases
2. Hypoplastic and aplastic anemia
3. Myeloproliferative disorders17,18
4. Miscellaneous causes.
Anemia Associated with Chronic Diseases16

Chronic infections and neoplasms result in moderate and sometimes
severe anemia usually with slightly microcytic hypochromic erythrocytes.
Tuberculosis, osteomyelitis and endocarditis were important causes in
olden days, but are less common these days due to antimicrobial therapy.
However, tuberculosis and malaria continue to be still common in India
and can cause refractory anemia during pregnancy if not properly taken
care of. Chronic renal diseases, cancer, use of anti-cancer drugs, human
immunodeficiency virus (HIV) infection and chronic inflammation are
the common causes of this type of anemia. It is speculated that increased
production of cytokines in these conditions mediate the immune or
inflammatory response. In pregnancy various chronic diseases like
chronic renal diseases, systemic lupus erythematosis (SLE), rheumatoid
arthritis, inflammatory bowel disease and granulomatous infections can
cause anemia which worsens during pregnancy due to disproportionate
rise of plasma volume in contrast to red cell mass expansion. Women
with acute pyelonephritis can develop anemia due to increased red cell
destruction but with normal erythropoietin production. Most of these

chronic diseases cause alterations in reticuloendothelium function and
iron metabolism and decreased erythropoesis. In chronic renal disease,
which is common in pregnancy apart from anemia chronic disease, there
is concomitant erythropoietin deficiency worsening the pre-existing
anemia.
Diagnosis
Hemoglobin rarely falls below 7.00 gm/dl. Serum iron concentration is
decreased and serum iron binding capacity is lower than in normal
pregnancy. Serum ferritin is usually elevated to differentiate it from
iron deficiency anemia. Bone marrow morphology is normal.
Treatment
Anemia of chronic disorders usually responds to recombinant human
erythropoietin which is now easily available in India but is expensive. It
is available as injection Epofer (Emcure) in one ml vials containing 2000,
4000 and 6000 units. It should be combined with parenteral iron as
administration of erythropoietin increases the requirements of iron
significantly which cannot be easily fulfilled by diet or oral iron alone.
Any brand of parenteral iron like iron dextran (Imferon), iron sorbitol
(Jectocos) or low molecular weight fractionated iron dextran (Ferri).
The last being low molecular weight is associated with least anaphylactic
reactions and is preferred over other two brands, but is slightly more
expensive than them. There are various regimens, which can be used.
The one used by the authors in the All India Institute of Medical Sciences,
New Delhi is as follows (Sharma JB, unreported data):
i. Injection erythropoietin (Epofer) 6000 units (1 ml vial) subcuta-
neously on day 1, day 3 and day 5 (in total three injections).
ii. Injection iron (low molecular weight fractionated iron, Ferri) 100
mg (2 ml) intramuscularly by long needle in buttocks using Z
technique every day for five days (total 500 mg in five days). The
first injection is given after sensitivity test using 0.5 ml of the
injection intramuscularly and watching the patient for 30 minutes
for any reaction. Although risk of anaphylaxis is very small,
precautions for anaphylactic reactions in the form of injection
hydrocortisone, avil, adrenaline and oxygen cylinder should be
available in the rare event of reaction. Rest 1.5 ml of iron is given
after 30 minutes.
Another regimen is total dose regimen: injection erythropoietin

(Epofer) 18,000 units ( 3 vials) subcutaneously as single dose and 500 mg
(5 vials : 10 ml) of injection iron (Ferri) in 100 ml saline as slow intravenous
infusion after sensitivity test. It has the advantage of one day treatment
and should be given in hospital setting with all the precautions for
anaphylactic reactions.
Erythropoietin and inject able iron are usually well tolerated and can
raise the Hb by up to 3 gm/dl in two weeks time and can be repeated at
regular intervals. Blood transfusion is rarely required for very severe
anemia. Apart from treatment of anemia the basic chronic disease like
renal disease needs to be treated in consultation with the medical expert.
Hypoplastic and Aplastic Anemia during Pregnancy16,19,24

Aplastic anemia is a pancytopenia with bone marrow hypocellularity.
They are rarely seen during pregnancy and are serious diseases with
high morbidity and mortality.
Causes16,19-24
i. Drugs like chemotherapeutic drugs, idiosyncratic reaction with non-
steroidal anti-inflammatory drugs (NSAIDs, sulfonamide,
penicillamine, allopurinol, gold and chloramphenicol, etc.20,21
ii. Chemicals like benzene.
iii. Infections like hepatitis, fulminant liver failure, Epstein-Barr virus
infection, infectious mononucleosis, etc.
iv. Irradiation
v. Leukemia and other myeloproliferative disorders
vi. Immunological disorders
vii. Inherited disorders like Fanconi anemia which is an autosomal
recessive disorder with progressive pancytopenia, increased
incidence of anomalies (of bones and genitourinary tract), short
stature and Diamond-Blackfan syndrome with pancytopenia along
with pancreatic insufficiency, malabsorption and neutropenia.16
viii. Unknown causes.
Basic underlying defect is marked reduction in committed marrow
stem cells. The patients usually present with bleeding, bruising, oozing
from gums and nose, hemorrhage, refractory anemia, weakness, weight
loss and shortness of breath. There may be history of infection, viral
illness or chemical exposure.16,20-24
Diagnosis16,20,23
1. Anemia
2. Thrombocytopenia
3. Leukopenia
4. Markedly hypocellular bone marrow
5. Lack of response of anemia to iron therapy
Course of disease
Aplastic anemia is a serious disease in pregnancy with high mortality
with only 20 percent one year survival in very severe disease. In some
cases of hypoplastic and aplastic anemia, termination of pregnancy
improves the condition.19,20 In Diamond-Blackfan syndrome which is a
pure red cell aplasia usually inherited as autosomally recessive, repeated
blood transfusions are usually required though some patients may
respond to glucocorticoid therapy. Gaucher’s disease can also cause
hypoplastic anemia. Hemorrhage and infection are the two leading causes
of mortality during pregnancy and puerperium. Fanconi’s anemia has
better prognosis.16
Management
Hypoplastic and aplastic anemia usually do not respond to erythropoetic
agents. For less severe disease antithymocyte globulin has been used
with good result. 22 Immunosuppressive therapy with cyclosporine
improves the response to antithymocyte globulin. Corticosteroids, large
doses of testosterone or other androgenic steroids have also been used
with mixed results.21 Infection should be searched continuously and
should be vigorously treated with appropriate antimicrobial therapy.
Red cell transfusions are given repeatedly keeping the hematocrit at
about 20. Platelet transfusion may be needed to control hemorrhage for
low platelets.24
Bone Marrow Transplantation23

Bone marrow or stem cell transplantation is the most effective treatment
for severe aplastic anemia. It requires immunosuppressive therapy for
many months. Many successful pregnancies and deliveries have been
reported after bone marrow transplantations, although risk graft rejection
increases during pregnancy and up to 25 percent pregnancies were
complicated by preterm delivery and hypotension.23
Miscellaneous Refractory Anemias

1. Beta-thalassemia minor (trait) patients usually present as microcytosis
and hypochromia and may be misdiagnosed as iron deficiency anemia.
There are target cells. Hb electrophoresis reveals an elevated Hb A2.
Iron loading should be avoided.11
2. Hypoproliferative anemias 16
i. Anemia in hypometabolic states and endocrine deficiency states
like hypothyroidism, Addison’s disease, hypoparathyroidism can
cause anemia. Treatment of primary condition along with treatment
of anemia is required for complete relief, which may include blood
transfusion.
ii. Anemia of protein starvation and liver disease. They cause mild to
moderate hypoproliferative anemia along with deficiency of
nutrients. Red cell survival is shortened and production of
erythropoietin is inadequate. They require treatment of underlying
disease in consultation with the specialists and may require
erythropoietin therapy or blood transfusion.
iii. Hypoferric anemia and hypoproliferative anemia in pregnancy not
responding to iron therapy are often seen in clinical practice. Blood
transfusions are usually required to keep their Hb in normal range.
Erythropoietin with parenteral iron in doses mentioned above can
also be effective and should be tried.
CONCLUSION
Refractory anemias during pregnancy are uncommon diseases and can
be caused by miscellaneous conditions. The aplastic and hypoplastic
anemia are rare but serious conditions and require multispeciality
treatment in collaboration with a hematologist, obstetrician and physician
and require special treatment in the form of antithymocyte globulin.
Blood transfusions are usually required. Bone marrow transplantation
is the best treatment, if available with successful pregnancy outcome.
REFERENCES
1. Diejomaon FME, Abdulaziz A, Adekile AD. Anemia in pregnancy. Int J Gynecol
Obstet 1999; 65:299-301.
2. Schwartz WJ,Thurnau Gr. Iron deficiency anemia in pregnancy. Clin Obstet
Gynecol 1995; 38:443-54.
3. Bhatt R. Maternal mortality in India. FOGSI-WHO study. J Obstet Gynec Ind
1997; 47:207-14.
4. Viteri FE. The consequences of iron deficiency and anemia in pregnancy. Adv
Exp Med Biol 1994; 352:127-39.
5. World Health Organization. Report of a WHO group of experts on nutritional

anemia’s. Technical Report Series number 503; Geneva: WHO, 1972.
6. Malhotra M, Sharma JB, Batra S, Murthy NS, Sharma S, Arora R. Maternal and
perinatal outcome in varying degrees of anemia. Int J Gynecol Obstet 2002;
79:93-100.
7. Sharma JB, Soni D, Murthy NS, Malhotra M. Effect of dietary habits on prevalence
of anemia in pregnant women of Delhi. J Obstet Gynaecol Res 2003; 29:73-78.
8. Sharma JB. Nutritional anemia during pregnancy in non-industrialised countries.
In: Studd J (Ed): Progress in Obstetrics and Gynaecology. Edinburgh: Churchill
Livingstone 2003; 15; 103-22.
9. Sharma JB. Iron deficiency anemia during pregnancy-still a major cause of
maternal mortality and morbidity in India. Obs and Gynae Today 1999; 4: 693-
701.
10. Sharma JB, Arora BS, Kumar S, Goel S, Dhamija A. Helminth and protozoan
intestinal infestations: An important cause for anemia in pregnant women of
Delhi, India. J Obstet Gynec Ind 2001; 51:58-61.
11. Sharma JB. Medical complications in pregnancy. In Sharma JB (Eds). The Obstetric
Protocol, 1st ed. Delhi: Jaypee Brothers Medical Publishers (P) Ltd., 1998:78-98.
12. Ridwan E, Schultink W, Dillon D, Gross R. Effect of weekly iron supplementation
on pregnant Indonesian women are similar to those of daily supplementation.
Am J Clin Nutr 1996; 63:884-90.
13. Hallberg L. Combating iron deficiency: Daily administration of iron is far superior
to weekly administration. Am J Clin Nutr 1998; 68:213-7.
14. Bhatt RV. Poor iron compliance-the way out. J Obstet Gynec Ind 1997; 47:185-90.
15. Sharma JB, Jain S, Mallika V, Singh T, Kumar A, Arora R, Murthy NS. A
prospective, partially randomized study of pregnancy outcomes and
hematological responses to oral and intramuscular iron treatment in moderately
anemic pregnant women. Am J Clin Nutr 2004; 79:116-22.
16. Young NS. Aplastic anemia, myelodysplasia and related bone marrow failure
syndrome. In Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson
JL (Eds). Harrison’s Principles of Internal Medicine, 15th edn. New York: McGraw
Hill, 2001; 692-701.
17. Heaney ML, Golde DW. Myelodysplasia. N Engl J Med 1999; 340: 1649-51.
18. Hofman WK, Ottoman WK, Gansen A. Myelodysplastic syndrome: Clinical
features. Semin Hematol 1996; 33:177-185.
19. Atchison RG, Marsh JC, Hows JM, Russel NH, Gordon-Smith EC. Pregnancy
associated aplastic anemia: A report of five cases and review of current
management. Br J Hematol 1989; 73:541-45.
20. Marsh J, Keating A. Aplastic anemias. In Gross S, Roath S (Eds). Hematology: A
problem oriented approach. Maryland: Williams and Wilkins, 1st edn, 1996; 187-
203.
21. Rappeport J. Aplastic anemia and bone marrow failure syndromes. In David
Hemes H (Eds): Kelly’s Textbook of Internal Medicine, 4th edn, Philadelphia:
Williams and Wilkins, 2000; 1680-84.
22. Frickhofen N, Kaltwassen JP, Schrezenmeier H. Treatment of aplastic anemia
with anti-thymocyte globulin and methyl prednisolone with or without
cyclosporine. N Eng J Med 1991; 324:1297-1304.
23. Gluckman E, Horowitz MM, Champlin RE. Bone marrow transplantation for
severe aplastic anemia: Influence of conditioning and graft versus host disease
prophylaxis regimen on outcome. Blood 1992; 79:269-75.
24. Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood
1995; 85:3367-70.
Section 2
Gynecology
8
Monali Desai
Current Concepts in
Screening for Ovarian
Cancer
INTRODUCTION
Ovarian cancer is a major killer and every year more and more cases are
being diagnosed with ovarian cancer. The lifetime risk of dying from
ovarian cancer is 1.1%.1,2 The overall 5-year survival rate is at least 75%
if the cancer is confined to the ovaries and decreases to 17% in women
diagnosed with distant metastases. Symptoms usually do not become
apparent until the tumor compresses or invades adjacent structures,
ascites develops, or metastases become clinically evident. As a result, in
India, approximately 80% of the patients are diagnosed in advanced
stages of disease and hence the morbidity and mortality is very high.
We know that carcinoma of the ovary is most common in women
over age 60.3 Other important risk factors are low parity and a family
history of ovarian cancer. Less than 0.1% of women are affected by
hereditary ovarian cancer syndrome, but these women may face a 40%
lifetime risk of developing ovarian cancer. Ovarian cancers are often
observed within hereditary breast cancer families.
Like in all malignancies survival from ovarian cancer is related to
stage at diagnosis. The 5-year survival rate is 89% for localized disease,
36% for women with regional metastases, and 17% for women with
distant metastases. Studies have shown that the most important
prognostic factor in patients with advanced ovarian cancer is the size of
residual tumor after treatment.2 Surgical debulking and chemotherapy
for ovarian cancer appear to be more effective in reducing the size of
residual tumor when ovarian cancer is detected early.
Thus, screening for ovarian cancer is of paramount importance.
SCREENING TESTS
Potential screening tests for ovarian cancer include the bimanual pelvic
examination, the Papanicolaou (Pap) smear, tumor markers, and
ultrasound imaging.
Annual Pelvic Examination

The pelvic examination, which can detect a variety of gynecologic
disorders, is of unknown sensitivity in detecting ovarian cancer. Although
pelvic examinations can occasionally detect ovarian cancer, small, early-
stage ovarian tumors are often not detected by palpation, due to the
deep anatomic location of the ovary. Thus, ovarian cancers detected by
pelvic examination are generally advanced and associated with poor
survival. The pelvic examination may also produce false positives when
benign adnexal masses (e.g. functional cysts) are found.2 Palpable ovary
in a postmenopausal women should definitely raise suspicion of ovarian
cancer.
A large clinical trial has recently been launched by the National Cancer
Institute4 to determine if annual pelvic examination can have a role in
screening. Under the most optimistic assumptions (100% sensitivity, 30%
reduction in 5-year mortality with screening, no lead-time bias), annual
pelvic examinations of 40-year-old women could reduce 5-year mortality
from ovarian cancer in the population by less than 0.0001%.
PAP Smear
The Pap smear is extensively used in screening for cervical disease in
most countries. The Pap smear may occasionally reveal malignant ovarian
cells, but it is not considered a valid screening test for ovarian
carcinoma.2,3 Studies indicate that the Pap smear has a sensitivity for
ovarian cancer of only 10-30%.
Serum Tumor Markers

Serum tumor markers are often elevated in women with ovarian cancer.
Examples of these markers include carcinoembryonic antigen, ovarian
cystadenocarcinoma antigen, lipid-associated sialic acid, NB/70K, TAG
72.3, CA15-3, and CA-125. 5 Of these, the CA-125 ovarian cancer-
associated antigen is present at elevated levels in the serum of up to
90% of all ovarian cancer patients, including approximately 50% of patients
with early-stage disease, suggesting its potential utility in the early
Current Concepts in Screening for Ovarian Cancer 117
detection of ovarian cancer. However, it has been reported that CA-

125 is elevated in 1% of healthy women, 6-40% of women with benign
masses (e.g. uterine fibroids, endometriosis, pancreatic pseudocyst,
pulmonary hamartoma), and 29% of women with nongynecologic cancers
(e.g. pancreas, stomach, colon, breast) and so false-positive results are
common.6,7 This high false-positive rate relative to the low incidence of
ovarian cancer has led to the general consensus that a single CA-125
assessment is not useful in detecting early-stage ovarian cancer. So serial
measurements may be required.
Also evidence is limited on whether tumor markers become elevated
early enough in the natural history of occult ovarian cancer to provide
adequate sensitivity for screening in asymptomatic women. Studies of
stored sera have found that about one half of women who developed
ovarian cancer had elevated CA-125 levels (>35 U/mL) 18 months to 3
years8 before their diagnosis. Further research is needed, however, to
provide more reliable data on the sensitivity of this and other tumor
markers in detecting early-stage ovarian cancer in asymptomatic women.
It may be possible to improve the specificity of CA-125 measurement
by selective screening of postmenopausal women, modifying the assay
technique, adding other tumor markers to CA-125, requiring a higher
concentration or persistent elevation of CA-125 levels over time, or
combining CA-125 measurement with ultrasound.5
Ultrasound
Ultrasound imaging is able to estimate ovarian size, detect masses as
small as 1 cm, and distinguish solid lesions from cysts. Transvaginal
color-flow Doppler ultrasound9,10 can also identify vascular patterns
associated with tumors. In screening studies, the reported sensitivity
and specificity of transabdominal or transvaginal ultrasound are 50-100%
and 76-97%, respectively, but small sample sizes, limited follow-up, and
outdated techniques may limit the validity of the data.9-11
A total of 14,356 ultrasound examinations performed over 3 years on
5,489 asymptomatic women over age 45 detected five ovarian cancers.10
Although the sensitivity and specificity of the test were excellent (100%
and 94.6%, respectively), the positive predictive value in this low-risk
study population was only 2.6% and follow-up was of short duration.
Another study using transvaginal sonography (TVS) for the detection
of ovarian cancer consisted of 14,469 asymptomatic women, all of whom
were either >/= 50 years of age or >/= 30 years of age with a family
history of ovarian cancer, followed between 1987 and 1999 at the

University of Kentucky.9-11 An abnormal sonogram was defined as one
in which the ovarian volume was greater than 10 cm3 in postmenopausal
women, and greater than 20 cm3 in premenopausal women, or one in
which a papillary or complex tissue projection into a cystic ovarian tumor
was evident. All women with an abnormal TVS underwent a repeat
sonogram after 4-6 weeks, and if abnormal scans persisted, surgery was
recommended.
Of the 180 patients with persistent TVS abnormalities that underwent
exploratory laparoscopy or laparotomy, 17 ovarian cancers were
detected, 14 of which were stage I or II at diagnosis. With a mean follow-
up of 4.6 years (range, 0.8-9.6 years), all of the patients with early-stage
disease were still alive without recurrence, whereas 2 of the 3 patients
with advanced-stage disease had died. Of the group without evidence
of TVS abnormality, 4 patients developed ovarian or primary peritoneal
cancers within 1 year of a negative scan, 2 of which were early stage and
2 of which were advanced stage.
In this study, TVS was associated with a sensitivity of 81%, a
specificity of 98.9%, a positive predictive value of 9.4%, and a negative
predictive value of 99.9%. After a total of 46,113 screening years, there
have been 3 ovarian cancer deaths in the annually screened population
and a 5-year survival of 88% for the ovarian cancer patients in the study
population.
These studies show that TVS screening for ovarian cancer in the
general population may be effective at detecting disease at an earlier,
more curable stage, thus improving long-term survival from this
malignancy but it has relatively low positive predictive value of only
9%, which is probably not acceptable from the standpoint of cost-
effectiveness and patient acceptance. It should also be noted that this
methodology does not appear to be effective at detecting primary
peritoneal cancer, which is perhaps not surprising, given the frequent
absence of enlarged ovaries associated with this malignancy. Clearly,
further studies of the utility of TVS in detecting early-stage ovarian
cancer are warranted.
COMBINED MODALITIES
It may be possible to improve accuracy by combining ultrasound with
other screening tests, such as the measurement of CA-125. 12 One
prospective study screened 1,010 asymptomatic postmenopausal women
over age 45 with pelvic examination and CA-125 measurement; those

with abnormal results received an ultrasound examination. Although
one ovarian cancer was detected (all three screening tests were positive
in this woman), the study demonstrated poor positive predictive value
with each of the three screening tests. No abnormality was discovered
in 28 of the 31 women with elevated CA-125. Fibroids and benign cysts
were responsible for over half of the 28 abnormal pelvic examinations.
Various studies reported that the combination of abdominal ultrasound
and sequential CA-125 measurements had a sensitivity of 58-79%, a
specificity of about 100%, and a positive predictive value of 27%.12-14
In our own study we have found that pelvic examination gave a
sensitivity of 82.1% and specificity of 73.07%. Transvaginal ultrasound
gave a sensitivity and specificity of 75% and 76.9% while CA-125 levels
had a sensitivity and specificity of 92.8% and 75% respectively. When a
combined modality was used the sensivity and specificity improved to
95.2% and 94.2%.
GENETIC SCREENING
Women with germline BRCA1 or BRCA2 mutations are at substantially
increased risk for breast and ovarian cancer, although the risks may not
be as high as originally reported. It appears that both breast and ovarian
cancer risk may be lower among BRCA2 carriers than among BRCA1
carriers, these cancers may occur at later ages, on average, in BRCA2
carriers, and risk may also vary with the location of the mutation within
the gene. The choice of whether to undergo genetic testing is a difficult
one as it is expensive, there are several variants to the gene and once
detected there are no definitive prophylactic methods to prevent the
occurrence of the disease. It has also proved to be very phycologically
disturbing to the women.15,16
Several very large, prospective trials designed to test the efficacy of
this type of multimodality screening in both the general and high-risk
populations are currently under way.17,18
SUMMARY
There is no direct evidence from prospective studies till date that women
with early-stage ovarian cancer detected through screening have lower
mortality from ovarian cancer than do women with more advanced
disease. A large body of indirect evidence, however, suggests that this
is the case. Conclusive proof will require properly conducted prospective
studies comparing long-term mortality from ovarian cancer between

screened and nonscreened cohorts.
The sensitivity and specificity of available screening tests for ovarian
cancer in asymptomatic women are uncertain and require further study.
Although various tests can detect occasional asymptomatic tumors, there
is currently no evidence that a particular test or combined approach is
definitely effective for routine screening. The large majority of women
with abnormal screening test results do not have cancer, yet will require
invasive procedures (laparoscopy or laparotomy) to rule out malignancy.
Given the risks, inconvenience, and substantial costs of follow-up testing,
and the current lack of evidence that screening reduces morbidity or
mortality from ovarian cancer, routine screening cannot be recommended.
RECOMMENDATIONS OF OTHER GROUPS

There are no official recommendations to screen routinely for ovarian
cancer in asymptomatic women by performing ultrasound or serum
tumor marker measurements. The American College of Physicians (ACP),
the Canadian Task Force on the Periodic Health Examination, and the
American College of Obstetricians and Gynecologists recommend against
such screening.
CURRENT RECOMMENDATIONS
The current recommendations made are pelvic examination to be
performed with the Pap test every 1-3 years in women aged 18-40 years
and annually thereafter. Identified high risk women or women with
presumed hereditary cancer syndrome should undergo annual pelvic
examinations, CA-125 measurements and transvaginal ultrasound.
REFERENCES
1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995;45:8-
30.
2. Goswamy RK, Campbell S, Whitehead MI. Screening for ovarian cancer. Clin
Obstet Gynecol 1983;10:621-43.
3. Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med
1994;121:124-32
4. Kramer BS, Gohagan J, Prorok PC, Smart C. A National Cancer Institute
sponsored screening trial for prostatic, lung, colorectal, and ovarian cancers.
Cancer 1993;71:589-93.
5. Jacobs IJ, Oram DH, Bast RC. Strategies for improving the specificity of screening
for ovarian cancer with tumor-associated antigens CA-125, CA15-3, and TAG
72.3. Obstet Gynecol 1992;80:396-99.
6. Einhorn N, Sjovall K, Knapp RC, Hall P, Scully RE, Bast RC, Zurawski VR.
Prospective evaluation of serum CA-125 levels for the early detection of ovarian
cancer. Obstet Gynecol 1992;80:14-18.
7. Zurawski VR Jr, Orjaseter H, Andersen A et al. Elevated serum CA-125 levels
prior to diagnosis of ovarian cancer neoplasia: Relevance for early detection of
ovarian cancer. Int J Cancer 1988;42:677-80.
8. Helzllsouer KJ, Bush TL, Alberg AJ, Bass KM, Zacer H, Comstock GW. Prospective
study of serum CA-125 levels as markers of ovarian cancer. JAMA 1993;269:1123-
26.
9. Van Nagell JR, DePriest PD, Puls NE, Donaldson ES, Gallion HH, Pavlik EJ et al.
Ovarian cancer screening in asymptomatic postmenopausal women by
transvaginal sonography. Cancer 1991;68:458-62.
10. Andolf E, Jorgensen C, Astedt B. Ultrasound examination for detection of ovarian
carcinoma in risk groups. Obstet Gynecol 1990;75:106-9.
11. Bourne T, Campbell S, Steer C, Whitehead MI, Collins WP. Transvaginal colour
flow imaging: A possible new screening technique for ovarian cancer. BMJ
1989;299:1367-70.
12. Campbell S, Royston P, Bhan V, Whitehead MI, Collins WP. Novel screening
strategies for early ovarian cancer by transabdominal ultrasonography. Br J
Obstet Gynaecol 1990;97:304-11.
13. Jacobs I, Davies AP, Bridges J et al. Prevalence screening for ovarian cancer in
postmenopausal women by CA-125 measurement and ultrasonography. BMJ
1993;306:1030-34.
14. Jacobs I, Stabile I, Bridges J et al. Multimodal approach to screening for ovarian
cancer. Lancet 1988;1:268-71.
15. Finkler NJ, Benacerraf B, Lavin PT et al. Comparison of serum CA-125, clinical
impression, and ultrasound in the preoperative evaluation of ovarian masses.
16. Karlan BY, Raffel LJ, Crvenkovic G et al. A multidisciplinary approach to the
early detection of ovarian carcinoma: Rationale, protocol design, and early results.
Am J Obstet Gynecol 1993;169:494-501.
17. Amos CI, Struewing JP. Genetic epidemiology of epithelial ovarian cancer. Cancer
1993;71:566-72.
18. Biesecker B, Boehnke M, Calzone K. Genetic counseling for families with inherited
susceptibility to breast and ovarian cancer. JAMA 1993;269:1970-74.
9
Purvi Patel
Sacrospinous Ligament
Fixation for the
Treatment of
Uterovaginal Prolapse
INTRODUCTION
Historic records suggest that vaginal eversion has been affecting women
for quite some time.1 As the life expectancy has been increasing; more
and more women suffer from this condition. Most aged women are
disturbed with the decreased quality of life owing to such pelvic floor
relaxation. Also, some women are interested in maintaining sexual
activity beyond menopause. Vaginal eversion sometimes may also recur
after previous surgical treatment; reported incidence following
hysterectomy is 0.2-43%.2
The treatment of vaginal eversion is essentially surgical except in
rare situations. The surgical method chosen to correct vaginal eversion
should address to the following objectives: relief of symptoms, restoration
of normal vaginal anatomy; and restoration of potential vaginal coital
function. There are a variety of methods to treat vaginal eversion;
through either the abdominal or the vaginal route. With the advent of
the sacrospinous fixation procedure, the transvaginal approach has
become increasingly popular. The operation was first described in
principle by Zweifel in 1892. He attempted to secure the vault to the
sacrotuberous ligament. In 1968, Richter described fixation of the vaginal
vault to sacrospinous ligament through the vaginal route.3 Randall and
Nichols introduced sacrospinous colpopexy in 1971 in the USA after
which it has gained popularity.4
Sacrospinous Ligament Fixation 123
SURGICAL TECHNIQUE
The sacrospinous ligament is a 7-8 cm fibromuscular structure arising
from the ischial spine and it fans out to get inserted into the lower
lateral aspect of sacrum. The ligament lies within the belly of the
coccygeus muscle. Important structures in the region of the ligament
may be injured at surgery. The pudendal vessels and the nerve course
around the ischial spines. The sacral plexus and sciatic nerve are located
above the superior border of the ligament. Gluteus maximus lies posterior
to the ligament. Inferior to the ligament is the ischiorectal fossa fat.
While operating a vaginal vault prolapse; any cystocele, if present, is
dealt with first. The sacrospinous colpopexy begins with an incision
through the perineum and the posterior vaginal wall to enter the recto-
vaginal space. Enterocele, if present, is dealt with. The rectum is displaced
to the patient‘s left side with a retractor. A window is formed through
the descending rectal septum over the ischial spine on the right side,
with the help of a hemostat. The sacrospinous ligament is palpated and
visualized. If a patient has undergone a previous surgery in this area,
the resultant fibrosis and scarring may make the dissection difficult.
The window is enlarged to around 4 cm size with fingers. A retractor is
introduced and placed at twelve o‘clock position to keep the cardinal
ligament away. Another retractor displaces the rectum to the left side.
One more retractor may be used along the lateral pelvic wall.
An Allies’ forceps or a Babcock’s forceps is used to grasp the ligament
at a point 2-3 cm medial to the ischial spine. Two or three synthetic
absorbable (or permanent) sutures are taken through the ligament at
this point by piercing through (not around) the ligament. The sutures
are then passed through the mid-portion of the vaginal apex sub-
epithelially. These sutures are to be held long to be tied at a later stage.
Posterior colporrhaphy is begun at the vault and continued till the
mid-portion of the posterior vaginal wall. At this point, the sacrospinous
colpopexy stitches are tied to attach the vagina to the sacrospinous
ligament, taking care to avoid an intervening suture bridge. The posterior
colporrhaphy is completed. A P/R examination is done to confirm the
integrity of rectum. Urinary bladder is drained with an indwelling
cathetor. Vagina is packed for 24 hours. The patient can usually be
discharged from the hospital in 3-5 days.
Usually, unilateral colpopexy gives satisfactory results. It can be done
bilaterally in case of a recurrent prolapse; if the patient has chronic
respiratory disease, or if the vaginal vault is very wide. Usually, it is
done on the right side, as most surgeons are right-handed. Because of

the pliability and mobility of the vagina, the slight deviation of the newly
positioned vaginal apex to the right is of no consequence and does not
interfere with sexual activity.9
The choice of instruments for this procedure depends on the
preference of the operating surgeon. Various types of retractors for
exposure of the ligament have been suggested. Similarly, for the insertion
of the suture material into the ligament, various suture carriers and
hooks have been used. However, the retractors and needle-holders used
routinely in pelvic surgeries may also serve the purpose.
RESULTS
Various studies have shown quite satisfactory results with this procedure;
the success rates exceeding 90%.5-8 Besides recurrence of vaginal prolapse,
other complications which have been described are excessive bleeding,
sciatic nerve entrapment, temporary urinary incontinence, rectal injury,
febrile morbidity and new onset cystocele. However, the incidence of
these has not been significantly high. Sacrospinous ligament fixation has
not been associated with dyspareunia unless vaginal narrowing occurs
due to repair of associated defects.
The notable advantages of this procedure are:
• The long-term results compare favorably with the trans-abdominal
procedures.
• The procedure requires lesser time.
• It is associated with minimal blood loss (<100 ml).
• Avoidance of an abdominal incision.
• Shorter hospital stay.
• Direct repair of the cystocele/rectocele can be carried out at the same
time.
• Maintains vaginal length.
COMPARISON WITH OTHER PROCEDURES

The alternatives to sacrospinous fixation in vaginal vault prolapse are
colporrhaphy, colpectomy and colpocleisis, culdoplasty, ilio-coccygeus
ligament fixation, intra-vaginal slingplasty and abdominal sacro-
colpopexy
Colporrhaphy cannot be expected to be effective in restoring the
vault support when vaginal eversion is present. Also, it is likely to shorten
and narrow the vagina causing dyspareunia and apareunia.
As regards McCall’s culdoplasty, it is unlikely that the attenuated

uterosacral ligaments in a case of vault prolapse can provide adequate
and sustained vault support.
Colpectomy and colpocleisis can have a role only in the elderly and
sexually inactive women.
The “Iliococcygeus Hitch”, wherein the vault is fixed to the
Iliococcygeal ligament, does not have a possibility of vascular and
neurological sequele related to sacrospinous fixation and is equally safe
and effective.10 However, the patient satisfaction was found to be higher
with sacrospinous fixation (91% vs. 78%).
Intravaginal slingplasty has been tried recently but the outcome data
from various studies are pending.
Abdominal sacrocolpopexy is equally effective but is associated with
complications like intestinal obstruction, graft extrusion, vaginal rupture;
mesh erosion apart from the morbidities associated with abdominal
procedure. Unless a laparotomy is indicated for other reasons, the vaginal
surgeon should choose the vaginal approach.
PROPHYLACTIC SACROSPINOUS COLPOPEXY AT

VAGINAL HYSTERECTOMY
At vaginal hysterectomy; sometimes, there is insufficient Cardinal-
uterosacral ligament strength for vault suspension, particularly in cases
of procidentia. In such cases, the vault may be fixed to a stronger pelvic
support i.e. sacrospinous ligament.
Here sacrospinous colpopexy is done as a part of the primary
procedure to prevent a possible future vault prolapse. It has been found
to be associated with a high success rate without an increase in the intra-
operative and postoperative complications. 11 Modified McCall’s
culdoplasty has also been used for vault suspension in such cases. In a
comparative study,12 culdoplasty was found to be equally effective.
SACROSPINOUS LIGAMENT FIXATION WITH UTERINE

CONSERVATION AT PROLAPSE SURGERY
Uterosacral ligaments can also be anchored to the sacrospinous ligament,
thus conserving the uterus. This procedure has found to be of use in
two settings.
In women wishing to conserve the uterus or to retain fertility,
sacrospinous hysteropexy has been tried and has been found to restore
the uterus to its normal anatomic position; preserving the uterine function
and allowing childbearing.
In a study,13 five out of nineteen operated cases delivered successfully

vaginally.
In elderly and medically infirm patients, sacrospinous hysteropexy
was compared with vaginal hysterectomy along with sacrospinous
colpopexy.14,15 It was found to have similar success rates and patient
satisfaction and was associated with significantly less operative time
and less intraoperative blood loss compared to the vaginal hysterectomy
cases. The study suggested that hysterectomy may not be necessary in
the surgical treatment of uterine prolapse in such women.
PERSONAL EXPERIENCE
During the period from 1 June 2000 to 1 June 2004, 35 women underwent
sacrospinous colpopexy at our unit in medical college and SSG Hospital,
Baroda. The procedure was used as a surgical technique for treatment
of vault prolapse and as a part of vaginal repair procedure for procidentia
and advanced uterovaginal prolapse with vaginal eversion. Out of the
35 women, 9 had vault prolapse following hysterectomy and 26 had
marked vaginal eversion (where it was done as a prophylactic measure
to prevent future vault prolapse).
Patients with vault prolapse underwent anterior and posterior vaginal
repair, obliteration of enterocele and sacrospinous colpopexy. Patients
with advanced uterovaginal prolapse underwent vaginal hysterectomy
along with enterocele repair, anterior and posterior vaginal repair and
sacrospinous colpopexy. All the patients were examined after 2 weeks,
6 weeks and 1 year of surgery.
The operative time was found to be increased by an average of 20
minutes when it was done as a prophylactic measure. Intra-operatively,
2 patients had significant bleeding (not requiring blood transfusion
though). Two patients had postoperative buttock pain. On subsequent
follow-up; no patient had recurrence, 2 had grade 1 cystocele which was
asymptomatic and did not require any further treatment. No other intra-
operative or post-operative complications attributable to the procedure
were noted. The results were thus, found to be very satisfactory.
Sacrospinous ligament fixation is a safe, effective and feasible
procedure for the treatment of vaginal eversion and should assume a
high priority in our therapeutic regimen.
REFERENCES
1. Emge LA, Durfee RB. Pelvic organ prolapse: Four thousand years of treatment.
Clin Obstet Gynecol 1966; 997-1032.
2. Cruikshank SH. Sacrospinous fixation-should this be performed at the time of

vaginal hysterectomy? Am J Obstet Gynecol 1991; 164:1072-76.
3. Richter K. Die chirurgische anatomie der vaginafixatio sacrospinous vaginalis.
Ein Beitrag zur operativen Behandlung des Scheidenblindsach prolapses.
Geburtshilfe Frauenheilkd 1968; 28:321-327.
4. Randall CL, Nichols DH. Surgical treatment of vaginal inversion. Obstet Gynecol
1971;38:327-332.
5. Richter K, Albrich W. Long term results following fixation of the vagina on the
sacrospinal ligament by the vaginal route. Am J Obstet Gynecol 1981; 141:811-
16.
6. Morley GN, DeLancey JO. Sacrospinous ligament fixation for the eversion of the
vagina. Am J Obstet Gynecol 1988; 158:872-79.
7. Nichols DH. Sacrospinous fixation for massive eversion of the vagina. Am J
Obstet Gynecol 1982; 142:901-904.
8. Imparato E, Aspesi G, Rovetha E, Presti M. Surgical management and prevention
of vaginal vault prolapse. Surg Gynecol Obstet 1992; 175:233-37.
9. Holley RL, Varner RE, Gleason BP, Apffel LA, Scott S. Sexual function after
sacrospinous ligament fixation for vaginal vault prolapse. J Reprod Med 1996
May; 41(5): 355-358.
10. Maher CF, Murray CJ, Carey MP et al. Iliococcygeus or sacrospinous fixation for
vaginal vault prolapse. Obstet Gynecol 2001 Jul: 98(1): 40-44.
11. Guner H, Noyan V, Tiras MB, Yildiz A, Yildirim M. Transvaginal sacrospinous
colpopexy for marked uterovaginal and vault prolapse. Int J Gynaecol Obstet
2001 Aug; 74(2): 165-70.
12. Colombo M, Milani R. Sacrospinous ligament fixation and modified McCall
culdoplasty during vaginal hysterectomy for advanced uterovaginal prolapse.
Am J Obstet Gynecol 1998 Jul; 179(1): 13-20.
13. Kovac SR, Cruikshank SH. Successful pregnancies and vaginal deliveries after
sacrospinous uterosacral fixation in five of nineteen patients. Am J Obstet Gynecol
1993 Jun; 168(6 Pt 1): 1778-83; discussion 1783-6.
14. Hefni M, El-Toukhy T, Bhaumik J, Katsimanis E. Sacrospinous cervicocolpopexy
with uterine conservation for uterovaginal prolapse in elderly women:
An evolving concept. Am J Obstet Gynecol 2003 Mar; 188(3): 645-50.
15. Maher CF, Cary MP, Slack MC, Murray CJ, Milligan M, Schluter P. Uterine
preservation or hysterectomy at sacrospinous colpopexy for uterovaginal
prolapse? Int Urogynecol J Pelvic Floor Dysfunct 2001; 12(6): 381-4; discussion
384-5.
10
Uma Wankhede, Sanjay Gupte
The Challenge of
Posthysterectomy
Hemorrhage
INTRODUCTION
Hysterectomy is one of the most frequently performed operations today.
Like any other operation it has its own set of complications. Adherence
to good surgical principles such as gentle handling of tissues, sharp
dissection, careful attention to hemostasis, avoiding leaving behind large
pedicles of devitalized tissue and large areas of dead space, use of less
reactive suture material, and close attention to aseptic techniques have
reduced complications considerably.
PRIMARY HEMORRHAGE
It is bleeding at the time of hysterectomy.
Causes
1. Acute vascular injury.
2. Ineffective local hemostasis.
3. Complication of blood transfusion.
4. A previously present but undetected coagulation defect.
5. Sepsis.
It is more common at hysterectomy done for large fibroids especially
cervical and broad ligament types, extensive endometriosis, chronic
pelvic inflammatory disease and genital tuberculosis. There is also higher
incidence of primary hemorrhage at the time of vaginal hysterectomy
with extensive pelvic floor repair. Patient with previous history of
The Challenge of Posthysterectomy Hemorrhage 129
radiotherapy or previous surgeries with extensive pelvic adhesions also

have more intraoperative bleeding. In radical surgeries for malignancy
there can be extensive hemorrhage during dissection of ureteric tunnel,
paracolpos, vaginal edges, obturator fossa, preaortic lymph nodes and
great vessels.
During laparoscopic hysterectomy great vessel trauma can occur
during placement of the Verres needle, the primary port or the lateral
port. Iliac vessel injury may also occur during placement of lateral ports
which may be initially misplaced retroperitoneally. The placement of
lateral ports too medially may damage the inferior epigastric vessels.
Dissection of adhesions on the side wall may result in significant venous
side wall bleeding close to the great vessels. Bleeding can also occur
during ligation and division of the uterine and ovarian vessels.
Primary hemorrhage is due to failure to securely ligate significant
blood vessels, slippage of previously placed ligatures, bleeding from
vaginal cuff or avulsion of tissues before clamping. Most intraoperative
bleeding can be avoided with good exposure and good operative
technique. Proper attention to knot tying is important. Transfixation of
sutures prevents ligature slippage. Traction should not be applied to
sutures on vascular pedicles.
Prevention
If primary hemorrhage is anticipated good preparation and good
assistance is important. All local infection should be cleared preopera-
tively. Patients hemoglobin should be at least 10 gm% preoperatively.
Cases of genital kochs should be operated only under cover of at least
six weeks of antitubercular therapy. Before the operation vaginal
infection must be treated and vagina should be cleansed with povidone
iodine or gentian violet.
Prior to vaginal hysterectomy adequate packing should be done if
vagina is very congested. Proper attention must be given to vascular
pedicles. Good hemostasis is a must. Polyglycolic non-absorbable sutures
are preferred to catgut due to their higher tensile strength. In vaginal
hysterectomy bleeding can be decreased by saline adrenaline infiltration,
dissection in correct planes, and proper hemostasis. In extensive pelvic
floor repair there is significant hemorrhage from rich venous plexus of
urogenital diaphragm. Small bleeding points on vaginal mucosa, bladder
and rectal muscle should be clamped and ligated or cauterized.
Occasionally, vessels of urogenital diaphragm are difficult to expose but
can be controlled by figure of eight sutures. Hematomas are prevented

by not leaving any dead space behind and packing of the vagina
postoperatively. As a prevention in patients with extremely congested
tissues, chronic infections, radical operations it is prudent to leave part
of the vaginal cuff open for drainage or keep an intraperitonial drain.
Use of regional anesthesia considerably reduces small vessel oozing.
Antibiotic prophylaxis must be given to all patients undergoing
hysterectomy.
Management
Surgical causes must be distinguished from non-surgical causes in the
management of intraoperative and postoperative bleeding.
1. Non-surgical bleeding: Coagulation abnormalities may arise during
and after the procedure.
a. Transfusion may give rise to dilutional abnormalities. For every 6
to 8 units of packed red blood cells administered. Two units of
fresh frozen plasma is recommended, for every 10 units of PRBC
10 units of platelets should be given.
b. Infection or sepsis may lead to the development of disseminated
intravascular coagulopathy.
2. Surgical bleeding: the most conservative and least invasive approaches
to surgical bleeding should be considered first to avoid complications.
Aggressive supportive therapy with fluids and blood products is
essential. Unnecessary delay must be avoided, with intraoperative
bleeding, initial tamponade of bleeding vessels can allow time to
communicate with the anesthesiologist, clear the surgical field of
blood, and maximize exposure.
a. Arterial bleeding is usually easy to identify. The thickness of
arterial walls allows them to be grasped and clipped or ligated as
appropriate.
1. Arterial puncture may be handled by placement of a figure-of-
eight stitches with fine, permanent suture(e.g. 5-0 proline)
2. Large arteries that have been lacerated can be sutured using a
fine, permanent suture(e.g. 5-0 proline). If needed arterial
clamps can be placed above and below the site to reduce tension
and interrupted stitches used to control bleeding.
b. Venous bleeding can be more problematic to repair, because veins
are thin-walled and easily torn.
1. A venous puncture may be handled by placing a local

hemostatic agent at the breach and applying pressure for 5 to
15 minutes.
2. The vessel may need to be freed of surrounding tissues to be
precisely ligated or clipped. Major veins that cannot be ligated
but must be repaired if lacerated include the common and
external iliacs. Continuous side-to-side closures with 5-0 proline
is the repair of choice.
Postoperative intraperitoneal bleeding may cause only subtle
changes in vital signs and urine output. A high index of suspicion
must be maintained.
a. Vital signs may remain stable for 12 to 18 hours before reflecting
significant blood loss in a healthy patient.
b. Abdominal distention does not always follow significant
intraoperative bleeding (2 L or more)
c. Delay in re-exploration can be fatal.
Postoperative bleeding from the vaginal vault is most often from
the vaginal artery in the lateral vaginal fornix.
The patient’s return to the operating room should not be
excessively delayed.
In repairing bleeding, care should be taken to avoid bladder,
ureter, and rectum.
If bleeding can not be visualized or controlled vaginally, an
abdominal approach may be necessary.
Local hemostatic agents: Can aid in the intraoperative control of bleeding
from needle holes, vascular suture lines, or areas of extensive tissue
dissection. Anastomotic bleeding usually is best controlled with local
pressure or a simple suture. These agents speed hemostasis by providing
a matrix for thrombus formation.
A. Gelatin sponge (e.g. gelfoam) can absorb many times its weight of
whole blood by capillary action and provides a platform for
coagulation. Gelfoam itself is not intrinsically hemostatic. It reabsorbs
in 4-6 weeks without significant inflammatory reaction.
B. Oxidized cellulose (e.g. surgical) is a knitted fabric of cellulose that
allows clotting by absorbing blood and swelling into a scaffold. Its
slow resorption can create a foreign body reaction.
C. Collagen sponge (e.g. helistat) is produced from bovine tendon
collagen and promotes platelet adhesion. It is only slowly resorbed
and creates a foreign body reaction similar to that of cellulose.
Invasive Radiologic Embolization for Hemostasis

Gelfoam can also be used for arterial embolization when surgical
intervention is questionable. The technique utilizes radiographic image
visualization and selective arterial embolization. Gelfoam pads are cut
into particles small enough to obstruct the intraarterial lumen but too
large to reach the arteriolar level. Thus minimizing the risk of acute
infarction and tissue necrosis. Gelfoam is completely reabsorbed in
2 days to 2 weeks, minimizing the likelihood of any long-term
compromise of the viability and function of the treated organ. Several
complications have been described with this technique, such as
vesicovaginal fistula, thrombosis of the femoral artery, and renal toxicity
from excessive volumes of contrast medium. However, these can be
avoided by careful attention to angiographic technique.
In hemorrhage during laparoscopic hysterectomy early recourse
should be made to laparotomy if bleeding is not being controlled laparo-
scopically by diathermy or suturing. If it is suspected that a great vessel
has been transfixed leave the trocar in place till the abdomen is being
opened as this will tamponade the flow. In great vessel bleeding
aortocaval compression will dramatically reduce the bleeding till the
arrival of a vascular surgeon.
In venous oozing pressure to the site should be applied via the
laparoscope and maintained for 5 minutes. Following withdrawal of
pressure the site may be observed for bleeding. Leave a redivac or other
drain adjacent to the oozing site.
If the uterine or ovarian vessels are bleeding, they must be well-
exposed and the bleeder secured with diathermy, with bipolar cautery,
or by staples or ligated with extra or intracorporeal knots. If bleeding
cannot be easily controlled, the laparoscopic surgeon should not hesitate
in proceeding to a open laparotomy.
REACTIONARY HEMORRHAGE
It is defined as hemorrhage within 24 hours of surgery.
It may be caused by suboptimum management of primary
hemorrhage, rise in postoperative blood pressure, ligature slippage or
removal of primary clot following coughing or movement. Bleeding may
be visible from the vagina or as excessive loss in drainage bottle or it
could be invisible due to intraperitoneal hemorrhage. It should be
suspected if patient becomes restless, cold and clammy, postoperatively
with a rising pulse. Most reactionary hemorrhages occur from vaginal

cuff due to slippage of ligature at vaginal vault or failure to include
mucosa in vaginal suture.
Resuscitation should be started immediately while making
arrangements to return to the operation theatre to tackle the problem.
Surgery is part of the resuscitation and one must not waste time trying
to restore the patients blood pressure and pulse to normal before taking
patient to operation theatre. Ultrasonography if available is a useful
tool and must be done to look for intraperitoneal hemorrhage or a pelvic
hematoma. Adequate blood must be cross matched. In cases of vaginal
bleeding under anesthesia with good light, gently insert a speculum in
the vagina. If only oozing is seen, pack tightly with plain gauze or
adrenaline pack. If obvious bleeder is seen, insert sutures as appropriate
with Vicryl, pack and catheterize. If bleeding from suture line use
additional sutures to secure bleeding point and catheterize. If bleeding
is not controlled from below open the old incision at the vault, identify
the bleeder and ligate or cauterize. Close the incision and pack. Brisk
hemorrhage suggests that a large blood vessel has slipped and is likely
to be bleeding intra-abdominally. Pack the vagina for identification and
proceed to laparotomy. Keep adequate blood, suction, assistance, good
anesthetist and plenty of packs available.
In case of intraperitoneal hemorrhage relaparotomy is to be done.
Suck blood out and use packs to mop out blood. Examine the vaginal
vault. Many times bleeding may be from angles of the vagina. Be careful
while inserting sutures at angles of vagina. There is risk of uretic injury.
If the vault is intact look at the ovarian and uterine pedicles. Sometimes
the uterine or ovarian pedicles may be bleeding. If obvious bleeder is
seen ligate it or consider internal iliac ligation. A slipped pedicle can
cause not only intraperitoneal bleeding but also retroperitoneal
hemorrhage. If there is a retroperitoneal hematoma, open the peritoneum,
dissect out bleeding vessel. Internal iliac ligation may help. If
ultrasonography shows a pelvic hematoma with no free fluid and if
patients general condition is stabilized with intravenous fluids one of
two approaches may be tried. First is to give blood transfusion and to
follow-up the patient with serial ultrasonography, PCV, and vital signs.
Many times retroperitoneal hemotoma will tamponade and stop forming.
The hematoma will eventually get absorbed. There is only the risk of
infection later on. Another approach is to do immediate exploratory
laparotomy. This adds to the morbidity of a second procedure but avoids
the possibility of abscess. and detoriation of the patients condition due

to delay. The peritoneum over the hematoma should be incised and
blood should be evacuated. All bleeding vessels should be identified
and ligated. If control of bleeding is difficult, unilateral or bilateral iliac
artery ligation should be done. The pelvis should be drained, once
hemostasis has been achieved.
SECONDARY HEMORRHAGE
Hemorrhage occurs up to 6 weeks postoperatively and is usually thought
to be due to infection.
The higher pelvic infection rate may be due to collections of 10-200
ml of blood serum above the vaginal surgical margin. These collections
are ideal culture media for the normal flora of the lower reproductive
tract. Theoretically, reduction of this volume should lower the infection
rate. Indeed, Swartz and Tanaree 5 reported that T-tube suction drainage
of this extraperitoneal space was as effective as prophylactic antibiotics
in preventing postoperative pelvic infections. They showed that when
suction drain was combined with a prophylactic antibiotic, a significant
lowering of the infection rate did n occur. This result has not been
uniformly observed. Poulsen 6 and coworkers reported significant
reduction in the incidence of febrile morbidity, infectious morbidity and
urinary tract infection after hysterectomy if a prophylactic antibiotic
was administered, but not with suction drainage alone.
We have found that cleaning the vagina with Povidone-Iodine and
pouring 10 ml of Povidone-Iodine from above before closing the vault
in abdominal hysterectomy has helped in decreasing the vaginal bacterial
count and cuff cellulitis.
Secondary hemorrhage is usually not very heavy and is usually
manifested as vaginal bleeding. Take a good history and do a thorough
general examination. A gentle speculum examination can be done without
anesthesia. If there is only oozing from the vault the vagina is packed.
Catheter is inserted and appropriate antibiotics are started. Resuscitation
should be undertaken immediately if required and appropriate
bacteriological investigations must be sent before commencing broad
spectrum antibiotics. Investigations like hemogram, urine, coagulation
studies and cross matching of blood should be done. Emergency USG
will help to identify pelvic hematoma. Vault hematomas are easily
identified on vaginal examination when gentle probing can often achieve
drainage of hematoma. If there is a draining pelvic hematoma observe
and manage conservatively. Majority of pelvic hematomas drain in 48

hours. If there is fresh bleeding from vagina, one will have to pack
vagina and catheterize the bladder. If there is significant bleeding patient
may require examination under anesthesia and suturing of bleeders.
Try and identify specific bleeding points and ligate. One should be careful
while inserting hemostatic sutures near vault. Laparotomy is rarely
indicated in secondary hemorrhage, laparotomy is often an unproductive
exercise revealing an organizing hematoma in the pelvis with gross
anatomical distortion. Specific bleeding points are rarely found and one
may have to think of unilateral or bilateral internal iliac artery ligation
or embolization of the bleeding vessel.
Abdominal wall hematomas especially those under the rectus sheath
are very hard to identify but may be seen on a good USG. Superficial
wound hematomas often drain spontaneously. The sinus may be
enlarged to facilitate drainage; otherwise, abdominal wall hematomas
should be incised and evacuated if they are growing.
Thus, posthysterectomy hemorrhage though troublesome can be
managed efficiently by cool mind, good teamwork and sound surgical
skills.
BIBLIOGRAPHY
1. Glickman MG Pelvic embolisation. In: Berkovitz RL (Ed): Critical care of the
obstetrical patient. New York: Churchill-Livingstone, 1983.
2. Haseltine FP, Glickman MG, Marchesi S et al. Uterine embolisation in a patient
with postabortal hemorrhage. Obstet Gynecol 1984;63:78S-80S.
3. Pais SO, Glickman MG, SchwartzP, et al. Embolization of pelvic arteries for
controlof postpartum hemorrhage. Obstet Gynecol 1980;55:754-763.
4. Swartz WH, Tanaree P. Suction drainage as an alternative to prophylactic
antibiotics for hysterectomy. Obstet Gynecol 1975;45;305-310.
5. Swartz WH, Tanaree P. T-tube section drainage and/or prophylactic antibiotics:
A randomized study of 451 hysterectomies. Obstet Gynecol 1976;47;665-670.
6. The Johns Hopkins Manual of Gynecology and Obstetrics. Lambrou, Morse and
Allach.
7. Washington Manual of Surgery. 3rd edn, 2001.
11
Pratap Kumar, Rupinder Kaur (Ruprai)
Ovulogens Revisited
INTRODUCTION
In the past 30 years there has been a profound development in ovulation
induction (OI) agents that has enabled clinicians to treat a spectrum of
subfertile patients. With a deeper insight into these agents, their
indications for use have also expanded. In the past decade, more refined,
genetically engineered agents and adjuncts have been tailored to provide
clinicians with new opportunities in reproductive medicine. This chapter
will address briefly on the evolution of these agents, referred to here as
ovulogens, changing times, current trends and recommendations and
future prospects.
EVOLUTION
Pharmaceutical preparations containing biologically active gonadotro-
pins (Gn) for ovarian stimulation have been in use for about 70 years.
Initially, gonadotropins were obtained from pregnant mare’s serum. These
preparations, however, resulted in the development of antibodies against
the equine proteins.1
In the 1950s, gonadotropins derived from extracts of postmortem
human pituitary glands were successfully used to treat women, but the
low availability of raw material allowed only a few women to be treated.
A breakthrough came when clomiphene citrate (CC) and the first human
urinary gonadotropins, also known as urofollitropins [(human menopausal
gonadotropins (hMG)] became available for ovarian stimulation to treat
hypogonadotropic hypogonadal women in the early 1960s.2 They were
made by taking bulk urine from menopausal donors and had a
combination of follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) (approximately 3% of the total protein load of the solution)
and a large amount of urinary protein, which could contain (in addition
to an impressive variety of nonspecific proteins normally found in urine)
Ovulogens Revisited 137
cytokines, growth factors, transferrins, and other proteins that might

modulate ovarian actions. The first pregnancy following the use of hMG
was reported in 1962.3
Until the late 1970s, exogenous gonadotropins were administered to
achieve monofollicular development and ovulation of one follicle in CC-
resistant women with anovulatory infertility. With the introduction of
in vitro fertilization (IVF) and other assisted reproductive technologies
(ART), the principles for ovarian stimulation changed; and instead of
monofollicular development, a maximal yield of mature oocytes available
for IVF was the aim. In addition, a much higher number of women,
including normogonadotropic women, were subjected to ovarian
stimulation.
About 10 years ago, purified FSH was produced. More than 90% of
the highly purified preparations contain FSH, whereas only less than
2% of the urofollitropin preparations are FSH. When administering a
very pure drug, we can give it by the subcutaneous rather than the
intramuscular route. If the large and diverse protein load found in
urofollitropin is given subcutaneously, it may theoretically induce an
antibody response. It is possible, however, to administer highly purified
drugs subcutaneously, which also makes self-administration easier for
patients.2
Highly purified FSH (hp-FSH) has now been evaluated in extended
clinical trials that compared it with existing urofollitropin preparations
in a population of World Health Organization (WHO) group II
anovulatory women. The drugs were equivalent in ovulation and
pregnancy rates (PR) associated with their use.2
Now gonadotropins are produced from transformed cell-lines. The
recombinant human FSH (rh-FSH), made in mammalian (Chinese hamster
ovary) cells, is virtually identical to urofollitropin preparations. Both
their initial and terminal half-lives (t½) in serum are the same, as are
maximum serum concentrations and mean lengths of time that the drug
is found in tissue.2 In addition, the bioactivity to immunoactivity ratios
is similar. Ovulation induction (OI) trials have shown that hormonal
outcomes as measured by progesterone levels, pregnancy rates, and
ovulatory events were similar. These findings indicate that recombinant
FSH is equivalent to hMG, urofollitropin, and hp-FSH in its action.2
The near-100% pure FSH preparations might, in some situations, cause
abnormally low LH levels and it is likely that the addition of LH may be
beneficial in these situations. It is possible that r-LH will become available
in sufficient dosages to replace hCG for OI and this may reduce the
incidence of ovarian hyperstimulation syndrome (OHSS) due to its
shorter half-life. All 3 gonadotropins— FSH, LH and human chorionic
gonadotropin (hCG) are now marketed as recombinant (r-) products.
In parallel to the development of gonadotropin preparations, protocols
for ovarian stimulation are now more comfortable for the patients,
especially with the introduction of gonadotropin receptor hormone (GnRH)-
agonists in the early 1980s and, more recently, the introduction of GnRH-
antagonists.
Genetically engineered gonadotropin preparations available include those
of FSH, which has a very short half-life (t½ = 3-4 hours) in circulation,
and hCG, which has a substantial serum half-life (t½ = 35 hours). The
hCG consists of LH (t½ = 20 min) with the addition of 30 amino acids
and a series of carbohydrate residues to its carboxyl terminal. The hCG
molecule interacts with LH receptors and is capable of the same biologic
functions as the LH molecule, but because of the carbohydrate residues,
it persists in the circulation and has a longer biologic effect than does
LH.2
PHYSIOLOGY OF OVULATION: PRACTICAL ASPECTS

It is important to understand the physiology of ovulation to have a good
overview of ovulogens and their use.
The onset of oogenesis occurs in the ovary from the first trimester of
embryonic life and is completed by 28-30 weeks of gestation at which
time approximately 7 million oocytes are present. These are arrested at
the prophase stage of the first meiotic division. Subsequently, the number
of oocytes decreases because of a continuous process of atresia; and at
birth, the pool of oocytes is reduced to approximately 2 million. By
menarche, approximately 500,000 oocytes are present. These oocytes
are used throughout the reproductive years until menopause but only
about 300-400 ovum will actually be released in the lifespan of a woman
which tells us that the remaining perish in the process of ovum recruitment
and selection.
The ovulatory process is initiated once the hypothalamus-pituitary-
ovarian (HPO) axis matures and FSH and LH, under the regulation of
GnRH, acquire their normal secretory patterns. From the cohort of
follicles available each month, only a single oocyte is selected that
establishes dominance, and develops to the preovulatory stage. During
follicular development, the granulosa cells secrete increasing amounts
of estradiol (E2), which, initially, through downregulation, decreases

the secretion of FSH. Later, through a positive feedback mechanism, E2
participates in the LH surge that triggers the ovulatory process, induces
the resumption of meiosis by the oocyte, and stimulates the formation
of the corpus luteum and subsequent progesterone secretion.
Induction of ovulation is the treatment for infertile patients who still
have oocytes within the ovaries, but in whom a dysfunction of the HPO
axis exists. It is also used for assisted reproductive techniques.
Considering the follicular development, the natural design of all
ovarian follicles is destined to perish. Three months prior to ovulation,
approximately 300 follicles are recruited for development. This initial
recruitment is independent of gonadotropins (Gn) and this takes about
10 weeks for the primordial follicles to develop to be responsive to
gonadotropins. The Gn-independent part of folliculogenesis is controlled
by genetic components and modulated by growth factors. About 90%
will degenerate and about 30 precursor follicles are likely to become Gn
dependent and are likely to be present at the beginning of menstrual
cycle. Under physiological conditions of optimal FSH and LH, a few are
selected and one will mature as dominant follicle.
The recruitment and development of small antral follicles followed
by ovulation of one of them obey the dual concept of ‘FSH threshold’
and ‘FSH window’:
• The ‘FSH threshold’ implies that the levels of circulating FSH must
rise above a threshold value in order to initiate the development of
antral follicles.
• The ‘FSH window’ concept states that the duration of the FSH signal
is normally of short duration because the ovarian response to FSH
(E2 and inhibin) feeds back negatively on FSH levels, which secure
the single follicular dominance and ovulation.
As the sensitivity of ovarian follicles to FSH increases with size, only
the largest continues to grow and ultimately ovulates in the face of
declining FSH levels. The last steps of follicular maturation and growth
of the dominant follicle are LH rather than FSH driven.
Hence, the 3 phases of ovulation have to be understood prior to initiating
therapy:
1. Recruitment (which we do not have a control as it takes place before
the menstruation).
2. Selection (which we can manipulate by the ovulogens).
3. Dominance (which we once again have control to certain extent if we
can improve the selection process).
Anovulatory infertility comprises about one-quarter of patients

attending an infertility clinic.5 The main causes of anovulatory infertility
are:6
• PCOS (in approximately 80% of cases),
• Hyperprolactinemia (5%) and
• Hypogonadotropic hypogonadism (HH, 5%).
• Premature ovarian failure (which may be preceded by incipient
ovarian failure or ‘resistant ovary syndrome’, accounts for approxi-
mately 4% of cases).
• Hypopituitarism is less common (<1%).
Treatment options broadly include pulsatile GnRH for HH, dopamine
agonists for hyperprolactinemia or antiestrogen therapy for PCOS.
Premature ovarian failure can only be treated by oocyte donation.
POLYCYSTIC OVARY SYNDROME (PCOS)

A recent international consensus has been agreed on the definitions of
PCOS and the polycystic ovary: the new definition requires the presence
of two out of the following three criteria:6
• Oligo- and/or anovulation;
• Hyperandrogenism (clinical and/or biochemical);
• Polycystic ovaries, with the exclusion of other etiologies.
The polycystic ovary is one that contains 12 or more follicles (multiple
small cysts, most of which contain potentially viable oocytes but within
dysfunctional follicles) measuring 2-9 mm in diameter and/or increased
ovarian volume (>10 cm3). Polycystic ovaries are commonly detected by
ultrasound, with estimates of the prevalence in the general population
being in the order of 20-33%. However, not all women with polycystic
ovaries demonstrate the clinical and biochemical features that define
PCOS.
The PCOS is the hardest condition to manage because of the additional
metabolic problems, frequent obesity and sensitivity of the ovaries to
stimulation, all of which increase risks of ovarian hyperstimulation
syndrome (OHSS) and multiple pregnancy. It is associated with insulin
resistance, particularly in those who are overweight. Fertility in these
women is adversely affected by them being overweight or having an
elevated serum LH concentration. The OI in these women has to be
carefully monitored with serial ultrasound scans.
Strategies to induce ovulation should include weight loss in addition to
CC as first line of therapy. For those who fail to ovulate with this, the
principal options include parenteral gonadotropin therapy or laparo-

scopic ovarian diathermy (LOD). Insulin-sensitizing agents (such as
metformin), that helps by ameliorating the biochemical profile and
improving the reproductive function and aromatase inhibitors (such as
letrozole), which have shown promising results in current trials.
WEIGHT-RELATED AMENORRHEA
A body mass index (BMI) of < 20 kg/m2 is subnormal, and menarche
will usually not arrive until a BMI of >19 kg/m2 is reached. It is essential
to encourage weight gain as the main therapy. In some, ovulation will
not resume after a return to normal weight, especially after a prolonged
period of amenorrhea. In such cases, ovulation can be restored by
resorting to pulsatile GnRH therapy.5
Exercise and Weight Loss

Hyperinsulinemia is the key to the pathogenesis of the PCOS. Insulin
stimulates androgen secretion by the ovarian stroma and affects the
normal development of ovarian follicles both, by the adverse effects of
androgens on follicular growth and possibly also by suppressing apoptosis
and permitting the survival of follicles otherwise destined to disappear.
In a PCOS patient, BMI correlates both, with an increased rate of cycle
disturbance and infertility, secondary to disturbances in insulin
metabolism. Measurement of impaired glucose tolerance is important if
the BMI is greater than 30 kg/m2.5
A study by Clark et al observed the effect of weight loss and exercise
program on women with anovulatory infertility, clomiphene resistance
and a BMI >30 kg/m2. Weight loss had a significant effect on endocrine
function, ovulation and subsequent pregnancy. Fasting insulin and serum
testosterone concentrations decreased. Patients resumed ovulation,
becoming pregnant.7
Pasquali et al showed that even a 5% reduction in BMI results in
improved insulin sensitivity, menstrual cycle pattern and fertility rates
and should be the first line of management in patients with PCOS.8
A reduction in body weight of 5-10% causes a 30% reduction in visceral
fat, which is often sufficient to restore ovulation and reduce markers
for metabolic disease. Exercise is important in helping to achieve weight
loss, improve insulin sensitivity and reproductive function. Visceral fat
is affected more than subcutaneous fat, and as little as 2 hours of exercise
every week may be sufficient. Physical activity is the strongest
independent predictor of central abdominal fat and total fat mass. A

difference of 1 hr exercise every week can account for a 1 kg difference
in body fat. Regular aerobic exercise is most beneficial and a strategy
should be developed to maintain exercise activity.6
Thus, with appropriate support, patients may ovulate spontaneously
without medical therapy. An extension of this study, in women with a
variety of diagnoses, demonstrated that, weight loss resulted in
spontaneous ovulation with lower than anticipated rates of miscarriage
and a significant saving in the cost of treatment.6 Weight loss should
also be encouraged prior to ovulation induction treatments, as they
appear to be less effective when the BMI is > 28-30 kg/m2.
A weight loss program may improve ovulation and pregnancy
outcomes in women who are obese and infertile for all forms of fertility
treatment, including OI, IUI and IVF. Advice on weight reduction may
improve response to CC in endocrine and ovulatory function of obese
women with PCOS.10,11 Lifestyle modification may improve insulin
sensitivity and restore ovulation in women with PCOS.11
ANTIESTROGENS
This category includes selective estrogen receptor modulators (SERM)
such as CC, tamoxifen, and raloxiphene. SERMs are nonsteroidal
compounds that selectively bind to estrogen receptors (ER) exhibiting
tissue-dependent agonistic and antagonistic effects.
Clomiphene Citrate (CC)

The CC was synthesized in 1956 and has been used for ovulation induction
since 1967. For many years, CC (1st line SERM) has been the most
extensively used ovulogen. Although initially it was used for OI in
women with PCOS, it is now widely used either alone or in combination
with hMG or r-FSH as part of OI/IUI protocols in the treatment of
anovulatory and unexplained infertility and also for superovulation.12,13
The CC binds to ERs in the hypothalamus and pituitary, acting as a
competitive estrogen antagonist. This results in a reduction in negative
feedback of endogenous estrogens, producing a rise in the amount of
GnRH released by the hypothalamus and thus promoting an increased
pulsatile release of FSH and LH. The pituitary then responds by
increasing the release of the gonadotropins: FSH and LH. The end-organ
effect is that of follicle recruitment, growth, maturation and, ultimately,
ovulation.14
It is excreted mainly in the gut and a small amount in the urine. It is

concentrated in the hepatoportal circulation and can be detected in the
circulation up to 30 days after administration.
Clomiphene Administration
Dose
The CC is administered orally in daily doses of 50-150 mg. The
recommended starting dose is 50 mg.1 The dose can be raised in increments
of 50 mg per day per cycle until an ovulatory cycle is achieved.10 If the
patient is ovulating, it is not necessary to increase the dose as conception
is expected to occur at a rate determined by factors such as the patient’s
age, etc. The dose should only be increased if there is no response after
2 cycles as, of those women who will respond to 50 mg; only 2/3rd will
do so in the 1st cycle. Doses of 150 mg or more confer no benefit and
only worsen the side effects, particularly of a thickened cervical mucus.6,15
An ovulatory trigger in the form of hCG is rarely required and should
only be given if there has been repeated evidence of an unruptured
follicle, by ultrasound monitoring. If there is an exuberant response to
50 mg, as in some women with PCOS, the dose can be decreased to
25 mg.
Time of Therapy
Antiestrogen therapy should be commenced on day 2 of the cycle and
given for 5 days. If the patient has oligo-/amenorrhea it is necessary to
exclude pregnancy and then induce a withdrawal bleed with a short
course of progestogen (e.g. 10-20 mg medroxyprogesterone acetate for
5 days).5,14,15
A study by Scharnowski et al to evaluate the effect on PR when the
initiation of CC was changed from cycle day 5 to cycle day 1 or 2 reported
the PRs to be significantly lower. Their study did not support a beneficial
outcome of beginning CC early in the follicular phase. Cycle length and
ovulation day are advanced by 2 days when CC is initiated day 1 or 2.
They concluded that despite the evidence of CC’s negative effects on
uterine perfusion and endometrial lining growth, early use might result
in the inadvertent administration of CC during early pregnancy.16
However, persuasive arguments citing the negative antiestrogenic
effects on endometrial receptivity and cervical mucous, along with the
long half-life of CC, suggest that initiation of CC earlier in the cycle
might minimize these adverse effects during the peri-implantation time.
Duration of Therapy
A course of 3 to 6 ovulatory cycles is usually sufficient to know whether
pregnancy will be achieved using CC before moving on to a more
complex treatment as 75% of the pregnancies achieved with CC occur
within the first 3 cycles of treatment.15
Although the British National Formulary recommends a maximum of 6
cycles of CC, this relates to the number of cycles in one course of
treatment. In clinical practice, many women will require > 1 course of
treatment and this will result in administration of > 6 cycles of CC. Also,
there may be benefit in receiving CC in up to 12 cycles as cumulative PRs
continue to rise after 6 treatment cycles before reaching a plateau,
comparable to that of the normal fertile population, by cycle 12. It is
acceptable to prescribe CC for up to 12 months if there is a normal
ovulatory response and there are no other infertility factors.9
However, use of CC for 12 or more cycles has been associated with
an increased risk of borderline ovarian tumor in one study.17 It is
therefore, appropriate to consider alternative treatments after 12 cycles
of poor results from CC.
Monitoring
The CC has been available for many years and its use has tended not to
be closely monitored. A residual ovarian follicle is a frequent finding
among infertile women selected for OI therapy.5,6,14 A basal ultrasound
should be recommended before starting OI. The reported incidence of
ovarian cysts is 15.4-21.5% in CC-OI cycles.18
All women who are prescribed CC should be carefully monitored
with a combination of endocrine and ultrasonographic assessment of
follicular growth and ovulation, because of the risk of multiple
pregnancy.
Side Effects
Side effects include visual disturbances (stop drug immediately), multiple
pregnancy (10%), abdominal distension, ovarian cysts, hot flushes, breast
tenderness, dizziness and nausea. Recent reviews about the safety of
CC, with respect to congenital anomalies, indicate that there is no
increased risk.5,6
Outcome
The CC is effective in women with normal FSH levels and sufficient
endogenous estrogen and is much less effective with elevated FSH levels
or hypothalamic amenorrhea.19 As CC induces a discharge of LH as
well as FSH, and elevated LH concentrations are believed to impede
conception, those women with high basal LH levels are also less likely
to respond to CC treatment.15
In anovulatory women with PCOS: CC has been the first line of therapy. It
induces ovulation in approximately 80% of oligo-ovulatory or
anovulatory women.
Although CC induces ovulation in approximately 70-85% of patients,
only 40-50% actually conceive.6 Kousta et al reported a cumulative PR of
67.3% over 6 months, which continued to rise for up to 12 cycles of
therapy. They reported a multiple pregnancy rate of 11% (similar to
that described in other series), and a miscarriage rate of 23.6% (those
who miscarried had a higher serum LH concentration immediately after
CC administration).20
As cumulative conception rates continue to rise up to 12 months of
therapy, particularly if the treatment is monitored closely, if pregnancy
has not occurred after 10-12 of normal ovulatory cycles, it is then
appropriate to offer the couple assisted conception.5,6,14 The incidence
of twins is < 10% and of triplets is < 1%.21
Antiestrogenic Effect of CC on Endometrium

On CC therapy, 20-25% women show resistance and do not ovulate.14,22
In addition, clinical data have revealed a discrepancy between ovulation
and conception rates during CC treatment and a higher than expected
incidence of miscarriage in conception cycles.23-26 Unfortunately, despite
high rates of ovulation, PRs per cycle remain relatively low.
These observations have been attributed to the antiestrogenic mechanism
of action of CC, which involves long-lasting estrogen receptor (ER)
depletion.14 It also appears that CC accumulates in the body because of
its long half-life.27 As a result, CC may have a negative effect on the
quality and quantity of cervical mucus,28 on endometrial development,29
and on other as yet undetermined fertility factors.30,31
The CC results in a 60-85% ovulation rate and a 10-20% pregnancy
rate per cycle.12,30,32-36 A considerable body of experimental evidence
suggests that, in addition to its desirable central action of stimulating a
transient increase in gonadotropin secretion, CC may have other

unintended and potentially detrimental effects on peripheral estrogen
target tissues 37and these peripheral antiestrogenic effects are frequently
cited as a possible explanation for the relatively low pregnancy rates
with clomiphene despite the high rate of ovulation observed.4
Prolonged endometrial ER depletion29,38,39results in the significant
thinning of the endometrium (endometrium thickness < 8 mm) that is
associated with CC cycles compared with natural cycles and in CC/
hMG cycles compared with hMG alone.29,38,40,41 This endometrial thinning
has been observed in 15-50% patients on CC.29,41,42
Despite normal ovulation, 15-50% of women on CC will develop a
thin endometrium (< 8 mm) with a tendency toward a non-trilaminar
pattern of the endometrium at midcycle. This has been shown to be a
repetitive phenomenon in subsequent cycles and is not improved by
addition of supplemental estrogen, suggesting that it is a result of ER
depletion. Both thin endometrium and non-trilaminar pattern of the
endometrium at midcycle have been associated with low pregnancy rates
and early pregnancy loss.43 Dickey and Holtkamp36 as well as Gonen
and Casper29 reported no pregnancies occurring in cycles with endometrial
thickness < 6 mm at midcycle and a significantly higher rate of biochemical
pregnancies when the endometrial thickness was 6-8 mm.44
Clomiphene Resistance
The term clomiphene resistance should be applied to a mean failure to
ovulate (i.e. no response), rather than failure to conceive despite
ovulation, which should be termed clomiphene failure.6 About 70% of
anovulatory women ovulate in response to CC treatment, and they do
so at a dose of 50-100 mg, the maximum dose being 250 mg. Anovulatory
women who do not ovulate while receiving the 150 mg dose of CC are
considered to be resistant to the drug.9
In anovulatory women, there is a significant association between CC
failure and increased BMI (BMI > 27.2 kg/m2 or > 30.6 kg/m2).20,45 A
weight loss program and advice on weight reduction may improve
response to CC treatment.9 Lifestyle modification may improve insulin
sensitivity and restore ovulation in women with PCOS, as described
above. CC-resistant cases of PCOS can be managed with gonadotropin
therapy or laparoscopic ovarian diathermy (LOD).5,6
Women with ovulatory disorders who are resistant to standard doses
of CC generally become candidates for gonadotropin therapy. However,
severe OHSS and the high risk of multiple pregnancy are major
disadvantages of gonadotropin treatment, especially in young women
with PCOS.14
Some investigators have proposed combined CC and low-dose
glucocorticoid therapy for the treatment of CC-resistant anovulation.15,46-49
Although this form of therapy can be successful in women with
hyperandrogenism (it suppresses the adrenal androgen secretion), a
disadvantage is the potential for glucocorticoid-related side effects. Other
investigators have described the use of extended duration and higher
doses of CC.50-53
In women who fail to ovulate with CC alone: Metformin and CC may
achieve ovulation, especially if women are obese/have evidence of insulin
resistance.54,55
There has been recent interest in the aromatase inhibitor letrozole,
which has yet to be licensed but appears to have a similar effect to CC
on ovulatory function in normal women and may possibly be beneficial
to women with CC-resistant PCOS.
Clomiphene Citrate in Unexplained Fertility Problems

Although it has been established that PRs for women who take CC are
lower than expected on the basis of ovulation rates, CC therapy is widely
administered to induce multiple ovulation in ovulatory women suffering
from unexplained infertility.9,14 In these women, CC is anticipated to
improve the outcome of infertility treatment by increasing the number
of oocytes available for fertilization.54 However, the use of CC in
unexplained infertility may be complicated because of antiestrogenic
effects on endometrial development and its use in unexplained infertility
remains controversial.
A Cochrane review of clinical data suggests a modest improvement
in pregnancy rates. However, the Royal College of Obstetricians and
Gynaecologists (RCOG) guidelines on evidence-based fertility
management do not support its use in these patients, and recommends
its use only in the context of a randomized controlled trial.5
Tamoxifen
Tamoxifen has been used for OI as early as 1970 and has been subject of
clinical trials since.57,58 It is homologous to CC in structure and properties.
It also occupies ERs in the hypothalamus and thereby interferes with
normal feedback mechanism, which leads to increased gonadotropin

release and stimulation of the ovary to produce more follicles.
Dose: 20 mg (maximum of 40 mg) per day orally from day 3 to day 7.
Clomiphene Citrate versus Tamoxifen

The CC and tamoxifen have been shown to have similar effects on
pregnancy rate and ovulation in anovulatory women with infertility.9
A recent randomized controlled trial (RCT) compared efficacy of
tamoxifen with CC for OI in anovulatory women54 and found similar
ovulation and pregnancy rates in both groups. Others have reported
superiority of tamoxifen in that it does not have an inhibitory effect on
the endometrium60 and has shown success in patients in whom CC
treatment failed.61 It has not been evaluated for superovulation.
Combination of CC and Tamoxifen

Other novel uses of the SERMs have included the combination of tamoxifen
and CC. Their combined effects in the treatment of anovulation appeared
to result in increased ovulation and pregnancy rates.62
RCOG Recommendations
• Women with WHO Group II ovulation disorders (hypothalamic
pituitary dysfunction) such as PCOS should be offered treatment with
CC (or tamoxifen) as the first line of treatment for up to 12 months
because it is likely to induce ovulation.
• Women should be informed of the risk of multiple pregnancies
associated with both CC and tamoxifen.
• Women with unexplained fertility problems should be informed that
CC treatment increases the chance of pregnancy, but that this needs
to be balanced by the possible risks of treatment, especially multiple
pregnancy.
• Women undergoing treatment with CC should be offered ultrasound
monitoring during at least the first cycle of treatment to ensure that
they receive a dose that minimizes the risk of multiple pregnancy.
Raloxifene
Raloxifene also appears to increase follicular phase FSH with a resultant
rise in estradiol (E2) levels. However, it may have a primary antagonistic
effect at the level of endometrium.63 It is yet to be tested as a potential

ovulogen.
AROMATASE INHIBITORS (AI)14,43

After failure of CC, gonadotropin preparations such as hMG or pure
FSH have been used as a second-line treatment for OI. In women with
PCOS, because of the high sensitivity of the ovaries to gonadotropin
stimulation, treatment with hMG or pure FSH is difficult to control and
characteristically induces several ovulatory follicles, leading to the risk
of multiple pregnancies and OHSS.22 Therefore, a simple oral treatment
that could be used without risk of hyperstimulation and with minimal
monitoring would be the preferred therapy.
The third-generation AIs were initially introduced to treat
postmenopausal breast cancer. We now realize that many other potential
indications for AI exist, especially in the field of gynecology. Since they
act by decreasing circulating E2 levels, aromatase inhibitors have been used
to treat endometriosis, estrogen responsive cancers, and leiomyomata
uteri as well as to induce ovulation.
The third generation AIs can be divided into 2 classes: the competitive
inhibitors that bind to the active site of the enzyme and the inactivators,
which destroy the enzyme by binding covalently to it. 64 Two 3rd
generation competitive inhibitors (anastrozole and letrozole) and one
inactivator (exemestane) have now been approved for use in the United
States and worldwide; however, they are yet to be licensed as fertility
enhancing drugs.65
Letrozole is the most well known of the aromatase inhibitors. It is a
specific, reversible, nonsteroidal aromatase inhibitor that suppresses
estrogen biosynthesis.
A single daily dose of 2.5 mg/day has been shown to achieve optimal
suppression of serum estrogen levels in postmenopausal women.66 When
administered to normally cycling female rats, letrozole resulted in
> 80% suppression of ovarian E2 levels and caused a marked increase in
LH and FSH, with a 35% increase in ovarian weights within 1 week of
treatment. 67 Similar effects were observed when letrozole was
administered to normally cycling bonnet monkeys. Letrozole resulted
in elevated FSH levels and a corresponding increase in the number of
multiple mature follicles that were ovulated after administration of
exogenous hCG.68 Based on the above animal experiments, it was
postulated that letrozole might have an important application in OI
protocols for the treatment of infertility.43
Mitwally and Casper69 first reported the clinical use of an AI in OI

and concluded that it appears to be safe, convenient and inexpensive
drug with the potential to replace CC as a first-line treatment for OI.
Mechanism of Action
Aromatase is the rate-limiting enzyme that catalyzes the conversion of
androgens to estrogens. It is a cytochrome p450 enzyme, which catalyzes
the conversion of androgens to estrogens. The AIs decrease estrogen
synthesis without having direct antiestrogenic effects themselves.
• Centrally, inhibition of estrogen synthesis by an AI may release the
estrogenic negative feedback on the hypothalamus and/or pituitary
resulting in an increase in endogenous Gn secretion leading to
enhancement of ovarian follicular development.
• A peripheral mechanism of action is by increasing follicle sensitivity to
FSH through an increase in local androgens in the ovary (temporary
PCOS-like effect). This may result from accumulation of intraovarian
androgens because conversion of androgen substrate to estrogen is
blocked. Recent data support a stimulatory role for androgens in
early follicular growth in primates, in contrast to the inhibitory effect
observed in rodents.70 Testosterone was found to augment follicular
FSH receptor expression in primates, which suggests that androgens
promote follicular growth and estrogen biosynthesis indirectly by
amplifying FSH effects.71-73 As such, it is possible that letrozole-
induced accumulation of ovarian androstenedione may result in
increased expression of FSH receptors. This would result in enhanced
sensitivity of the developing follicles to existing FSH.43
• Locally, androgen accumulation in the follicle may stimulate insulin-
like growth factor (IGF), along with other endocrine and paracrine
factors, which may synergize with FSH to promote folliculogenesis.74-76
• Additionally, they may block brain aromatase as another mechanism
to increase FSH. The blocking effects of AIs can be counteracted in
premenopausal women by the large increase in androstenedione as
substrate, which is induced by the rise in LH. In addition, the FSH
increments stimulate production of aromatase itself.65
In women with PCOS, increased intraovarian androgen levels may
synergize with central effects of decreased estrogen to enhance the
ovarian response to Gn stimulation. This increased sensitivity to FSH
may be especially useful in poor responders.
Administration of Letrozole
Administration of an AI in the early part of the menstrual cycle is a
simple, inexpensive, and safe alternative to CC for use in normally
ovulatory women that mimics the action of CC without depletion of
ERs.
Letrozole reaches a steady-state plasma concentration in 4-8 hours
and has a half-life of approximately 45 hours. The absolute systemic oral
bioavailability is 100%.77
Dose and Timing

Letrozole has been used in a dose of 2.5 mg/day on day 3 to 7 of the
menstrual cycle.
Mitwally et al78 studied the possible use of letrozole as a single dose
administration of 20 mg on day 3 of the menstrual cycle to stimulate
follicular development and proposed that it has the advantage of allowing
rapid clearance of the drug from the body due to its short half-life. This
leads to lower negligible levels of letrozole in the body around the
ovulation and early embryogenesis period. Besides the increased safety
of the single dose administration, it is more convenient; and in addition,
there is a decreased cost of medication preparation. Further research is
running to compare between various single administration doses of
letrozole for different indications of ovarian stimulation.
Letrozole versus CC (Effects on Endometrium)

The AIs differ from the estrogen antagonist CC in that they do not exert
a direct unfavorable effect on endometrial growth and development
during the menstrual cycle.13,65 Owing to a relatively short half-life
compared with CC, letrozole gets eliminated from the body rapidly.78-80
Moreover, because it is more rapidly eliminated than CC and does not
cause ER depletion (downregulation), it is likely that letrozole
administration in the early part of the menstrual cycle releases the
hypothalamic/pituitary axis from estrogenic negative feedback, similar
to the effect of CC but without any adverse endometrial effects observed
with CC. The subsequent increase in Gn secretion then stimulates ovarian
follicle development, ultimately resulting in improved PRs.68
Mitwally et al 22 have reported the novel use of letrozole for inducing
ovulation in anovulatory women with PCOS and for augmenting ovulation in
ovulatory (unexplained) infertile women. In PCOS women without an
adequate response to CC (thin endometrium; mean, 5 mm), ovulation

occurred in 75% of letrozole treatment cycles and clinical pregnancy
was achieved in 17% of the cycles. In the group of ovulatory women,
ovulation was augmented and > 1 mature follicle was obtained in 90%
of patients. Letrozole treatment in the early follicular phase resulted in
a significant increase in midcycle endometrial thickness (mean, 9 mm),
with spontaneous ovulation occurring in both letrozole- and CC-treated
cycles.22
In the letrozole-treated cycles, the endometrium has been shown to
be of adequate thickness to allow implantation even though estrogen
levels were two- to three-fold lower than observed in CC cycles. This
observation supports the absence of any direct antiestrogenic effects of
letrozole on the endometrium. Ovarian folliculogenesis is similar to that
seen with CC with no apparent adverse effect on endometrial thickness
or pattern at midcycle.
In another study, Mitwally and Casper81 compared letrozole with CC
alone in patients who failed to ovulate with CC or ovulated with CC but
had inadequate endometrial thickness after CC treatment. When
administered in a 5-day regimen similar to CC, letrozole resulted in
ovulation among 77% of the patients, with a pregnancy rate of 33%.
Fisher et al,43 in a randomized double-blind comparison study
between letrozole and CC, reported that CC results in a significant
(supraphysiological) increase in E2 levels, while E2 levels in letrozole-
stimulated cycles appeared lower than in natural cycles. Compared with
CC, letrozole is shown to produce a significantly thicker endometrium on
the day of hCG administration despite the significantly lower E2 levels,
both in patients with PCOS and the ovulatory patients. This observation
confirms the deleterious effect of CC on endometrial growth that is
believed to be due to depletion of endometrial ERs.
Despite the relatively short duration of letrozole treatment, the
reduction in E2 levels per follicle suggests a persistent reduction of
aromatase activity, which lasts to midcycle. Whether this has any
detrimental effect on implantation or luteal function is unknown. There
is accumulating evidence that supraphysiological levels of estrogen may
be detrimental to developing embryos. In this regard, more physiological
levels of E2 in letrozole-stimulated cycles may further improve pregnancy rates
compared with CC-stimulated cycles.43
Letrozole versus CC for Superovulation before IUI

Sammour et al82 compared letrozole with CC for superovulation before
IUI and found that although fewer follicles developed, a superior uterine
environment was achieved.82,83
Letrozole plus Gonadotropins

Letrozole and h-FSH in Poor Responders
Mitwally and Casper84 demonstrated a significant improvement in ovarian
response to h-FSH in women undergoing OI and IUI. Women who were
known poor responders to FSH stimulation (<3 follicles/cycle; mean,
1.9 mature follicles/cycle) were administered letrozole (2.5 mg/day) on
days 3-7 before commencing FSH on day 7. In these women, addition of
letrozole to the stimulation protocol resulted in a significant increase in
the number of mature follicles at midcycle (3.5 versus 1.9).
Addition of AIs to Gn also reduces the Gn dose (compared with use of
Gn alone) required for controlled ovarian stimulation.83,85,86 This was
demonstrated in another study by Mitwally and Casper.86 They had
reported that the dose of FSH required to achieve COH in PCOS and
unexplained infertility was decreased with concurrent letrozole use. In
that study, the number of follicles, endometrial thickness, and PRs were
the same regardless of whether letrozole was added to the regimen.
In the study by Healey et al,87 on the effects of the addition of an AI
to Gn injections for superovulation, an apparent inconsistency in the
effects of AIs among patients who were anovulatory was seen. In
anovulation, letrozole did not decrease the Gn requirement. Furthermore, the
endometrial measurement was significantly smaller with the use of
letrozole. They reported that the addition of letrozole to an OI regimen
using injectable Gn in patients with infertility does not seem to offer any
benefit over Gn-only cycles, because the decreased Gn dose (the only apparent
benefit) was offset by increased complexity of the treatment.
It is tempting to speculate, therefore, that different modes of ovulatory
stimulation may be applicable to conditions of anovulation versus super-
ovulation. It may be that certain agents or combinations of agents are
most effective for superovulation, whereas others are best used for
anovulatory states.88
Outcome
Thus, 3 possible advantages are seen in using AIs such as letrozole in
COH:
• Cycles without antiestrogenic effects on endometrium and mucus
• Increased responsiveness to FSH in poor responders and
• Decreased tendency for premature luteinization.
The rapid elimination and reversibility of letrozole appear to allow
the endometrium to respond well to rising estrogen levels in the late
follicular phase. Consequently, ovulation and implantation can take place
without hindrance. Potential benefits of letrozole therapy include:
• Improved sensitivity to FSH,
• Improved endometrial development compared with CC, and
• Improved implantation rates due to more physiological E2 levels.
These properties make letrozole a viable alternative to CC and a
useful adjunct to FSH in ovarian hyperstimulation protocols for both
IUI and IVF. The above data suggest that the letrozole is an orally
effective, inexpensive method for stimulating follicular development
and has the potential as an alternative to, or even replacement for, CC as a
first-line treatment for OI in anovulatory infertility, in CC-resistant cases
and for augmentation of ovulation in ovulatory (unexplained) inferti-
lity.20,22,43,65
HYPERPROLACTINEMIA
There are many causes of a mildly elevated serum prolactin concentration,
including stress, and a recent physical or breast examination.
Hyperprolactinemia may result from a prolactin-secreting pituitary
adenoma, or from a non-functioning‚ disconnection tumor in the region
of the hypothalamus or pituitary, which disrupts the inhibitory influence
of dopamine on prolactin secretion. Other causes include hypothyroidism,
PCOS and several drugs (e.g. the dopaminergic antagonist pheno-
thiazines, domperidone and metoclopramide, tricyclic antidepression
medications, cimetidine, chlorpromazine, haloperidol, methyldopa, and
levodopa can cause mild to moderate increase in prolactin levels. If the
prolactin concentration is > 100 ng/ml, then the test should be repeated;
and if still elevated, it is necessary to image the pituitary fossa (CT or
MRI scan).5
DOPAMINE AGONISTS
Bromocriptine
The management of hyperprolactinemia centers around the use of a
dopamine agonist, of which bromocriptine is still the most widely used.
Dose: Treatment should be started with a dose of 1.25 mg (taken with
food) at night for 1st fortnight and then increased to 2.5 mg for another
fortnight.89
The dose should be monitored with serum prolatin level estimation—
if < 20 ng/ml, maintain the same dose. Once the level has returned to a
level below this, 70-80% of women will ovulate.
Outcome
Most patients show a fall in prolactin levels within a few days of
commencing bromocriptine therapy and a reduction of tumor volume
within 6 weeks.21 For women with hyperprolactinemia, the dopamine
agonist bromocriptine leads to ovulation in approximately 80%.19 A
systematic review of three RCTs found no improvement in PRs following
treatment with bromocriptine versus placebo in couples with unexplained
infertility.90
Side effects can be troublesome (nausea, vomiting, headache, postural
hypotension) and are minimized by commencing the therapy at night
for the first 3 days of treatment and taking the tablets in the middle of
a mouthful of food. Long-term side effects include Raynaud’s syndrome,
constipation and psychiatric changes, especially aggression, which can
occur at the start of treatment.
Cabergoline
Cabergoline, a long-acting dopamine agonist, is at least as effective as
bromocriptine and appears to be better tolerated.91 It has now become
the drug of choice for hyperprolactinemia. However, the manufacturer
advises discontinuation of cabergoline at least 1 month before
pregnancy.92 It is administered twice weekly.
Cabergoline versus Bromocriptine

Two RCTs comparing cabergoline to bromocriptine in women with
hyperprolactinaemic amenorrhea reported that cabergoline was more
effective in restoring ovulation and increased pregnancy rates (72% and
72% with cabergoline versus 52% and 48% with bromocriptine, respec-
tively).91,93
However, bromocriptine is still the most widely used preparation,
despite cabergoline being today’s drug of choice. Women with a
microprolactinoma who wish to conceive should be prescribed
bromocriptine, as there are limited safety data for the use of cabergoline
in pregnancy. Bromocriptine may be discontinued when pregnancy is
diagnosed and no further monitoring is required, as the likelihood of
significant tumor expansion is very small (< 2%). On the other hand, if a
patient with a macroprolactinoma is not treated with bromocriptine,
the tumor has a 25% risk of expanding during pregnancy.6
RCOG Recommendation
• Women with ovulatory disorders due to hyperprolactinemia should
be offered treatment with dopamine agonists such as bromocriptine.
• Consideration should be given to safety for use in pregnancy and
minimizing cost when prescribing.
SURGICAL OVULATION INDUCTION

For many years, between the 1930s and the early 1960s, wedge resection
of the ovary was the only treatment for PCOS. Wedge resection required
a laparotomy, removal of up to 75% of each ovary and often resulted in
extensive pelvic adhesions.6
The modern day, minimal access alternative to Gn therapy for CC-
resistant PCOS women that either persistently hypersecrete LH, need a
laparoscopic assessment of their pelvis, or who live too far away from
the hospital to be able to attend for the intensive monitoring required
of Gn therapy is laparoscopic ovarian surgery. Laparoscopic ovarian
surgery is free of the risks of multiple pregnancy and OHSS and does
not require intensive ultrasound monitoring. Furthermore, ovarian
diathermy appears to be as effective as routine gonadotropin therapy in
the treatment of CC-insensitive PCOS.5,95 Surgery does, of course, carry
its own risks and must be performed only by fully trained laparoscopic
surgeons.5,6.
Commonly employed methods for laparoscopic surgery include lapa-
roscopic ovarian drilling with monopolar electrocautery [laparoscopic
ovarian diathermy (LOD)] and laser.
Ovarian drilling: A retrospective study showed that 3 punctures per
ovary appeared to be the plateau dose for LOD.95
Concerns with Laparoscopic Ovarian Surgery

• Wedge resection of the ovaries results in significant adhesion. The
risk of adhesion formation is far less after LOD (10-20% of cases),
and the adhesions that do form are usually fine and of limited clinical
significance. Adam Balen6 reports the use of a technique involving
instillation of 200 ml of Adept® solution into the pouch of Douglas,
which by cooling the ovaries prevents heat injury to adjacent tissues
and reduces the adhesion formation.
• An additional concern is the possibility of ovarian destruction leading
to ovarian failure, an event that is, fortunately, very uncommon. Cases
of ovarian failure have been reported after both wedge resection
and laparoscopic surgery. It is, therefore, important that a minimum
amount of ovarian destruction should be employed.
• The LOD can impose technical problems and anesthetic risks in obese
women with PCOS.96 There are no data on the long-term health
consequences of ovarian drilling or the formation of adhesions.
Outcome
The response to LOD appears to depend on the pretreatment charac-
teristics of patients. Patients with high basal LH concentrations have a
better clinical and endocrine response. After laparoscopic ovarian
surgery, with restoration of ovarian activity, serum concentrations of
LH and testosterone fall.
For those in whom LOD is successful, the duration of effect is variable.
A recently reported large series of 116 patients found that the beneficial
effects could be sustained for up to 9 years in the majority of cases.6
Ovulation occurred in over 80% of patients, with a normalization of
serum LH levels and good rates of pregnancy with a low miscarriage
rate (14%).5
Furthermore, a combined approach may be suitable for some women
whereby low-dose diathermy is followed by low-dose ovarian
stimulation with either CC or FSH therapy, immediately after laser wedge
resection. This increases the ovarian sensitivity to Gn.6
LOD versus Gonadotropins

The meta-analysis in the Cochrane database94 compared LOD with Gn
and observed that the ongoing PR differed according to the length of
follow-up. The meta-analysis found that when comparing 6 months after
LOD with 6 cycles of Gn therapy, the ongoing cumulative PR was higher
amongst women who received Gn. Multiple pregnancy rates were

considerably reduced in the LOD arms. There was no difference in
miscarriage rates.
It was concluded that there is no significant differences between LOD
after 6-12 months follow-up and 3-6 cycles of OI with Gn in cumulative
PR or miscarriage rate in women with CC-resistant PCOS.5,19
RCOG Recommendation
Women with PCOS who have not responded to CC should be offered
LOD because it is as effective as Gn treatment and is not associated with
an increased risk of multiple pregnancy.
PITUITARY AND HYPOTHALAMIC CAUSES OF ANOVULATION

Ovulation is optimally induced in women with intact pituitary function
by application of pulsatile luteinizing hormone-releasing hormone
(LHRH or GnRH), administered subcutaneously or intravenously by
a miniaturized infusion pump. The injections are given at intervals of 90
min at a dose of 15 mg subcutaneously. This therapy provides the most
physiological correction of the primary disturbance with little risk of
multiple pregnancy or OHSS.5
The OHHS, of whatever cause, responds better to hMG than to
purified FSH, because the former contains the LH, which is necessary to
stimulate androgen steroidogenesis, which is the substrate for estrogen
biosynthesis.
GONADOTROPINS (GN)
For women with PCOS who do not respond to CC, gonadotropins have
been used as OI agents.97 For an appropriate selection, an understanding
of the different preparations available is essential prior to initiating
therapy with Gn.
Gonadotropins are fertility enhancing drugs that contain FSH, alone
or combined with LH, (which are produced naturally by the pituitary
gland). A related medication is human chorionic gonadotropin (hCG), which
is structurally similar to LH and simulates the natural LH (ovulation)
surge.
Human menopausal gonadotropin (hMG) is extracted from the urine of
postmenopausal women and hence contains equal amount of FSH and
LH per ampoule. It contains 75 U of FSH and 75 U of LH per ml, although
the concentration may vary among batches (ranges from FSH at 60-90 U
and LH at 60-120 U). Furthermore, the specific activity of FSH and LH
in hMG preparations is low, with more than 95% of the proteins present
being non-active contaminants, not purified by the manufacturing process
and only 4% of protein content being Gn.98
Urinary FSH (u-FSH) contains 75 U of FSH and < 1% of LH activity,
but still 95% of contaminating proteins.
hMG versus Urinary FSH (u-FSH)

The Cochrane database analyzed the available randomized protocols
published comparing u-FSH versus hMG therapy for CC-resistant PCOS
and found no difference in pregnancy rate. However, u-FSH is associated
with a reduction of moderate or severe OHSS.99
According to the RCOG literature, a systematic review of 14 RCTs
found no significant differences between hMG and urinary FSH (u-FSH)
in terms of pregnancy rate per cycle, multiple pregnancy rate, miscarriage
rate, ovulation rate per cycle or overstimulation rate per cycle.
No significant differences on the above outcomes were found between
the use of subcutaneous pulsatile and intramuscular injection of Gn;
daily and alternate day administration; or step-up’ and standard
regimens.97
With improvization of the purification procedures, the removal of
impurities including LH and LH-like activity became possible resulting
in so-called “pure” FSH and highly purified FSH (hp-FSH) that have only
trace amounts of LH activity. In 1993, highly purified FSH was made
available to clinicians: it contains the same amount of FSH, but less than
0.1% of LH. Moreover, the content of contaminant proteins is reduced
to only 4%, allowing therefore a subcutaneous injection for
administration.
Purified FSH versus hMG

For women with the WHO Group I ovulation disorders (hypothalamic
pituitary failure, characterized by hypothalamic amenorrhea or HH),
treatment with hMG (which includes FSH and LH) was reported to be
more effective in improving ovulation than FSH alone.100
The new generations of available Gn are produced by genetically
engineered mammalian cells (i.e., Chinese hamster ovary cells), in which
the gene coding for the human α and β FSH subunit has been inserted
called the recombinant FSH (r-FSH).101 Only when r-FSH preparation was
introduced a few years ago did a near 100% pure FSH preparation totally
devoid of LH-like activity became available.
Finally, recombinant human FSH (rh-FSH) has been available in the
USA since 1997, but earlier (1995) in Europe. The preparation does not
contain LH and is free of impurity. In addition, it offers a consistency
between different batches, fact that is highly desirable in clinical practice.
Recombinant FSH (r-FSH) versus Urinary FSH (u-FSH)

The Cochrane database102 reviewed the available evidence (4 RCT)
comparing r-FSH versus u-FSH in PCOS patients who were resistant to
CC and found no significant differences for ovulation rate, PR,
miscarriage rate, multiple pregnancy rate and OHSS. No significant
differences were shown in these outcomes between administering
r-FSH as a chronic low dose or conventional regimen. It appears,
therefore, that at present sufficient data to determine weather r-FSH or
u-FSH is preferable for OI in women with PCOS is lacking.
Recombinant LH (r-LH) is currently undergoing clinical trials.
PROTOCOLS OF ADMINISTRATION
When the initial treatment of CC induction fails, then Gn is chosen. In
PCOS generally hMG is not chosen as there is more of LH and hence
pure-FSH is chosen to avoid excess LH, which can cause more of atresia
in the granulosa cells.
Conventional (Classical) Step Up Dose Regimen

The classical protocol used in the 1970s for PCOS patients included
stimulation with 150 U of hMG (containing 75 U FSH and 75 U LH), that
was increased every 3-5 days by 50% until an ovarian response occurred.
However, PCOS patients often respond in a dramatic way to this
protocol and the rate of OHSS is unacceptably high which is 1.1-14%.103
Low Dose Step Up Protocol

Brown104 introduced the concept of FSH threshold. A follicle can be rescued
only when FSH is above a certain level. In patients with PCOS the
chronically low and constant level of FSH allows initial development of
multiple follicles that, however, do not continue development and
undergo atresia. Increasing the level of FSH in a gradual and step-wise
fashion allows the rescue of a limited number of follicles mirroring what
happens in the normal hormonal cycle. This approach reduces the

incidence of OHSS. The general recommendation of the incrementing
the dose of Gn here is only 10-30% of the initial dose every 5 days.
The most widely used current step up protocol is characterized by a
low starting dose (75U), maintained for a longer period of time (14
days,) and then increased only of a small amount (37.5 U) per week.
This protocol is associated with a low incidence of severe OHSS (0-
0.5%) and multiple pregnancy (6-18%) with good fecundity per cycle
(11-17%).105
One prospective study compared the standard protocol versus the
low dose step up protocol and confirmed the safety of the latter with a
concomitant comparable PR.106.
Low Dose Step Down Protocol

This protocol is based on the assumptions that the high starting dose
replicates the midcycle FSH surge and the fact that the dominant follicle
is less dependent for its development to FSH levels than smaller
follicles.107
The initial dose is between 1.5 and 2.5 ampoules (75 IU FSH/ampoule)
per day (dependent on body weight), and decreasing steps (every 2-3
days) of 0.5 ampoules/day (based on sonographic findings). PRs are
comparable with those reported for step-up regimens, with a low
incidence of complications (i.e. multiple gestation and OHSS).
Sequential (Step Up-Step Down) Low Dose Protocol

This protocol combines characteristic of the 2 prior protocols.108 The
initial step up phase is followed by a step down phase when the leading
follicle reaches 14 mm in diameter. The FSH dose is then reduced by half
until hCG administration. This randomized prospective study showed
that the sequential protocol is as effective as the low dose step up protocol
in terms of PR and safety, while reducing the level of estradiol at the time
of hCG administration and the number of midsize follicles (14-15 mm).
• Women with the WHO Group II ovulation disorders such as PCOS
who do not ovulate with CC (or tamoxifen) can be offered treatment
with gonadotropins. The hMG, u-FSH and r-FSH are equally effective
in achieving pregnancy and consideration should be given to
minimizing cost when prescribing.
• Women with the WHO Group II ovulation disorders such as PCOS

who ovulate with CC but have not become pregnant after 6 months
of treatment should be offered CC-stimulated IUI.
CC plus hMG
Although the combination of CC and hMG successfully induced ovulation
in anovulatory patients,109 patients undergoing IVF110 and those who
have had a poor response to Gn alone,111 the combination of the newer
SERMs and hMG re-track record of successful use in both anovulation
and superovulation. Studies have successfully reported a higher PR per
treatment cycle, with low miscarriage rate and a high fecundity rate
than that with CC alone.112, 113
It is well known that there are some patients who cannot respond
properly by the exogenous administration of Gn preparations. In addition,
it is reported that plasma estrogen levels can modify the activities of Gn
receptor. A study 114 performed to elucidate whether exogenous
administration of estrogen preparation was effective to improve the
response of Gn administration in the patients of gonadotropin resistance
syndrome showed that administration of exogenous estrogens, and the
controlled ovarian stimulation using hMG with GnRH agonist after
exogenous estrogen priming was effective for the treatment of the
intractable ovulatory disturbances.
GONADOTROPIN-RELEASING HORMONE-ANALOGUES
(GnRH-a)
Gonadotropin-releasing hormone (GnRH) agonists can be used in
conjunction with Gn to achieve pituitary downregulation and facilitate
cycle control in ovarian stimulation. However, they are not widely used
in ovulation induction therapy for ovulatory disorders. There are several
short-acting preparations such as Buserelin and Nafarelin that are
administered by depot injectables, subcutaneous injectables or
intranasally.
While the goal of induction of ovulation is the development of one
or few ovulatory follicles, the goal of stimulation in IVF cycles is to
obtain multiple follicles, but without incurring in OHSS. High-dose
exogenous Gn is given to over-ride the mechanism of follicular selection.
A reversible hypogonadotropic hypogonadism is induced with GnRH
analogues.
The GnRH agonists can be used in differnet protocols known as the

flare-up protocol(s) and the luteal-phase protocol.115
The flare-up (ultrashort) protocol has the advantage of using the
transitory elevation of FSH (agonist effect) that occurs during the first 4
days of the follicular phase. This elevation helps in the follicular
recruitment process; after 5 days of GnRH-a administration, the pituitary
gland undergoes downregulation, which prevents premature
luteinization and the spontaneous LH surge. The administration of Gn
must be initiated on the fifth menstrual cycle day.
The modified flare-up protocol is the administration of birth control pills
for 21 days during the preceding IVF menstrual cycle. A micro dose of
GnRH-agonist: leuprolide acetate is administered twice daily
subcutaneously starting on day 1 of the menstrual cycle, and the
gonadotropin begins on day 4 of the menstrual cycle.
Long protocol: In the luteal-phase protocol, GnRH-a is started on the
17th or 21st menstrual cycle day (1 week prior to onset of menses). With
the onset of the menstrual cycle, the phenomenon of pituitary down-
regulation is in effect, so the administration of the Gn begins on the
second day of bleeding. However, GnRH is continued till the day of
hCG.
GnRH Agonist: Long versus Short versus Ultrashort Protocol

In long protocols, GnRH agonists are started either in the midluteal phase
or in the early follicular phase to achieve pituitary downregulation in
about 8 to 21 days after which Gns are commenced.
In the short protocol, the duration of GnRH agonist administration is
about 10 to 14 days and about 3 days in the ultra short protocol. It is
started on the 2nd day of menses instead of the midluteal phase. This is
not popular as the downregulation of the LH is not good.
The pooled OR for clinical PR per cycle in long versus short GnRH
agonist protocol was 1.27 (95% CI 1.04 to 1.56) and in long versus ultra-
short GnRH agonist protocols was 1.47 (95% CI 1.02 to 2.12).116
The adjunctive use of GnRH-a in ovarian stimulation leads to an overall
improvement in IVF. This accounts for the increase in the number, quality,
and synchronization of the oocytes recovered per cycle and improves
the fertilization rate, the number of embryos, and the PR. Furthermore,
because more embryos are available than the number used in fresh
embryo transfer, an opportunity exists to cryopreserve the excessive
number of embryos for future embryo transfer(s).
Potential risks and disadvantages with the use of GnRH-a include:

1. Increased requirements of gonadotropins,
2. Increased costs due to additional days of therapy,
3. The risk of OHSS due to excessively high E2 levels, and
4. An increased rate of multiple pregnancies.
PULSATILE GONADOTROPIN-RELEASING HORMONE

Women with the WHO Group I ovulation disorders (hypothalamic pituitary
failure, characterized by hypothalamic amenorrhea or HH) should be
offered pulsatile administration of GnRH or Gn with LH activity because
these are effective in inducing ovulation. The effectiveness of pulsatile
GnRH in women with CC-resistant PCOS is uncertain and is therefore
not recommended outside a research context.9
GONADOTROPIN-RELEASING HORMONE ANTAGONISTS

(GnRH Antagonists)
The GnRH antagonists produce immediate and direct pituitary
suppression. These allow treatment cycles to be shorter (less than 1
month) and avoid estrogen withdrawal effects associated with the use
of GnRH agonists. They may also reduce the dose of Gn required. The
GnRH antagonists are the latest generation of GnRH-a that block LH
secretion without a flare-up effect. Commonly used GnRH antagonists
include Cetrorelix and Ganirelix.
The GnRH antagonists are administered:117
1. As a single dose on the 8th menstrual cycle day, or
2. In small amounts over 4 days, starting on the 7th menstrual cycle
day, or
3. When the largest follicle reaches a diameter of 14 mm, or
4. When the LH levels in serum are greater than 10 mIU/mL
The GnRH antagonists have the advantage of blocking the LH surge
at the periovulatory period; therefore, premature luteinization or
spontaneous LH surge does not occur. Because the pituitary gland is
not downregulated at the beginning of the menstrual cycle, smaller
amounts of Gns are required to stimulate ovulation. Another advantage
with this protocol is the prevention of OHSS, especially in patients with
elevated E2 levels (>3000 pg/ml) or more than 15 follicles during the
stimulation.
For pituitary downregulation as part of IVF, using GnRH agonist in
addition to Gn stimulation facilitates cycle control and results in higher
PRs than the use of Gn alone. The routine use of GnRH agonist in long
protocols during IVF is, therefore, recommended. The use of GnRH
antagonists is associated with reduced PRs and is, therefore, not
recommended outside a research context.
The GnRH agonist micro flare (micro dose luprolide flare) protocol is the
primary regimen for controlled ovarian stimulation (COS) in poor
responders undergoing IVF. GnRH antagonist offers an alternative
regimen for these women. Use of the antagonist protocol in poor
responders does not increase the likelihood of improved clinical outcome
compared with the micro flare regimen. However, the findings suggest
that use of antagonist may afford an economic benefit since PRs were
the same despite fewer ampoules of Gn required and more cycles
cancelled in this group.118
GROWTH HORMONE (GH): As an Adjunct to

Ovulation Induction Therapy
For women with clomiphene citrate-resistant PCOS, co-treatment with
recombinant human growth hormone (rh-GH) plus GnRH-a, or GH plus
hMG has no significant effect on the amount and duration of hMG used,
ovulation (93% versus 93%; 88% versus 100%, respectively) and pregnancy
rates (26% versus 20%; 25% versus 13%) when compared with GnRH-a
and hMG alone.9 It has been suggested that co-treatment with GH may
improve ovarian responses to exogenous Gn, thus reducing the overall
Gn requirement.119 The use of adjuvant GH with Gn during IVF cycles
does not improve PRs and is, therefore, not recommended.
RCOG Recommendation
The use of adjuvant GH treatment with GnRH agonist and/or hMG
during OI in women with PCOS who do not respond CC is not
recommended because it does not improve the PR.
DRUGS USED TO TRIGGER OVULATION AND

OOCYTE MATURATION9,13
Human Chorionic Gonadotropin (hCG)
In natural ovulatory cycles when the dominant follicle reaches an
appropriate size and its granulosa and theca cells exhibit LH receptors,
an LH surge will result from the anterior pituitary. This results in

granulosa cell luteinization, resumption of oocyte meiosis and ovulation
around 36 hr later. In ovarian stimulation, this LH surge is unpredictable,
and in downregulated cycles, it may not occur at all.13
The hCG has been adopted as a surrogate for LH to trigger this final
maturation of the oocyte. It has a similar structure to LH and both result
in luteinization of the same target cells. The hCG has a longer half-life
than LH; this may be associated with either a false-positive pregnancy
test or a higher incidence of OHSS due to prolonged stimulation of the
corpora lutea.
Recombinant hCG (r-hCG) versus Urinary hCG (u-hCG)

The hCG has traditionally been derived from purified urinary sources,
but recently, r-hCG has become available. A dose of 250 μg r-hCG is
reported to be as effective as 5000 IU and 10,000 IU of u-hCG in inducing
final follicle maturation in terms of clinical PR (33% with r-hCG versus
24.7% with u-hCG), live birth rate (27% with r-hCG versus 23% with
u-hCG) and OHSS incidence (7.2% with r-hCG versus 6.4% with
u-hCG).120 This has the same advantages associated with u-FSH with
very good tolerance when given subcutaneously.121
Another RCT showed no significant differences between 250 μg and
500 μg of r-hCG and u-hCG in clinical PR (35.1% versus 36% versus
35.9%), live births (87.9% versus 84.4% versus 84.8%) or OHSS incidence
(3.25% versus 9% versus 3.1%).122
In order to reduce the risks of multiple pregnancy and the OHSS, the
exclusion criteria for hCG administration are, respectively, the
development of more than 2 follicles > 16 mm in diameter and more
than a total of 3 follicles > 14 mm in diameter.5
GnRH Agonist
In patients having IVF cycles where GnRH antagonists were used, a
single dose of GnRH agonist may be used to induce an LH surge which
results in successful oocyte maturation.13
Recombinant Human LH (rh-LH)

Recombinant human LH (rh-LH) has also recently become available. This
has not been marketed as an ovulation trigger but more as a source of
LH in patients needing ovarian stimulation who have insufficient
endogenous LH production (LH <1.2 IU/l) such as patients with HH.13
RCOG Recommendation
Couples should be informed that, in effecting oocyte maturation, r-hCG
similar results to urinary hCG in terms of pregnancy rates and incidence
of OHSS. Consideration should be given to minimizing cost when
prescribing.
INSULIN SENSITIZERS
Metformin
Metformin is an oral biguanide (nonsteroidal compound) that is well
established for the treatment of noninsulin-dependent diabetes mellitus.
There is a strong association between hyperinsulinemia and anovulation.
Metformin acts as an insulin sensitizer, and leads to a lowering of
circulating androgen levels by reducing insulin levels.13
Metformin is not an OI agent. Indeed, unlike Gn or CC, metformin
does not accelerate ovarian follicular recruitment or growth. Rather,
the physiologic aim of metformin therapy in PCOS is the resumption of
normal, monofollicular gonadal function. Metformin has no known direct
stimulant effect on the ovarian stromal or germ cell compartment.
Therefore, there is no associated increased risk for multiple gestation
when metformin is used to enhance fertility in PCOS. While many women
with PCOS may benefit from treatment with insulin-lowering agents,
the ideal candidates for such therapy are probably those who are
overweight, with elevated serum androgen concentrations and/or
fasting insulin levels of ≥10 μg/l.6
Mechanism of Action6,9
It acts principally by suppression of gluconeogenesis in the liver. It
appears to both indirectly and directly, influence ovarian function. It is
claimed to have a multifactorial action with primary effects on insulin
sensitivity. This enhances the sensitivity of peripheral tissue to insulin,
thereby decreasing insulin secretion at postreceptor levels, resulting in
decreased insulin secretion and also increases GLU4, which improves
peripheral uptake of glucose. Metformin also has a direct effect on
androstenedione and testosterone production by theca cells in vitro, by
inhibiting the expression of steroidogenic acute regulatory (StAR) protein
and 17-alpha-hydroxylase (CYP17).
Dose
Most studies have used doses of 1500-2000 mg/day. The starting dose
is 500 mg initially once, then twice to thrice daily, following an incremental
dosage protocol.
Effects of Metformin on Insulin Sensitivity and

Endocrine Profile in Women with PCOS
In the last few years, a number of mostly uncontrolled short-term studies
have assessed the effects of metformin on insulin sensitivity and endocrine
profile in women with PCOS.6
Velazquez et al123 demonstrated that an improvement in insulin
sensitivity, a favorable change in serum concentrations of androgens,
SHBG and Gns. Metformin resulted in a rapid fall in insulin and the
insulin to glucose ratio, with a concurrent significant decrease in serum
concentrations of testosterone (T), free T, DHEAS and androstenedione.
A significant increase in the concentration of SHBG was also noted along
with normalization of the LH : FSH ratio. They demonstrated a
restoration of menstrual cyclicity in 96% of oligo/amenorrheic women.
This menstrual regularization was accompanied by an ovulatory response
in 87% of patients with regular menses, and pregnancy rates of 19%.
Many other studies have shown, to varying degrees, improvements
in both spontaneous and drug-induced ovulatory function, development
of normal menses and restoration of fertility, independent of changes in
body weight. A significant decline in serum concentrations of testosterone
and LH occurred within 1 week in a small group of patients, indicating
the rapid effect of metformin on ovarian function.
Not all the data, however, have been so encouraging. Two trials
showed little or no benefit with respect to insulin metabolism, hormone
concentrations or lipid variables.
A study that was designed to balance dietary intake and sustain
body weight, found that hyperinsulinemia and androgen excess in obese
nondiabetic women with PCOS were not improved by the administration
of high dose metformin. The reasons for these disagreements are unclear
but could be due to different methods used to assess insulin action and
large BMI differences (29 versus 39 kg/m2) between the study groups.
In fact, it has been claimed that the ability of metformin to alter insulin
sensitivity in individuals with major obesity (BMIs of 40 kg/m2 and
above) is limited.6
The largest prospective RCT to date is that of Fleming et al124 who

randomized 94 patients to receive either metformin 850 mg bd or placebo.
Interestingly, significantly more patients withdrew from the metformin
arm due to side effects. The patients treated with metformin were found
to have an increased rate of ovulation, and a quicker first time to
ovulation and significant weight loss. The study also reported an inverse
relationship between body mass and efficacy of metformin.
Differences in the reported studies may be due to:
• Variations in patient populations,
• Definitions of PCOS,
• Degrees of obesity and insulin resistance and
• The definition of CC resistance (that is failure of response or failure
of conception).
• Heterogeneity in the pathogenesis of the syndrome and different
patient populations.
Metformin plus CC
In a randomized controlled trial of CC-resistant patients, the use of
metformin and CC produced significant improvements in ovulation (by
almost three-fold) and PRs (by almost eight-fold) when compared with
CC and placebo. In addition, a conception rate of 21% after ovulation,
similar to normal cycle fecundity, was observed, suggesting that
combined metformin and CC use have no adverse effects on post-
ovulatory reproductive events. However, other studies have failed to
show any benefit.6,13
Pretreatment with metformin in CC-resistant patients undergoing IVF has
also been shown to be associated with improved PR, although follicle
numbers were decreased and the number of oocytes collected was
unchanged.125
Metformin versus Meformin plus CC versus CC

A recent review125 has evaluated the use of metformin alone or in
combination with CC. In women with CC-resistant PCOS and a mean
BMI above 25 kg/m², metformin as a single agent was not found to
increase clinical PR when compared with placebo. However, treatment
with both metformin and CC did increase clinical PR compared with CC
alone. Metformin as a single agent was found to induce ovulation when
compared with placebo. Metformin in combination with CC was also
effective in inducing ovulation compared with CC alone.
A recent meta-analysis published in the Cochrane library,13 based on

11 randomized controlled double-blind trials reported metformin to
have a statistically significant effect on inducing ovulation, either as a
sole agent when compared with placebo, or when combined with CC
compared to CC alone. Metformin was also found to have a significant
effect in reducing free androgens and androstenedione, but no significant
effect was found on total testosterone or SHBG. Metformin improved
aspects of the metabolic syndrome including fasting insulin (weighted
mean difference, systolic blood pressure and low-density lipoprotein.
No effect was found in altering BMI or waist : hip ratio.
Metformin plus CC or FSH

Improvements in ovulatory function in women given metformin plus
CC or FSH may be due to:
• A decrease in the direct effects of insulin on ovaries,
• To the normalization of CC-induced Gn secretion, or
• To a direct tissue-sensitizing effect of the drug at the ovarian level.
Outcome
Metformin, by reducing fasting insulin and insulin response to glucose
in hyperinsulinemic PCOS patients, reduces the hyperinsulinemia-driven
hyperandrogenism and can reverse the endocrinopathy (abnormalities
of Gn secretion), often enough to allow regular menstrual cycles, reversal
of infertility and spontaneous pregnancy. The achievement of normal
menstrual cycles may also reduce the risk of endometrial hyperplasia
and adenocarcinoma associated with PCOS.5,6
From the above data, it has been shown that metformin may have
benefits for short and long-term health, by improving obesity,
hyperandrogenism, fertility, insulin sensitivity and lipid profile.
Additional data on the use of metformin together with CC have indicated
striking results with a 90% PR. Metformin is the most promising and
safe insulin sensitizer.5
Adverse Effects
It is well tolerated with minimal side effects of nausea, vomiting, bloating,
flatulence and diarrhoea. Lactic acidosis and hypoglycemia are rare.6,9,126
These symptoms appear to be dose-dependent and may be substantially
minimized by taking the tablet with meals. It is likely that an incremental
dosage protocol (500 mg up to 850 mg, initially once and then twice daily)
will be helpful to acclimatize patients and minimize undesirable
gastrointestinal complaints.
The major concern with biguanides has been the risk of lactic acidosis.
This is a very rare and serious metabolic complication of metformin
therapy, occurring mainly in women with renal impairment, and does
not appear to be a problem for otherwise fit women with PCOS who are
not frankly diabetic and who have normal renal and liver function.
During Pregnancy
Metformin is usually discontinued during pregnancy, although there is
accumulating evidence that it may reduce the risk of gestational diabetes,
and of its safety during pregnancy. Furthermore, there has been a suggestion
of a reduction in the risk of miscarriage, although this has yet to be
demonstrated in prospective randomized studies.
• Anovulatory women with PCOS who have not responded to CC and
who have a BMI of > 25 should be offered metformin combined with
CC because this increases ovulation and pregnancy rates.
• Women prescribed metformin should be informed of the side effects
associated with its use (such as nausea, vomiting and other
gastrointestinal disturbances).
Thiazolidinedione Group of Drugs

Troglitazone was found to enhance insulin sensitivity and improve ovarian
function in women with PCOS, but it has been withdrawn
from clinical practice because of its hepatotoxicity. Later generations
of thiazolidinediones, such as rosiglitazone and pyoglitazone, may
have a role in the future, although there is natural reluctance to
introduce them for the treatment of women in their reproductive years
because of the uncertainty regarding long-term side effects and
teratogenicity.
Rosiglitazone increases the intracellular glucose update while the
metformin decreases circulating glucose by inhibiting the gluconeogenesis
along with being anorexiant and decrease glucose absorption by gut.
However, this is under trial.
WOMEN WITH A POOR OVARIAN RESPONSE

The lack of a consistent definition of poor ovarian response makes it
difficult to develop or assess any protocol to improve the outcome.
Women with poor ovarian response have lower PRs characterized by
fewer follicles and number of oocytes retrieved, likely to be associated
with diminished ovarian reserve.127,128
A systematic review of available studies including RCTs found limited
data that assessed the effectiveness of different management strategies
in women with poor ovarian response.128
• There is minimal or no benefit with the use of increased dose of Gn.
• There is insufficient evidence that the use of r-FSH improved PRs
when compared with u-FSH in poor responders.
• Flare-up GnRH agonist protocols were reported to produce better
results than standard long luteal protocols.
• Luteal initiation of FSH has not been shown to improve pregnancy
outcome.
• The use of GnRH antagonists did not show any benefits.
• There were no studies reporting the use of corticosteroids involving
poor responders.
• Data were limited on the use of nitrous oxide donors such as L-
arginine in improving PR in poor responders.
• Pretreatment with combined oral contraceptives before ovarian
stimulation may be beneficial.
• No benefit was shown with standard use of ICSI or assisted hatching
of zona pellucida.
Comparable PRs were reported between natural and stimulated
cycles in poor responders.128 Further evaluation with large-scale and
well-designed RCTs is needed to verify the role of these different
approaches.
EFFECTIVENESS OF TREATMENTS FOR

UNEXPLAINED INFERTILITY 19
Proposed treatments for unexplained infertility include IUI, COH/IUI
and the ART.129 The IUI alone appears to have a minimal effect on the
likelihood of conception for couples with unexplained infertility.129,130
CC alone appears to lead to a higher chance of pregnancy than no treatment
or placebo.131 Many clinicians have studied the relationship between
endometriosis and unexplained infertility; ovulation stimulation appears
to benefit both.130,131
With COH/IUI, a wide range of success has been reported. 130,133

Generally, 3-6 cycles of ovarian hyperstimulation and IUI are clinically
appropriate in couples with unexplained infertility.
Predictors of Success
• Cycle fecundity with COH/IUI is expected to be lower when the
diagnosis is unexplained infertility than when the diagnosis is
anovulation.
• In couples with unexplained infertility it is quite possible that oocyte
quality is compromised.
• Cycle fecundity is also expected to be lower if significant male factor
infertility/sperm dysfunction is present than if the semen analysis is
normal.
Female age is also one of the most important predictors of success, as
discussed below.
EFFECTIVENESS OF TREATMENTS FOR

AGE-RELATED INFERTILITY 19
Advancing age is associated with reduced ovarian responsiveness to
Gn and the chance of live birth is virtually zero when FSH levels rise
above the normal limit, particularly for older women, irrespective of
menstrual cyclicity.
COH with IUI has limited efficacy for older women, with a delivery
rate of 5% or less per cycle (range 1.4-5.2%) for women over 40 with
unexplained infertility.134-137 This compares with a live birth rate per
cycle of 17-22% for women under 35, and 8-10% for women aged
35-40.137,138
The presence of infertility factors, such as male factor, tubal disease,
endometriosis, or pelvic adhesions, would argue for proceeding directly
to IVF in women of advanced reproductive age.
Pregnancy rates from IVF are higher than with COH/IUI, but decline
significantly with age. According to the 1999 Society for Assisted
Reproductive Technology (SART) report, live birth rates per cycle were
32% in women aged under 35 years, 26% in women aged 35-37, 18% in
women aged 38-40, 10% in women aged 41-42 and 5% in women over
42.139 Thus, the difference in live birth rate between IVF and COH/IUI
becomes smaller for women in their forties. This age-related decline in
IVF success is attributable not only to decreased ovarian responsiveness to
Gn but also to a marked decline in embryo implantation rates as a function
of female age (18.2% at age 25-29, 16.1% at 30-34, 15.3% at 35-39 and
6.1% at 40-44).140 Embryonic aneuploidy is, probably, a major reason for
implantation failure in older women.141
Oocyte donation yields the highest live birth rate (a live birth rate per
transfer of approximately 40% reported)139 of any assisted reproductive
technology (ART) treatment and is the treatment of choice for age-related
infertility that is not successfully addressed by other treatments. PRs
with donor oocytes are much higher than those with the usual infertile
population because of the improved egg quality and are dependent on
the age of the donor.
Recommendation for IVF

• After a maximum of 3-4 cycles of COH/IUI for women in their late
thirties and older as repeated cycles of COH/IUI may lead to a delay
in the initiation of an IVF cycle, a delay that may be particularly
detrimental for women in this age group.
• If infertility factors, such as male factor or tubal disease, are present
in addition to age-related infertility, couples should be encouraged
to proceed to IVF without first pursuing COH/IUI.
MONITORING OF STIMULATED CYCLES 9
In assisted reproduction, the purpose of monitoring ovarian response is

to ensure safe practice in reducing the incidence and severity of OHSS,
and to optimize the timing of luteinization before oocyte retrieval.
Ovarian monitoring provides information on ovarian response to OI
agents by ascertaining the number and size of the developing follicles.
Ultrasonography is regarded as a safe, accurate and efficient method of
monitoring follicular development in response to ovulation induction,
in helping to reduce multiple pregnancy rates, especially in women
with PCOS142 when compared with estrogen monitoring. Estrogen
monitoring provides no additional information compared with ovarian
ultrasound.143
An average number of 3 ultrasound-scan monitoring is commonly
practiced: at the start of ovarian stimulation in GnRH agonist-controlled
cycle, to assess at day 7 to 9 and to determine timing of hCG
administration at days 11 to 14. The extent of monitoring is reduced in
GnRH antagonist controlled cycles.144
• Ultrasound monitoring of ovarian response should form an integral
part of the IVF treatment cycle.
• Monitoring estrogen levels during OI as part of in vitro fertilization
treatment is not recommended as a means of improving IVF success
rates because it does not give additional information with regard to
live birth rates or pregnancy rates compared with ultrasound
monitoring.
COMPLICATIONS OF OVULATION INDUCTION

Ovarian Hyperstimulation Syndrome (OHSS)
The aim of OI therapy is to stimulate the ovaries to produce more than
one egg. This carries the risk of overstimulation and OHSS.5 The OHSS
is an iatrogenic and potentially life-threatening complication of super-
ovulation. The exact incidence of severe OHSS when fertility drug therapy
is used has not yet been determined. Available data suggest an incidence
of 3% of cycles when hMG is used, between 0.6% and 10% in IVF cycles
and in 0.2% to 1.0% of all assisted reproduction cycles. The severe form
of the condition occurs in 0.5-2% of IVF cycles.9
The pathophysiology of OHSS is still not completely understood and
so it is difficult to prevent and to treat. It occurs if many follicles are
stimulated leading to ascites, pleural and, sometimes, pericardial
effusions, hemoconcentration and coagulopathy with the symptoms of
abdominal distension, discomfort, nausea, vomiting and difficulty in
breathing.
Several risk factors have been associated with the development of
OHSS: young age (less than 30 years), lean physique, PCOS, high serum
estradiol (> 2500 pg/ml or 9000 pmol/l), rapidly increasing estradiol
levels (> 75% from previous day), size and number of follicles and
ultrasonographic ovarian ‘necklace sign’ of multiple small follicles, hCG
administration, number of oocytes retrieved (greater than or equal to
20), multiple pregnancy.
Prevention
There is no evidence to support the superiority of either hMG or r-FSH
or urinary preparations in preventing OHSS. Some commonly adopted
strategies include:9,15
• Cycle cancellation
• Coasting Coasting, an alternative to cycle cancellation, involves

discontinuation of Gns in cycles with an excessive response and
delaying hCG administration, while continuing GnRH agonist
administration in the presence of ultrasound and endocrine
monitoring. It can potentially reduce the number of oocytes recovered
and may even compromise PRs.
• Elective cryopreservation of all embryos
• Luteal-phase support A systematic review has confirmed the
effectiveness of routine luteal phase support after embryo transfer in
IVF cycles involving the use of GnRH agonists. The use of hCG in
this situation can aggravate OHSS and progesterone should be the
preparation of choice in high-risk women.
• Prophylactic albumin administration around the time of oocyte
recovery could be used as a preventive measure in the high-risk
women. It is thought to bind to vasoactive substances involved in
the pathogenesis of OHSS and also increases the intravascular oncotic
pressure, thereby preventing loss of water from the intravascular
compartment. However, the optimal timing and dose of albumin are
unclear, as is its effect on implantation. There are also growing
concerns about the possibility of febrile reactions, anaphylactic shock
and the potential risk of virus and prion transmission.
• The alternative to albumin is infusion of hydroxyethyl starch solution,
which is a plasma colloidal substitute. It may be a safer, cheaper and
effective method. There are concerns about its interaction with the
blood-coagulation system.
• Role of follicular aspiration: Recovery of immature oocytes (which
can then be cultured in vitro and subsequently used for IVF) has been
suggested as a means of preventing OHSS when hCG is withheld.
• Use of recombinant LH and GnRH antagonists such as ganirelix or
cetrorelix.
Treatment
Treatment of OHSS is mainly supportive. The condition is self-limiting
and resolution parallels the decline in serum hCG levels (about 7 days in
non-pregnant women and 10-20 days in pregnant women). Mild OHSS
is usually benign and resolves with the onset of the first period. Moderate
to severe cases need hospital admission and monitoring. The principles
of care include appropriate specialist involvement, circulatory support
using intravenous fluids (colloids preferable to crystalloids), maintenance
of renal function, thromboprophylaxis (heparin) and drainage of 3rd

space accumulation.
Multiple Pregnancy
There is a strong correlation between the initial number of embryos, the
final number and the risks of pregnancy loss and prematurity.146,147
However, assisted reproduction multiple pregnancies do not appear to
be at any more risk of poor obstetric and neonatal outcomes than those
conceived spontaneously.148,149
Recent surveys have suggested that multiple pregnancies may not be
viewed as an adverse outcome by women with fertility problems.150-154
Multiple pregnancy occurs in 2-13% of women with all causes of infertility
taking clomifene citrate.155 This compares with a spontaneous multiple
pregnancy rate of about 1-2% of women in the North American and
European populations.156,157
Women with CC-resistant PCOS treated with conventional regimens
of Gn have a 36% multiple pregnancy rate.155
Especially in young women, a decrease in currently used peak serum
estradiol level thresholds may reduce the incidence of high-order births.
Such a reduction would, however, also result in a significant reduction
of overall PRs. These observations further suggest that IVF should be
considered earlier in a traditional infertility treatment algorithm if the
occurrence of high-order multiples, is of concern.
RCOG Recommendation
• Women who are offered OI with Gn should be informed about the
risk of multiple pregnancy and OHSS before starting treatment.
Ovarian ultrasound monitoring to measure follicular size and number
should be an integral part of patient management during Gn therapy
to reduce the risk of multiple pregnancy and OHSS.
CANCER
There has been concern in recent years about whether ovarian stimulation
is associated with an increased risk of cancer, particularly breast and
ovarian carcinoma. Several epidemiological studies have attempted to
establish whether such an association exists, but some uncertainty
remains. There have been two major hypotheses to connect ovarian cancer
and fertility treatment. The first is that incessant ovulation with repeated
epithelial trauma is carcinogenic. The second is that exposure to supra-

physiological levels of Gn may be a mitogenic stimulus.9,13
There have been several major studies to investigate this issue,
including 4 cohort studies and 6 case-controlled studies, and an overview
of this data has been presented. Case reports and epidemiological studies
examining ovarian cancer risk in relation to the use of fertility drugs
have shown conflicting results, which may in part be explained by
methodological problems such as low study power and misclassification
bias.
Reviews of these studies found insufficient evidence to support a direct
causal relationship. The conflicting results may stem from the interaction
between nulliparity, infertility and ovarian cancer. It is well established
that there is an association between nulliparity and increased risk of
ovarian cancer.158-163 It is also uncertain whether the relatively high
proportion of nulliparous women in this population, or the use of
infertility treatments causes the increased risk of ovarian cancer amongst
infertile women per se. It is also uncertain which of these two factors
carries the higher risk.
Rossing et al 17 identified an increased risk for ovarian tumor
(borderline) among women who had received 12 or more cycles of CC.
This finding has not been reproduced in other studies, but many clinicians
will now limit the number of CC cycles that patients should have.
Infertility itself is associated with an increase of fertility drug exposure
and underlying predisposition has been very difficult.
Venn et al164 found that the incidence of ovarian cancer was no greater
than expected. There was also no association between the number of
treatment cycles per patient or the number of eggs collected and risk for
ovarian cancer.
Many breast cancers are known to be hormone sensitive, giving rise to
concerns that there may be an increased risk among women exposed to
fertility drugs. Case-controlled and cohort studies have not suggested
an increased risk of breast cancer in these patients, although a higher
number of breast cancers are diagnosed within 12 months of an IVF
cycle, suggesting that fertility drugs may promote the development of
pre-existing cancers in a similar manner to the oral contraceptive pill.
Concerns have also been expressed about cancer predisposition in children
born as a result of fertility treatment, particularly neuroblastoma. Larger studies
of cohorts of children conceived through ART have failed to show any
association with childhood cancer.
Concerns about the carcinogenic effects of infertility drugs do not

seem to be supported by epidemiological evidence, but because of a
possible time-lag effect, this area merits surveillance.13
The association between OI therapy and thyroid cancer, endometrial
cancer, cervical cancer, colorectal cancer and melanoma has not been
established.165 Further studies are needed in this area.
RCOG Recommendation
• Women who are offered OI should be informed that a possible
association between OI therapy and ovarian cancer remains uncertain.
Practitioners should confine the use of OI agents to the lowest effective
dose and duration of use.
Prion Disease9
The theoretical risk of transmitting prion disease, however unlikely,
must always be considered when medicinal products are derived from
or contain materials of human or bovine origin. It is a disease that
primarily affects the nervous system with presence of spongiform
degeneration (microscopic vacuolization of the brain tissue), and of an
abnormal form of the prion protein, (which is a normal component in
brain and other tissues). The abnormal prion protein is resistant to
digestion with enzymes that breakdown normal proteins, and
accumulates in the brain. It has been reported that abnormal prion protein
has been identified in urine from patients with Creutzfeldt-Jacob disease.166
In the case of Gn, such theoretical risks could arise from the human
source material used to manufacture urinary-derived products or from
bovine reagents used in the manufacture of recombinant products.
However, there is no evidence of transmission of prion disease by any
Gn.
Other Case Reports (definite causal link for these is not known)
Deep calf vein thrombosis: A case167 of activated protein C (APC) resistance
and deep calf vein thrombosis under COS for IVF has been reported.
The thrombosis occurred before administration of hCG for OI on the
8th day of hMG. The patient was stimulated according to the long luteal
protocol. Cases of arterial and venous thrombosis as a result of ovarian
stimulations are reviewed.
Thromboembolic disease: Associated with OI has been reported by

Stewart et al in their review of 54 cases.168 It has been suggested that
hormone therapy causes and increase in serum estradiol during OI.
Another case has been reported on intracardiac thrombosis with fever
possibly triggered by OI in a patient with antiphospholipid antibody
syndrome.169
SLE: Lupus peritonitis and cystitis; has also been reported in 3 case
reports.170-172
NEW DEVELOPMENTS
New Drug-Delivery Techniques13
One of the most important areas of development in reproductive
pharmacology is in drug-delivery systems. Future developments include
more patient-friendly drug-delivery systems. Conventional Gn treatment
has involved daily injections to stimulate follicle development. Initially,
these injections were intramuscular, but the development of recombinant
products and highly purified urinary products has allowed these
injections to be administered subcutaneously.
One of the most interesting recent developments has been the
introduction of a ‘pen’ device. The concept is borrowed from the insulin
pens used in diabetic patients. There are good data to show that Gns
administered this way are as efficacious as the conventional subcutaneous
needle/syringe modality, and some evidence that less patients experience
moderate to severe pain and more patients find improved convenience
using the pen. There have also been improvements in the conventional
needle and syringe approach. A prefilled syringe of solvent is reconstituted
once with the Gn, which has a multidose formulation allowing treatment
for up to 14 days.
Recently, a needle-free device for the administration of Gn has been
evaluated. The device (J-tip) is a single-use, disposable, gas-powered
system that allows subcutaneous delivery of the drug without a needle
puncture. Preliminary data suggest promising levels of efficacy and
patient acceptability.
New Reproductive Drugs

Currently in the ‘pipeline’ of development include:
• Micro-encapsulated form of recombinant FSH to decrease frequency
of administration
• Recombinant LIF (leukemia inhibitory factor) for patients with

embryo-implantation failure
• Anastrazole, an aromatase inhibitor for ovulation induction.
Role of Cytokines173
Ovarian dysfunction, which is resistant to normal OI therapies and
known to the clinician as ‘‘poor response’’, is a heterogenic syndrome.
Recent molecular techniques have clarified the subtle defects in function
of the cells surrounding the oocyte.
CSF-1 induces proliferation and differentiation of monocyte-
macrophage progenitor cells and acts on mature monocytes and
macrophages to maintain their survival. Additionally, CSF-1 has indirect
effects on cellular proliferation through the stimulation of cytokine
production and release by macrophages.
Macrophages, essential in the immune response, are also thought to
have tropic roles, through their capabilities of cytokine production.
Macrophages are found in the corpus luteum and are also recognized in
the developing follicle.174,175 Data suggest that macrophages are implicated
in the process of folliculogenesis and ovulation. They promote the
proliferation of granulosa cells as local mediators in developing
follicles.176
Changes of CSF-1 concentration are seen in serum and follicular fluid
in IVF cycles. Serum CSF-1 concentration gradually increased throughout
ovarian stimulation and reached a peak from the day of oocyte retrieval
for 2 days. However, no significant change in CSF-1 was observed in
women with poor ovarian response to hMG (in whom fewer than two
developing follicles were observed by transvaginal ultrasonography on
the day of hCG administration or the day of cancellation of IVF). The
concentrations of CSF-1 in follicles from which an oocyte could be
retrieved were significantly higher than in those from which an oocyte
could not be retrieved. These results suggest that follicle-synthesized
CSF-1 may play a role in promoting follicular development.
Hitoshi Okamuraa et al have reported that Gns lead to increased
human ovarian CSF-1 (also known as macrophage colony-stimulating
factor, M-CSF) production and that this augmentation of CSF-1 in
response to human menopausal gonadotropins (hMG) administration is
lost in poor responders. By concomitant administration of CSF-1 with
hMG, follicle development is improved in poor responders who show
low serum CSF-1 levels in the follicular phase. They demonstrated that
controlled ovarian hyperstimulation was superior in GnRH/FSH/hMG

plus CSF-1 stimulation cycles, compared with the prior cycles with GnRH/
FSH/hMG. There were more mature follicles, fewer cycle cancellations
(8.3% versus 83.3%), and lower doses of gonadotropin required. Five
(16.7%) pregnancies were achieved in association with the CSF-1 co-
treatment among 30 poor responders.
They concluded that macrophages are considered as important
accessory cells for reproductive function and CSF-1 may be a useful
therapeutic tool for selected poor responders, particularly those who
have insufficient serum levels of CSF-1 measured on day 3 of the cycle.
FUTURE PROSPECTS2
Genetically Engineered Gonadotropin Preparations
With this technology, one could give a long-lasting Gn to a patient once
every several days as opposed to daily administration. If we can make a
drug long acting, the molecule could be theoretically modified to create
ultra-long-acting, short-acting, and medium-acting gonadotropins, (FSH, LH
or hCG), that can pave way to personalize therapies for patients using a
spectrum of Gns instead of relying on the patient’s natural responses,
which can be unpredictable.
Like the GnRH analogues that act at the level of the pituitary gland,
LH-like and FSH-like proteins can be engineered, combining their best
parts to direct them specifically to the follicle, corpus luteum, or
periovulatory follicle by identifying characteristics that direct them to
granulosa cells, theca cells, and other sites.
Nongonadotropin Agents in OI
Ovarian molecules that influence the pituitary gland and compounds
that regulate the actions of the oocytes and other cells in the ovary
through paracrine mechanisms can be used, such as insulin-like growth
factor (IGF) receptor analogues that will bind receptors, create or block
actions of the cells of the ovaries. These therapies are specific for ovarian
cells instead of working at the less effective level of the hypothalamus,
as occurs when we administer compounds such as clomiphene.
The binding proteins (that can influence the ovulation process) are
another promising group of pharmaceutical proteins. These substances
can block the actions of a specific protein by binding it and thereby
rendering it inactive.
The last group of nongonadotropin agents is the narrow-action

oligopeptides that include activins, inhibins, and follistatins.
Genetic Treatments for OI

Gene therapy is another promising approach. It relies on the use of vectors
to deliver genetic material to the cell nucleus so that it is possible to
achieve genomic protein activation. This will enable clinicians to insert a
gene inside a cell so it can be overexpressed, or hyperactivated. In
ovulation induction, we might be able to deliver paracrine-active
components of the growth factor system (such as IGF-binding protein
proteases) into a cell to enhance ovulation by delivering their gene into
the ovarian cell and allowing the cell’s own protein synthetic mechanisms
to produce the desired pharmacological effect.
SUMMARY
• Hypogonadotropic hypogonadism is treated with either pulsatile
GnRH or hMG.
• The dopamine agonist of choice for hyperprolactinemia is cabergo-
line.
• Women with PCOS are at the greatest risk of OHSS and multiple
pregnancy and careful monitoring of OI with ultrasound should be
provided.
• It is essential to consider general health and, in particular, body
weight before administering drugs to stimulate ovulation.
• Management of anovulatory PCOS is carried out with weight loss,
CC and then gonadotropins or LOD for refractory cases. Insulin
sensitizing agents, such as metformin, may also play a role.
• CC is effective first-line treatment for WHO II anovulation and
remains the first-line medical therapy for anovulatory PCOS, but its
role in unexplained infertility remains controversial.
• Resistance to CC can be treated with either gonadotropin therapy
or LOD.
• Gonadotropins are effective for ovulation induction in CC-resistant
cases but must be monitored carefully to prevent multiple pregnancy.
• Compared with medical OI with Gn for the CC-resistant patient, the
advantage of LOD is that it need only be performed once and intensive
monitoring is not required as there is no danger of multiple ovulation
or OHSS. Gonadotropin therapy, however, is still the mainstay of
OI therapy, and protocols are available that permit unifollicular

ovulation.
• Women with anovulatory PCOS should be encouraged to improve
their fitness and lose weight if they are overweight prior to receiving
OI therapies.
• Metformin and aromatase inhibitors show promise in the
management of anovulation, but further evidence is needed to support
their routine use. The early experience of metformin to enhance insulin
sensitivity suggests potential benefits either alone or as an adjunct to
CC or gonadotropin therapy.
• Advances in recombinant DNA technology have resulted in the
development of long-acting FSH preparations, a single shot of which
might be sufficient to induce unifollicular ovulation.
• Both GnRH agonists and antagonists are effective at preventing a
premature surge of LH.
Concerns about the carcinogenic effects of infertility drugs do not seem
to be supported by epidemiological evidence.
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Current Approach to Abnormal Uterine Bleeding 195
12
Hema Divakar, Uday Thanawalla,
Madhuri Patil
Current Approach to
Abnormal Uterine
Bleeding in Adolescents
INTRODUCTION—HYPERMENORRHEA
Abnormal uterine bleeding is a clinical problem that is encountered
frequently during the adolescent years. Hypermenorrhea implies a
regular cycle but with bleeding for more than 7 days. In the first 5 years
after menarche, anovulation that arises from a lack of the hypothalamic-
pituitary-ovarian axis is the most common cause of such bleeding. Other
pathologic conditions, such as reproductive tract anomalies, trauma,
infections, systemic illnesses, complications of pregnancy and disorders
of coagulation may closely resemble anovulatory bleeding and thus it
remains a diagnosis of exclusion. Knowledge of the menstrual cycle, as
well as the expected physiologic events that are associated with the
perimenarchal period, is essential to develop careful diagnostic protocols
and adolescent-specific treatment regimens.
Although the onset of menstrual bleeding is recognized as a pubertal
milestone, the hypothalamic-pituitary-ovarian axis continues to mature
after menarche through the first 5 years of the menstrual cycle.
McDonough and Gant found that 55% to 82% of the cycles were
anovulatory in the first 2 years, by the fourth and fifth years only 20%
of cycles were anovulatory. Anovulatory bleeding was the cause in 50%
to 74% of patients who were admitted for inpatient stay because of
severe bleeding.
In addition to pure anovulatory cycles, adolescents may experience
dysfunctional ovulation with a prolongation of the follicular phase that
results in an estrogenic endometrium without progesterone influence.
The effect of estrogen stimulation, in the absence of progesterone, results

in increased fragility of blood vessels within the endometrium and
overgrowth of glandular elements with inadequate stoma support.
Clinically, the endometrium is at risk to shed irregularly and
unpredictably. This may lead to erratic bleeding or heavy, prolonged
menstruation.
However, because DUB is a diagnosis of exclusion, other potential
causes of hypermenorrhea should be ruled out. In this article, a practical
approach to evaluation and treatment of adolescent hypermenorrhea is
discussed.
Evaluation
The initial goal in the approach to evaluation of an adolescent with
abnormal bleeding is to determine hemodynamic stability, locate the
origin of bleeding, identify any organic causes and classify whether the
bleeding is ovulatory or anovulatory.
History
An accurate and complete menstrual history is critical. The history should
include age at menarche, frequency, amount, and duration of menses,
pain with menses, and last menstrual period. A menstrual calendar can
accurately and prospectively keep track of the cycles, especially because
adolescents often have difficulty remembering exactly the dates of their
cycles. Age at menarche, month and year, is important to calculate
gynecologic age because it may take at least 2 years to become ovulatory.
Menstrual flow needs to be assessed in detail, including number of pads,
the saturation of these pads, the passage of clots and the soaking of
clothes and bedding. Special attention should also be paid to a careful
sexual history because pregnancy and sexually transmitted infections
(STIs) can also present with abnormal bleeding. One should also enquire
about any period of ammenorrhea or missed periods before the episode
of hypermenorrhea. Presence of associated symptoms of syncope,
dizziness, nausea, breast tenderness or any GIT or UT symptoms asked
for. It is also important to enquire about past history of any surgeries,
medications taken and intake of hormones. Medication history with
special attention to use of NSAIDS, aspirin, psychiatric medication or
hormones, oral contraceptives should be elicited. NSAIDS and aspirin
are known to affect coagulation, psychiatric medications often impair
gonadotropin function and hormones may influence the endometrial
development and sheeding. A thorough review of systems should be

obtained, with particular emphasis on symptoms of bleeding
abnormalities (easy bruising tendency, epistaxis, and gingival bleeding),
endocrine disorders, and eating disorders, exercise and sport
participation.
History related to systemic diseases—hepatic, thyroid, renal diseases
must be enquired about. In addition, family history should be obtained
to rule out any familial diseases including bleeding disorders.
Physical Examination
A thorough physical examination should include height and weight and
evaluation of overall general physical and nutritional status. Generally,
pubertal development is assessed by Tanner staging. Bruises should be
noted in search of a bleeding abnormality. Evidence of chronic disease
of liver or kidneys looked for. Any signs of hyperandrogenism, such as
acne or hirsutism, should be noted. The thyroid gland should be assessed
for enlargement and the neck for acanthosis nigricans. This is a gray-
brown velvety, sometimes verrucous, discoloration of the skin, usually
at the neck, groin, axilla, or under the breasts, which is a marker for
insulin resistance, as sometimes found in PCOS. The breasts should be
examined, not only for pubertal staging but also for galactorrhea to
screen for hyperprolactinemia. The abdomen should be assessed for
masses, pregnancy, ascities and hirsutism. The decision to perform a
pelvic examination primarily depends on the sexual history. If the patient
denies sexual activity, it may not be possible or necessary to perform a
pelvic examination. She should have an evaluation of the external
genitalia, looking for signs of clitoromegaly or hirsutism or any urethral
pathology. The pelvic examination should assess the possibility of
infection, complications of pregnancy, or demonstrate evidence of trauma
If indicated; a rectoabdominal examination can be done. This is usually
well-tolerated and can be very helpful in girls with a pelvic mass. All
sexually active girls should have an internal examination with a narrow
speculum, screening for sexually transmitted diseases, a Papanicolaou
smear (if not done in the last 12 months), and a bimanual examination to
assess for masses.
Investigations
Tailor the choice of laboratory tests to the presenting clinical situation.
Focus routine laboratory studies to discover common complications and
rule out serious medical conditions that can mimic DUB. Reserve
secondary laboratory studies for patients with abnormal bleeding; for
patients who are unresponsive to therapy; and for patients with findings
on history, physical examination, or laboratory studies suggestive of a
systemic disorder.
Complete blood count (CBC) Documents blood loss. Useful to reveal
anemia, infections, and thrombocytopenia
Baseline CBC for hemoglobin and hematocrit.
Obtain a differential with platelet count if hematologic disease is
suspected.
Serum ferritin.
Coagulation Profile
A coagulation profile, including prothombin time, partial thromboplastin
time, and a bleeding/clotting time
Platelet count in primary or secondary thrombocytopenia
von Willebrand disease and factor XI deficiency initially might
manifest during adolescence. Recommend a von Willebrand panel,
including von Willebrand factor antigen and ristocetin cofactor activity
if a bleeding disorder is highly suspected.
Hormonal Profile
• Thyroid-stimulating hormone (TSH), T3, T4
• Anti-thyroid antibodies
• Midluteal progesterone levels
• Hormone levels to evaluate for hirsutism or polycystic ovary disease-
DHEAS, testosterone, 17-OH progesterone, LH, FSH
Serum Prolactin Level

Perform thyroid function tests and prolactin because hyperthyroidism,
hypothyroidism, and hyperprolactinemia are associated with ovulatory
dysfunction. Androgen profile is indicated in women with signs of
hyperandrogenism, such as those with polycystic ovarian syndrome, 21
hydroxylase deficiency, or ovarian or adrenal tumors.
Human Chorionic Gonadotropin

The most common cause of abnormal uterine bleeding during the
reproductive years is abnormal pregnancy.
• Rule out threatened abortion, incomplete abortion, and ectopic

pregnancy.
• Fasting glucose—To rule out occult diabetes.
Other Tests
• STD screen
• If the woman is sexually active, cultures should be done for gonococci
and Chlamydia
• Vaginal and PAPsmear—Cervical cancer still is the most common
gynecologic cancer affecting women of reproductive age in the world
population.
• Liver function test: Any condition affecting liver metabolism of
estrogen can be associated with abnormal uterine bleeding.
Imaging studies: Reserve imaging studies for women who do not
respond to routine management.
Generally, patients with DUB can be managed appropriately without
the use of expensive imaging studies.
In obese patients with suboptimal pelvic examination or in patients
with suspected ovarian tumors, pelvic ultrasound evaluation might be
most helpful.
Ultrasonography is the method of choice for evaluation of the female
pelvis. It is useful for demonstrating structural abnormalities of the uterus
and ovarian neoplasms.
Pelvic ultrasound also might be confirmatory for polycystic ovaries
(PCO), which frequently are present in individuals with chronic
eugonadal anovulation.
Confirmation of PCO by imaging is not mandatory for the diagnosis.
The absence of the traditional string of pearls appearance does not
exclude polycystic ovarian syndrome diagnosis.
Ultrasound can be used to examine the status of the endometrium.
Endometrial hyperplasia, endometrial polyps, and uterine fibroids can
be identified easily by this technology.
Sonohysterography is a less invasive but less accurate method of
evaluating the uterine cavity. The procedure consists of injecting fluid
into the uterus under ultrasonographic visualization. It can be used to
enhance the detection of fibroids and polyps.1,2
Magnetic resonance imaging (MRI) of the pelvic region can also be
used to locate fibroids and tumors.
CT scanning is useful for the work-up of the rare woman in this age
group with a confirmed neoplasm.
Endometrial biopsy: Endometrial biopsy is rarely required and should
be reserved for adolescents with unresponsive uterine bleeding.
Endometrial curetting often demonstrates a disordered proliferative
pattern without secretory activity (absence of progesterone effect).
Findings of endometrial biopsies in patients who are currently receiving
hormonal therapy demonstrate the hormonal effects and sometimes
interfere with biopsy interpretation.
Dilation and curettage (D and C), once common, is rarely done today
for diagnosis of DUB. Uterine curettage is rarely indicated in the
adolescent with DUB. This procedure is usually reserved for women
with significant and prolonged hemorrhage unresponsive to medical
therapy.
Hysteroscopy preferred over the technique of dilation and curettage (D
and C), which can miss areas of bleeding in the uterus and delay the
diagnosis of dysfunctional uterine bleeding in 10% to 25% of women.
Diagnostic hysteroscopy can be used to look for structural abnormalities
as a cause of persistent DUB. It will rule out polyp, myoma, malfor-
mations and remnant of conception.3,4
Gonadotropins and/or medical work-up, endometrial biopsy, D and
C and hysteroscopy required only with specific indication.
TREATMENT OF HYPERMENORRHEA
The goals of therapy for hypermenorrhea in adolescent women are three-
fold. The first goal is to assess how serious the abnormal bleeding is,
while ruling out any anatomic or pathologic causes. The second goal is
to find out what her expectations and needs are. It is important to realize
that often adolescent women may have a different goal for an office
visit than she articulates to her parents or office staff; for example, she
may have a need for birth control more than she needs regulation of her
cycles. The third goal is to educate about normal irregular bleeding in
adolescents. If she is not anemic or does not have symptoms
that warrant a referral for medical evaluation and she does not need
birth control, then reassurance and education may be all the treatment
required. Prospective charting of menses will help to document cycle
frequency.
History, physical examination, menstrual diary, CBS

with platelets, beta HCG, progesterone level
Ovulatroy Anovulatroy
progestrone > 10 ng/ml
TSH, USG, Saline infusion TSH, prolactin, FSH,

sonography LH
endometrial biopsy, hysteroscopy
If no response to OCPs, cyclic

MPA
Reconsider etiology
USG, Saline infusion sonography
Endometrial biospsy, Hysteroscopy
Fig. 12.1: Algorithm for evaluating adolescent hypermorrhea
Clinical Approach
Problems associated with menstruation affect 75% of adolescent females
and are a leading reason for visits to physicians.5 More than 90% of
patients with true DUB have anovulatory menstrual cycles (the rest have
regular or irregular ovulatory cycles.6 In order to treat appropriately, it
is usually important to determine whether the bleeding is ovulatory or
anovulatory in nature. Bleeding that occurs at regular cyclic intervals
and is preceded by premenstrual symptoms such as breast tenderness
or fullness, water weight gain, mood swings, abdominal bloating or
cramping, is likely to be ovulatory.
“A clinical approach to a case of adolescent hypermenorrhea should aim at
eliciting an accurate menstrual history, providing confidentiality and
communicating therapeutically, administering culturally sensitive care, and
promoting independence and self-care.”
An adolescent requires special care and attention from the clinician.
One must remember that for these girls menstruating itself is a new
experience and upon that they are dealing excessively bleeding which,
besides adding to the embarrassment and fear, leaves them with a
disrupted schedule for school and play.
In the first meeting, questions should be simple and aimed at making

the girl more comfortable. Unlike most adult patients who can talk easily
about their menstrual problems to the gynecologist, the adolescent may
be very shy and also scared when facing the doctor (a stranger). Trust
has to be gained by a sympathetic and friendly attitude. A reassurance
right at the offset that the problem she has is not unusual, and can be
easily sorted out with drugs, will put many of them at ease.
An accurate menstrual history helps in arriving at a diagnosis. This is
usually furnished by the patient herself, or by the accompanying mother.
Dates of flow and amount have to be ascertained and here one may help
the girl by posing the following questions:
• the need to use a tampon and pad together?
• the need to change tampon/pad every 1/2 hour to 2 hours?
• staining of underclothes with tampon/pad use?
In a normal cycle, an average of approximately 35 ml blood is lost
(range 20-60 ml). The amount of blood loss is difficult to estimate by
sight. A good guideline may be to consider 8 pads or 12 tampons, well
soaked, as the upper limit of normal; however even these estimates are
user-dependent and may not correlate well with actual blood loss. The
normal duration of flow is 3-7 days, with more than 7 days considered
prolonged. A normal cycle interval ranges from 21-35 days, with less
than 21 or more than 35 days considered abnormal.
(The most accurate method to quantify the amount of menstrual blood loss is
the alkaline hematin method. Blood loss can be accurately measured by collecting
all tampons and pads used during the menses, blended with a known amount of
sodium hydroxide, extracting the hemoglobin, and quantifying it by
spectrophotometry. Although this is an easy laboratory method to perform in
research circumstances, it is far too laborious in general practice.)
Questions that may be more clearly answered by the accompanying
parent or guardian include the following:
Has the patient ever experienced excessive bleeding associated with
trauma, dental work, or surgery?
Does she have a family history of a bleeding disorder or an endocrine
disorder?
Has the family noticed behavioral changes (e.g. sexual activity, eating
disorders) that might be relevant?
However, the clinician should also see the patient privately to obtain
information regarding past or present use of contraception and the
possibility of pregnancy or exposure to a sexually transmitted disease
(STD). During this private session, the clinician should emphasize the
importance of doctor–patient confidentiality and, at the same time,
acknowledge its limitations (e.g. as in life-threatening situations). Other
topics that may be more comfortably discussed one-on-one include self-
medication, weight changes, and social stresses.
Once the condition of hypermenorrhea is established an attempt is
made to find the underling cause.
MANAGEMENT
Most cases of menorrhagia fall under the category of DUB. In situations
where a specific etiology is identified, treatment of the underlying cause
is necessary. Therapy should be individualized and based on
physiological principles.
Nonhormonal Forms of Treatment

If anaemic or recurrent/severe bleeding: Iron supplements
First line to decrease flow:
NSAIDS (Mefenamic Acid, Naproxen, Brufen)—also good if
dysmenorrhea (anti-prostaglandin). Can decrease flow up to 30%.
Tranexamic acid, 500 mg, every 8 hours—can decrease flow 50% (is an
antifibrinolytic).
Desmopressin: particularly in von Willebrand disease (vWD), and other
clotting disorders.
NSAIDs—Inhibits inflammatory reactions and pain by decreasing
activity of cyclooxygenase, which results in a decrease of prostaglandin
synthesis. NSAIDs reduce menstrual flow, have the advantage of also
reducing dysmenorrhea, and may be used in combination of with OCPs.
The advantages of NSAIDs include their relative paucity of side-effects,
low cost, and need for use only at the time of bleeding. They are
particularly suitable as first-line therapy for the large group of women
with ovulatory menorrhagia. Dose—500 mg orally followed by 250 mg
every 6-8 hr; not to exceed 1.25 g/day.
Bonnar and Sheppard demonstrated that commencement of
mefenamic acid for 5 days from day 1 of menstrual bleeding only resulted
in a 20% decrease in blood loss, which was unacceptable to their patients
(Fig. 12.1). It is usually recommended that mefenamic acid be commenced,
if possible, about 4 days before the onset of menstrual bleeding and this
cannot always easily be predicted
200 Cyklokapron •p<0.001

mefenamic acid ••P<0.0001
150 20%
100 54%
50 Reduction of menstrual
blood loss (untreated and
0 treated) over 3 cycles
Control cycles Treatment cycles
Fig. 12.2: Prediction of menstrual blood loss over 3 cycles comparing

tranexamic acid with mefenamic acid
Tranexamic Acid
Tranexamic acid (Cyklokapron) is a new medicine which has recently
become available for the treatment of heavy periods. Tranexamic acid is
an inhibitor of plasminogen activator. It therefore inhibits endometrial
fibrinolysis.
A particular gynecological advantage of tranexamic acid is that
treatment can commence on the first day of menstrual bleeding or the
menstrual period. Several studies have shown that 1 gm of tranexamic
acid, 4 times per day for 4 days, beginning with menstruation will
decrease measured menstrual blood loss by 50-54% in women with heavy
periods (Fig. 12.2). Gastrointestinal upset (nausea, vomiting and diarrhea)
may rarely occur as a side-effect, but these symptoms usually resolve if
the dosage is reduced. It may also be given by intravenous injection.7
Desmopressin
The injectable form of this medicine [desmopressin acetate], Injection, 4
mg/ml, is usually used at the hospital for serious bleeding. However,
for heavy bleeding during menstrual periods, an easy-to-use nasal spray
[Stimate (desmopressin acetate) nasal spray, 1.5 mg/ml] can be used by
some women at home. Side-effects of desmopressin acetate include facial
flushing, headache, and changes in blood pressure.
Desmopressin causes a dose-dependent increase in plasma factor VIII
(antihemophilic factor), plasminogen activator, and, to a smaller degree,
factor VIII-related antigen and ristocetin cofactor activities. Large IV
doses of desmopressin acetate (0.2–0.5 mcg/kg) increase factor VIII
activity in healthy individuals, in patients with mild to moderate
hemophilia A and B, in patients with certain types of von Willebrand
disease, and in patients with uremia. Patients with severe hemophilia or

severe von Willebrand disease are unresponsive to desmopressin. The
drug has also been reported to induce platelet aggregation and
thrombocytopenia in patients with platelet-type (pseudo) von Willebrand
disease; however, the specific mechanism of this effect may be different.8
Hormonal Forms of Treatment

Progesterone (Norethisterone = Primolut, Medroxy-progesterone acetate
= Provera). Good with anovulation (infrequent periods) due to the lack
of progesterone.
Acute treatment: 5-10 mg × 21 days (N.B. Will bleed when ceased!)
Prophylactic treatment: 7-10 days/month
Combined oral contraceptive pill: can decrease flow by 50%. Good with
anovulation/irregular menses.
Depo-Provera (75% amenorrhea after one year use)
For acute severe bleeding: Premarin IV (25 mg IV every 4 hours)—will
require admission.
Excessive bleeding is the most dramatic symptom, but the most common
complaints concern the frequency, duration, and variability of menstrual
flow. Often the oral contraceptive (OC) pill is the panacea for the patient,
her family, and the physician. This solution has several advantages. It is
attractive, inexpensive, easy to use, and regulates the menstrual cycle.
The patient is advised to take tablets every 6 hours till the bleeding
stops and then taper the dose to 2 tablets a day for the next 20 days. She
is warned to expect a heavy bleed after stopping the tablets and is
advised to take the pill again from the 5th day of the bleed to regularize
the next period.
One must beware that the use of the OC pill may mask the underlying
problem and delay the diagnosis of a medical disorder, and will interfere
with the normal maturation of the hypothalamic-pituitary-ovarian axis,
which is necessary for regular menses to occur. Therapy should last for
at least 3 months to allow sufficient time for resolution of a problem
involving the HPO axis. For those patients placed on hormonal therapy,
an antiemetic is often required during the first few days of this hormonal
regimen, as nausea and vomiting frequently accompany the high estrogen
doses.
Some of the cases can be controlled with the progesterone alone—

especially if polymenorrhea or delayed periods is an added complaint.
Progestin therapy in adolescents produces regular cyclic withdrawal
bleeding until maturity of positive feedback system is achieved.
Progestins stop endometrial cell proliferation, allowing organized
sloughing of cells after withdrawal. Typically does not stop acute
bleeding episode but produces a normal bleeding.
For those patients with intractable severe bleeding or life-threatening
vaginal bleeding, an emergent D and C may be necessary. The evacuation
of blood clots from the cavity and the removal of hypertrophic
endometrial tissue will cause a temporary cessation of bleeding. The
reduction of bleeding can be short-lived, and without further treatment,
many patients resume a pattern of menorrhagia. D and C may remedy
bleeding from polyps, submucous leiomyomas, or retained products of
conception.
The use of synthetic gonadotropin-releasing hormone agonists
(GnRH-a) have also been used to control abnormal uterine bleeding.
The mechanisms of menstrual blood loss reduction are probably related
to the low-circulating estrogen levels.
Guidelines of Management based on the Patient’s Hemoglobin

Level, Hemodynamic Status, and Desire for Ongoing Therapy 9
A patient whose hemoglobin level exceeds 12 g per dl may not require
hormonal intervention; the clinician should reassure her that, despite
any irregularity in menstrual pattern or flow, her general health is not
in danger. A multivitamin with iron and periodic evaluation may be all
that is required. Asking her to keep an ongoing menstrual diary will
facilitate future evaluation and discussion.
A patient whose hemoglobin level is between 10 and 12 g per dl
should be offered iron supplementation and advised to consider
hormonal regulation of menses, with re-evaluation in 6 months. A
menstrual diary is recommended.
A patient who has a hemoglobin value below 10 g per dl but who has
no active bleeding is a candidate for hormonal management of menses
(e.g. combination OCs, MPA). Iron supplementation is also indicated. In
these cases, the clinician should rule out coagulopathies, endocrine
disorders, and systemic disease.
A patient who presents with acute profuse vaginal bleeding and a
hemoglobin level of far less than 10 g per dl should undergo fluid
resuscitation and restoration of blood volume with transfusion of blood

products, including packed red blood cells and specific coagulation
factors (depending on any hematological disorders identified).
Immediate administration of hormone therapy is also indicated. Patients
able to take oral medications should be treated with a monophasic
combination OC (e.g. norgestrel 0.5 mg and ethinyl estradiol 50 μg),
one tablet 4 times daily or two tablets twice daily. Patients unable to
take oral medications intravenous Premarin every 4 hours can be given,
until the bleeding stops, up to 4 doses. Simultaneously administer a
monophasic oral contraceptive pill for 24-48 hours and then bid to
complete a 28-day course. If Premarin does not stop bleeding after 4
doses, consider pelvic pathology. Examination under anesthesia and
dilatation and curettage may then be necessary. When IV estrogen is
used, intensive therapy with progesterone—either oral or intramuscular
MPA—must be instituted to stabilize the endometrium.
In patients who are not actively bleeding, some anecdotal reports
have recommended placement of OCs intravaginally. Although this off-
label use of OCs has not been thoroughly studied, these reports indicate
that this route of administration can achieve adequate serum hormone
levels.
Acute or chronic anovulatory states may be treated with a 10-day
course of oral MPA each month (or OCs, if birth control is needed).
Therapy should last for at least 3 months to allow sufficient time for
resolution of a problem involving the HPO axis. Additional medication
choices that also provide adequate contraception include depot MPA,
progestin-only OCs, and levonorgestrel contraceptive implants. All these
regimens may cause scant spotting.
Case Situations
Clinical Situation 1
A 9-year-old who had menarche at 8 years of age (normal physical
development) came with polymenorrhea. She had prolonged bleeding
lasting for almost 10 days with just a bleed free interval of 10 days, and
then again she would bleed. She had become an introvert during the
last couple of months since the bleeding caused acute embarrassment,
because none of her friends has menstruated as yet, and she would
rarely go out to play during these days. She was put on cyclic MPA from
16th day to 25th day of each cycle.
This restored her menses, and so pleased the girl was with the effect
of the drug she refused to give stop it up even after completion of
therapy, for the fear of slipping back into the old routine. She was made
to understand that this is a short therapy and after 3 months of therapy
she has resumed regular periods.
A 16-year-old patient—known case of idiopathic thrombocytopenic
Purpura, came with an acute episode of bleeding PV. She was pale, with
tachycardia and a low BP.
Admission was required, pt was stabilized haemodynamically, and
bleeding was controlled by administrating IV premarin. Her hemoglobin
level was 6 mg% and also required packed cells and platelet transfusions.
Once the emergency was tided was put on oral pills for that month. In
future she was advised to take cyclic MPA to regularize her cycles.
Ms. Roshni, a 10-year-old presented with bleeding since menarche, which
was 2 months back. She has been bleeding everyday and soaking about
5-7 pads daily.
No associated complains of pain.
Physically the girl is tall, and all secondary sexual characters have
developed. Per abdomen there is no abnormality found. Does not seem
very anemic, and vital parameters all normal. Hemoglobin was 11g%.
At the first consultation tranexamic acid tablets (500 mg thrice daily)
were prescribed for 5 days.
These bought a temporary relief in the flow, which reduced to just
spotting.
Again after another 10 days of spotting she started bleeding heavily,
soaking a pad every 3 hours. Now a combined OC pill (Ovral L) was
given as 3 tabs a day till bleeding stops and then 2 daily for the next 10
days. Bleeding stopped within 3 days, the patient was bleed free till the
pills continued and then at withdrawal she again had a heavy bleed.
However Ovral L was restarted once daily from the fifth day and
this time the withdrawal bleeding was very much under control. Therapy
was discontinued after the third month. Till now—a year after treatment
—her periods have been regular and moderate.
Prognosis
The majority of adolescents with hypermenorrhea will spontaneously
convert to normal menstrual cycles within 1 to 2 years, and this
information and reassurance should be relayed to her. Education and

support for the adolescent and her family are very important, because
sustained heavy bleeding is a confusing and frightening event.
The prognosis is more guarded in the presence of acute anemia and
in those women with continued irregular bleeding after several years.
A 25-year prospective evaluation of adolescents with dysfunctional
uterine bleeding showed that of those who continued to have abnormal
bleeding after 2 years, persistent problems were noted in 50% after 4
years and in 30% after 10 years.
SUMMARY
Most adolescents with hypermenorrhea have dysfunctional uterine
bleeding secondary to anovulatory bleeding and are easily treated with
either prostaglandin inhibitors or oral contraceptives. A thorough history
and physical examination rules out the majority of disorders in the
differential diagnosis. However, if an adolescent does not respond in
the expected fashion in 3 to 6 months, or has initial low hemoglobin, a
further evaluation and work-up and/or referral is in order.
REFERENCES
1. Laughead ML, Stones LM. Clinical utility of saline solution infusion
sonohysterography in a primary care obstetric-gynecologic practice. Am J
Obstet Gynecol 1997; 176:1313-16.
2. Widrich T, Bradley LD, Mitchinson AR, Collins RL. Comparison of saline
infusion sonography with office hysteroscopy for the evaluation of the
endometrium. Am J Obstet Gynecol 1996; 174: 1327-34.
3. Lewis BV. Hysteroscopy for the investigation of abnormal uterine bleeding.
Br J Obstet Gynaecol 1990; 97:283-84.
4. Loffer FD. Hysteroscopy with selective endometrial sampling compared with D
and C for abnormal bleeding: The value of negative hysteroscopic view. Obstet
Gynecol 1989; 73:16-20.
5. Slap GB. Menstrual disorders in adolescence Best Pract Res Clin Obstet Gynaecol.
2003 Feb; 17(1): 75-92.
6. Hall P, Maclachlan N, Thorn N et al. Control of menorrhagia by the cyclo-
oxygenase inhibitors naproxen sodium and mefenamic acid. Br J Obstet Gynaecol.
1987; 94:554–58.
7. Antifibrinolitics, Management options, International Women’s Health Update.
(Oct 2003) Dept of OBGY Monash University.
8. Comment In: RefSource: Med J Aust. 2003 Oct 20; 179(8): 454-55.
9. Janice L Bacon. Dysfunctional Uterine Bleeding Diagnosis and Treatment in the
Adolescent. North American Society for Pediatric and Adolescent Gynecology
2004.
13
Usha Krishna
Hormone Replacement
Therapy: Current
Controversies and
Evidences
By 2025 approximately 165 million Indians, i.e. more than 12% of the
country’s population will be 60 years or above in age. This will represent
167% increase over the corresponding figure for 1996. The women go
through a complex phase of menopause which needs a multidimensional
approach as they are influenced by various factors such as change in the
home life, diet, physical activity, social and environmental factors and
their careers. These along with the hormonal changes in the reproductive
system can affect their wellbeing and their health needs consideration
and care so that the menopausal women can enjoy good quality of life.
Management of menopause is not simply hormone replacement
therapy (HRT) but a holistic approach to health where medicines along
with social and psychological support, physical exercise and appropriate
lifestyle are important. The HRT treatment which certainly helps
menopausal symptoms specially vasomotor and urogenital can also
prevent osteoporosis and have benefits for dentition, skin and collagen
tissues, cognitive functions as well as the eyes. Even muscle wasting has
been recognized as a possible menopause related issue. There are
confusing and conflicting messages but the current available scientific
data indicates that HRT given to appropriate patients under close
monitoring specially for short-term problems such as hot flushes,
irritability, insomia as well as dysuria, dyspareunia and senile vulvo-
vaginitis is certainly a useful therapy to give good relief to the patients.
Hormone Replacement Therapy 211
The need for preventive problems may vary and the therapy for
prevention of osteoporosis is long-term. It is therefore, essential that
individualization, good monitoring and approach to alternative treatment
is wisely accepted. A holistic approach with counseling, lifestyle change
and good communication during therapy certainly benefits these women
to have good quality of life.
CONTROVERSIAL ISSUES
There have been tremendous changes in the attitudes and concepts in
management of menopause. HRT which was hitherto acknowledged to
have been significant achievement in promoting mature women’s health
and preventing problems of debilitation of advanced age is now a subject
of controversy, especially after some recent research work of great value.
We are now aware that the 8-year trial period of estrogen plus
Progestins initiated by the Women’s Health Initiative (WHI) was halted
after 5.2 years due to increased breast cancer risk and lack of overall
benefits. The large multicenter trial, a component of WHI also found
increase in coronary heart disease, stroke and pulmonary embolism in
study participants on estrogen plus progestin compared to women taking
placebo pills. However, there were fewer cases of hip fractures and
colon cancer but on balance, the harm was greater than the benefit. This
study was to run until 2005 but was stopped after an average follow-up
of 5.2 years. The participants of WHI study received conjugated equine
estrogens 0.625 mg/day plus medroxyprogestrone acetate (MP) 2.5 mg/
day or placebo. The relative risk for breast cancer was 1.27 and that for
stroke 1.41 and pulmonary embolism 2.16. As mentioned earlier, the
study was terminated prematurely.1
A million women study in the UK is a landmark study recently
published. 1,084,110 women between 50-64 years were recruited between
1996-2001. They were followed up for cancer incidence and death. Half
the women had used HRT. 9364 invasive breast cancer and 637 breast cancer
deaths were registered after an average of 2.6 and 4.1 years of follow-up.
Current users were at higher risk than never users. The risk with estrogen-
progestogen was higher than other types of HRT. There was no variation
between different types of estrogens. The risk was highest with implants
of estrogen than oral and transdermal routes. The risk of breast cancer
increased with duration of use. 10 years of use increased 5 additional breast
cancers per 1000 users only with estrogen preparations and 19 additional
cancers per 1000 with estrogen-progestogen combination. 2
The National Heart, Lung, and Blood Institute (NHLBI) of the

National Institutes of Health (NIH) has stopped early a major clinical
trial of the risks and benefits of combined estrogen and progestin in
healthy menopausal women due to an increased risk of invasive breast
cancer.3
Women with intact uterus were given estrogen plus progestin, as
progestins could prevent endometrial hyperplasia and carcinoma. But
although this combination seems to give short-term relief to symptoms,
the recent studies indicate that the benefits are outweighed by the risk.
A separate WHI study of estrogen alone in women who had a
hysterectomy has continued and the balance of risk and benefit are yet
to be ascertained.
In last few years, more information and data has come to light.
The role of HRT in secondary cardioprotection has been seriously
questioned.
Cardiovascular Disease
This is a major cause for morbidity and mortality for both men and
women. Bierman (1994) noted that in women below 65 years only 48 of
217 deaths were a result of cardiovascular disease whereas after 65 more
than half, 432 of 717 were cardiovascular related deaths.4 Similar data
from British Heart Foundation revealed that cardiovascular mortality
was 2.7 times greater in men as compared to women below the age 55
years. At menopause there is decreased myocardial contractility,
decreased stroke volume and peak flow velocity as well as left
ventricular function. There is a gradual increase in peripheral vascular
resistance, which could be attributed to estrogen receptors that have
been found in vascular smooth muscle of vessels and myocardium.5,6
The discrepancy in cardiovascular disease between men and women
had been attributed to the differences in hormones and menopause. At
menopause increased level of fibrinogen, factor VII and plasminogen
activator inhibitor-I (PAI-1) are seen. These are associated with higher
blood viscosity and increased platelet aggregation and size of thrombus.
There is sufficient evidence to show that risk of ischemic heart disease is
higher with high fibrinogen and lower with high antithrombin III. There
is overall increased coagulability in postmenopausal women. Besides,
increase in total cholesterol, low-density lipoprotein cholesterol (LDL-
C) and lipoprotein (a) and decrease high density cholesterol HDH-C) is
seen at menopause. There is also a possible increase in insulin resistance
Table 13.1: Results WHI trial9

Health event Relate risk Increase in True increased Duration of CCEPT in
vs. Placebo absolute risk incidence as years when risk
group at per 10,000 per cent appears or is greatest
5.2 years women/year per year
CHD events 1.29 7 0.09 Higher in the first year
with another peak at
year 5
Beneficial effect seen in
year 6
Stroke 1.41 8 0.02 Risk appeared during
the 2nd year and
persisted through to
5th year.
Beneficial effect seen in
the 6th year.
Total 2.11 18 Greatest in first 2 years
Thrombo- 2.13 8 0.17 With a second peak at
embolic year 5.
events Beneficial effect seen in
pulmonary year 6.
embolism
and hyperinsulinemia since endogenous and exogenous sex steroids

modulate glucose metabolism. The PEPI trial revealed no significant
change in glucose or 2-hour insulin levels with HRT, but an unexplained
lowering of post-challenge insulin was seen without a concomitant
decrease in post-challenge glucose. However, fasting glucose levels
decrease slightly with HRT.6
Till recently the estrogens were given the credit for cardioprotection
and the role of progestogens were not adequately investigated.
However, the recent reports of randomized controlled WHI trials and
HERS I and II trials have challenged the earlier evidence and
demonstrated that at least with continuous combined use of conjugated
equine estrogen and medroxyprogesterone there is neither primary nor
secondary cardioprotection.
Result and outcome of WHI trial as shown in Table 13.1 showed
increase in cardiac events in the 1st year. This could be because the age
group of women who were 63.3 years of age and were really an at-risk
population. This observation is similar to the HERS trial on women with
documented preexisting CHD where the mean age was 67 years. The
women should be informed that this data need not necessarily apply to
women in their fifties. As per the existing observational data the incidence
of CVD is less in postmenopausal women undergoing estrogen

replacement therapy (ERT) compared to those who were not. 7 From
viewpoint of secondary prevention, data collected from the HERS study
suggests that hormone therapy was not significantly associated with
risk of nonfatal stroke, fatal stroke or transient ischemic attack. 8
The results of WHI trial when tabulated gives a fairly clear picture
and therefore HRT is not recommended for either primary or secondary
prevention of cardiovascular disease until some more ongoing studies
reveal more data.
Osteoporosis
Osteoporosis is a special problem in India as dietary deficiency of calcium
starts early in life and there is lower peak bone mass. Besides, there is
malabsorption of calcium and subclinical deficiency of vitamin D. Hip
fractures occur about 10 years earlier in India and there may be a genetic
component responsible for bone mass which may be linked to
polymorphism in the gene for vit. D receptor. The mortality morbidity
and lifetime disability is considerable and women with thin stature,
Asian and Caucasian race, premature menopause, sedentary lifestyle,
low dietary vit. D and calcium and poor sunlight exposure have higher
risk factors for osteoporosis, besides chronic illnesses, immobilization,
corticosteroids, thyrotoxicosis and excess of alcohol, tobacco and caffeine
also increase the chances of osteoporosis. Hormone replacement therapy
is certainly important in preserving bone health in women specially those
who have premature, natural or surgical menopause. However, long-
term HRT treatment is required to be effective in preventing or treating
osteoporosis. The WHI study clearly established the efficacy of estrogen
in decreasing the fracture hazard ratio to 0.7 with 33% reduction in
clinical vertebral fractures. There were 5 fewer fractures per 10,000
persons years (HR 0.7, unadjusted 95%, CI 0.4 to 1.0).
The bone turnover can be judged by the laboratory evaluation where
biochemical tests can be carried out on blood and urine. This also helps
to evaluate the response to treatment. The higher the bone turnover
greater the fragility of the bones and possibility of fractures. Serum
calcium, serum phosphorus, serum alkaline phosphates, serum vit. D
and DPD/creatinine ratio can be measured. As the bone remodeling is
dynamic, the biochemistry also changes and is related to bone resorption.
There is a decrease in serum calcium and serum phosphorus and increase
in serum alkaline phosphates. Osteocalcin crosslinks (Deoxypyidinoline)
increase in urine. There is also increase in urinary calcium. DPD is specific

of bone resorption and is increased with rapid bone loss. DPD creatinine
ratio in urine is therefore used to diagnose the extent of bone resorption
Rashmi Shah et al studied the BMD values for Indian women across
different age groups. 450 women between ages of 25 to 75, 100 women
in each ten year period and 50 women between age 65 and 75 years
were recruited for BMD study. The study showed that across every 5
year of age band the BMD measurements of the Indian women were 10-
15% lower than their American counterparts both at the spine and hip.
There was an age-related increase in osteoporosis. The reduction in bone
mass appeared earlier in the spine than at the hip. Detection rate of
osteopenia and osteoporosis by ultrasonography was lower than that
by DEXA. Forty-nine percent of women were diagnosed to be osteopenic
and 12% osteoporotic. Each 10 year increase in age was associated with
a 2.9-fold increase in risk of hip fracture.10
The predisposition for Indian patients to develop osteoporosis and
ultimately complications are more compared to other women around
the world. And it is estimated that almost 35% of postmenopausal women
in Indian are osteoporotic. As many as 20-30 million women in India
have osteoporosis.
AUTHOR’S EXPERIENCE
A total of 656 menopausal women were studied over the last nine years
in the Clinic for Women by the author. In the first study of 450 women,
which focused on urogenital and climacteric problems, the commonest
presenting symptoms were urogenital problems in 85% and these were
associated with atrophic changes and loss of collagen from connective
tissue. Twenty five percent of women had musculoskeletal problem such
as backache. Climacteric symptoms, depression, insomnia and irritability
were noted in 22%. The average age of menopause in this study was
48.3 years. There was good compliance in 40%, 11% had excellent relief,
71% good relief, 14% had moderate relief and 4% had no relief. A
significant number of women required estrogen cream for senile
vaginitis.11 Of 206 cases in the age group of 45 to 75 who underwent
bone mineral density measurements (BMD), 48% had osteoporosis, 38.4%
had osteopenia and 13.1% were normal.12 The incidence was highest in
the age group of 51 to 60 years. There was a definite relationship of
osteoporosis with age and even greater correlation with the number of
years of menopause. Of cases on HRT followed up for 11 to 24 months,
64% showed some improvement in BMD.12-14 Out of 40 women who

were admitted with fractures at Jagjivan Railway Hospital, 35 were
detected to have osteoporosis by DXA. Of 60 women with high-risk
factors such as history of bilateral oopherectomy, premature ovarian
failure or thyroid and corticosteroid medication, 45 women had
osteoporosis. Thirty cases were treated with bisphosphonates and 80%
of these showed definite improvements.
It is therefore, essential that alternative treatment is considered when
long term HRT is essential.
Selective Estrogen Receptor Modulators (SERMS)

Selective estrogen receptor modulators (SERMS). Raloxifene, a synthetic
compound with estrogen like effect on bone without endometrial
stimulation is useful for prevention and treatment of osteoporosis and
also reduces the risk of breast cancer and cardiovascular risk to some
extent. However, it increases the vasomotor symptoms to some extent.
Raloxifene has been issued 60 mg/day is used for prevention of
osteoporosis very successfully. Though it does not improve vasomotor
symptoms, it certainly increases bone mineral density (BMD) and
decreases biochemical markers of bone turnover, and lowers low-density
lipoprotein (LDL) cholesterol, without effects on high-density lipoprotein
(HDL) cholesterol and triglycerides. No case of venus thromboembolism
was reported. At 6 months raloxifene 60 mg/d significantly decreased
osteocalcin, N-telopeptide, total cholesterol, and LDL cholesterol by
medians of 15.9%, 14.6%, 5.3% and 7.7% respectively, from placebo.
The incidence of diabetes in this group was 11%, hypertension 17% and
ischemic 3%. These women need appropriate medical treatment. About
5 years ago, many authors recommended long-term treatment of HRT
especially for prevention of osteoporosis. It has been established that
long-term ERT confers significant protection against wrist and vertebral
fractures. In contrast, the incidence of hip fractures did not diminish.
These views are controversial today and women requiring HRT for more
than 3 years should be monitored very strictly or changed over to
alternative therapies such as bisphosophonates, calcitrial, calcitonin, and
in extreme cases short-term period of anabolic steroids.13
Bisphosphonates
Alendronate and risedronate increase bone mineral density (BMD) at
the spine and hip, reduce the risk of vertebral and nonvertebral fractures.
They are particularly useful in established osteoporosis and glucocorticoid

induced osteoporosis. Daily as well as once a week dose is now available
and specific instructions must be followed to prevent gastrointestinal
symptoms. Following the oral dose, the patient should not eat or drink
for at least half an hour nor lie down supine.
Calcitonin
Calcitonin is less effective than bisphosphonates and serms but has
analgesic properties and can be used for pain alleviation after fracture.
Nasal calcitonin spray 100-200 unit per day can be used for treatment
and prevention.
Phytoestrogens
They are bioactive compounds of plant origin and have high concentration
of compounds having structure similar to body’s natural estrogens. They
have been found to alleviate the menopausal symptoms such as
vasomotor and urogenital problems. Soyabeans is a staple diet in east
Asian countries and the incidence of breast and ovarian cancer as well
as coronary artery disease have been found to have lower incidence
compared to the women in the West. Besides, it may offer prophylaxis
against osteoporosis and cardiovascular disease. However, more data
is essential to prove their effectiveness in prevention and treatment of
osteoporosis. They are thought to be hypocholesterolemic, anticarcino-
genic, antiproliferative and antiosteoporotic, and hormone altering. In
available controlled studies, the strongest data support phytoestrogens
for their role in diminishing menopausal symptoms related to estrogen
deficiency and possible protective effects on bones and cardiovascular
system. Women hesitant to take HRT can certainly be given
phytoestrogens and in our study of 70 perimenopausal women (of
average age 51.5 years) who receive capsule Evanova (30 mg) twice a
day. About 81.8% of patients had good relief of vasomotor problems
and 73.9% were relieved of urogenital problems significantly. However,
the relief was not as dramatic as with HRT. There was no weight gain
and no change in blood sugar, lipid profile and liver function tests.
As per Dr RK Bhathena, the benefits of HRT need to be balanced
against the small increased risk of breast cancer after 5 or more years of
use, and a slightly increased risk of venous thromboembolic disease. The
decision to take or discontinue HRT should be based on established
noncardiovascular benefits, as well as risks, and the woman’s preference.14
With a flood of evidence in past and present literature, there are

contra-indications for HRT and if the clinician understands these and
monitors those on HRT meticulously, there is a definite place for hormone
replacement therapy. However, the long-term therapy required for
osteoporosis needs special care as well as consideration to alternative
therapy.
REFERENCES
1. Writing Group for Women’s Health Initiative Investigators Risk and Benefit for
Estrogen and Progestin in Healthy Postmenopausal Women. Principal results
from the women’s Health initiative randomized controlled trial. A Am Med
Asso 2002; 288: 321-33.
2. Million women Study Collaborators, Breast Cancer and Hormone Replacement
Therapy in the Million Women Study, Lancet 2003; 362: 419-27.
3. News Release-NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased …
on page 1 NIH New Release, July 9, 2002.
4. Bierman EL. Atherosclerosis and other forms of atherosclerosis. In Harrison’s
Principles of Internal Medicine. London: McGraw-Hill, 1994.
5. Mijatovic V, Pines A. Menopause-induced changes in cardiovascular functions
and HRT. Eur Menopause 1995; 2: 4-9.
6. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin
regimens on heart disease risk factors in postmenopausal women. The
Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995 ;
273: 199-208.
7. Barrett-Connor E F, Bust T L. Estrogen and coronary heart disease in women.
JAMA 1991; 265: 1861-67
8. Simon JA, Hsia J et al. Postmenopausal hormone therapy and risk of stroke: The
Heart and estrogen-progestin replacement study (HERS). Circulation 2001;
103(5): 638-42
9. Data from Risks and benefits of estrogen and progestin in healthy
postmenopausal women: Principal results from the Women’s Health Initiative
randomized controlled trial. JAMA 2002; 288: 321.
10. Rashmi S Shah, Lalita S Savardekar, U Iddya, D Balaiah, A Parihar, B Jankharia.
First Indian Study, published by Dr. Reddy’s Laboratories Ltd., Hyderabad 500
016 on bone mass density measurement in Indian Women. Osteoporosis Alert
Issue 1 (In Press).
11. Usha Krishna, Ajita Mandlekar. Urogenital problems in menopausal women.
place of HRT. The Journal of Obstetric and Gynaecology of India, 54-59.
12. Usha Krishna, Rajeev U Mehta. Osteoporosis: Incidence and implications. The
Journal of Obstetrics and Gynecology of India 2000; 50 (5): 150.
13. Usha Krishna, Dipti Mahimtura, Ajita Mandlekar. Clinical Evaluation of
Phytoestrogens in Perimenopausal Symptoms – sent for publication.
14. RK Bhatthena. Menopause Digest. Excerpta Medca, Medical communications.
Communications BV, 2004;30.
The Enigma called Endometriosis: Current Choices in Treatment 219
14
Mandakini Parihar, Vandana Gaikwad,
Sarbjeet Kaur
The Enigma called

Endometriosis: Current
Choices in Treatment
INTRODUCTION
Endometriosis is an important benign gynecology disease that is
pathologically defined by the ectopic presence of endometrial glands
and stroma within the pelvic peritoneum and other extrauterine sites
and is linked to pelvic pain and infertility. It is estimated to affect
2-10% of women in the reproductive age group. 1-3 Although
endometriosis is traditionally considered a disease of women in the
reproductive age period, the natural history of this disorder, including
onset and progression, has not been well-established. For example, the
incidences of endometriosis in teenagers and postmenopausal women
are probably underestimated.4,5
Endometriosis is considered a polygenically inherited disease with a
complex, multifactorial etiology.6 Sampson’s theory7 of transplantation
of endometrial tissue on the pelvic peritoneum through retrograde
menstruation is the most widely explanation for the development of
pelvic endometriosis because of convincing circumstantial and
experimental evidence. Because retrograde menstruation is observed in
almost all cycling women, endometriosis is postulated to develop as a
result of a coexisting defect in clearance of the menstrual efflux from the
pelvic peritoneal surfaces, possibly involving the immune system. Some
of these molecular defects include aberrant expression of aromatase,8
certain cytokines, and tissue metalloproteinases9,10 and deficiency of 17β-
hydroxydehydrogenase. Because endometriosis is an estrogen-
dependent disorder, aromatase expression and deficiency of 17β-HSD
are of paramount importance in the pathophysiology.
ORIGIN OF ENDOMETRIOTIC IMPLANTS

Various theories have been put forth to explain the mechanisms for the
development of this disease. However, the exact cause is still unknown
though it seems to be due to multiple factors rather than a single cause.
Sampson’s Theory of Retrograde Menstruation

(Implantation Theory)
This theory proposes that viable endometrial tissues is refluxed through
the fallopian tubes during menstruation and implants on peritoneal
surface or pelvic organs. Recent studies using laparoscopy have shows
that retrograde mensturation is common phenomenon in 76 to 90% of
women with patent fallopian tubes. The demonstration of the viability
of shed endometrial cells and their capacity to implant was proof of
Sampson’s theory. Endometrial cells collected from the peritoneal cavity
after uterine lavage stayed viable for up to 2 months . There is increased
risk of endometriosis in patients with müllerian anomalies and obstructed
flow. However, it still does not explain all cases of endometriosis and
hence many other theories were postulated.7,11,12
Coelomic Metaplasia Theory

Initially was introduced at the turn of twentieth century by Meyer who
suggested that endometriosis develops from metaplasia of cells that line
the pelvic endometrium. Clinical evidence that supports the theory of
coelomic metaplasia lies in case reports of endometriosis that occurs in
men, in prepubertal and adolescent girls, in women who never
menstruated.13,14
Induction Theory
An extension of the coelomic metaplasia theory and the process that
endogenous, biochemical or immunologic factors can induce undifferen-
tiated cells to differentiate into endometrial tissue.
There is a high concentration of these in the vicinity of the ovary and
may explain endometriosis.
Embryonic Rest Theory

In 1890, Von Reckling Hansen and Russell15 introduced the embryonic
rest theory. This theory proposed that cell rests of mullerian origin could
be activated to differentiate into endometrium in the presence of specific

stimulus.
Lymphatic and vascular metastasis theory: In 1920’s Halban and
Sampson16 suggested that endometriosis also could result from hemato-
genous dissemination of endometrial cells: metastasis of endometrial
cells through lymphatic system to distant area, such as pleura, umbilicus,
bone, muscle, brain, nerves, lung parenchyma, etc.
AROMATASE EXPRESSION IN MÜLLERIAN-DERIVED TISSUES

Until recently, estrogen action was classically viewed to occur only
through an “endocrine” mechanism. Studies on aromatase expression in
breast cancer have demonstrated that paracrine mechanisms play an
importance role in estrogen action in this tissue.17-19 Estrogen produced
by aromatase activity in breast adipose fibroblasts was demonstrated
to promote the growth of adjacent malignant breast epithelial cells.
Müllerian tissues are known targets of estrogen action. Disease-free
endometrium and myometrium lack aromatase expression. On the other
hand, neoplastic counterparts of these tissues display high levels of
aromatase expression and activity.20,21 The expression of aromatase
mRNA and protein is regulated by cAMP.
ROLE OF AROMATASE EXPRESSION IN ENDOMETRIOSIS

Extremely high levels of aromatase mRNA were found in extraovarian
endometriotic implants and endometriomas. Additionally, aromatase
mRNA was detected in the ectopic endometrial samples of women with
moderate to severe endometriosis but not in those of disease-free
women.17 This might suggest a genetic defect in women with endomet-
riosis, which is manifest by this subtle finding in the ectopic endometrium.
It has been proposed that when defective endometrium with low levels
of aberrant aromatase expression reaches the pelvic peritoneum by
retrograde menstruation, it causes an inflammatory reaction that
exponentially increases local aromatase activity, i.e., estrogen formation,
induced directly or indirectly by PGs and cytokines (Table 14.1). This
may be a major contributing factor in the formation of endometriotic
implants.19-21
The development of endometriosis in an individual woman probably
requires the coexistence of a threshold number of these genetic
aberrations.
Table 14.1: Factors affecting growth and survival of endometriotic implants
Integrins-mainly 2B1 and 3B1
Ultracellular adhesion molecule-1
Vascular adhesion molecule -1
Immune factors—cell mediated and humoral immunity
Macrophages
Extracellular matrix components
Scavenger receptors
NK cells
Lymphocytes
Autoimmunity
Growth factor
Genetic factors
Environment factors
Staging System for Endometriosis

Sampson began to classify endometriosis in graded stages as early as
1921. Since then many different classifications have been described. In a
collaborative effort, Acosta et al7 proposed a classification of endometriosis
based on surgical findings. These categories included the
a. Site by lesions
b. Presence of adhesions
c. Presence of scarring or retraction.
ACOSTA’S CLASSIFICATION
Mild
1. Scattered fresh lesions in anterior or posterior cul-de-sac (i.e. implants
not associated with scarring or retraction of the peritoneum).
2. Rare surface implant on ovary, with no endometrioma, without
surface scarring and retraction.
3. No peritubal adhesions.
Moderate
1. Endometriosis involving one or both ovaries with several surface
lesions, with scaring and retraction or small endometrioma.
2. Minimal periovarian adhesions associated with ovarian lesions
described.
3. Minimal peritubular adhesions associated with ovarian lesions
described.
4. Superficial implants in the ant and post cul-de-sac with scarring and
retraction.
Severe
1. Endometriosis involving one or both ovaries with endometrioma
>2 × 2 cm (usually both)
2. One or both ovaries bound down by adhesions associated with
endometriosis with or without tubal adhesions to ovaries.
3. One or both tubes down or obstructed by endometriosis associated
adhesions or lesions.
4. Obliteration of the cul-de-sac from adhesions or lesions associated
with endometriosis.
5. Thickening of uterosacrals and cul-de-sac lesions with obliteration
of cul-de-sac.
6. Significant bowel or urinary tract involvement
The most recently described and now the accepted classification is
the AFS classification (Table 14.2).
Stage 1 Minimal 1-5
Stage 2 Mild 6-15
Stage 3 Moderate 16-40
Stage 4 Severe > 40
Table 14.2: American fertility society revised classification of endometriosis
Endometriosis site
<1 cm 1-3 cm >3 cm
Peritoneum
Superficial 1 2 4
Deep 2 4 6
Ovarian implants
R- superficial 1 2 4
R -deep 4 16 20
L- superficial 1 2 4
L -deep 4 16 20
Ovarian adhesions <1/3 enclosed 1/3-2/3 >2/3 enclosed
R-flimsy 1 2 4
R-dense 4 8 16
L-flimsy 1 2 4
L-dense 4 8 16
Tubal Adhesions <1/3 enclosed 1/3 - 2/3 >2/3 enclosed
R-flimsy 1 2 4
R-dense 4* 8* 16
L -flimsy 1 2 4
L-dense 4* 8* 16
Cul-de-sac obliteration Partial complete
4 40
* Fimbriated end of tube is enclosed, change score to 16.
Diagnosis of Endometriosis
Though extensive research is being carried out on this subject, most
authors do concur on the fact that there is no completely accurate method
of diagnosing endometriosis. Although published data suggests that
the diagnosis can be confirmed only by laparoscopy and biopsy, it is
impossible even for the most experienced surgeon to identify microscopic
disease, while on the other hand, the presence of gross pathology does
not indicate active disease.
History
A large percentage of women with pelvic endometriosis are essentially
asymptomatic, this disease may produce severe and potentially
incapacitating symptoms which often merge with those produced during
normal ovulatory menstrual cycles (Table 14.3).
Table 14.3: Common symptoms associated with endometriosis
1. No symptoms
2. Chronic pelvic pain
3. Worsening dysmenorrhea
4. Acquired dyspareunia
5. Premenstrual spotting (80%)
A number of factors have also been proposed to predict the occurrence

of endometriosis. A polygenic/multifactorial mode of inheritance
indicates a 69% risk in first degree relatives. 22 Some authors have
recommended serious consideration of the risk of endometriosis when
there is a uterine anomaly.23 Other risk factors include shorter menstrual
cycles, longer duration of menstrual flow and low parity (Table 14.4).
Table 14.4: Risk factors for endometriosis
1. First degree relative affected
2. Short menstrual cycles
3. Long duration of menstrual flow
4. Low parity
5. Reproductive tract anomalies
Examination
Some findings on pelvic examination have been classically attributed to
the presence of endometriosis. These include uterosacral nodularity, a
fixed retroverted uterus, bilateral pelvic tenderness, fixed or enlarged
ovaries. However, in most cases, clinical examination may not reveal

any abnormality.
Investigations
As mentioned before there is no foolproof method of diagnosing
endometriosis. Though, laparoscopy is referred to as the “gold
standard”, it does have its drawbacks as microscopic deposits still cannot
be identified. Investigations used in the diagnosis of endometriosis are
listed in Table 14.5.
Table 14.5: Investigations in endometriosis
1. Laparoscopy-gold standard
2. Ultrasound
3. Magnetic resonance imaging (MRI)
4. Serum CA-125
Laparoscopy (Table 14.6)

Laparoscopy is the gold standard for diagnosing endometriosis. But, it
must be remembered that this method too, has its fallacies, since
sometimes it is impossible to diagnose microscopic involvement! Visual
diagnosis has a sensitivity of 97% and specificity of 95% (Figs 14.1 to
14.6, Plates 1 to 4).24
Table 14.6: Types of lesions seen on laparoscopy
1. “Powder burn”/black lesions
2. White opacified peritoneum
3. Glandular excrescences
4. Flame like red lesions
5. Peritoneal pockets/windows
6. Clear vesicles
7. Yellow-brown patches
8. Unexplained adherence of ovary to peritoneum of ovarian fossa
9. Encysted collections of thick ‘chocolate color or tarry fluid’
10. Adhesions to the posterior leaf of broad ligament/other pelvic structures.
Ultrasonography
The main disadvantage of ultrasound is that most of the features are
nonspecific and often it may be impossible to distinguish between
endometriotic and other types of ovarian cysts. Also, smaller implants
may be difficult to identify. A further improvement on the transvaginal
ultrasound is the addition of color Doppler. In fact, recent studies have
claimed a sensitivity of 91.8% and specificity of 95.3% of color Doppler

sonography in detecting endometriotic cysts (Table 14.7). The positive
and negative predictive valves are about 95.5% and 91.5% respectively
(Figs 14.7, Plate 5 and 14.8).25
Fig. 14.8: Ultrasonography of endometriosis
Table 14.7: Sonographic features of endometriosis

1. Endometriotic cysts—oval/round
— Capsulated
— Fine homogeneous, uniform, granular echoes
— Anechoic
— Single/multiple
— Unilateral/bilateral
2. Doppler—No vascularity within the mass
3. Ovarian adhesions to uterus
4. Free floating fimbria on sonosalpingography
* Small implants are difficult to detect
Magnetic Resonance Imaging (MRI)

MRI appears to be very accurate in diagnosing ovarian endometrioma,
though it is less specific in identifying isolated endometriotic foci in the
rectovaginal septum and uterosacral ligaments. Endometriotic cysts
appear to have a typical high signal intensity on TI-weighted images
and demonstrate ‘shading’ on T2 weighted images. A study comparing
endosonography and MRI, concluded that though endosonography is
the best method of diagnosing endometriotic infiltration which may
affect treatment options, MRI would perhaps allow a more complete

staging.26
Serum CA-125
The serum levels of this antigen are found to be elevated in women
with active endometriosis. Though, this is a useful tool in predicting
activity of the disease, it cannot predict the presence/severity of
adhesions, and, more importantly cannot be used as diagnostic aid since
it is elevated in a variety of conditions including epithelial ovarian cancer.
However, the general consensus is that it is useful in monitoring therapy
and long-term follow-up in women with advanced disease. It is ideal to
perform a CA-125 assay before surgery/any form of therapy in all
women with advanced or multiloculated endometriosis. Some authors
have suggested clinical examination combined with CA-125 assay during
menstruation as a noninvasive means of detecting severe endomet-
riosis.27,28
TREATMENT
Recently, a debate was published discussing whether the combination
of laparoscopic surgery by laser, coagulation or excision and adjuvant
medical therapy with GnRH agonists (GnRH-a) is the most appropriate
treatment for endometriosis.29 The optimal treatment protocol is difficult
to define because most of the studies are retrospective and lack proper
controls. Even the prospective studies have their limitations mainly
because of the differences in the treatment groups. The treatment of
women with endometriosis is a challenging prospect. Therapeutic
strategies must be individualized according to age, symptoms and desire
for fertility. We will discuss treatment options available along with an
overview of the medical options available today (Table 14.8).
Table 14.8: Treatment options in endometriosis
1. Expectant treatment
2. Medical therapy
3. Surgical therapy — Laparotomy
— Laparoscopy
EXPECTANT TREATMENT
Even without active management, monthly fecundity rates of 2-20% have
been noted.30 These figures have to be kept in mind while treating women
with infertility caused by endometriosis.
MEDICAL THERAPY
In the last 2 decades, many drugs/drug combinations have been
introduced in the treatment of endometriosis with varying degrees of
success. These include NSAID’s, combined oral contraceptives,
progestogens, danazol, gestrinone, antiprogestins, GnRH agonists and
antagonists. Disadvantages include the side-effects and cost of the drugs
as well as a longer duration of treatment—usually 3-6 months are
required before there is any evidence of improvement (Table 14.9).
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Although NSAIDs do not directly treat endometriosis lesions, they long
have been a mainstay in the treatment of endometriosis associated pain.
NSAIDs are particularly well suited for dysmenorrhea, because the
symptom is mediated by prostaglandins synthesis. By inhibiting cyclo-
oxygenase, NSAID reduce prostaglandin production and alleviates pain.
Table 14.9: Advantages/ disadvantages of medical therapy in endometriosis

Advantages Disadvantages
1. Not operator dependant 1. Prolonged treatment
2. Less expensive 2. Side-effects of drugs used
3. Avoids risks of surgery/anesthesia 3. Cost
4. Avoids risk of post-op adhesion 4. Temporary Relief
formation
5. Treats lesions that are invisible to
operators eye.
Medical therapy for endometriosis can be used either as primary

therapy or in conjunction with surgery preoperatively or postoperatively.
This is called as the “Sandwich” therapy.
Pre-operative treatment will reduce the inflammation and vascularity,
thus reducing the risk of postoperative adhesion formation. It will also
reduce the risk of formation of functional ovarian cysts, thus preventing
unnecessary surgical manipulation of the ovaries. Usually, 3 months of
drug therapy is advocated before attempting any form of surgery.
The rationale behind postoperative treatment is that it will eradicate
the residual implants—both visible and invisible (Table 14.10). But, studies
have shown that success rates are less than 30% with this form of therapy.31 This
poor efficacy of postoperative medication precludes its use in women with
endometriosis and infertility as it will only further delay conception.
Table 14.10: Preoperative versus postoperative medical therapy
Preoperative Postoperative
1. Reduces inflammation 1. Treats residual implants
2. Reduces vascularity visible/ invisible
3. Reduces postoperative adhesions
formation
4. Reduces functional ovarian cysts
GnRH ANALOGS
GnRH analogs act by downregulating the pituitary gland resulting in a
pseudomenopausal state (Table 14.11). Today, this forms the backbone
of medical therapy of endometriosis. Various doses and formulations
are in use, but long-acting implants produce the best results in terms of
pituitary desensitization, laparoscopic scoring and histological
regression.32 GnRH-a are usually used preoperatively.
Table 14.11: Advantages of presurgical GnRH-a treatment
1. Reduction in pelvic vascularity and inflammation
2. Reduction in size and activity of endometriotic implants
3. Reduction in ovarian cyst diameter
4. Thinning of cyst wall
5. Absence of follicles/corpus luteum
One study, comparing the effects of leuprolide and buserelin, found

that though the therapeutic efficacy of both these drugs are similar.33
When goserelin was compared with naferelin for the treatment of
endometriosis, no statistically significant difference was found in
treatment results or side-effects.34 Pregnancy rates reported after GnRHa
therapy have varied between 24-62%.35,36
Side-effects with these drugs are consistent with the hypoestrogenic
state and include hot flashes, breast atrophy, dry skin, mood swings,
decreased libido, etc. The most important of these is the trabecular bone
loss 6-7% if used continuously for more than 6 months. This bone loss
can be controlled to some extent by the use of estrogen progesterone
add back therapy. This is the “add back” therapy, and is not only effective
but is associated with fewer side-effects.37
COMBINED ORAL CONTRACEPTIVES

Till a few years ago, combined oral contraceptives were advocated in
the treatment of endometriosis. This was mainly to reduce the frequent
prolonged bleeding that is commonly associated with it. But, in view of

further delaying fertility therapy, oral contraceptives are not
recommended in infertile women with endometriosis. However,
extensive studies have proved that COC pills are the only effective
prophylaxis against endometriosis.38
PROGESTOGENS
Progesterone acts by causing decidualization and atrophy of the estrogen
dependant endometriotic foci. The action not only depends upon the
dose and duration of therapy, but also upon the activity of the individual
agent. Common progestogens used include medroxy progesterone
acetate, norethisterone, and dydrogesterone. Depot medroxy proges-
terone acetate has been used as a cost-effective, readily available
medication with up to 66% complete resolution of endometriosis.39 Side-
effects include irregular, bleeding, weight gain, fluid retention, breast
tenderness, mood changes, depression, headache, etc.
PROGESTERONE RECEPTOR ANTAGONISTS

A newly created synthetic progesterone receptor antagonist ZK 230211
has been described as having exclusive antiprogestogenic activity with
minimal or no other endocrinological effects. This could prove to be
useful in the treatment of endometriosis in the future.40
DANAZOL
Danazol, a derivative of 17 ethinyl testosterone, was for the last few
decades, considered to be the standard treatment for endometriosis.41
This acts directly on the intracellular steroid receptors, inhibits ovarian
steroidogensis and also reduces the GnRH pulse frequency as well as
secretion of gonadotrophins. The cumulative effects are anti-estrogenic,
anti-progestogenic and androgenic. It also has an immunosuppressive
effect, though the importance of this action in the treatment of
endometriosis is not yet established.42,43
As the half life of danazol is approximately 4.5 hours, ideally the
drug should be administered at least every 8 hours. A minimum starting
dose of 400 mg/day is adequate for most women. This is increased if
necessary to suppress ovulation and relieve symptoms. 44,45 Large
retrospective studies on the efficacy of danazol have reported crude
pregnancy rates between 28-47%, with monthly fecundity rates between
4% and 6%.46,47
Side-effects are androgenic (weight gain, acne, oily skin, hirsuitism)

and hypoestrogenic (hot flashes, decreased libido, breast atrophy,
depression). Another important adverse action is its effect on the lipid
profile.
GESTRINONE
Gestrinone is a 19 nor-steroid derivative with androgenic, progestogenic
and antiestrogenic actions. Because of its long half life, this drug can be
administered twice a week. Usually 1.25-2.5 mg biweekly is the
recommended dose.48 The side-effects are similar to danazol, though
hypoestrogenic effects are less severe. There was also a significant
reduction in other symptoms such as dysmenorrhea, and pelvic pain.
INTERFERONS
The association between suppression of the immune system and
endometriosis has been recently established. As a result of this, interferon
therapy for endometriosis has come into vogue. Studies conducted using
interferon in combination with GnRH-a have resulted in higher
cumulative pregnancy rates and monthly fecundity rates.40,42
SURGICAL TREATMENT
The main advantage today is the advent of operative laparoscopic surgery
and this can be done at the same sitting as the diagnostic laparoscopy
and the delays/side-effects of medications are avoided.
Surgical options available are multiple-again this has to be
individualized depending on the presentation, stage of the disease as
well as the age of the patient and duration of infertility. The aim of
management whatever is the type of surgery is to minimize tissue
damage and avoid injury to adjacent organs.
Aims of Surgery in Endometriosis

The main goals of surgery are to restore pelvic anatomy in treatment of
infertility and interruption of sensory pathway in the symptomatic
treatment to pelvic pain. Restoration of normal pelvic anatomy is
performed by cytoreduction of endometrial implant either in peritoneum
or on ovary, restoration of tubo-ovarian anatomy and excision or
photocoagulation of ovarian endometrioma. This is most often carried
out by laparoscopy today, although laparotomy still has place in certain
selected cases. Vaporization or coagulation of implants was shown to

improve the fertility rate when compared with expectant management
(Table 14.12).83,84 Chronic pelvic pain is associated with endometriosis
respond to nerve ablation of uterosacral ligament in about 60% of
patients.49,50
Table 14.12: Major indications for surgery in endometriosis :

• Ovarian cysts
• Infertility
• Adhesions
• Rectovaginal endometriosis
• Peritoneal endometriosis
• Ureteric/intestinal infiltrative endometriosis
Superficial ovarian endometriosis can be treated by coagulation or

vaporization. In the cases of deep endometrioma >3 cm drainage of
cyst, laparoscopic cystotomy and biopsy followed by a 3 months course
of GnRH has been shown to be effective. Endometriosis of the recto-
vaginal septum can be removed by laparoscopy if discrete and well
localized. In patient with severe symptomatic endometriosis who have
completed their family hysterectomy may be treatment of choice with
removal of ovaries and subsequent hormonal replacement therapy such
patient would be counseled regarding risk (0.01%) of post-castration
endometriosis which often involves the gut. A small percentage of cases
can be treated with USG-guided aspiration of the cyst, as a temporary
measure, especially during ART procedures.51-55
Implants may be treated by vaporization/coagulation or excision.
This is done using electricity (40-60 watts of cutting current) or laser
(CO2/Nd-YAG/KTP). Though, the CO2 laser is associated with least
complications, this can further be reduced by combining it with hydro-
dissection.51 This method is especially useful when the endometriotic
foci are close to the ureters, great vessels, bladder and intestines. Implants
< 2 mm in diameter can be coagulated, vaporized or excised. Lesions
> 3 mm in diameter can be vaporized or excised, while those > 5 mm
require deep vaporization/advanced excisional techniques.52 Small
ovarian endometriomas are usually fibrotic and difficult to enucleate.
These may be vaporized after biopsy. Larger endometriomas must be
removed completely (including the cyst wall) since there is increased
risk of recurrence.53 Simple aspiration and fenestration is generally
avoided as there is an associated risk of recurrence. Though, laparoscopic
ovarian fenestration and coagulation of endometriomas is associated

with a shorter surgery-conception interval than cystectomy done by
laparotomy, cumulative pregnancy rates as well as recurrence were
similar in both routes of surgery.54 Recent studies have shown that pre-
operative GnRH-a therapy of 6-8 weeks reduces vascularity, thus
reducing intraoperative hemorrhage and improves preservation of normal
ovarian tissue. If the ovaries are adherent to the broad ligament,
hydrodissection is used to remove the involved broad ligament to reduce
the risk of leaving ovarian tissue behind.55
ULTRASOUND-GUIDED ASPIRATION
With the current trend towards conservative management, ultrasound-
guided aspiration of endometriomas has emerged as a new therapeutic
option. Though, total recurrence rates are slightly higher (30-32%),
cumulative pregnancy rates of up to 41% have been noted.56 A well-
established, time-tested method of reducing recurrence is ‘ethanol
sclerotherapy’. Instillation of ethanol (following transvaginal aspiration)
for more than 10 minutes is extremely effective in reducing recurrence.57
With all these treatment options available, we would like to divide
the treatment options as follows:
a. Endometriosis causing pain and not interested in fertility
b. Endometriosis causing infertility with or without pain
i. Minimal and mild endometriosis
ii. Moderate and severe endometriosis.
Endometriosis-associated Pelvic Pain is not Interested in Fertility

Although laparoscopy is commonly used for the diagnosis and treatment
of women with endometriosis and pelvic pain, Winkel58 suggested, in a
recent review, that surgical therapy offers no better results in terms of
pain relief than medical therapy with GnRH-a (Table 14.13). Long-acting
agonist treatment with add back therapy is another option that should
also be considered among the armamentarium of therapy for patients
with extensive and severe endometriosis.59 Four hundred and twenty
patients were followed up and cumulative 3- and 5-year recurrence rates
of 13.5% and 40.3% respectively were obtained. The severity of the
disease was not predictive of recurrence. Bearing this in mind, the better
results achieved after GnRH-a administration and surgery look
promising. According to Telimaa et al,60 medically treated patients had
significantly less pelvic pain and smaller peritoneal implants at second-
look laparoscopy. Therefore, postoperative medical treatment, causing

hypoestrogenism and amenorrhea, might delay the recurrence of
endometriotic symptoms.61,62 The results of endometriosis therapy with
GnRH-a alone are even more disappointing. Following laparoscopic
diagnosis of endometriosis in 130 patients, Waller and Shaw 63
administered GnRH-a treatment for 6 months. Most of the women
underwent second-look laparoscopy. The cumulative recurrence rate
for the fifth year after cessation of treatment was 53.4% (36.9% for
minimal disease and 74% for severe disease). Miller et al61 retrospectively
analysed data from 327 patients treated for 6 months with danazol (128/
327) or GnRH-a (199/327). The mean interval before pain recurred was
6.1 months in the danazol group and 5.2 in the GnRH-a group. Recurrence
times varied with the stage of endometriosis. Donnez et al64 have clearly
demonstrated that relatively hormone-independent endometriotic
lesions persisted after GnRH-a treatment. Therefore, medical therapy
alone is not efficacious. Indeed, histology has proven the persistence of
endometriotic implants after GnRH agonist (GnRH-a) administration64
and the persistence of residual activity (high mitotic index and KI 67) in
hormone-independent residual foci with low steroid levels. The adhesion
score has been proved to be unchanged after GnRH-a.61,63-65 This is
especially true for lesions like rectovaginal endometriotic nodule,
considered as a distinct entity, which requires a surgical approach due
to poor response to any medical therapy.51
Table 14.13: Management of endometriosis-associated pain
Surgical correction followed by
• 1st line continuous low-dose monophasic oral contraceptives with NSAIDs
• 2nd line progestin start with oral dosing, consider, switching to levonorgestrel
intrauterine device or depo if well-tolerated.
• 3rd line GnRH agonist with immediate add back therapy
• 4th line repeat surgery followed by 1, 2, or 3 or one may consider for low-dose
(100-200 mg everyday) danazol if other therapies are poorly tolerated.
Endometriosis-associated Infertility
The first concept we should bear in mind is that peritoneal, ovarian
and rectovaginal endometriotic lesions must be considered as three
different entities.66,67 The second is to differentiate patients with minimal
or mild endometriosis from those with moderate or severe endo-
metriosis.
Minimal and Mild Endometriosis-associated Infertility

In infertile women presenting with minimal or mild endometriosis (AFS
classification), laparoscopic “destruction” was proven to be the first line
of therapy68 but the recently published Italian study69demonstrated
exactly the opposite. It is very curious that two evidence-based medicine
(EBM) (degree 1) studies on the same subject reach two completely
different conclusions. One study suggests that there is no difference in
laparoscopic ablation of the endometritic implants and leaving the
implants alone and treating for infertility. The other study, quotes that
cumulative pregnancy rates of 30.7% and 17.7% respectively were
achieved after laparoscopic ablation. Hence, the authors concluded that
laparoscopic resection or ablation of minimal and mild endometriosis
enhances fecundity in infertile women. The most frequently cited bias is
that patients were aware of the randomization. Nevertheless, it seems
that there are more arguments in favor of treating minimal and mild
endometriosis at laparoscopy, if laparoscopy is decided upon. RCOG
recommendation is that patients with minimal or mild endometriosis
should be treated as having unexplained infertility and the management
should be the same as unexplained infertility. 68.69
Moderate and Severe Endometriosis-associated Infertility

Consensus can be more easily established in the management of moderate
and severe endometriosis. Indeed, in moderate and severe endometriosis,
most patients present with ovarian endometriosis and/or periadnexal
adhesions. Medical therapy alone is not effective in reducing
endometriotic cysts and adhesions.70
Combined therapy with surgery and GnRH-a 71 results in pregnancy
rates of more than 52% were achieved in moderate endometriosis and
more than 45% in severe endometriosis. The majority of pregnancies
occurred within 10 months of surgery. In case of ovarian endometriomas,
drainage alone of chocolate cysts is ineffective and only subsequent
GnRH-a administration can reduce size, periovarian inflammation and
glandular mitotic activity.70 Another obvious benefit is that absence of
corpus luteum and/or follicles makes ovarian surgery easier. It is
therefore recommended that, surgical removal of the residual
endometriosis is better after medical therapy.
Endometriomas have been described in patients with Rokitansky-
Küstner-Hauser syndrome who do not have a uterus and, therefore, do
not have retrograde menstruation.72 These findings favor the surgical
technique of vaporization of the internal wall of the cyst. The depth of

vaporization is shallow; only the glandular epithelium and the subjacent
stroma have to be vaporized. There is no need to destroy the fibrotic
capsule usually found surrounding the endometrioma. This technique
avoids the removal of oocytes, frequently observed when the
endometriotic capsule is removed during ovarian cystectomy. Brosens
et al73 also confirmed that ovarian cystectomy was not mandatory for
the management of large endometrioma and that it is only necessary to
destroy the internal lining of the endometrioma, histologically
represented by glandular epithelium, endometrial glands, and stroma,
to minimize ovarian trauma and avoid the risk of premature ovarian
failure. Performing the procedure after GnRH-a therapy is easier because
of the reduced thickness of the endometrial wall.
Audebert et al74 showed that, in the case of combined medicosurgical
treatment for stage III-IV endometriosis, preoperative medical therapy
with GnRH-a gives a greater improvement in the AFS score. But the
authors confirmed that no conclusion could be reached if preoperative
treatment facilitates surgery. Johnson75 concluded, in a recent review,
that all symptomatic endometriotic diseases should be treated early and
aggressively and followed up with medical treatment with GnRH-a.
Some authors76 suggest that combined GnRH-a and operative treatment
for endometriosis is the best therapy currently available. After analyzing
data, they confirmed the great clinical benefits of the combined medico-
surgical approach. Average pregnancy rates, reported in the literature,
after laparoscopic surgery are thus approximately 42% and 50% after
combined medicolaparoscopic surgical treatment. Preponderance of data
suggest that preoperative or postoperative adjuvent medical therapy
adds little to benefit achieved with surgery alone in overcoming
endometriosis associated infertility in asymptomatic patient.
Controlled Ovarian Hyperstimulation

After reconstruction or in patient with less extensive disease controlled
ovarian hyperstimulation techniques potentially in conjuction with
intrauterine inseminations can be effective. It is important to monitor
patients carefully given the risk of high order, multiple gestation reported
with these techniques. This is usually the recommended protocol for
3-6 cycles and if there is no pregnancy it would be advisable to down
regulate the patient and then start on an IVF protocol.77 IVF represent
on effective means of bypassing the hostile peritoneal environment and
anatomic distortion associated with this disease state although medical

suppression of endometriosis alone has virtually no benefit in the
asymptomatic patient, there seems to be significant benefits of pre-
treatment with GnRH agonist immediately before IVF cycle initiation
whether only a specific subset of all patients with endometriosis would
benefit from this approach has not yet been determined the use of
endometrial implantation markers may be helpful in this regards.78,79
The selection of most effective approach to overcome infertility must be
individualized and based on extend of disease, additional infertility
factors. There are no easy answers and treatment decision depends on
factor such as severity of disease and its location in pelvis, age of woman,
length of infertility and presence of pain or other symptoms. Some
general issues regarding treatment have been discussed in this chapter.
Unfortunately, the infertility in women with severe endometriosis is
often resistant to treatment with ovarian stimulation plus intrauterine
insemination. If the pelvic anatomy is very distorted, insemination would
probably be futile. These women will often require in vitro fertilization
in order to conceive (Table 14.14). Although the studies done of in vitro
fertilization for a women with severe endometriosis not all show similar
results, pregnancy rate are usually good if women is relatively young
(under 40) and if she can produce enough eggs during ovarian
stimulation. Endometriosis by itself can hamper the outcome of
pregnancy following IVF and especially if there is contamination of the
oocytes with endometriotic material. Hence, during ovum pick-up that
should be the care taken that there is no contamination of the oocytes.
Table 14.14: Recommended protocol for moderate and severe endometriosis
If tubes are blocked or damamged:
In vitro fertilization using the ultralong protocol
If patient is young and tubes are patent:
Controlled ovarian hyperstimulation combined with IUI for 3 cycles
If no, pregnancy, then:
In vitro fertilization with embryo transfer using the ultralong protocol
If the patient is older:
In vitro fertilization with embryo transfer using the ultralong protocol.
CONCLUSION
Endometriosis is an important benign gynecology disease that is
pathologically defined by the ectopic presence of endometerial glands
and stroma and is clinically associated with pelvic pain and infertility.
The development and growth of endometriotic lesions are estrogen
dependent. The mechanisms and effectiveness of hormonal treatments

for endometriosis should be re-evaluated in view of the new advances
that have increased our understanding of the body sites of estrogen
production in women with endometriosis. Aberrant aromatase activity
and defective E2 metabolism in endometriosis are consequences of specific
molecular defects and hence successful treatment of a severe case of
recurrent endometriosis with use of an aromatase inhibitor may be
helpful.
Endometriosis is the cause of pelvic pain (dysmenorrhea, dyspareunia)
and infertility in more than 35% of women of reproductive age. Complete
resolution of endometriosis is not yet possible but therapy has essentially
three main objectives:
1. To reduce pain
2. To increase the possibility of pregnancy
3. To delay recurrence for as long as possible.
It could be concluded that a consensus will probably never be reached
on minimal and mild endometriosis. Nevertheless, it is strongly suggested
that visible endometriosis must be removed at the time of surgery.
In cases of moderate and severe endometriosis-associated infertility,
the combined approach (operative laparoscopy with GnRH-a) must be
considered as “first-line” treatment. The mean pregnancy rate of 50%
reported in the literature following surgery provides scientific proof
that operative treatment should first be undertaken to give our patients
the best chance of conceiving naturally.
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presented 57th Annual meeting American society for reproductive medicine
Atlanta 2001 October;20-25.
Understanding Endometrial Hyperplasia 243
15
AP Manjunath, Girija S
Understanding
Endometrial
Hyperplasia
INTRODUCTION
Endometrial hyperplasia represents a spectrum of morphologic and
biologic changes affecting both glandular and stromal parts of endomet-
rium. Their main clinical significance is that they may be precursors of
one of the most common female genital malignancies, endometrial
carcinoma. They are somewhat analogous to dysplasias of cervix.
Hyperestrogenic states, due to endogenous or exogenous estrogen,
have been shown to increase the likelihood of endometrial hyperplasia
and endometrial carcinoma.1,2 The diagnosis of hyperplasia can be made
only on pathologic examination of the endometrium after a woman
presents to her gynecologist with abnormal uterine bleeding. An
overview on definition, terminology, current classification, diagnosis
and clinical implications in the optimal management of endometrial
hyperplasia is presented.
CURRENT VIEWS ON DEFINITION AND CLASSIFICATION OF

ENDOMETRIAL HYPERPLASIA
The classification of endometrial hyperplasia has been amply discussed
over the years because of the need for a uniform terminology to describe
the behavior of its various forms. Keeping these differences in
terminology in mind is essential not only in evaluating the various studies
in literature but also in communicating with gynecologist and pathologist.
The clinician is faced with seemingly endless variations in terminology
that almost preclude a rational approach to management.
The view that hyperplasias of endometrium were precursors of

endometrial cancer and frequent coexistence of hyperplastic lesions with
invasive cancer were expressed by many authors since early 1900s.3-5
In 1947, Gusberg drew attention to the role of both endogenous and
exogenous estrogen in the etiology of endometrial hyperplasia.6 Late in
his study, he classified adenomatous hyperplasia as mild, moderate and
severe groups and demonstrated that higher the grade of lesion, more
immediate precursor of malignancy.7 This is based on the study of 191
cases of adenomatous hyperplasia over a 20-year period.
The first complete classification of endometrial hyperplasia was
proposed by Herting and Sommers.8 They classified this into four groups:
1. Cystic hyperplasia
2. Adenomatous hyperplasia
3. Anaplasia
4. Carcinoma in situ
In his series, all six patients of carcinoma in situ developed carcinoma
between 1 and 11 years. The first three groups could be either coexistent
or sequential and were capable of regression, whereas carcinoma in situ
invariably progressed to cancer without treatment.
Campbell and Becker9 classified endometrial hyperplasia into three
groups, types I, II and III corresponding respectively to mild, moderate
and severe forms of hyperplasia described by Gusberg.7 Carcinoma in
situ was included in type III.
Beutler et al10 included the entire spectrum of hyperplasias under
the name of glandular hyperplasia with two subgroups, one with atypical
glandular proliferation and another with atypical epithelial proliferation.
They did not accept the term “carcinoma in situ”.
In 1972, Vellos 11 made another attempt to define endometrial
hyperplasias in a clinically relevant manner. In his conclusion, although
carcinoma in situ of endometrium existed, atypical hyperplasia was a
more frequent precursor of frank carcinoma. Later, in 1974,12 he concluded
that various forms of hyperplasia would be better designated as
dysplasias comparable to the preinvasive lesions of the cervix. This concept
has not been generally accepted.
In 1975, the World Health Organization proposed a simplified
classification.13 The three categories are:
1. Cystic hyperplasia, characterized by dilated glands lined by normal
epithelium
2. Adenomatous hyperplasia, characterized by increased number of
glands
3. Atypical endometrial hyperplasia, characterized by epithelial cells

showing irregular overgrowth and resulting in atypical glandular
pattern.
This classification was not felt to precisely define the particular entity
in a clinically relevant manner.
The issue was raised again in 1977 by Welch and Scully.14 They deleted
the term adenomatous hyperplasia, and preferred to use the term atypical
hyperplasia, which includes both architectural and cellular atypia. They
recognized carcinoma in situ, but only as a focal lesion affecting a few
glands; if these changes are extensive they represent invasive cancer.
Kurman and Noris in 198215 defined four criteria to resolve the issue
on distinguishing between invasive adenocarcinoma from what they
termed ‘atypical hyperplasia-carcinoma in situ’ in uterine curetting.
Briefly the four criteria of invasion are as follows:
1. An irregular infiltration of glands associated with an altered
fibroblastic stroma or desmoplastic response
2. A confluent glandular pattern in which individual glands,
uninterrupted by stroma, merge and form a cribriform pattern
3. An extensive papillary pattern
4. Replacement of stroma by masses of squamous epithelium.
The process of manifesting the features of invasion in criteria 2 through
4 must be sufficiently extensive to involve 50% (2.1 mm) of a low power
field measuring 4.2 mm in diameter without intervening stroma.
Later, a landmark study by Kurman and his colleagues in 198516
showed the behavior of untreated endometrial hyperplasia in 170 patients
with a mean follow-up of 13.4 years. They classified endometrial
hyperplasia into four groups:
1. Simple hyperplasia (SA): Benign proliferation characterized by an
increase in the number of endometrial glands. The glands may be
dilated with little crowding or have an irregular outline and exhibit
crowding. The glandular crowding in the latter falls short of back-
to-back crowding and cytologic atypia is absent.
2. Complex hyperplasia (CH): Characterized by glands with irregular
outlines that demonstrate marked structural complexity and back-
to-back crowding, but no cellular atypia.
3. Simple atypical hyperplasia (SAH): Cytologic atypia in the absence
of back-to-back glandular crowding.
4. Complex atypical hyperplasia (CAH): Cytologic atypia accompanied
by marked back-to-back glandular crowding.
The classification and risk of cancer is summarized in Table 15.1.

Table 15.1: Classification of endometrial hyperplasia and risk of cancer16
Types of hyperplasia Number of Regressed Persisted Progressed to
patients cancer
Simple (cystic without atypia) 92 74 (80%) 17 (19%) 1 (1%)
Complex (adenomatous 29 23 (80%) 5 (17%) 1 (3%)
without atypia)
Simple atypical (cystic 13 9 (69%) 3 (23%) 1 (8%)
with atypia)
Complex atypical 25 20 (57%) 5 (14%) 10 (29%)
(adenomatous with atypia)
This classification scheme is endorsed by the WHO and International

Society of Gynecological Pathologists which primarily take into account
cytological abnormalities. Currently, this is the most widely used
classification of endometrial hyperplasia.
Orbo et al17 recently showed computerized morphological assessment
of endometrial hyperplasia for prediction of cancer risk. They showed
that the D score is a reproducible and more accurate predictor of outcome
of endometrial hyperplasia than the WHO classification. The D score is
as follows; less than 0 is high risk, more than 1 is low risk and score 0 is
uncertain.
Muttler LG18,19 recently popularized the term endometrial intra-
epithelial neoplasia (EIN) for the premalignant endometrial disease. In
his recent paper, he proposed a new architectural criterion volume
percentage stroma (VPS) where less than 50% of the total sample volume
of curetting will assist in discriminating between benign lesions from
premalignant endometrial lesions. He has developed and maintained
the online resource www.endometrium.org, which is an educational resource
for health care professionals. It focuses on premalignant lesions of the
endometrium including background knowledge and diagnostic aspects
of EIN. This site has EIN central and postgraduate educational course
containing images and interactive tutorials.
PATHOLOGIC CRITERIA
The gross appearance of the endometrial cavity containing the hyperplasic
tissue is variable. In general endometrial hyperplasia is characterized
by thick velvety, creamy yellow, often lobulated or pseudopolypoid
appearance. The process may be generalized throughout the endo-
metrium or localized to one or more areas. Focal overgrowth of glands
and stroma produces a diffuse thickening that increases the volume of

tissue. A major criterion for hyperplasia is that the endometrium is
thickened by an increase in the number and size of proliferating glands.
Swiss cheese hyperplasia is an outdated term that describes an
inactive endometrium with cystic change. Cystic change can be seen to a
limited extent in virtually any endometrium. It is a prominent feature in
the endometrium of some menopausal women. Since the endometrium
in these cases is not hyperplastic, but thin and atrophic, the term is a
misnomer. No premalignant potential exists in the patient with pure
inactive endometrium with cystic change.
In adenomatous hyperplasia the endometrial glands proliferate at
the expense of stroma. The glands increase in number and complexity as
the degree of hyperplasia increases; and conversely, the intervening
stroma diminishes in amount. The crowding of glands may progress to
a point where they are “back to back” or separate from one another by
only a delicate band of fibrous stroma. Mild degree of adenomatous
hyperplasia is sometimes called glandular hyperplasia where the
crowding of the gland is only focal.
The classification of endometrial hyperplasia (Table 15.1) was based
on the finding that only cytologically atypical lesions progressed readily
to carcinoma.16 This classification has been accepted by the International
Society of Gynecological Pathologists. Proliferations displaying cytologic
atypia are classified as atypical hyperplasia, regardless of the architectural
pattern. Lesions with and without cytologic atypia are classified as simple
or complex hyperplasia, depending on architectural abnormalities, such
as glandular complexity and crowding.
The term atypical hyperplasia was previously used to designate
proliferations with glandular complexity or with nuclear atypia, or both.
Frequently, lesions were designated as atypical hyperplasia because they
were architecturally abnormal, but those with cytologic abnormalities
were also considered atypical. Because only nuclear atypia is clearly
associated with a subsequent development of carcinoma, only lesions
with nuclear abnormalities should be designated atypical.
Microscopically, hyperplasias are designated simple or complex on
architectural grounds and as atypical hyperplasia on cytologic findings.
Simple Hyperplasia
In simple hyperplasia, the endometrium is thicker than usual, with dilated
glands that have outpouchings and invaginations, producing an irregular
outline to the enlarged glands. The glands are crowded, the stroma is
more densely cellular than usual, and some foam cells may exist within
the stroma (Fig. 15.1, Plate 5). Follow-up of patients with this condition
reveals little or no progression to carcinoma.
Complex Hyperplasia
The endometrium is increased in thickness by back-to-back glands in
cases of complex hyperplasia. Most glands have irregular outlines. There
are papillary processes and intraluminal bridges. The two main features
differentiating this from simple hyperplasia are the back-to-back glands
and the intraluminal papillae. Epithelial pseudostratification is a frequent
finding, producing an appearance of two to four cell layers. Mitotic
activity is highly variable, but may range to up to 10 mitotic figures per
10 high-power fields (Fig. 15.2, Plate 6).
Atypical Hyperplasia
Atypical hyperplasia is characterized by cytologic atypia of the glands.
The gland outlines may reflect simple or complex hyperplasia, although
it is usually complex. The cells lining the glands are enlarged, show
nuclear hyperchromatism and nuclear enlargement, and have an
increased nuclear-cytoplasmic ratio. Nuclei are irregular in size and shape
and have a thickened nuclear membrane, prominent nucleoli, and a coarse
chromatin texture. The nuclei may appear clear, with scattered, coarse
chromatin clumps (Fig. 15.3, Plate 6).
Progression from Hyperplasia to Cancer

The malignant potential of endometrial hyperplasia has been a subject
of intense investigation for over half a century and the degree to which
they are premalignant, however, is still debated.
Much of the confusion in the past literature regarding the malignant
potential of endometrial hyperplasia has been a result of inconsistent
application of pathological terms.
Follow-up of significant number of untreated patient to determine
the natural history of the various histological subtypes is difficult.
Difficulty lies in the ability to accurately recognizing the difference
between the more atypical hyperplasia and well-differentiated
endometrial cancer.
Since hyperplasia and endometrial cancer share a common factor,
estrogen, it is not surprising that both epithelial proliferations are
frequently found in the same specimen. The magnitude of this association

would seem to be dependent on the thoroughness of sampling and the
criteria for diagnosis.
However, in a landmark study by Kurman et al it is shown that
progression from hyperplasia to carcinoma occurs in only 1% of patients
with simple hyperplasia and in 3% of patients with complex hyperplasia.
Progression from atypical hyperplasia is much higher; 8% of patients
with simple atypical hyperplasia and 29% of those with complex atypical
hyperplasia develop carcinoma (Table 15.1).16 The mean duration of
progression of hyperplasia without atypia to carcinoma is 10 years
compared to 4 years for atypical hyperplasia.
Glandular complexity superimposed on atypia, probably, places the
patient at greater risk than does cytologic atypia alone, but the point is
unsettled.
CURRENT UNDERSTANDING OF THE MOLECULAR

BIOLOGY OF ENDOMETRIAL HYPERPLASIA
Recently developed modern molecular methods for precancerous
diagnosis have further pushed the detection limit of premalignant
endometrial disease to a truly preclinical level, disclosing a much higher
prevalence of early stage disease than previously suspected.
The PTEN Tumor Suppressor Gene

The PTEN is a major gene involved in the pathogenesis of endometrial
adenocarcinomas distinguished by the loss of this marker.20-22 The PTEN
gene acts as a gatekeeper for endometrial carcinogenesis, being one of
the initial genetic changes seen in this process.23 Thus, PTEN immuno-
histochemistry shows lesion specific loss of the PTEN protein in 63% of
EIN lesions24 confirming that these tightly aggregated glands are clonal
outgrowths of genetically abnormal cells. Thus decreased PTEN
expression or function is a biomarker of earliest endometrial precancers.
The use of PTEN immunostaining in a clinical setting may be informative
in identifying disease, which is not yet evident on routine hematoxylin
and eosin histology.19,22
The bcl-2 Oncogene and Fas/FasL Gene

The bcl-2 is an oncogene located on chromosome 18. Expression of bcl-
2 appears to be partly regulated through hormonal control. Its expression
is markedly decreased at the onset of the secretory phase of the menstrual

cycle25,26 bcl-2 expression has been demonstrated to be increased in
endometrial hyperplasia.25,27 The role of the Fas/FasL gene had been
investigated recently in the development of endometrial hyperplasia.
Fas is a member of the tumor necrosis factor/nerve growth family that
binds to FasL (Fas ligand) and initiates apoptosis. Fas and FasL expression
are increased in endometrium after progesterone treatment. 28 An
interaction between Fas and bcl-2 expression could contribute to the
development of endometrial hyperplasia. The bcl-2 expression has been
demonstrated to decrease in the presence of intrauterine progesterone,
whereas Fas expression was noted to increase.29
However, further studies are needed to investigate the role of Fas
and bcl-2 on the molecular pathogenesis of endometrial hyperplasia and
endometrial carcinoma.
CLINICAL PROFILE
The most frequent risk factor contributing to the development of
endometrial hyperplasia is protracted exposure to endogenous or
exogenous estrogen that is unopposed by progesterone. Anovulation is
the most common cause of such altered hormone production. Hyperplasia
is encountered most commonly at the two extremes of menstrual life,
puberty and menopause, since both of these periods are associated with
anovulation. In contrast, the use of combination oral contraceptive pills
may decrease the risk of endometrial hyperplasia and cancer.30
Abnormal uterine bleeding is the most common presenting symptom
of endometrial hyperplasia. The typical history is irregular, occasionally
profuse uterine bleeding. Patients reveal an interruption of cyclic menses
with skips and delay in menstrual flow or with prolonged period of
amenorrhea.
In younger patients, overexposure to endogenous estrogen occurs
secondary to polycystic ovarian syndrome (PCOS) or estrogen-producing
ovarian neoplasm (e.g. granulosa or theca cell tumor of the ovary). There
may be increased level of estrogen secondary to peripheral conversion
of androstenedione in the adipose tissue of obese women.
Postmenopausal patients with endometrial hyperplasia typically
present with vaginal bleeding. It is estimated that 10% of these patients
will subsequently be found to harbor an endometrial carcinoma and
about 20-40% will have either hyperplasia, an endometrial polyp or
endometrial atrophy as the cause of their bleding.31,32 Hyperplasia and
carcinoma typically present with heavy bleeding, whereas patients with

atrophy usually present with light spotting.33
Like endometrial cancer, the risk factors for development of
hyperplasia are as follows, obesity, diabetes mellitus and hypertension.
In estrogen-related conditions, endometrial cancer most likely
progresses from endometrial hyperplasia, tends to be well differentiated,
and is associated with a generally favorable prognosis.
Pap Test and Endometrial Hyperplasia

The significance of atypical endometrial cells detected by cervical cytology
has been a subject of great interest to cytologists and gynecologists. The
presence of atypical endometrial cells detected by routine cervical
cytology is associated with endometrial hyperplasia (11%), adeno-
carcinoma (20%), and endometrial polyps (10%).34 Hence, a complete
endometrial evaluation is indicated even in the asymptomatic patient
who has the atypical endometrial cell on a routine Pap test.
A new classification system arose in 1988 after the shake up in
Papanicolaou smear reporting by the Bethesda System to provide uniform
diagnostic terminology. It was at this time that the term atypical glandular
cells of undetermined significance (AGCUS) and its squamous counterpart,
atypical squamous cells of undetermined significance (ASCUS) were first used
in cytologic diagnoses.35
The term AGCUS is used to describe “cells showing either endometrial
or endocervical differentiation, displaying nuclear atypia that exceeds
obvious reactive or reparative changes but lack unequivocal features of
invasive adenocarcinoma.”
Even though the incidence of AGCUS is less than 1%, high incidence
of finding significant abnormality has been reported. The term atypical
glandular cells of undetermined significance is a misnomer. The significance
of this cytologic finding has been defined and represents a marker for
serious pathologic processes. About 30% to 50% of women with the
diagnosis of AGCUS will have high-grade squamous lesions (CIN 2-3),
adenocarcinoma in situ, endometrial hyperplasia, or frankly invasive
malignancies of the cervix or uterus.36 Thus, a Papanicolaou smear
showing AGCUS is a clinical “red flag,” which should prompt immediate
clinical evaluation.
The terminology for AGCUS Pap smears has been recently revised.
The 2001 Bethesda System37 classifies glandular cell abnormalities less
severe than adenocarcinoma into three categories. Atypical glandular
cells endocervical, endometrial or glandular cells not otherwise specified

(AGC NOS). Atypical glandular cells, either endocervical or glandular
cells, favor neoplasia (AGC favor neoplasia) and endocervical
adenocarcinoma in situ (AIS).
The incidence of underlying uterine pathology is increased in women
with Pap smears with atypical glandular cells (AGC). Age is a key factor
in determining the frequency and type of neoplasia found in women
with AGC. Patients over the age of 50 years with AGC Pap smears were
almost 13 times more likely to have uterine cancer than women less than
50 years.38 There is a higher risk of CIN 2, 3 and AIS in premenopausal
women compared with postmenopausal women and premenopausal
women with AGC have a lower risk of endometrial hyperplasia or
cancer.36
According to the recommendations by 2001 consensus guidelines,37
the management of women with AGC is as follows. In the initial
evaluation, colposcopy with endocervical sampling is recommended for
women with all subcategories of AGC, with the exception that women
with atypical endometrial cells should initially be evaluated by
endometrial sampling. Endometrial sampling should be performed in
conjunction with colposcopy in women older than 35 years with AGC
who have unexplained vaginal bleeding.
ENDOMETRIAL HYPERPLASIA AND SELECTIVE ESTROGEN

RECEPTOR MODULATORS
Tamoxifen
Tamoxifen is a selective estrogen receptor modulator (SERM) that has a
therapeutic antiestrogen effect on the breast and an estrogenic effect on
the endometrium. It has been recently shown to be effective chemo-
prophylaxis for women at high risk of developing carcinoma of the
breast.39 However, patients with breast cancer on prolonged tamoxifen
therapy are reported to have increased risk of developing endometrial
polyps, hyperplasia, and cancer.
The molecular structure of tamoxifen and another commonly used
drug raloxifene is shown in Figure 15.4. The structure of 17-β estradiol
is shown for comparison.
Relative risk of endometrial cancer due to tamoxifen accounts for
2-3/1000 women annually. The increased risk of endometrial cancer in
this group of patients caused concern over the safety of long-term
tamoxifen treatment. The increased risk of endometrial cancer occurs
Fig. 15.4: Chemical structures of Selective Estrogen Receptors Modulators; Tamoxifen and
Raloxifene. The structure of 17-β estradiol is shown for comparison
predominantly among women who are 50 years or older and is related

to the total dose of tamoxifen that has been given40 and also to the
duration of treatment.
The ultrasonography picture of tamoxifen-treated patients
demonstrates thick, cystic and irregular endometrium, which is typically
described as Gruyère cheese appearance (Fig. 15.5). Endometrial
thickening appears as early as six months after the start of tamoxifen
therapy and continues progressively with increased duration of
tamoxifen use.41 Even when tamoxifen is stopped, the increased risk for
endometrial malignancy remains. (There is a protective carry-over effect
in the breast).42
Four different sonographic patterns of tamoxifen-treated endomet-
rium has been described:43
1. An echogenic endometrium with regular borders, integrity of the
subendometrial halo and homogeneous echo texture
2. An echogenic endometrium with regular borders, containing small
anechoic cysts (Fig. 15.6)
3. An echogenic endometrium with inhomogeneous echotexture
sometimes with small cystic areas, irregular borders and integrity of
the subendometrial halo (Fig. 15.7)
Fig. 15.5: Gruyère cheese appearance
Fig. 15.6: Tamoxifen-stimulated hyperplasia
4. An echogenic endometrium with in homogeneous echotexture,

irregular borders and interrupted subendometrial halo
Increased endometrial perfusion of tamoxifen-treated endometrium
is demonstrated in Figure 15.8 (Plate 7). The presence of large dilated
Fig. 15.7: Tamoxifen-induced cystic changes
cystic glands, as well as edematous endometrium of tamoxifen-treated

patients give rise to an alarming picture of the endometrium on
sonography. Even the worst pictures caused by endometrial cysts are
now considered to be of little or no concern because of the false-positive
scan.44, 45 The endometrial thickness observed may be related to stromal
change and not related to significant epithelial change.46,47 Edema and
hyperplasia of the myometrium during tamoxifen treatment could also
contribute to the thickened endometrium and thus result in false
sonographic appearance of endometrial hyperplasia.48
The action of tamoxifen on human endometrium seems to be more
complex than a simple estrogenic effect-induced hyperplasia. The
simultaneous presence of an atrophic mucosa dilated cystic glands and
dense edematous stroma can be due to a dissociated effect of tamoxifen,
which varies according to the various endometrial tissue components.
Tamoxifen might exert weak estrogenic effect on glandular epithelium
thus increasing the volume of fluid in gland and therefore the size. This
contrasts with the absence of any stimulatory effect on the epithelial
growth, which remains thin and atrophic. Finally, the thick edematous
stroma is due to the estrogenic effect of tamoxifen.49
Fig. 15.9: TVS endometrial polyp
Once the endometrium becomes thickened, the positive predictive

value and specificity of transvaginal sonography (TVS) are poor. The TVS
cannot differentiate between endometrial polyp (Fig. 15.9) potentially
containing cancer and the clinically insignificant glandulocystic appearance
of endometrial stroma (Fig. 15.10, Plate 7). Therefore, tissue diagnosis is
mandatory in women with sonographically abnormal endometrium. Blind
endometrial sampling has serious limitations in the investigation of
endometrial thickening. Moreover, tamoxifen’s subepithelial changes make
it difficult to biopsy. The tissue obtained is almost always too scant in
volume to give any pathological opinion. This is not the case with
endometrial polyps and cancers where enough tissue volume should be
available. Tamoxifen induced polyps and localized endometrial changes
with an atrophic background can be easily missed and thus the blind
endometrial sampling may lead to false reassurance in these women.50
Vigorous evaluation requires saline infusion sonography (SIS) or
hysteroscopy with guided endometrial biopsies. The pseudopolypoid
glandulocystic endometrium on hysteroscopy appears as a smooth white,
hypervascularized but transparent thin endometrial mucosa with patches
of pseudocystic endometrial stroma (Figs 15.11 to 15.13, Plates 8 and 9).
According to pathological correlation, these protuberances consist of a
thin atrophic endometrium overlying a cystic dilated gland with an
edematous stroma (Fig. 15.14).
Fig. 15.14: SIS glandulocystic endometrium
In SIS there is an empty cavity with a Gruyère cheese appearance of

the subepithelial layer of the endometrium (Fig. 15.15, Plate 9). On
histological examination this endometrium typically shows periglandular
stromal condensation, epithelial metaplasia and proliferative activity,
sometimes with a varying degree of cytological atypia.
Is Screening Worthwhile?
Role of endometrial screening on women taking tamoxifen has been
studied extensively. Unfortunately, the optimal surveillance of women
on tamoxifen is yet to be determined.
It had been shown that the endometrial thickness of > 8 mm had a
positive predictive value of 100% in detecting endometrial pathology in
tamoxifen-treated patients.51 But Seoud and his colleagues did not find
any correlation between endometrial thickness and endometrial
pathology.52 It is demonstrated that the endometrial abnormalities were
more common in the symptomatic subjects, while atrophy was more
common in asymptomatic subjects. 53 Some authors have suggested
pretreatment screening. In a study, 17% of asymptomatic postmenopausal
women with breast cancer had a thickened endometrial lining when
evaluated with transvaginal ultrasound prior to tamoxifen treatment.54
These findings suggest that women at risk for developing endometrial
malignancies as a result of tamoxifen treatment may possibly be
identified with pretreatment surveillance. But routine screening with
either ultrasound or endometrial biopsy has not proven effective in
following tamoxifen treated patients.55, 56 In a recent study, hysteroscopy

with targeted sampling appears to be the most effective method to assess
endometrium in tamoxifen-treated patients.57
The American College of Obstetricians and Gynecologists (ACOG)
committee opinion, recommended that all women with breast cancer
who take tamoxifen undergo an annual gynecologic evaluation including
pelvic examination and cytology. They also advocated endometrial
biopsy to evaluate any abnormal uterine bleeding. The ACOG further
stated that screening procedures should be left to the clinical discretion
of the provider, but they made no comment as to which screening
technique(s) should be utilized.58
According to the Royal College of Obstetricians and Gynaecologists
(RCOG) guidelines the recommendations (Table 15.2) for clinical practice
is as follows:59
1. There is no current evidence to recommend uterine screening of
asymptomatic women taking tamoxifen (Grade C)
2. Women with abnormal bleeding on tamoxifen must be fully
investigated because of the known risk of polyps and endometrial
cancer:
• Pipelle biopsy should be performed in the first instance, but a
negative result is not to be considered conclusive
• Patients with negative Pipelle findings require hysteroscopy and
transvaginal ultrasound scan (Grade C)
Table 15.2: Key to grading of RCOG recommendations
Grade Recommendation
A Requires at least one randomized controlled trial as part of the body of
literature of overall good quality and consistency addressing the specific
recommendation.
B Requires availability of well-conducted clinical studies but no randomized
clinical trials on the topic of recommendation.
C Requires evidence from expert committee reports or opinions and/or
clinical experience of respected authorities. Indicates absence of directly
applicable studies of good quality.
Raloxifene
Raloxifene is the second most used new generation of antiestrogens,
also called selective estrogen receptor modulators–II (SERMs-II). It
exhibits a favorable safety profile on the uterus as expressed in the
bleeding spotting incidence and the effect on endometrial thickness and
uterine volume. 60 The MORE (Multiple Outcomes of Raloxifene
Evaluation) Trial confirms that raloxifene does not increase the risk of
endometrial cancer.61 Subsequent studies comparing raloxifene with
unopposed estrogen and combined hormone replacement therapy (HRT)
have confirmed the safety of raloxifene on the endometrium.62,63
HORMONE REPLACEMENT THERAPY AND

ENDOMETRIAL HYPERPLASIA
Unopposed estrogen (daily use of estrogen without the addition of
progestogen) can result in endometrial hyperplasia that is both dose
and duration related. The incidence of endometrial hyperplasia is
approximately 15–20% per year in postmenopausal women on unopposed
estrogen therapy.64 The prevalence of endometrial hyperplasia is 3.4%
when combined estrogen and progesterone is used (PEPI trial).65 The
relative risk of endometrial carcinoma in women taking all types of
hormone replacement therapy is 1.3.66 Women who have used estrogen
replacement therapy (ERT), even at a low dose, have an increased
incidence of endometrial cancer (Relative risk of 9.5). The type of
estrogen and the route of administration seems uninfluential67,68 as the
proliferative potential of clinical equivalent doses of conjugated equine
estrogens, the most commonly used in ERT/HRT, is similar.67,69 It appears
that the chronic administration of any dose of known estrogen could
lead to an increased risk of endometrial cancer. The increased incidence
of endometrial cancer continues to be present for up to 15 years after
discontinuation of the use of ERT.69 The addition of a progestin to ERT
reduces the incidence of endometrial cancer. The duration of progestogen
treatment in each cycle in sequential regimens is critical: the risk of
endometrial cancer is greater when progestogen is taken for less than
10 days.70,71 In addition to the length of the progestogen phase, the
dose and type of progestogen may be important factors. However, the
risk is not completely eliminated.
A recent Cochrane review on HRT and endometrial hyperplasia
shows that the addition of oral progestogen administered either cyclically
or continuously is associated with reduced rates of hyperplasia. The
continuous therapy over long duration is more protective than sequential
therapy in the prevention of endometrial hyperplasia.
Hyperplasia is more likely when progestogen is given every three
months in a sequential regimen compared to a monthly progestogen
sequential regimen.72
The results of the WHI trial demonstrated that endometrial cancer

rates are not increased by a 5-year continuous combined hormone
therapy.73 The largest and longest study of continuous combined hor-
mone replacement therapy, containing estradiol 2 mg and norethisterone
1 mg daily was associated with neither endometrial hyperplasia nor
malignancy. In women who had complex hyperplasia during previous
sequential or unopposed regimens, the endometrium returned to normal
during treatment with continuous combined hormone replacement
therapy. These findings provide reassurance about the long-term safety
of this continuous combined regimen in terms of the endometrium.74
Whether asymptomatic women on HRT would benefit from regular
assessment of endometrium to screen for abnormalities in highly
contentious. Many investigators have shown the high prevalence of
benign abnormalities on hysteroscopic biopsy when endometrial
thickness is > 4 mm in women taking HRT.75,76 This suggests that invasive
procedures are not justified for the assessment of asymptomatic women
taking HRT as the benign pathology observed may never become
clinically relevant.
Ferrzzi E and Leone FPG in a recent review suggested that women
should undergo a baseline examination of the endometrial cavity before
starting HRT—and then on a 1 to 2 year basis or if there is any abnormal
bleeding.77 They recommend sonographic-based triage for endometrial
assessment, which is a protocol similar to that applied to post-
menopausal women without HRT (Fig. 15.16). This is discussed elsewhere
in this chapter (Diagnosis).
DIAGNOSIS
The diagnosis of endometrial hyperplasia and carcinoma forms a key
part of the evaluation of patients with abnormal uterine bleeding before
and after the menopause. Numerous diagnostic modalities have been
investigated to optimally diagnose the cause of abnormal uterine
bleeding. The principle diagnostic tools used in evaluation of the
endometrium are transvaginal ultrasound, hydrosonography, dilatation
and curettage (D&C), office endometrial biopsy and hysteroscopy.
Ultrasonography
Ultrasonography is the initial diagnostic modality in the evaluation of a
patient with abnormal uterine bleeding. There is a strong association
between the thickness of the endometrial stripe measured by transvaginal
ultrasound and the presence of endometrial disease. Endometrial
Fig. 15.16: Clinical guidelines for the management of postmenopausal bleeding
thickness is the maximal total measurement that can be obtained across

the lumen of the cavity from one endomyometrial interface to another.
This measurement excludes any intracavitary fluid and includes any
tissue. This measurement is usually taken in mid sagital plane of the
uterus just below the fundus. Hence, endometrial thickness is a combined
anterior and posterior endometrial layers (Fig. 15.17). The hypoechoic
halo sometimes surrounding the endometrium should not be included
in the measurements. One should have knowledge of different
endometrial pattern during normal menstrual cycle (Fig. 15.18). Normal
endometrial appearance of postmenopausal women is shown in Fig. 15.19.
Many authors have reported the cut off of 5 mm or greater to define
pathologic endometrium in postmenopausal patients.78-81 Similar results
were obtained by using a cut-off value of 4 mm. In 339 women with
postmenopausal bleeding (PMB), no women with endometrial thickness

less than or equal to 4 mm developed endometrial carcinoma over a
10-year follow-up period.82 Some investigators have allowed as great as
8 mm thickness if the patient is on HRT.83 The meta-analysis of Smith-
Bindman et al84 showed that a 5 mm cut off is equally accurate at
identifying women with endometrial pathology irrespective of whether
they were using HRT.
Appearance of endometrial hyperplasia by endovaginal sonography
is shown in Fig. 15.20.
Fig. 15.17: Measurement of endometrium
Fig. 15.18: Endometrial pattern in normal menstrual cycle

Fig. 15.19: Normal postmenopausal endometrium
Fig. 15.20: Endometrial hyperplasia

Endometrial Cavity Fluid

During endometrial assessment consideration should be given to the
presence or absence of intracavitary fluid (Fig. 15.21). It has been claimed
that endometrial cavity fluid is associated with an increased risk of
endometrial pathology.85 In contrast to this finding in a follow-up study
of 50 asymptomatic postmenopausal women found to have fluid in the
endometrial cavity, no malignant disease was found at hysteroscopy
after 1 year of follow-up.86 It is not unusual to find cavity fluid to be
present within the endometrial cavity of women taking HRT particularly
in the progesterone phase of cyclical therapy.87
Clear fluid in a cavity surrounded by a thin smooth endometrium
throughout the endometrial cavity is a normal finding. Presence of any
focal lesion or presence of echogenic fluid (which could be blood or pus)
is an abnormal finding, necessitating further evaluation irrespective of
endometrial thickness.88
Endometrial cavity containing echogenic fluid in a postmenopausal
lady with pyometra is shown in Fig. 15.22.
Recently Bardicef89 has proposed a new sonographic parameter in
detection of endometrial malignancy. Three sonographic parameters are
assessesd in this study:
Fig. 15.21: Intracavitary fluid cavity

Fig. 15.22: Echogenic fluid in endometrial cavity
i. Variable echogenicity (VE); appearance of two or more shades of

the assessed endometrium
ii. Irregularity of endometrial margins; appearance of papillations or
distortion of the endometrial contour
iii. Presence of intrauterine opaque fluid.
Variable echogenicity had a sensitivity of 81%, specificity of 95.6%
and PPV of 94.4% for detecting endometrial cancer. Endometrial
irregularity had sensitivity 62%, specificity of 89% and PPV of 83.8% for
detecting endometrial cancer.
Hydrosonography or Sonohysterography or
Saline Infusion Sonohysterography
Transvaginal ultrasound with selected saline infusion sonohysterography
has emerged as a safe, noninvasive and inexpensive method of triaging
patients with abnormal uterine bleeding. It is an extension of transvaginal
ultrasound examination. Hydrosonography is more accurate than
transvaginal ultrasonography in the detection of intracavitary pathologies
in women with abnormal uterine bleeding.90 It can assist in choosing the
most appropriate biopsy method when endometrial biopsy is required.
Procedure of Hydrosonography
The choice of catheter can be soft pliable infant feeding tubes or a 5 Fr
rigid insemination catheter. A catheter without an inflatable balloon is
better tolerated by patients. Pelvic inflammatory disease must be ruled
out prior to procedure. There is no need of any premedication or
prophylactic antibiotics. A 20 ml syringe containing sterile saline is
attached to a catheter, which is flushed before it is inserted through the
cervical canal and advanced to the uterine fundus. The speculum and
vulsellum are removed. The vaginal transducer is introduced. When the
endometrium is seen on the screen, the infusion is started. Usually, 5-10
ml of saline is sufficient to expand the cavity. The saline acts both to
distend the cavity and to provide acoustic window to the walls of the
endometrial cavity. Uterine cavity should be evaluated in both
longitudinal and transverse planes (Fig. 15.23).
The role of sonohysterography is to discriminate between focal
pathology (polyps and fibroids) and diffuse endometrial thickening
(Figs 15.24 and 15.25). An extension to this approach can be made using
a novel instrument that functions both as a sonohysterography catheter
and endometrial sampling device.77
Fig. 15.23: Hydrosonography

Fig. 15.24: SIS showing endometrial polyp
Fig. 15.25: SIS focal endometrial lesion

Hydrosonography in Postmenopausal Bleeding

Hydrosonography should be performed in women with PMB and an
endometrial thickness of > 5 mm is used to confirm or exclude the
presence of focally growing lesion. In a study of 105 women with PMB
presence of focal lesion at hydrosonography predicted endometrial
pathology with a sensitivity of 95%, specificity of 75%, positive predictive
value of 93% and negative predictive value of 80%.91 Here are simple
clinical guidelines for the management of women with PMB88 (Fig. 15.16).
Hysteroscopy provides direct visualization of the uterine cavity.
Approximately 50% of women with abnormal uterine bleeding have
some abnormality on hysteroscopy.
Hydrosonography in Perimenopausal Bleeding

In perimenopausal patients saline infusion sonohysterography can
reliably distinguish between dysfunctional bleeding (no anatomical
abnormality) from those with globally thickened endometria or those
with focal abnormalities.92
A clinical algorithm has been proposed and studied in premenopausal
women with abnormal uterine bleeding. This has utilized enhanced
transvaginal ultrasonography, followed by saline infusion sonography
for selected patients, and then either no endometrial sampling, undirected
endometrial sampling or visually directed endometrial sampling,
depending on whether the ultrasonography based triage revealed no
anatomical abnormality, globally thickened endometrium or focal
abnormalities respectively93 (Fig. 15.26).
It must be emphasized that, if the endometrium cannot be clearly
delineated even after hydrosonography, then this is an indication for
invasive biopsy.
Endometrial Sampling
Endometrial sampling modalities can be divided into two broad classes:
cytologic and histologic. For cytologic evaluation many devices have
been developed which use sponge or a brush to collect cell samples by
rotating an instrument inside the uterine cavity. Cytologic samples are
placed in Bovin’s solution, rather than formalin, so as to preserve the
cytonuclear characteristics.
Even though patient tolerance to these devices are excellent, they
have not been widely used as the specimen fails to yield enough material
for reliable cytologic evaluation and diagnosis. Other added
Fig. 15.26: Flow chart for perimenopausal patients with abnormal uterine bleeding.
DX—diagnosis; EM—endometrium
disadvantages of endometrial cytology include great decrease in

sensitivity and specificity. In one study with an EndoPap sampler the
sensitivity of detecting endometrial hyperplasia was 58%.94
Dilatation and Curettage

Dilatation and curettage (D and C) has traditionally been the gold
standard for obtaining sample of endometrium for histological evaluation
in abnormal uterine bleeding. The diagnostic accuracy of D and C has
not been well studied. As it is a blind procedure in approximately 60%
of D and Cs, less than half the uterine cavity is actually curetted.95 In
about 10-15% of cases endometrial carcinomas were missed by D and
C. 96,97 It failed to diagnose 44% of pathological lesions. It missed
approximately half of the benign pathological lesions. On the other hand,
the agreement between the D and C diagnosis and the final diagnosis
(based on hysteroscopic resection and/or hysterectomy) was excellent
(94%) in women without focally growing lesions at hysteroscopy. The
D and C is inappropriate for women with focally growing lesions.97
Although serious complication with this procedure is uncommon, up
to 5 per 1000 women proceed unexpectedly to a major operation as a
result of complication arising from a D and C. Moreover, many patients
requiring endometrial evaluation for PMB have associated medical
conditions such as diabetes, hypertension and obesity that put them at
increased risk from anesthetic complications. For this reason, there has
been much interest in the potential use of endometrial sampling devices,
which are cheaper, smaller, less painful, plastic catheters with their own
internal piston to generate suction becoming popular. A variety of
instruments have been developed over the last decade for use in the
office as alternatives to the expense, risk and inconvenience of fractional
D and C. The Pipelle and similar instruments, for example, the Pipette,
the Tis-U-Trap, Vabra Aspirator and the Z-sampler were devised. With
the use of these devices, the sensitivity for detecting endometrial cancer
ranges from 67 to 96 percent
Pipelle Endometrial Sampling

Endometrial biopsy with the Pipelle was superior to other endometrial
techniques in the detection of endometrial carcinoma and atypical
hyperplasia (Fig. 15.27, Plate 10). Pipelle had a 99% sensitivity in
identifying endometrial cancer and 75% sensitivity for endometrial
hyperplasia.98 It has better patient acceptance. Pipelle is excellent for
detecting global process in the endometrium. If the tumor is localized in
a polyp or a small area of endometrium the pathology may go
undetected.99 The accuracy of the Pipelle was higher in postmenopausal
women than in premenopausal women.100
However, an endometrial biopsy is not required in the initial
assessment of menorrhagia.
Table 15.3 elaborates the various progesterone preparations that are
commonly used in treating endometrial hyperplasia in clinical practice.101
Table 15.3: Progesterone preparations for treatment of endometrial hyperplasia
Progestogen administration
• Medroxyprogesterone acetate—10-20 mg for 12-14 days per month
• Norethindrone acetate—5 mg for 12-14 days per month
• Micronized progesterone—200 mg for 12-14 days per month
• Progesterone—containing intrauterine device
Progestasert (Mirena) for 1-5 years
High-dose progestogens
• Medroxyprogesterone acetate—40-100 mg per day for at least 3 months
• Megestrol acetate—40 mg per day
Hysteroscopy
Hysteroscopy provides direct visualization of the uterine cavity.
Approximately 50% of women with abnormal uterine bleeding will have
evidence of uterine pathology at hysteroscopy. Endometrial hyperplasia

usually shows macroscopic morphologic changes of the mucosa, which
can easily be detected by hysteroscopy (Fig. 15.28, Plate 10). Furthermore,
the accuracy of hysteroscopy in endometrial hyperplasia diagnosis
increases with endometrial mucosa abnormalities (Fig. 15.29, Plate 10).
Compared with traditional methods such as dilatation and curettage,
hysteroscopy offers the possibility of visualizing macroscopic or focal
abnormalities suggestive of endometrial hyperplasia or carcinoma
(Figs 15.30 and 15.31, Plate 11) and of taking a biopsy under visual control.
Hysteroscopy with directed biopsy has been shown to be superior to
blind uterine curetting.102 The critical point in this procedure is the
difficulty in obtaining an adequate amount of tissue for histological
diagnosis: using small 5-Fr biopsy forceps and the punch, technique.
Colafranceschi et al103 and Bakour et al104 calculated an adequate amount
of tissue to be not less than 0.8 mm2.
The lack of established hysteroscopic criteria for the diagnosis and
classification of endometrial hyperplasia and its overlapping pattern with
the normal late secretory endometrium, especially in premenopausal
women, is unreliable in differentiating malignant and premalignant
lesions if the diagnosis is based only on ‘visualization’ of the uterine
cavity. Hence, hysteroscopy with endometrial biopsy is essential to
confirm the diagnosis. It may be possible to omit endometrial sampling
if the cavity is clearly atrophic.105 However, hysteroscopy is known to
be a superior method for the detection of endometrial polyps and
submucosal myomas.
Office hysteroscopy has recently been evaluated as a diagnostic
modality for intrauterine pathology. In conjunction with targeted
hysteroscopic biopsy it had a sensitivity, specificity, PPV and NPV of
98%, 95%, 96% and 98% respectively, when compared with histologic
findings at the time of hysterectomy.106 In a recent review the authors
state that hysteroscopy is highly accurate, and thereby clinically useful
in diagnosing endometrial cancer in women with abnormal uterine
bleeding. It is moderately useful in diagnosing endometrial disease.107
As endometrial hyperplasia presents most commonly with abnormal
uterine bleeding, it may be worthwhile to go through the RCOG National
Evidence-Based Clinical Guidelines for the initial management of
menorrhagia (Table 15.4) and management of menorrhagia in secondary
care setting (Table 15.5).101
Table 15.4: RCOG national evidence-based clinical guidelines: The initial
management of menorrhagia101
Recommendations
1. A history of heavy cyclical menstrual blood loss over several consecutive cycles
without any intermenstrual or postcoital bleeding should be obtained (C).
2. An abdominal and pelvic examination should be performed in all women
complaining of menorrhagia (C).
3. Full blood count should be obtained in all women complaining of menorrhagia
(B)
4. Thyroid function tests do not need to be routinely performed in the initial
evaluation of menorrhagia unless the woman has symptoms or signs of
hypothyroidism (C).
5. No other endocrine investigations are necessary in the investigation of
menorrhagia (B).
6. An endometrial biopsy is not required in the initial assessment of menorrhagia
(C).
7. Tranexamic acid and mefenamic acid are effective treatments for reducing heavy
menstrual blood loss (A).
8. Antifibrinolytic drugs and nonsteroidal anti-inflammatory drugs are both effective
in reducing heavy menstrual blood loss in women with intrauterine contraceptive
devices (A).
9. Combined oral contraceptives can be used to reduce menstrual blood loss (A).
10. A progestogen-releasing intrauterine device is an effective treatment for
menorrhagia (A).
11. Continued use of long-acting progestogens renders most women amenorrheic
and therefore could be considered for use in menorrhagia (C).
12. Low dose, luteal phase administration of norethisterone is not an effective
treatment for menorrhagia (A).
13. Ethamsylate, at currently recommended doses, is not an effective treatment for
menorrhagia (A).
TREATMENT
The therapeutic approach to endometrial hyperplasias can be hormonal
or surgical and should be based on the patient’s age, pathologic findings
from the endometrial evaluation, reproductive status and the patient’s
general health.
It should be kept in mind that various types of endometrial
hyperplasias may be found in nonmalignant endometrium of patients
with concomitant endometrial carcinoma. In almost every series of
hysterectomies for endometrial hyperplasia, the risk of having
concomitant unrecognized invasive adenocarcinoma is in the range of
35 to 50%.11,108,109
The problem of insufficient sampling even with thorough D and C is
high and it should be kept in mind when the management option for
conservative therapy is given to the patient.
Table 15.5: RCOG national evidence-based clinical guidelines:

The management of menorrhagia in secondary care101
Recommendations
Indications
1. If a woman continues to complain of heavy menstrual bleeding, despite having used a
drug treatment recommended in the first guideline, her menstrual history should be re-
evaluated and an abdominal, bimanual and speculum examination performed (C).
Investigations
2. A full blood count should be performed (B).
3. Tests for thyroid function and bleeding disorders should only be performed if there are
suggestive features present in the history or on examination (C).
4. No other endocrine investigations are necessary in the investigation of menorrhagia (B).
5. The uterine cavity should initially be investigated using transvaginal ultrasound (B).
6. An endometrial biopsy should be considered for all women with persistent menorrhagia
(C).
7. A D&C does not give additional diagnostic information over and above a hysteroscopy
with endometrial biopsy (B).
8. When hysteroscopy is indicated, it allows direct visualization of the uterine cavity and
the opportunity for an endometrial biopsy without the need for a general anesthetic
(A).
9. Consideration should be given to performing an objective or semi-objective measurement
of menstrual blood loss before deciding upon definitive surgical treatment (C).
Treatment
Patient Issues
10. Patients must be involved in the decision-making process regarding their treatment and
be provided with appropriate information to enable them to do this (C).
11. If definitive surgical treatment is intended, the likely outcomes and complications
should be discussed with the woman beforehand. These discussions should be backed
up with appropriate written information (C).
12. Quality of life issues are important and must be addressed during the collaborative
decision-making process (C).
Drug Treatments
13. Second-line drugs such as danazol, gestrinone, and gonadotropin-releasing hormone
analogues are effective in reducing heavy menstrual blood loss but side effects limit
their long-term use (A).
14. A progestogen-releasing IUD is an effective treatment for reducing heavy menstrual
blood loss and should be considered as an alternative to surgical treatment (A).
Surgical Treatments
15. A D&C is not therapeutic in cases of heavy menstrual bleeding (B).
16. If intrauterine pathology such as submucous fibroids or polyps are found during
ultrasonic or hysteroscopic investigation, these should be removed hysteroscopically
(B).
17. Endometrial ablative procedures are effective in treating menorrhagia (A).
18. Hysterectomy is an established, effective treatment for menorrhagia (A).
19. The widespread use of hysterectomy as a treatment for menorrhagia should be balanced
against its potential mortality and morbidity (C).
20. Prophylactic antibiotics should be given to all women undergoing major surgical
treatment for menorrhagia (A).
21. Risk factors for venous thromboembolism should be assessed before hysterectomy and
appropriate prophylactic measures instituted (C).
In postmenopausal women, treatment options are clearly different

from younger women who wish to preserve reproductive potential.
Teenage Girls
Teenage girls having anovular cycles and metropathia hemorrhagica
should be treated with oral contraceptives to induce artificial cycles for
at least 6 months. The patient is observed for evidence of regular menses
and pattern of ovulation. In the absence of ovulation she should be given
periodic doses of medroxyprogesterone 10 mg daily for 10 days to oppose
the estrogen stimulation of the endometrium. This periodic progestogen
is continued till she has established an ovulatory pattern or she is ready
for ovulation induction and childbearing.
Reproductive Age Women

In active reproductive age women, three cycles of oral contraceptive
pills is a reasonable choice in whom no cellular atypia is present. It can
be used to reduce menstrual blood loss. This period of treatment is
immediately followed by careful sampling of endometrium to ensure
revision to a benign pattern. Should anovulatory cycles continue,
ovulation induction with clomifine or menotropins may be undertaken.
If the patient is not interested in childbearing at that time, continuous
use of oral contraceptive pills is recommended.
Perimenopausal Women
These groups of patients are treated either with hysterectomy or
moderate doses of progesterone alone. The decision for hysterectomy
would depend on the severity of the hyperplasia, presence or suspicion
of estrogen producing ovarian tumors. In general, hysterectomy is
recommended for patients with moderate to severe atypical hyperplasia,
whereas a trial of progesterone is given for patients with lesser lesions
and no associated pathologic findings. The endometrial cavity should
be sampled every three months.
Postmenopausal Women
For postmenopausal patients, hysterectomy may be the preferred
definitive treatment, unless this is strongly contraindicated. A true
postmenopausal woman (last menses one year or more) with endometrial
hyperplasia is often found to have coexisting foci of invasive
adenocarcinoma or concomitant estrogen-producing ovarian tumors. It

is also observed that the malignant potential of endometrial hyperplasias
is more pronounced in postmenopausal women.111 Progesterone therapy
is reserved for patients with severe medical problems where they are
not fit for surgery.
Majority of patients with endometrial hyperplasia will respond to
medical treatment, but those who do not respond are at a significantly
increase risk of endometrial cancer. Therefore, they should be advised
to undergo hysterectomy.
The likelihood to respond to hormonal treatment is directly related
to the absence of cytologic atypia. Hence, when treating atypical
hyperplasia with progestogen one should remember that there is a
significant increase risk of progression to carcinoma and there is higher
incidence of resistance to regression to benign endometrium.112 The type
of progesterone and dose of progesterone for optimal treatment of
endometrial hyperplasia has not been investigated. The regimens
advocated are essentially arbitrary. One interesting observation is that
the response to progesterone therapy cannot be predicted by receptor
status.113,114 Progesterone-releasing IUCD has also been shown to cause
regression of hyperplasic lesions.115 It is also effective in treatment of
menorrhagia. 101 Complex endometrial hyperplasia in women on
sequential HRT can be managed by a change to continuous combined
HRT.59
Based on the concept of induction of the endometrial progesterone
receptor by tamoxifen, combining tamoxifen with progesterone therapy
may be beneficial. In a randomized controlled trial, levonorgestrol-
releasing intrauterine system had shown a protective action against the
uterine effects of tamoxifen.116
Regression of endometrial hyperplasia has been reported with natural
micronized progesterone when used vaginally in premenopausal
women.117
The different progesterone preparations used for endometrial
hyperplasia are summarized in Table 15.3.
Danazol has also been reported to be effective in reversing
endometrial hyperplasia.118,119 Recently, danazol-releasing IUCD is also
shown to be effective in reversing endometrial hyperplasia.120
The use of gonadotropin-releasing hormone analogues for the
treatment of endometrial hyperplasia has been shown to be effective
and well tolerated.121 Progestogen have been added to GnRH-agonist
regimens with favorable results in treating women with atypical

hyperplasia who were either at risk for surgery or who desire to retain
their reproduction potential.122
Endometrial cancer and hyperplasia have long been associated with
diabetes. Hyperinsulinemia may have a direct mitogenic effect on the
endometrium and may inhibit the effect of progestogen therapy. Based
on this concept, a case of atypical endometrial hyperplasia after failed
treatment with progestogen shows regression with metformin, an insulin-
sensitizing agent. This relatively new class of drugs may provide an
adjunct to the therapy of endometrial hyperplasia.123
Even though transcervical hysteroscopic ablation of endometrium
has been proposed as an alternative to hysterectomy for managing
endometrial hyperplasia with good results, 124 the possibility of developing
endometrial carcinoma, after ablation should be kept in mind.125
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Current Status of Endometrial Ablation in Gynecology Practice 283
16
Arun H Nayak
Current Status of
Endometrial Ablation in
Gynecology Practice
INTRODUCTION
Menorrhagia is a significant health problem in premenopausal women
that can cause anemia and the affect quality of life. It is estimated to
affect up to 22% of otherwise healthy women older than 35 years of
age.1 Very often, there is no obvious pathology to explain the heavy
menstrual bleeding. The first line therapy, traditionally has been medical,
in form of nonsteroidal anti-inflammatory drugs and hormonal therapies.
However, when it fails, hysterectomy is often being used as a definitive
treatment. As per audit report in the UK within 5 years of referral, 60%
of women will have undergone hysterectomy, making it the commonest
major gynecological operation.2,3 Hysterectomy is 100% effective as it
ensures cessation of menstrual flow and most patients are extremely
satisfied postoperatively. However, it is a major operative procedure
with inherent risks and complications. Recent VALUE survey of over
35000 hysterectomies reported the mortality rate of 0.38 per 1000 and
serious morbidity rate of 3%, 4 which included return to theatre to stop
bleeding, visceral injury or severe postoperative complications. Over
the last two decades, a number of techniques have been developed to
ablate or destruct the endometrial lining for women with menorrhagia
who wish to retain their uteri. Many of these newer techniques can be
performed blindly and are less time consuming, though a few of them
are still under development, refinement and investigation.
Although amenorrhea following curettage, due to endometrial
destruction, was described by Ashermann as early as 1948,5 the concept
of therapeutic endometrial destruction came much later. In America,

Goldrath started endometrial ablation with lasers, in late 1970,6 while
in the UK. Adam Magos introduced hysteroscopic transcervical
endometrial resection.7 Since then, a number of surgical techniques to
destroy the endometrium have been developed.
Many of these techniques have been extensively evaluated in
randomized trials and based on these trials, endometrial ablative
techniques have been given a grade A recommendation by the Royal
College of Obstetricians and Gynaecologists for treatment of heavy
menstrual bleeding.8
Various methods of endometrial destruction can be broadly classified
into two groups:
a. Endometrial resection techniques—which provide endometrial
specimen for histological analysis.
b. Endometrial ablation technique—which cannot provide endometrial
specimen.
Another way of classifying these methods is as hysteroscopic
techniques and nonhysteroscopic or blind or global techniques.
ROLE OF ENDOMETRIAL DESTRUCTION

Does endometrial destructive surgery has any place in the management
of women with menorrhagia? Certainly yes. Though initially its role
was limited as an alternative to hysterectomy, subsequently a number
of randomized trials have been undertaken. Hysteroscopic endometrial
destructive techniques have been shown to be effective with quicker
recovery time and lower morbidity rates compared to hysterectomy.9-13
The long-term results which are available now, corroborate the earlier
trial results and observational data has demonstrated that hysteroscopic
surgery is an acceptable alternative to hysterectomy.12, 14,15 Satisfaction
rates have been shown to be as high as 80% or more in long-term while
reoperation rates have reached a plateau.
When compared with medial treatment, it would be logical to conclude
that high hysterectomy rates partly reflect the long-term failure of
medical treatment. A randomized controlled trial comparing transcervical
resection of endometrium with medical treatment found that at 4 months,
women allocated to transcervical resection were highly significantly
satisfied, found treatment acceptable and were willing to have treatment
again.16 Two year follow-up of the study cohorts further consolidated
short-term results.17
Hence, the present recommendations are to offer hysteroscopic

endometrial surgery or ablative technique once medical treatment has
failed and can even be offered as a selection of treatment modality to all
women with menorrhagia, who have completed their family.
It has been recognized that for optimal outcome with hysteroscopic
endometrial ablation, a certain level of skill and experience is required.
Furthermore, the risk of fluid intravasation has received much attention,
making many general gynecologists fearful of performing endometrial
ablation. The second-generation endometrial ablation techniques
overcome some of the shortcomings of hysteroscopic ablation techniques.
Non-hysteroscopic endometrial ablative techniques, which were
introduced as an alternative to hysterectomies for women with high
surgical risk, overcome these drawbacks of endometrial resection
techniques.6 They are technically simpler, avoid risk of fluid overload
and are more reproducible.
SELECTION CRITERIA FOR ENDOMETRIAL ABLATION

1. Excessive or intractable recurrent uterine bleeding
2. Patient unfit for hysterectomy due to medical condition
3. No relief from medical treatment for menorrhagia
4. Completed family or no desire for childbearing
5. Benign endometrial histology
Preoperative Endometrial Preparation

With a view of reducing endometrial thickness, drugs like danazol,
medroxyprogesterone acetate and GnRH analogues have been used.
Danazol is given in the dose of 400 mg daily for 4 to 6 weeks while
medroxyprogesterone acetate is given 20 to 30 mg daily. Alternatively,
Leoprolide acetate can be used daily subcutaneous or as intramuscular
depot injections.18-20
Anesthesia
Although these procedures can be done under sedation along with local
anesthesia, short lasting general anesthesia is preferred. TCRE can be
performed under spinal or epidural anesthesia, as it requires longer
duration.
Endometrial Ablation Techniques

Although laser was used for endometrial ablation earlier, other energy
sources like thermal or electrical can also be used.
Transcervical Resection of Endometrium

Electrosurgical techniques include endometrial resection, vaporization
and electrocoagulation. Although tissue effects of electricity are less
predictable than laser, clinical outcomes are similar and hence
electrosurgical techniques have superseded laser vaporization in clinical
practice.21-23
Continuous flow resectoscope (26 Fr) containing 30° oblique telescope
along with cutting loop is used for TCRE.23,24 Continuous flow system
with inner and outer sheath allows simultaneous in and outflow of
distension fluid which is 1.5% glycine. Inflow pressure is kept at around
100 to 120 mm Hg while outflow is connected to a suction pressure of
50 mm Hg. Endometrial slices can be resected up to 3-5 mm thickness
using cutting loop with either pure cutting current or a blended current.20
Occasionally resection may be carried in 2-3 layers to ablate complete
endometrial thickness. Few centers prefer using roller ball for fundal
and periosteal region and after endometrial resection whole cavity can
be treated with roller cylinder.25,26
Results of Endometrial Resection

Hysteroscopic endometrial resection became popular as a safe and
effective alternative to hysterectomy for treating heavy menstrual
bleeding. Although amenorrhea could be achieved rarely, usual outcome
was scanty menses, which was considered as good outcome, satisfying
majority of patients.
Maher and Hill reported improvement in 95% cases, while Adam
Magos reported 92% of cases improved after TCRE.27, 28
Although endometrial resection offers advantages of histological
sampling of endometrium, low risk of endometrial hyperplasia or
carcinoma and reduced failure rates, risks of uterine perforation,
intraoperative hemorrhage and fluid overload persist.29 When fluid
media are excessively absorbed in circulation it can result in
hyponatremia.30 In rare cases, long-term morbidity and deaths have been
reported. Hyponatraemia and hypo-osmolarity may result in brain edema
and permanent neurological damage. 19, 31,32 If fluid deficit reaches
750 to 1000 ml, serum electrolytes should be measured and intravenous
furosemide (40 mg) should be given. Other rare complications like thermal
injury to adjacent structures like pelvic vessels and ureter have also been
described33 and certainly TCRE requires extensive understanding of
uterine anatomy and greater hysteroscopic skills.
Endometrial Electrosurgical Vaporization

This technique was first reported by Vancaillie using a large electrode
capable of generating current density enough to vaporize tissue.34
Vancaillie used 2 mm ball electrode, attached to resectoscope
for endometrial coagulation. Alternatively, roller cylinder or barrel or
ovoid can be used, and entire endometrium is desiccated up to
myometrium by activating and moving these electrodes across
endometrial cavity.
Advantages of endometrial vaporization over resection are less
chances of postoperative bleeding, intravasation of fluid media and
shorter surgical time.
Endometrial Laser Ablation

Goldrath in 1980, first described use of Nd:YAG laser for photovapori-
zation of endometrium for treatment of menorrhagia.6 Laser energy
from the devices is passed through a flexible quartz fiber inserted through
operating channel of hysteroscope. Laser energy is unimpeded by various
fluid media and achieves uniform depth of tissue necrosis, of 4 to 5 mm
in all directions.
Among other lasers, CO2 laser is not appropriate for hysteroscopic
surgery as liquid distending media assorts its beam. The Argon laser is
also photocoagulator but causes superficial coagulation compared to
Nd:YAG laser. Although Nd:YAG laser has less precision than CO2 laser,
it causes better hemostasis due to better vaporizing effect. Nd:YAG
laser is invisible as its wavelength of 1060 nm falls near infrared portion
of light spectrum. Therefore, aiming beam is needed to direct and focus
the laser to selected area. The operative sheath used for laser endometrial
ablation is 8mm in diameter and contains separate channels for
hysteroscope, distension media and laser fibers.
The distending media used for laser ablation are low viscosity fluids
containing sodium and preset infusion pressure of about 80 mm Hg is
maintained using mechanical pumps. Alternatively, CO2 can also used
as distending medium for endometrial ablation with Nd:YAG lasers.
Laser endometrial ablation can be performed by two ways, either by
placing the fiber directly in contact with the tissue, which causes
vaporization and deep coagulation, or by non-touch method, where laser
fibers are held a few millimeters away from endometrial surface causing
blanching effect on a broader surface. The ablation is carried on serially,
starting from cornual ends and then to anterior wall and lastly posterior
wall, up to the level of internal os. Ablated areas show change in color
from initial pink to white and then to brownish color. Lamano, 35 has
compared dragging technique versus blanching technique for endometrial
ablation with Nd:YAG laser in treatment of chronic menorrhagia while
Loffer36 has described effects of non touch technique with Nd:YAG laser
for hysteroscopic ablation. Several published series have found that
majority of patients found significant reduction in menstrual blood flow
following laser endometrial ablation. 37-39,18
Endometrial Laser Intrauterine Thermo Therapy (ELITT)

Although, the original work on endometrial ablation with lasers was
done with Nd:YAG laser, it is cumbersome, expensive and requires fluid
distension. The ELITT by contrast, uses a 830 nm diode laser powered
by 20 W power source, and like Nd:YAG it creates coagulation. The
laser does not need to be in contact with endometrium, nor does the
technique require fluid distension of cavity. The cervix is dilated to
7 mm and the handset is inserted into the cavity in a blind manner. The
laser is then activated for 7 minute preprogrammed cycle.
The ELITT is reported to destroy the entire endometrium along with
1-3.5 mm of myometrium, leaving a safety buffer of 67% of myometrium.
In a prospective study, 40 women with documented menorrhagia
underwent ELITT. 40 At one-year, the rates of amenorrhea and
hypomenorrhea were 70% and 85% respectively and 85% women were
satisfied with their treatment. At one-year, 5 women had undergone
hysterectomy because of treatment failure.
Microwave Endometrial Ablation (MEA)

Microwaves are electromagnetic waves with a wavelength varying from
1 mm to 30 cm and frequency 300 to 300,000 MHz (between radiowaves
and infrared radiation). By varying the frequency of the microwave
and the power output of the microwave source, heating effect can be
created. This heating effect can destroy endometrium making it possible
in the management of dysfunctional uterine bleeding.
The current microwave device produced by Microsulis, operates at a

frequency of 9.2 GHz, which is the most effective in producing 6 mm depth
of necrosis necessary to completely destroy the basal layer of
endometrium. A microwave generator or magnetron, supplies microwave
energy to hand-held applicator which is 8 mm in diameter and 15 cm circular
metallic pipe, having thermocouple at the tip which records endometrial
temperatures (Figs 16.1A and B, Plate 12). The output from this is connected
to a computer display to show the operator real time endometrial
temperatures throughout the procedure. The whole procedure takes about
3.5 minutes. With power levels of 30 W, energies of 1.5 to 9.3 KJ result and
a hemispherical field pattern emanates from the dielectric tip, which causes
symmetrical ball of coagulum of constant thickness.
The procedure can be performed under general or local anesthesia.41
The cervix is dilated to 8 mm and the length of cavity measured. The
probe is inserted until the tip reaches the fundus. The microwave
generator is then activated by depressing foot-switch. Once the
temperature reaches 70-80°C, the probe is moved laterally in one of the
cornual region and then the other. The probe is then gradually
withdrawn, whilst maintaining the temperature in the 70-80°C range.
Endocervical area is not treated as it could result in stenosis and
subsequent hematometra and pain.
The MEA has undergone in vitro and in vivo safety test.42 These tests
have shown no rise in serosal temperatures and no leakage of
microwaves. The Safety and Efficacy Registrar of New Interventional
Procedures (SERNIP) has given MEA, category B status which means
‘sufficiently close to an established procedure to give no reasonable
grounds for questioning safety and efficacy, procedure may be used
subject to continuing audit.’
In randomized clinical trial, Cooper et al, compared and evaluated
MEA with transcervical endometrial resection.43 The main outcome
measures in this study were patients’ satisfaction with the procedure and
acceptability. Women included in trial were those with uterine size ≤ 10
weeks size and without histological abnormality of endometrium. There
was no significant difference in satisfaction rates or acceptability between
two forms of treatment. Both scored highly, MEA 77% and 94% and
TCRE 75% and 90% respectively. At 12 months, 10 (8%) women in MEA
group and 12 (9%) women in TCRE group had undergone hysterectomy.
Sharp et al treated 400 women over a 5-year period, with no major
complications.44 Amenorrhea was achieved in 37% and satisfaction in
84% of women at 3-year follow-up.
THERMAL BALLOON ABLATION

Thermal balloon ablation of the endometrium involves, inserting a balloon
tipped catheter into the uterine cavity, inflating the balloon so it conforms
to the shape of the cavity and then heating the fluid within it to 85°C.
This system utilizes 16 cm long, 5 mm diameter catheter with a heating
element contained in a latex balloon, which is connected to a control
unit which can monitor, display and adjust preset intrauterine balloon
pressure, temperature and duration of treatment. There are currently
two devices available, the Thermachoice system and the Cavaterm
system.
In Thermachoice system, the deflated balloon with catheter are
introduced transcervically into the uterine cavity and once in place, 5%
dextrose solution is used to inflate the balloon. A minimum pressure of
150 mmHg, must be achieved for the device to activate and the system
automatically shuts off if preset low and high pressures are achieved.
Once balloon pressure stabilizes at between 160-180 mmHg, the fluid is
then heated to 85°C. The treatment is undertaken at this temperature
for 8 minutes, after which balloon is deflated and removed from cavity.
The Thermachoice system has been tested in human uteri and has
achieved a grade B classification from SERNIP.45,46
The Thermachoice system has been evaluated clinically in a prospective
comparative study with endometrial resection and also in a randomized
multicentre trial with roller ball endometrial ablation.47,48 The outcomes
for operating times, menstrual diary scores, amenorrhea, dysmenorrhea
and patient satisfaction at 1 year follow up were comparable.
The Cavaterm Thermal Device

This was introduced by Friberg in 1996 and consists of a silastic balloon
catheter, filled with 1.5% glycine, instead of 5% dextrose used in
thermachoice system. The fluid is heated to 75°C and only a maximum
of 30 ml of fluid can be used per case. Higher pressures are achieved
(180-220 mm Hg) with this device in an effort to tamponade the uterine
vessels. In addition, the fluid is actively circulated in an effort to ensure
a uniform temperature and therefore, uniform depth of endometrial
ablation. The standard treatment time is 15 minutes.
The efficacy and safety of Cavaterm device has been assessed in a
study of 50 women with dysfunctional uterine bleeding.49 At 12 months
follow-up, rates of amenorrhea and hypomenorrhea were 64% and 24%
respectively. Cavaterm system has been awarded grade C status from
SERNIP. This system appears to be easy to use, has short learning curve
and is associated with low complication rate without the risk of fluid
absorption (Fig. 16.2).
Fig. 16.2: Thermachoice, thermal balloon system
Vesta System, Unipolar Electrodes

This system using an inflatable multielectrode balloon was first reported
by Soderstorm in 1996.50
It consists of a handset for electrodes carrier for inflatable balloon
that is covered with 12 thermocoupled electrodes, a control unit and a
Valleylab electrosurgical generator. This delivers 40 to 50 W of pure
cutting current. After dilating the cervix to 9 mm, the probe is inserted
into endometrial cavity. The silicone inflatable electrode carrier has a
triangular shape, which unfurls when the outer sheath is withdrawn.
The balloon is inflated with 8 to 12 ml of air. The warm up phase is
started which takes 3 minutes followed by treatment phase lasting for 4
minutes. The cornual plates have fixed set temperature of 72°C while
others are set at a temperature of 75°C. The control unit monitors the
temperature and impedance of the electrodes throughout the procedure.
The procedure results in damage up to 2 to 4 mm of myometrium. Corson
et al reported 88% satisfaction rate among patients undergoing
procedure.51
Three-Dimensional Bipolar Ablation (Novasure System)

The Novasure system is a bipolar electrode system, which uses a
combination of electrosurgical vaporization and coagulation. It is a
disposable, 3 dimensional, fan shaped, expandable bipolar device
composed of a porous metallic membrane draped over a metallic skeleton.
After introduction into the uterus, generator delivers constant power
up to 180 W at 500 kHz to the bipolar device to provide a controlled
depth of ablation. During the procedure, suction is required which draws
the steam and moisture from the tissues to allow for extensive
desiccation. Treatment time varies from 40 to 120 seconds depending

upon endometrial thickness. The depth of destruction is 4 to 4.5 mm in
uterine corpus and 2.2 to 2.9 mm in the cornual area.
The randomized double blind trial comparing the Cavaterm and
Novasure systems was carried by Abott et al.52 In the study, 37 women
underwent Novasure procedure while 18 were subjected to Cavaterm
procedure. At one-year follow-up, amenorrhea was seen in 43% of
Novasure group compared to only 11% in Cavaterm group. At one-year
83% were satisfied with Cavaterm procedure compared to 92% with
Novasure system.
Coaxial Bipolar Electrodes–Versapoint System (Fig. 16.3)

The first generation resectoscopes were based on a monopolar circuit,
which are more dangerous than a bipolar circuit for endoscopic
procedures. Versapoint is a new coaxial bipolar system, 1.6 mm in
diameter that can be inserted into the operative channel of a 5 mm
hysteroscope. There are currently, three electrode tips available as a
spring, a twizzle and a ball. The electrosurgical generator provides power
settings from 1-200 W. The uterine distension is achieved with normal
saline. When activated in the normal saline, a high resistance airpocket
is created that effectively insulates the active electrode. Only when the
electrode makes contact with tissue, the circuit is completed and cutting
occurs.
In the initial randomized trials, Versapoint has been reported to be
successful in hysteroscopic removal of submucous fibroids as well as
endometrial ablation. 53 Although no complications were reported,
further randomized trials and more data is awaited.
Fig. 16.3: Different types of electrode tips of Versapoint system
CRYOABLATION OF ENDOMETRIUM
Cryoablation or destruction of endometrium using freezing tempera-
tures, was one of the first ablative techniques to be described.54 However,
its application was hampered due to inconsistent results and reports of

pelvic abscess formation.55
Recently, Dobak et al have described use of cryotherapy under
ultrasonographic control.56 In this study, 10 women scheduled for
hysterectomy agreed to undergo prior cryoablation. The temperature
at the tip of the probe was –90°C. Thermocouples were used to monitor
the serosal temperatures and depth of necrosis achieved was 9 to 12
mm. Although cryoablation of endometrium may have been
rediscovered, adequate data is lacking for its application in clinical
practice.
Hydrothermal Ablation (HTA)

Hydrothermal ablation is carried out by instilling heated normal saline
into uterine cavity to achieve thermal coagulative necrosis of the
endometrium. The hydrothermal ablation system, is a 7.8 mm continuous
flow hysteroscope connected to a heater, a pump and a fluid chamber.
Normal saline at a temperature of 90°C circulates continuously around
the uterine cavity for 10 minutes at a pressure of 50 mmHg. Any leakage
of saline from cervix is prevented by applying tenaculum. If more than
10 ml of saline leaks from the system, the equipment automatically
switches off to avoid inadvertent thermal injury.
In a pilot study, 14 patients with menorrhagia who underwent
hydrothermal ablation, were followed up for 9 to 18 months.57 Eleven
patients were amenorrheic at 9-18 months.
Photodynamic Endometrial Ablation (PDT)

Photodynamic therapy is the destruction of tissues by singlet oxygen
through photoactivation of a light-sensitive compound. It is based on
the activation of a photosensitizer within tissues. This activation
generates highly reactive oxygen molecules that are toxic to cell
membranes. The effects of photodynamic therapy have been studied in
animal models58 in which effect of photosensitizer 5-amniolevulinic acid
(ALA) was evaluated. The ALA was instilled into the uterine cavity and
after 4 hours, monochromatic light at a wavelength of 635 nm and an
intensity of 300 mW was delivered for 60 minutes by a laser. In a feasibility
study,59 three women underwent PDT with ALA. Two were cases of
menorrhagia while third had persistent postmenopausal bleeding. At 6
months follow-up, women with menorrhagia reported reduction in
bleeding while postmenopausal women had undergone hysterectomy.
Further studies are needed to determine safety of this technique and to

evaluate whether endometrial regeneration can be prevented.
Radiofrequency-induced Thermal Endometrial Ablation

Phipps et al have described radiofrequency ablation by inserting a 10 mm
diameter probe into uterine cavity and generating electromagnetic
radiation which causes irreversible tissue damage.60 Satisfactory reduction
in menses were achieved in 93%, including 42% with amenorrhea.
Unfortunately, reports of vesicovaginal fistula and bowel burns compli-
cating the treatment, has made the future of this technique uncertain.
CONCLUSION
Dysfunctional uterine bleeding is a disabling condition for which many
women seek medical help. Unfortunately, medical management is not
effective in a significant number of women.
Hysterectomy is the definitive treatment and has high rates of patient
satisfaction. However, it is a major operation with all the attendant
morbidity and mortality. Less invasive techniques, conserve the uterus,
have shorter hospital stay and offer quicker return to full activity.
Hysteroscopic surgical techniques have undergone vigorous assessment
in randomized trials and long-term results comparing them with
hysterectomy are reassuring about safety and efficacy of these techniques.
There is now overwhelming evidence to show that first generation
techniques of ablation and resection are a genuine alternative to
hysterectomy.
Unfortunately, the original techniques require considerable surgical
skill and are still associated with significant morbidity rates. As a result,
the new generation ablative techniques have been introduced to simplify
endometrial ablation. Available evidence suggests that these ablative
procedures significantly reduce menstrual blood flow and in some
instances, decrease dysmenorrhea. It is not yet clear, which techniques
will stand the test of time. The ideal endometrial ablation technique
should be effective, safe, easy to learn, quick to perform, painless, able
to be performed in an outpatient setting under local anesthesia, applicable
to a wide population and cost-effective. From the number of technologies
being developed, it is clear that we have not yet found ideal therapy.
We shall strive toward these goals and must realize that this procedure
is not yet perfected.
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12. O’ Connor H, Broadbent JAM, Magos AL et al. Medical Research Council
randomised trial of endometiral resection versus hysterectomy in management
of menorrhagia. Lancet 1997;349:897-01.
13. Crosignani PG, Vercillini P, Apolone G et al. Endometrial resection versus vaginal
hysterectomy for menorrhagia: Long-term clinical and quality of life outcomes.
14. Aberdeen Endometrial Ablation Trials Group. A randomised trial of endometrial
ablation versus hysterectomy for the treatment of dysfunctionl uterine bleeding:
Clinical, psychological and economic outcomes at four years. Br J Obstect
Gynaecol. 1999;106:360-66.
15. O’ Connor H, Magos A. Endometrial resection for the treatment of menorrhagia.
N Engl J Med 1996;335:151-56.
16. Cooper KG, Parkin DE, Garratt AM et al. A randomised comparison of medical
and Hysteroscopic management in women consulting gynecologists for
treatment of heavy menstrual loss. Br J Obstect Gynaecol 1997;104:1360-66.
17. Cooper KG, Parkin DE, Garratt AM et al. Two year follow up of women
randomised to medical management or transcervical resection of the
endometrium for heavy menstrual loss: Clinical and quality of life outcomes. Br
J Obstect Gynaecol 1999;106:258-65.
18. Goldrath MH. Use of danazol in hysteroscopic surgery for menorrhagia. J Reprod
Med 1990;35:91-96.
19. Donnez J, Vilos G, Gannon MJ et al. Goserelin acetate (Zoladex) plus endometrial
ablation for dysfunctional uterine bleeding: A large randomized, double blind
study. Fertil Steril 1997;68:29-36.
20. Sowter MC, Singla AA, Lethaby A. Pre-operative endometrial thinning agents
before hysteroscopic surgery for heavy menstrual bleeding. Cochrane database
Syst Rev 2000 ;(3) update software.
21. Indman PD, Soderstrom RM. Depth of endometrial coagulation with the urologic
resectoscope. J Reprod Med 1990;35:633-35.
22. Kivnick S, Karter MH. Bowel injury from rollerball ablation of the endometrium.
23. DeCherney A, Polan ML. Hysteroscopic management of intrauterine lesions
and intractable uterine bleeding. Obstet Gynecol 1983;61:392-97.
24. DeCherney AH, Diamond MP, Lavy G et al. Endometrial ablation for intrauterine
bleeding: Hysteroscopic resection, Obstet Gynecol 1987;70:668-70.
25. Chullapram T, Song JY, Fraser I. Medium term follow-up women with
hemorrhage treated by rollerball endometrial ablation. Obstet Gynecol
1996;88:71-76.
26. Paskowitz RA. “Rollerball” ablation of endometrium. J Reprod Med 1995;40:333-
36.
27. Maher PH, Hill DJ. Transcervical endometrial resection for abnormal uterine
bleeding- Report of 100 cases and review of the literature. Aust N Z J Obstet
Gynecol 1990;30:357-60.
28. Magos AL, Baumann R, Lockwood GM et al. Experience with the first 250
endometrial resections for menorrhagia. Lancet 1991;337:1074-84.
29. Garry R. Hysteroscopic alternative to Hysterectomy. Br J Obstect Gynaecol
1990;97:199-207.
30. Istre O, Shahaa K, schjoenskey AP et al. Changes in serum electrolytes after
transcervical resection of endometrium and sub mucus fibroids with the use of
1.5% glycine for irrigation. Obstet Gynecol 1992;80:218-22.
31. Taskin O, Buhur A, Birincioglu M et al. endometrial Na+, K-ATPase pump function
and vasopressin levels during hysteroscopic surgery in patients pretreated with
GnRh agonist. J Am Assoc Gynecol Laparosc 1998;5:119-24.
32. Golderberg M, Zolti M, Bider D et al. The effect of intracervical vasopressin on
the systemic absorption of glycine during hysteroscopic endometrial ablation.
33. Pittrof R, Darwish DH, shabib G. Near fatal uterine perforation during transcevical
endometrial resection. Lancet 1991;338:197-98.
34. Vancaille TG. Electrocoagulation of the endometrium with the ball end
resectoscope. Obstet Gynecol 1989;74:425-27.
35. Lamano JM. Dragging Technique versus blanching technique for endometrial
ablation with the Nd; YAG laser in the treatment of chronic menorrhagia. Am J
36. Loffer FD. Hysteroscopic endometrial ablation with Nd:YAG laser using a
nontouch technique. Obstet Gynecol 1987;69:679-82.
37. Garry R, Shelly-Jones D, Mooney P et al. Six hundred endometrial laser ablations.
Obstet Gynecol 1995; 85: 24-29.
38. Daniell J, Tosh R, Meisels S. Photodynamic ablation of the endometrium with
the Nd: YAG laser hysteroscopically as a treatment of hemorrhagia. Colposc
Gynecol Laser Surg 1986; 2: 43-46.
39. Everette RB. Five-year review of endometrial ablation with SideFire laser fiber.
J Am Assoc Gynecol Laparosc 1999; 6: 65-69.
40. Jones K, Abbott J, Hawe J et al. Endometrial laser intrauterine thermotherapy

for the treatment of dysfunctional uterine bleeding: the first British experience.
Br J Obstect Gynaecol 2001; 108: 749-53.
41. Sharp NC, Hodgson DA, Feldberg I. Microwave endometrial ablation. An ultra-
rapid simple treatment for menorrhagia: 3 years’ experience. Br J Obstect
Gynaecol 1998; 105: 106.
42. Hodgson D, Feldberg I, Sharp N et al. Microwave endometrial ablation:
development, clinical trials and outcomes at three years. Br J Obstect Gynaecol
1999; 106: 684-94.
43. Cooper K, Bain C, Parkin D. Comparison of microwave endometrial ablation
and transcervical resection of the endometrium for treatment of heavy menstrual
loss: a randomised trial. Lancet 1999; 354: 1859-63.
44. Sharp NC, Cronin N, Feldberg IB et al. Microwaves for menorrhagia: A new fast
technique for endometrial ablation. Lancet 1995; 346: 1003-04.
45. Shah A, Stabinsk S, Klusak T et al. Measurement of serosal temperature and
depth of thermal injury generated by thermal balloon endometrial ablation in
ex vivo and in vivo models. Fertil Steril 1998; 70: 692-97.
46. Anderson L, Meinert L, Rygaard C et al. Thermal balloon endometrial ablation:
safety aspects evaluated by serosal temperature, light microscopy and electron
microscopy: Eur J Obstet Gynecol Reprod Biol 1998; 79: 63-68.
47. Gervaise A, Fernandez H, Capella-Allouc S et al. Thermal balloon ablation versus
endometrial resection for the treatment of abnormal uterine bleeding. Hum
Reprod 1999; 14: 2743-47.
48. Mayer W, Walsh B, Grainger D et al. Thermal balloon and rollerball ablation to
treat menorrhagia: a multicenter comparison. Obstet Gynecol 1998; 92: 98-103.
49. Hawe J, Phillips G, Chien P et al. Cavaterm thermal balloon ablation for the
treatment of menorrhagia. Br J Obstet Gynecol 1999; 106: 1143-48.
50. Soderstorm RM, Brooks PG, Corson SL et al. Endometrial ablation using a
distensible multielectrode balloon. J Am Assoc Gynecol Laparosc 1996; 3: 403-07.
51. Corson SL, Brill AI, Brooks PG et al. Interim results of the American Vesta TM
trial of endometrial ablation. J Am Assoc Gynecol Laparosc 1999; 6(1): 41-49.
52. Abott J. Fertil Steril 2003; 80(1): 203-08.
53. Overton C, Hargreaves H, Maresh M. A national survey of the complications of
endometrial destruction for menstrual disorders: the MISTLETOE study. Br J
Obstet Gynecol 1997; 104: 1351-59.
54. Droegenmuller W, Makowski EL, Macsalka R. Destruction of the endometrium
by cryosurgery. Am J Obstet Gynecol 1971; 110: 467-69.
55. Burke L, Rubin HW, Kim I. Uterine abscess formation secondary to endometrial
cryosurgery. Obstet Gynecol 1972; 41: 224-26.
56. Dobak JD, Willems J, Howard R et al. Endometrial cryoablation with ultrasound
visualisation in women undergoing hysterectomy. J Am Assoc Gynecol Laparosc
2000; 7: 89-93.
57. Perlitz Y, Rahav D, Moshe B. Endometrial ablation using hysteroscopic instillation
of hot saline solution into the uterus. Eur J Obstet Gynecol Reprod Biol 2001; 99:
90-92.
58. Wyass P, Tromberg J, Wyss M et al. Photodynamic destruction of endometrial
tissue using topical 5-aminolevulinic acid in rats and rabbits. Am J Obstet Gynecol
1994; 171: 1176-83.
59. Wyass P, Fehr M, Van den Bergh et al. Feasibility of photodynamic endometrial
ablation without anesthesia. Int J Gynecol Obstet 1998; 60: 287-88.
60. Phipps J, Lewis B, Roberts T et al. Treatment of functional menorrhagia by
radiofrequency induced thermal endometrial ablation. Lancet 1990; 335: 374-76.
Section 3
Allied
17
Prakash V Pawar, Amol P Pawar
Death after Female

Tubal Sterilization
INTRODUCTION
‘ It would not be correct to say that every moral obligation involves a legal duty;
but every legal duty is founded on a moral obligation.’
Lord Chief Justice Coleridge in R Vs Instan (1893) 1
Health care providers do not warranty or guaranty “cure”, he/she is

expected to provide “care”. The risk of death associated with pregnancy
is several hundred times more than that of death associated with
contraceptive methods, anywhere in the world.2
Government of India has accepted different methods of contraception
in the National Family Welfare Programme. In the initial years of this
programme, more stress was given to permanent methods of
contraception in the country. It remains the most popular method and
will most probably continue to remain so.3 During the recent decade,
the National Family Welfare Programme has begun to give priority to
spacing methods of contraception especially for the younger couples.
Whatever are the Government’s policies and priorities majority of even
the younger couples still prefer permanent methods of sterilization to
various spacing methods of contraception.
Sterilization procedure has always been linked to various Government
policies and preference. Since, it is the most preferred choice for
contraception and hence for limiting family, it directly reflects on the
Population Growth Stabilization Policies. Any adverse consequence in
the sterilization programme, especially female tubal sterilization
programme, adversely affects population growth stabilization
policies.
GUIDELINES FOR FEMALE TUBAL STERILIZATION PROCEDURE

The Government of India’s Family Welfare Department regularly
publishes guidelines and protocols for various aspects of Family Planning
procedures including sterilization procedure. These guidelines serve as
a protocol not only for government Medical Officers at the Rural Health
Centers but also they form ideal parameters within which a Medical
Practitioner is expected to practice, if he/she performs such a procedure.
The latest guidelines in the Female Tubal Sterilization Programme have
been published in the year 1999.3
Qualified Practitioner
The criteria for the qualified practitioner have been laid down according
to different procedures. For a minilap Tubal ligation, only MBBS
qualification is sufficient with the requisite training for the procedure
being a part of his/her experience in the graduation course. In
laparoscopic sterilization, a gynaecologist or a Surgeon who is ‘trained’
in laparoscopy procedure can perform the procedure. A qualified
gynaecologist is the one who has a postgraduate qualification in the
subject, a diploma or a degree being necessary. The term ‘trained’ implies
specialised training, which both a gynaecologist and a Surgeon has to
undergo in order to acquire the requisite skills as a laparoscopic surgeon
for doing laparoscopic tubal sterilization.4 Specific training centers have
been recognised by the State Governments and the Central Government.
The list of the same can be had from the State Medical Directorate.
According to the guidelines an untrained Practitioner cannot perform
laparoscopic tubal sterilization. This point has to be stressed upon as; if
there is any complication in the procedure the requisite qualification of
the operating surgeon is checked first.
If the medical consultant is operating under supervision of some senior
consultant, then the senior consultant will be responsible for all acts of
omission and commission. Seniors’ liability will be civil but the criminal
liability will be of the consultant who would be actually performing the
surgery. Therefore, this has to be taken under consideration when
working at a Trust or a Teaching Institution.
Place for Sterilization

Registration of a nursing home for sterilization operation is not at all
mandatory (i.e. legally binding). Hence, even at Primary Health Centre
and temporary camps, sterilization procedures are carried out.
Death after Female Tubal Sterilization 303
However, it is always prudent to register ones’ nursing home as a

place where sterilization takes place. There are two-fold advantages of
this. Firstly and most importantly there is the financial aspect. In case of
death taking place in a registered nursing home due to causes related to
sterilization procedure, the Government pays an ex-gratia of Rs. 50,000/-
(Rupees fifty thousand only) to the next of the kin of the patient, as
compensation. If the nursing home is unregistered then this payment
has to be done by the operating surgeon.5 Secondly from a legal point of
view, having a registered place gives a better impression to the
investigation authorities like Government Health Department, Police
and Judicial Authorities, that the medical practitioner is generally aware
of and follows regulations.
The procedure for registering nursing home for sterilization operation
is neither difficult nor costly.6 There are no Registration charges for it.
An application is to be made in requisite format to the authority along
with necessary certificates. The appropriate medical authority for a
nursing home situated in a municipal area is the medical officer of health
(MOH); civil surgeon in a district level place, district health officer (DHO)
in case of rural area.
Another aspect of registration worthwhile mentioning is that your
clinical establishment should be an authentically registered place for
performing various medical procedures. Nursing homes are registered
under different Acts in different states. In Maharashtra, there is “Bombay
Nursing Home Act”.7 Usually in most states, even if a specific registration
for nursing home is absent then there is at least the “Shop and
Establishment Act”8 under which one can register ones’ nursing home.
This registration has to be renewed every specific interval, usually
3 years.
At this junction with regards to gynecological practice it is worthwhile
mentioning that there are two more acts under which registration of the
nursing home/clinic is mandatory. The Acts being:
a. MTP Act, 1971 with latest amendments in 2003.
b. PNDT Act, 1986 with latest amendments in 2003; if one has an
ultrasound machine or performs ultrasound examination by an outside
machine.
These Acts have been mentioned for the sole purpose that registration
under these acts is mandatory. It also creates a good impression, shows
that one is following the law of land.
Eligibility Criteria
This criterion has to be followed strictly while making patient selection
for female tubal sterilization.
a. Client should be married at the time of the surgery (An unmarried woman
in Mumbai, whose ligation was refused by municipal as well as private
practitioner, has now complained to various authorities and has
threatened to take a legal action for refusing to do sterilization on
her).
b. Age of client should be between 22 to 45 years. She must have at
least one child of any sex but the age must be above one-year. The
client or her husband must not have either undergone any sterilization
procedure previously. Here, there is exception that if sterilization
has failed in any partner then she can undergo a repeat procedure.
c. Client must be in a perfectly normal state of mind. Psychiatrist must
certify mentally in client and consent should be obtained from legal
guardian/spouse.
d. Written Informed Consent3 is preferred, should be taken only after
proper counseling of the client and her husband. Written consent of
the spouse is not necessary in this case but to avoid social problems
for doctors and nursing home, one must take a written consent of
the souse and her other near relation, if possible.
Contraindication to Surgery
There is no absolute contraindication to Tubal Sterilization Surgery.3
Relative contraindications are many and the operating surgeon must
take these into consideration while taking the decision for the procedure.
The contraindication include:
• Psychiatric disorder,
• Physical illness,
• Anemia (minimum Hb required should be above 8 gm%)
• Jaundice and other liver disorders,
• Febrile illness,
• Tuberculosis,
• Malignancy,
• Pelvic inflammatory disease,
• Bleeding disorders,
• Continuing pregnancy (i.e., if MTP fails)
• Puerperal fever,
• Prolonged rupture of membrane, more than 24 hr.

• Pre-eclampsia,
• Eclampsia,
• Antepartum hemorrhage,
• Postpartum hemorrhage,
• Trauma to genital tract,
• History of postpartum psychosis.
Anesthetics, Analgesics and Premedication

As per guidelines when minilaparotomy or laparoscopy is done under,
local anesthesia, following steps are to be followed.
Skin sensitivity test for local anesthetic agent (lignocaine) is not
necessary, as it has no established predictive value for anaphylactic
reaction; most of the reactions of local anesthesia are due to its
inadvertent direct intravascular injection. The authors will like to differ
in this particular guideline and would strongly recommend that a skin
sensitivity test must be done before using local anesthetic and it should
be documented well in the case paper of the patient.
One percent lignocaine without adrenaline is the local anesthetic that
is to be infiltrated on the OT table. The maximum dose being 200 mg or
20 ml.
Preoperative or intraoperative sedation and analgesia has to be
administered depending on the need. Preoperative Inj. Atropine 0.6 mg
should be given in all cases.
Sedative and Analgesics3

Table 17.1: Sedative and analgesics
Name of Drugs Dose Route of Repeat Dose
Administration
Pentazocine + Phenergan 30 mg + 10 mg I.M. 15 mg + 5 mg IV
Diazepam 10 mg I.M./I.V. 5 mg IV
Pentazocine + Diazepam 30 mg + 10 mg I. V/IM 15 mg + 5 mg IV
Pethidine + Phenergan 50 mg + 50 mg I. M. 10 mg + 5 mg IV
At least 30 minutes must be allowed for premedication to be effective,

if given intramuscularly. Patient must be monitored and attended after
administration of the drugs; communication must be maintained with
the patient throughout the process.
General Anesthesia
General anesthesia is rarely necessary and utilized in the following
patients:
i. In case of non-cooperative patient,
ii. In case of excessive obesity,
iii. In case of history of allergy to local anesthetic drugs.
As far as provisions of general anesthesia are concerned, it will
depend upon the expertise of the qualified anesthesiologist. However,
the guidelines provide provisions for even ‘trained’ medical professional
implies, one who has undergone certified requisite training for the same
but not having a qualified degree or diploma in that specialty.
Timing of the Procedure

Guidelines allow the tubal sterilization procedure to be undertaken
either:
i. In interval period, after menses within first 7 days.
ii. Immediate postpartum period.
iii. In lactation amenorrhea after 6 weeks of delivery.
iv. During first trimester MTP procedure.
v. Immediate post second trimester MTP.
All these procedure timings are subject to after confirmation that the
client is not pregnant
At present in the state of Maharashtra the State Health Directorate
has issued a circular banning laparoscopic tubal sterilization along with
first trimester MTP.9
Types of Procedures
Female tubal sterilization procedure can be carried out by the following
procedures:
1. Minilaprotomy.
2. Open laparotomy.
3. Laparoscopic tubal sterilization.
4. Along with cesarean section.
5. Along with other surgical procedure, e.g. appendectomy.
6. Vaginal procedure, which is out of fashion now.
Procedural Details
The commonest procedure done in India is minilaprotomy. The use of
uterine manipulator is allowed during the procedure. The incision for
the surgery should be either longitudinal or transverse but length should

not exceed 4 cm. Tubes are to be ligated by Pomeroy’s technique using
1-0 chromic catgut. In laparoscopic sterilization following care should
be taken:
i. To avoid hypoventilation the patient must not be placed in
Lithotomy/Tredlenberg position in excess of 15 degree of head
low.
ii. Uterine Elevator is to be used for visualization of fallopian tubes.
iii. Intraperitoneal pressure must not exceed 20 mm of Hg or 1 liter of
air or gas. Preferably carbon dioxide slow insufflation and gradual
desufflation should be done.
iv. Skin incision should not exceed the diameter of the trocar.
v. The trocar is to be angled towards the hollow of the sacrum. The
operator must lift the abdominal wall before introducing the trocar.
vi. Tubal occlusion must always be done with good quality falope rings.
Please, remember that cautery is not to be used at all for occlusion
of tubes.
Monitoring of Patient
Preoperative monitoring of patient for pulse, blood pressure and
respiration should start prior to premedication and thereafter continue
every 15 min. Intraoperatively one has to maintain verbal communication
and check pulse, BP and respiration every 15 min.
Postoperatively all above mentioned parameters are to be monitored
and recorded every 15 minutes for one hour after surgery. Vital
parameters are to be monitored for a longer time, if the patient is unstable
or unconscious. All notes are to be written by the doctor and should be
signed with date and time. Recording of vital parameters by a nurse
qualified or otherwise cannot substitute for operating surgeon’s or
qualified doctors’ notes.
Postoperative Care and Safety

Postoperative care for laparoscopic ligation is nearly the same as that
for minilap sterilization. However, the major difference is in their length
of stay. It is necessary that the patients are kept overnight after
laparoscopic sterilization.4 In the case of minilaparotomy the stay advised
by Government is for seven days.9
The guidelines also imply that the patient who has undergone
laparoscopic sterilization can be discharged on the same day if the
operating surgeon is willing to certify so. It goes without saying that no

operating surgeon would discharge any patient if he/she were not fit to
be discharged.
Operated patient should not be discharged unless and until an adult
relative or an acquaintance is present, willing to accompany her home.
As far as medications are concerned patients may be given antibiotics
but it is not necessary. It is the surgeon’s discretion over the choice of
antibiotics and analgesics.
Discharge Card
Discharge card is a very important document.10 It is necessary to provide
discharge card, indicating the date and type of surgery, method used,
name of institution and date with place for follow-up. Both written and
verbal postoperative instructions must be provided in the patient’s
language or in Hindi. One instruction that has to be mentioned without
fail is regarding the follow-up of the patient, the patient should be
advised both orally as well as in writing that she has to follow-up
immediately in case she does not get her menses by 8 days beyond her
expected monthly date. On the discharge card along with the patients’
name, one must write patients two identification marks.
The authors feel that the operating surgeon or hospital authority
should preserve a photocopy of patients’ discharge card. This zerox
copy should contain the patients’ and her adult relatives’ signature. The
above two precautions would help in preventing the misuse of the
discharge card and safe guard the operating surgeon.
FALLACIES IN THE GUIDELINES

Unfortunately like most of the government programmes, these guidelines
are hardly ever adopted by the end user, the medical practitioner.
The most common reason, if we go to look as its non-implementation,
is that most of the practitioners are unaware of these guidelines. These
guidelines are left way back in the medical textbooks of medical colleges
with no regular CMEs to update them. Generally, the procedure being
deemed a ‘minor surgery’ it’s guidelines are also treated as insignificant,
to be neglected by senior consultants and forgotten or overlooked by
Junior performing consultant. The Government Medical Personnel in
the District or State, like the Civil Surgeon or District Health Officer
hardly ever pass on such guidelines or G Rs to those who are in private
medical practice. These regulations are only reminded of when there is

any mishap.
“Prevention is better than cure” is certainly is true and for that
“Ignorance is bliss” cannot be held as a defense. Only a prepared mind
can deal with the unexpected.
One must remember that the government does not permit to do MTP
along with laparoscopic sterilization9 operation in the camps. One can
understand the situation at campsite, which is not ideal at the best of
times. In case of unforeseeable or unfavorable consequences there is a
likelihood of adverse publicity to the National Family Planning
Programme. In the state of Maharashtra, Director General of Health
Services, has issued a circular informing and advising that even in a
hospital set-up laparoscopic sterilization are not to be done with first
trimester MTP. The pitfall of such a regulation is that like many
Government rules and regulations it is narrow minded, suitable for the
most ideal setting with no exceptions to the rule. Population growth
Control is a sensitive issue on the political and social front. It has to be
balanced in such a way that diverse feelings are taken into consideration
and respected. Regulation like that preventing sterilization procedure
along with MTP is one such, which is open for debate. It can be supported
for its primary intention for preventing unwarranted morbidity and
mortality in rural health set-up like primary health centre or sterilization
camps but its implementation in Tertiary Medical Teaching Institutions
and in Private Hospitals and Clinics with all facilities being available,
justification seems to be lacking.
Till few years ago, even when the primary procedure was not tubal
sterilization any death occurring as a result of complication of primary
procedure like cesarean section or appendectomy was considered as
‘death due to complication of tubal sterilization procedure”. However,
the Government of Maharashtra has issued a GR10 stating that if death
occurs as a complication of primary surgery, e.g. PPH in cesarean section,
then it would not be considered as sterilization death.11
Guidelines give parameters only in restricted areas like type of
anesthesia only local or general anesthesia, no protocol is given for spinal,
caudal or other types of anesthesia. The type of ligation is clearly
mentioned as Pomeroys’ method3, no other method is mentioned, even
when certain other methods have good success rates. The duration of
stay being determined, as 7 days is way too prolonged not only from
hospital expense point of view but also from the point of view of comfort
and adjustability of the patients’ lifestyle. Of no consequence are there

any provisions for the clients’ (patients’) demand. Patients wishes for
say preferring only general anesthesia is not addressed to in the
guidelines. When carrying out such demands/preferences, the indication
should term clearly as “being for patients demand”.
Of major concern are such GRs when any mishap occurs. Till the time
there is no complication, such GRs or protocols are guidelines without
any legal bindings for private practitioner, however, when there is any
mishap the government bodies—District Health Department or even
Police refer to these guidelines when they frame criminal misconduct or
acts of omission and commission charges against the operating surgeon.
These “ideal regulations” then become the “Law”, whose noncompliance
would result in irreparable damage to the medical professional.
Government Institutions will follow such guidelines to the letter.
However in practice, the economical aspects too under consideration,
the guidelines will usually be kept aside by private practitioners,
compelling him/her to take a calculated risk. In the long run it is the
compliance of the patient that will dither and which would give a major
blow to population control programme.
Morbidity of the Procedure

Minor mishaps in sterilization procedures are many. They include wound
sepsis, gaping of abdominal wound, allergy or sensitivity of anesthetic
agents or other drugs, psychosis after sterilization and even uterine
perforation due to the use of uterine elevator. One has to remember
that the above-mentioned mishaps, even when minor for a surgery, are
to be reported to the concerned Government Health Authorities.3 If the
Authorities are not informed about minor mishaps, even when they are
minor in nature, they are at liberty to take action against the particular
operating Doctor.
A survey of 494,319 laparoscopic sterilizations reported 8,800
complications (17.8 per 1000). Of these 98.7% were minor in nature.12
In the consumer era, litigation against doctors in case of sterilization
procedures is mainly for the failure of procedure resulting in unwanted
pregnancy. There were plenty of cases filed under this cause against
operating surgeons after the landmark case of Mrs. Santra Devi Vs. the
State of Haryana.13 This happened mainly because the Media gave a lot
of publicity to the case without explaining the details of the case. In fact,
the Hon. Supreme Court has accepted that “Failure of sterilization”
procedure can occur as a part of surgical failure rate.
Mortality of the Procedure

Incidence
Death following sterilization is a major mishap of a minor procedure.
Death is a rare sequealee to a relatively minor surgery. International
data also reflects the same. Death is about l in 25000 procedures in
Queensland, Australia.14 In India, death rate of 14 in 100,000 minilap
(Pomeroys’ Method) procedures15 has been reported. In the Mumbai
Municipal Corporation area approximately 4-5 tubal ligation deaths are
reported every year.16 These deaths are reported when tubal sterilization
surgery is the primary surgical procedure.
The data for state of Maharashtra is given as follows:17
Table 17.2: Deaths due to tubal sterilization surgery in Maharashtra
Year No of deaths related to tubal sterilization in females
1999-2000 34
2000-2001 43
2001-2002 38
2002-2003 22
2003-2004 18
Till 15-02-2004.
The number of deaths is statistically insignificant when one compares

it with deaths related to pregnancy complication or with any other
abdominal surgical procedure. The deaths due to female sterilization
procedure do not feature in the sample registration survey (SRS) of the
Government of India.
Major complications were reported in 117 cases of the 494,319
Laparoscopic sterilizations investigated (0.24 per 1000). The major
complication rate is 0.16 per 1000 for institutional cases and 0.27 per
1000(almost double) for “Camps Cases.”12 This is lower than the major
complications rate of 1.45 per 1000 quoted by Phillip,et al18; 2.23 per1000
reported by Reidel and Semm19 and 5.80 per 1000 by Chamberlain.20
The mortality rate in the above survey12 is 6.5 per 100,000,3.63 per
100,000 for Institutions and 7.57 per 100,000 for camps. Bhatt21 reports
13 deaths in 80,000 laparoscopic sterilizations done in camps giving a
mortality rate of 16.5 per 100,000. This is still much lower than mortality
rate of 25 per 100,000 reported by Wortman22 for nonlaparoscopic tubal
sterilizations. Chamberlain20 reports a mortality rate of 10.4 per 100,000;
Reidel and Semm19 reports mortality rate of 3.4 per 100,000.
Ectopic Pregnancy after tubal sterilization is not rare. In women,

below 30 years of age, 2% of women undergoing tubal sterilization
procedures will become pregnant within 10 years and l in 3 of these
pregnancies will be ectopic.23 If a patient has undergone sterilization
procedure and has developed ectopic pregnancy, the death occurring as
a complication of ectopic gestation should be considered as ‘Sterilization
death’. The surgeon operating on the ectopic gestation is duty bound to
inform the requisite medical authorities within 12 hours by telephone and
within 24 hours in writing. He/she should also inform Police immediately
and it is mandatory to ask for postmortem examination for the same.
Death following sterilization hence does not imply immediate or on the same
day. As far as the sterilization procedure is concerned there is no fixed time limit
to determine when the complication is not a sequealee to the procedure. To put
forward this point, example of a case is given as follows: sterilization was done
by minilap procedure modified Pomeroys’ method by an obstetrician
and gynaecologist at a District Hospital, where the doctor was a Medical
Officer (MO). Patient was discharges on 5th postoperative day, as skin
wound had healed. Patient attended OPD the particular medical officer
for almost one month after discharge with complaints of pain in abdomen
and fever. She was treated by M.O. as an outpatient for that period, the
patient not being relieved of her symptoms. Patient then changed the
OPD day of the same hospital, was admitted and investigated for her
symptoms. She was clinically diagnosed as suffering from subacute
intestinal obstruction, confirmed by radiological examination. On
exploratory laparotomy, the gynecologist along with a surgeon found
multiple bowel adhesion, pus pockets all over the abdomen. Post-
operatively she developed fecal fistulae, which were then treated at
a tertiary care government hospital. The patient eventually expired
3 months post-procedure due to complications related to fecal fistula.
This death was considered as death due to sterilization procedure.
Responsibility in Death
In case of any complication or death the final responsibility is that of the
‘Operating surgeon’. The operating surgeon is expected to be ‘qualified’
or ‘trained’. This qualified or trained surgeon must have verified the
eligibility of the client, the consent by the client and her relations and
confirmed the physical and mental fitness of the client. The physical
examination must include abdominal and pelvic examination before
conducting the surgery.
In a Trust or General Hospital whether it is a teaching or non-teaching

hospital, there is a hierarchy of doctors. It begins with the Head of
Institution, Head of Department, Unit Head and his assistants or
Lecturers. The Resident Doctors come next, since they too are Registered
Medical Practitioner, who may or may or may not be postgraduates.
The Resident Medical officers usually are from the Allopathic branch.
On the service part, the Nursing aspect, the staff sister, sister in charge
of ward, O.T. nurse are responsible with their registration with the
State Nursing Council being mandatory. When death occurs in a big
Trust/Teaching Hospital usually internal disagreement occurs. Blame
game starts immediately. Seniors try to find fault with juniors. Juniors
also try and shift the responsibility to other colleagues or even on seniors,
for nonavailability or dereliction of duty. One must remember that Hon.
Supreme Court held in its landmark judgement of Spring Meadows
(Noida) Hospital case, 24 that ‘Dereliction of duty is considered as
negligence’.
In private set of a small nursing home, the situation is entirely
different. There is no question of internal fighting as it is a ‘one man
show’. At the most it is the couple who are both medical practitioners,
who are running the show and on the ‘service’ part, 90% of nursing
homes will have unqualified and therefore unregistered Nurses in the
service. The net result is that liability criminal and civil lies on the owner
of nursing home, husband or wife or both, depending upon the
ownership of nursing home. Rarely ever can private nursing homes afford
to keep medical officers, and if at all they are kept then they would be
having qualification other than allopathy.
Places where Mistakes are made and their Preventions

Death in OBGY practice is rare and therefore problem begins when our
patient is either dead or dying. This can occur in private nursing homes,
in a Trust hospital or General hospital. From medicolegal point of view
the responsibilities are different in nature.
• Opt for second opinion when patients’ situation is critical. Choose to
take a senior colleague of the same specialty. Multidisciplinary
approach may prevent mishap; the points, which are overlooked by
one, can be glaringly obvious to others.
• Reasonable care has to be undertaken while discharging ones’ duty.
General neglect, over confidence over ones’ skill, etc are self-made
pitfalls for which there no excuses.
• Follow the guidelines in letter and spirit. It is better to be on the

right side of the law, even if they are not termed as the law.
• Have a complete and detailed account of the anesthesia procedure.
When employing the services of an anesthesiologist, confirm that the
surgical proceedings are written on a separate sheet of paper with
date, timing, choice of anesthesia, patients’ preference, intraoperative
monitoring and postoperative findings. Note that the respective
consultant should sign each page.
• Have a detailed paper work. Utilize the opinion, of other consultants
if called for, in writing. Verify the facts and then complete paperwork.
Do not manipulate anything.
When Patient Dies

When faced with the unforeseen consequence, the first reaction even
for the scientific mind is to disbelieve it. Then follows confusion, chaos,
denial and finally depression. It is the time when one has to collect ones’
senses. Even when the incident has occurred due to no fault of the
operating surgeon, the subsequent chaos and misunderstanding
contributes generously to the aftermath.
When a patient dies following tubal surgery depending upon the
time and sequence of events the following things have to be done in
order that procedures are followed and rules are obeyed.
• Sterilization procedural death is unnatural death. It is operative death.
In case of puerperal sterilization it comes undermaternal death, if
death occurs within 45 days postdelivery. Since, it is also family
planning procedural death, a postmortem examination of the body is
necessary.17 Point to be noted is, that in the State of Maharashtra out
of the total 37 deaths due to sterilization in 1994, in 6 cases post-
mortem were not ordered/performed.25
• As in the case with other death incident, do not remove the body
from the place where you have declared death, whether it may be
operation table or recovery room.
• Once death is declared, one can wait for maximum period of about
two hours. This is not a rule, but it is a reasonable time limit. These
two hours are very important and one has to utilize this time to its
optimum. If you had not called your colleagues for second opinion
or help then you can still call them for moral support. Their physical
presence will also give proper message to the deceased’s relation.
• Complete the case paper. Write notes in chronological order. Avoid

the use of adjectives. Check and recheck the papers. Ask your
colleagues to go through them. Accept the suggestions that you think
are right and will not harm you. Attach investigation reports, blood
requisition slips, notes, consent/refusal forms, anesthesia notes,
outdoor patients’ case paper, etc.
• After completing the paperwork, inform Police. Address a letter to
Inspector in charge of your area Police Station on your letterhead;
use only black carbon for the carbon copy.
• Never commit as to the cause of death or underlying diagnosis.
Always only mention facts of the case in short. Do not forget to
write time and date of the events, correctly corresponding to the
case paper and other notes.
• Always send your own employee to the Police Station; never hand
over any document to the relatives as it might be misused.
• Always insist as an acknowledgement on the carbon copy with date,
time and signature of the Police officer on duty.
• Do not shift the body till the Police Panchnama is over, it is an offence
to do so. Always keep all tubes, catheters in situ. Preserve all the
used vials and bottles of medications used, it will be mentioned in
the Panchnama.
• For Panchnama, keep two panchs (witness) ready, one of them being
a female since the patient was a lady.
• The witnesses have to be reliable and trustworthy. They should be
traceable for next 4-5 years as the case may come up at that time.
• After Panchnama, the Police would take the operating surgeons’
statement. This statement will be taken in the official state languages.
Understand the language well. If the language is not understood
well, get along a person who understands it so. Be careful to avoid
any discrepancy in the timings and facts in your statement and the
patients case paper, for this you can refer to your case paper while
giving the statement.
• You must be present while the Police are taking statements of your
subordinates, paramedical staff and anesthesiologist. Do not interfere
in their statement, only note whether it is being taken down properly
or not.
• Before signing any statement read the papers carefully understanding
the underlying meaning of sentences. If you do not agree to
something, inform the inspector that either you will put such a remark
or sign under protest. In such circumstances you can immediately

lodge a complaint to their senior officer in writing mentioning your
entire objection.
• Ask for a copy of the statement. It will be issued to you later. Always
preserve all correspondence with the authorities for future case
reading.
• Insist on a postmortem examination.17 It is your right. Patients’
relations, Politician, social workers or even police should not influence
your decision. It is only the operating surgeon who can certify death.
Asking postmortem examination in the case of sterilization death is
mandatory requirement.18
• Never give cause of death. It is the surgeon who performs post-
mortem, who has the responsibility to send the viscera for
histopathological and chemical analysis. Therefore, the cause of
sterilization procedural death will only be known after all reports of
histopathology and chemical analysis are available.
• The indoor case papers are the property of the Hospital/Nursing
Home. Do not hand over the original case papers. Number each page
on right hand side top corner. Take counter signature of police sub-
inspector near your signature on all pages. Xerox all pages and hand
over xerox to the Police. Take care to take an acknowledgement on
original mentioning how many pages he has received or taken from
your nursing home.
• If documents are still incomplete, take time to complete them so. If
the police try to take the paper, then protest and hand over the papers
and immediately inform their Seniors/Superiors, preferably the rank
of Assistant or Deputy Commissioner of Police (Deputy
Superintendent/Superintendent of Police at the District place)
explaining that the reason why you could not complete the paper
work, was that you were busy treating the patient first rather than
complete the paperwork.
• Leave the hospital premises only when the body is taken charge by
the Police. Take the signature, of the Police officer in charge that he/
she has taken charge of the body, on your case paper.
Aftermath of Sterilization Death

After the dead body is shifted out of your nursing home, inform the
Medical Officer of Health or Civil Surgeon or District Health officer or
a person designated by them and who is in charge of the Family Welfare
Department, depending upon the area where your nursing home is

situated.16 The information should be given in writing within 24 hours
of death to the above Authorities.
• The operating surgeon has to collect two preliminary reports, which
are to be filed within two days.
• Postmortem in sterilization death is to be performed by two post-
mortem surgeons. The Viscera is to be sent for histopathological and
chemical analysis.
• Thirteen xerox copies of case paper, consent paper, preliminary report,
P.M. report are to be submitted to the Health Authority office in
your area within 7 days. The sterilization death is informed by the
local Health Authority to the office of Additional Director of State
Health services by fax/Telegram within 24 hours.
• On receiving the complete case papers, the meeting of local technical
committee is conducted in the office of the local Health Authority in
charge. The experts on this committee would be either Professor or
Head of Department in Obstetrics and Gynecology of local area
Medical College or Head of Department of Obstetrics and Gynecology
of a Government secondary level institution.16
• The report of the findings of this committee are submitted to the
Deputy Director of Health Services of that region in eleven copies
and one copy is send to the Additional Director of Health Services of
the State.26
• A Quality Assurance Committee Meeting is conducted at the State
Capital under the chairmanship of Deputy Director of Health
Services.16 The experts in this panel are the Heads of Departments of
Gynecology; Surgery, Medicine, Pathology, and Anesthesiology
of the tertiary reference level Government Medical College and
Hospital.
• The operating Surgeon has to face an inquiry both at the technical
level committee as well as Quality Assurance Committee.
• The decision taken by the Quality Assurance Committee is
communicated to the State Government on the basis of which suitable
action is taken against guilty Consultant.
SUMMARY
Female Tubal Sterilization is the main stay in the Family Planning
Programme in India. The Population Growth Control depends on it.
Even though the incidence of death in this surgical procedure is very
rare, it is a sensitive political issue with widespread social impact. The

focus of the general population has to be gradually shifted to the more
convenient and safer alternative of male sterilization-vasectomy. For
this not only awareness but general will of the Government agencies
changed to get over their inhibitions regarding vasectomy.
Any surgical procedure has its own complication, whether it’s
procedural or related to its associated pre or postprocedural steps. Various
safety concerns have been described to enable the surgeon to take the
utmost precautions. However, in event of the unexpected one must not
loose ones’ presence of mind in dealing with difficulties. There is a need
for laws to be strengthened and made more adaptive to the changing
medical scenario.
ACKNOWLEDGMENT
Authors would like to sincerely thank Additional Directors of Family welfare,
Government of Maharashtra, Dr Prakash Bhatlawande and Dr PP Doke for
providing the necessary information. We would also like to thank Dr Surekha
Mehta for giving the latest GRs. We sincerely acknowledge and thank the authors
of “Standards for female and male sterilization”, booklet published by Division of
Research Studies and standards, Department of Family welfare, Ministry of Health
and Family Welfare, Government of India, 4th edition, 1999.
BIBLIOGRAPHY
1. Bhatt RV, Trivedi G K. Mortality in Laparoscopic Sterilization using Falope ring
in Rural Camps in Gujarat (abstr.) First Asian Congress on Gynaecological
Endoscopy, Bombay. February 1981;12.
2. Bombay Nursing Homes Act, 1946.
3. Chamberlain G, Carson Brown J. Gynaecological Laparoscopy, London; Royal
College of Obstetrician and Gynaecologist, 1978.
4. Circular of Directorate of Health Services, Government of Maharashtra, No:-
DHS/FW/Quality Con.Ster. /D-15/03,dt: 21st Oct, 2003.
5. Circular of Government of Maharashtra, Health Services, No: -RAKUKKA/
Dakshta-8/Kukashamarg, Instruction/95,dt: 3rd Aug 1995.
6. Government of Maharashtra, Government Circular from Additional Director
of Family Welfare, No: 360572175 dt: 17th July 2001.
7. Government of Maharashtra, Government Resolution, Public Health Dept, No
KUKAKA 1096/YOUR-85/FW-I, dt: 23rd Oct 1996.
8. Hendrix, Chavan SP, Morison S. Sterilization and its’ consequences. 1999; 54(12):
770.
9. ICMR guidelines as issued by Additional Secretary and Commissioner Family
Welfare, Government of India, dt: 7th Sept 1990.
10. JK Mason, RA McCall, GT Laurie. Law and Medical Ethics, 6th Edition.
11. JO Drife. The Third Generation Pill, controversy continues; BMJ, 2001; 323.119.
12. Khandwala SD. Laparoscopic Sterilization. Indian Association of Gynaecological

Endoscopists’ Membership Survey. J Obst Gynecol India 1993; 43:305-314.
13. Letter by Additional Director Family Welfare Department, State of Maharashtra.
No: - RAKUKKA/Kunish death/Dakshata/Section-8; dt: 25th April 1995.
14. Letter issued by Director of Health Services, Government of Maharashtra, vide
FWL/BGI/I/1982,dt: 7th Oct 1982.
15. Letter of Additional Director Health Services, Family Welfare, State of
Maharashtra, No: SFWB/Stern.Guidelines. D-8/04,dt: 9th Feb 2004.
16. Personal communication of Author with Additional Director of Family welfare,
State of Maharashtra, dt: 23rd Feb 2004.
17. Personal communication of Author with Special Officer Family Welfare and
Mother-Child Health, Municipal Corporation of Greater Mumbai. dt: 23rd Feb
2004.
18. Phillips JM, Hulka JF, Peterson HS. AAGL 1982 Membership Survey. J Reprod
Med 1984; 29-572.
19. Prof CS. Dawn, Textbook of Obstetrics and Neonatology, 11th Edition, 1990.
20. Reidel HH, Semm K. German Pelviscopic statistics for year 1978-1982 (abstr.). In
Handbook of Abstracts of 12th World Congress of Fertility and Sterility,
Singapore, October 1986, pg 415.
21. Shops and Establishments Act, 1948.
22. Spring Meadows Hospital Vs H. Ahluwalia. I (1998) CPJ 1SC.
23. Standards for Female & Male Sterilization, Ministry of Health and Family Welfare,
4th Edition, Government of India, October1999.
24. State of Haryana Vs Smt Santra. I (2000) CPJ 53C.
25. Wortman J, Piotrow PT. Laparoscopic Sterilization: II. What are the problems?
Pop 1973;16.
26. Yearbook of Obstetrics, Gynaecology and Women’s’ Health, 1998;409.
18
Rajat Gyaneshwar
Improving the Quality of

Clinical Care
INTRODUCTION
Inspite of the rapid increase in medical knowledge, availability of
sophisticated equipment and an ever-increasing range of drugs the
improvement in health care has been disappointing. In the field of
obstetrics, maternal mortality and morbidity remains an ever present
challenge in most parts of the developing world. Hemorrhage,
hypertension and infection remain the major curses. The lack of real
improvement in spite of rapidly increasing costs would suggest that the
approach to delivering health services needs review. There is a waste of
valuable resources and inefficiencies are common. There is perhaps a
need to develop a broader perspective if greater improvements in the
quality of health are to be achieved. We need to learn to work ‘smarter’
for patients. The care must be patient focused and their health needs
should be met efficiently, professionally and competently.
Adverse outcomes for patients are not uncommon in any health
system. Medication errors have been reported in up to 14% of patients
admitted to hospital. Leape has reported postmortem studies where up
to 40% of the diagnoses had been missed. Andrews reports up to 40%
inappropriate clinical decisions being made in one retrospective review
of surgical cases. Health care is complex. There are several factors, which
can lead to an adverse outcome. Human error is not the only problem.
For example, Dolchin et al reported human error in an Intensive Care
Unit and looked at the activity profile. The reported 178 health care
activities per patient per day. However only 1.7 errors per patient per
day was found. Severe or potentially detrimental errors occurred only
twice a day in the whole unit. However, physicians were involved in
only 4.7% of the activities as a whole but in 45% of the errors. In most of
Improving the Quality of Clinical Care 321
these, transfer of information between the nurses and doctors was the
most significant issue.
In order to ensure that a patient is not caused harm or not put at risk
of harm we should try and understand why medical error may occur. In
each clinical encounter the variables include the patient, the clinician,
the context, the physical resources, institutional factors and the broader
health care framework. These all contribute to the uncertainties of clinical
practice. They have an impact on clinical decisions. At every step errors
can occur. The greater the number of steps, the greater the risk of error.
When the clinician manages a case all the variables discussed will
complicate the decision making process. The management plan thus
evolves from a very complex series of activities. Therefore, one needs
to be cautious in analysing a particular clinical adverse outcome. When
one views an event afterwards, the wisdom of hindsight is a powerful
bias. Generally, the reviewer is a more experienced clinician. He is aware
of the adverse outcome so is consciously looking for errors. He is
removed from the immediate context of the events and therefore sees
issues clearly. For those who were involved in the initial care, decisions
and activities could have been made the complex by the prevailing
circumstances. These could include the confusing clinical presentation,
the experience and competence of the team caring for the patient, other
clinical activities at the time, pressures from relatives and a range of
other factors influencing events around a particular case. Disregarding
the influence of hindsight bias in the analysis of the case together with a
culture of blame and seeking out a scapegoat can harm attempts at
improving the quality of clinical care. It creates an environment of fear.
There is a strong temptation to cover up errors. No one wishes to be a
scapegoat. Hence the opportunity to learn from mistakes is lost. This
can lead to the same errors recurring. The airline industry has recognised
the fact that accidents are often preceded by near misses, which were
ignored.
Improving the quality of clinical care and reducing risks to the patient
are both increasingly important issues in health. Improving outcomes
for patients has been the driving force for many ‘discoveries’ such as
hygiene, antisepsis, antibiotics, blood transfusion, ergometrine, active
management of the third stage of labor to reduce postpartum hemorrhage
rates and many others. Most clinicians strive to care for their patients to
the best of their ability. They have a strong sense of personal responsibility
and are devastated when they inadvertently cause harm. Cozens and
Morrison reported in 1989 that 13% of doctors in one study reported

being stressed about making mistakes. This probably is a conservative
figure. Leape points out that there is a powerful emphasis on perfection
during medical training. This persists during everyday hospital practice
and mistakes are unacceptable. Doctors can view error as a failure of
character. They feel that they weren’t careful enough or that they didn’t
try hard enough. Worse the response to an error is often blame and
discipline. Christensen studied the impact of mistakes on clinicians. They
reported feeling worthless, losing self-confidence, being devastated by
having caused someone harm, not being able to concentrate and feeling
panicky. Suicides have also been reported. Thus, the blame model for
dealing with adverse outcomes can be dangerous. It can compromise
staff’s morale, productivity, quality and safety. In this discussion there
is a presumption that clinicians are trying their best.
There can be no excuse for unethical behavior leading to error. Neither
can there be any tolerance for clinicians causing harm when impaired by
drugs or alcohol. Nor can one condone laziness. Inappropriate clinical
behavior must be distinguished from a genuine error. The former calls
for disciplinary measures, the latter for educative support.
Unfortunately the consequences for adverse outcome for the patient
and their family can be devastating. In obstetrics we are all too familiar
with maternal and perinatal mortality and morbidity, which could have
been prevented if better care had been provided. Complications
associated with gynecological surgery can cause death and lifelong
suffering due to fistulae, organ damage and adhesions. Patients put great
trust in their doctors. When adverse events occur they feel betrayed
even if the medical view is that the injury was inadvertent. The damage
is not only physical but it is also psychological. Thus, improving the
quality of health care and making it safer for patients is an urgent priority.
More recently there have been increasing attempts to understand
the causation of medical error. McIntyre and Popper argued for the
need for new ethics in medicine in the British Medical Journal in 1983. In
the last 2 decades there has been a concerted effort within health care to
ensure greater patient safety. National Governments in many countries
are increasingly committed to improving quality of health care by
introducing strategies which ensure that patients receive the care they
need in a timely manner and that the provision of this care does not put
the patient at risk. Some examples of these initiatives are the setting up
of the ‘National Institute of Clinical Excellence in the United Kingdom’
and the ‘Australian Council for Safety and Quality in Health Care’. Some
of the catalysts for these types of initiatives have been the ‘Bristol
Inquiry’ in Britain. In addition the public and the press are becoming
more demanding that patients have a right to receive quality care and in
the process not be put at risk. Recently in Australia an entire Area Health
Board charged to provide health care to about one million people was
dissolved because it was shown that care was substandard and adverse
events had occurred because of this. Whist the Board was considered
primarily responsible for not providing adequate leadership; senior
management was held accountable for structural issues leading to the
adverse outcomes and dismissed from the health service. Clinicians were
also disciplined for their roles. An inquiry into the allegations of
substandard practice was told about ‘reckless operating theatre mistakes’,
and of ‘patients being carelessly misdiagnosed’. Clinicians told the inquiry
about the chronic understaffing. The editorial in the ‘Daily Telegraph’,
one of Sydney’s morning newspapers on 31st July, 2004 hoped ‘that the
inquiry leads to a thorough shake-up in the management of health care
complaints.
Whilst there needs to be no other justification for improving clinical
care than a good outcome for the patient some of the issues discussed
above have increased the urgency for addressing patient safety issues.
In many countries, however, there is yet another powerful incentive.
This is avoidance of medical litigation. The President of the Royal
Australian and New Zealand College of Obstetricians and Gynaecologists
wrote to all fellows of the College reporting the commencement of a
unique collaboration with a medical indemnity insurer, the United
Medical Protection Limited. The letter stated ‘the purpose of this
collaboration is to better understand the key issues involved in claims
against obstetricians and gynecologists. This understanding will identify
potential area for educative and risk management interventions.’ In the
United Kingdom hospital funding is influenced by strategies to improve
clinical care and reduce patient risk. Hospitals are rewarded for a good
safety record. The National Health Service has set-up a ‘Litigation
Authority’. A clinical negligence scheme for trusts has been developed.
A document entitled ‘Clinical Risk Management Standards for Maternity
Services’ has been produced. These standards are used to assess the
organization’s capacity to deliver safe, quality health care.
Clinical care can be considered to be like any other activity where a
product is offered to someone. The product must satisfy the needs of
the consumer. It must be of sufficiently good quality to ensure that there

are no flaws in the product, which will inconvenience or indeed harm
the consumer. Correcting flaws wastes time, incurs additional expense
and can potentially diverts resources from productivity. The faulty
product damages the producer’s reputation and profit margins.
Therefore the aim of any producer is to produce good quality product
the first time. Producing quality requires leadership, commitment from
the workers, supervision and audit. Above all good teamwork is
essential. Good quality product is rewarding for all concerned.
Much has been learnt from industry. Both in Japan and the United
States quality, efficiency and productivity have been studied in depth.
Many of the lessons learnt are applicable to the delivery of health care.
The health industry is complex. In this present dissertation we are
discussing clinical care and how clinicians can develop strategies to
improve the quality of care they provide. In order to understand how
improvements can occur we need to review the health care system and
the clinician’s role in it.
Often clinicians are frustrated in not being able to provide their best
in their daily clinical responsibilities. The context of their work can be
difficult. They have to work in settings, which are often poorly resourced.
The physical surroundings can be suboptimal. Large numbers of patients
need to be attended. The patients might have complex problems. Often
the equipment needed to make a diagnosis may not be available or be
malfunctioning. Investigations are not always possible. In these difficult
circumstances even if a diagnosis were made accurately drugs to treat
the patient are not affordable. The clinician frustration is increased
because they feel that they are unable to directly influence many of
these factors.
In addition to these frustrations there are issues relating to the
clinician, which need to be considered. The clinician may be overworked,
rushed and may have personal problems that affect their performance.
Often the clinician is expected to undertake tasks with which they are
not familiar. Indeed they may not have the training or expertise to
undertake the task. They may be unsupported, unsupervised and
isolated. They may be working in a cultural context where admission
that a task is beyond them will be regarded as failure and damaging to
their reputation. The recipe for disaster is there, it is recognized but
nothing is done because the errors do not result in harm or go
unchallenged.
The above highlights some of the complex problems facing clinicians.

They can, with justification, argue that many of the factors that confront
them are beyond their control. However, this frustration should not be
an excuse for not pursuing strategies to continuously improve the quality
of care that one can provide.
There are several factors within the control of the individual, which
should be explored. The clinician has a responsibility to know their level
of competence and to ensure that they obtain adequate training to
undertake the tasks they are confronted with. The old adage in medicine
is that the physician must first ‘do no harm’ to a patient. Improving the
performance of clinicians is a joint responsibility. It is an individual
responsibility and also that of the organization in which they work. It is
also the responsibility of the profession as a whole.
Clinicians generally have a strong commitment to help their patients.
Deliberate harm is seldom if ever intended. Yet several studies show
that clinicians contribute to adverse outcomes by either doing something
inappropriate or not doing what was necessary. Not all such actions or
lack of action leads to harm but even when no harm occurs the patient is
put at risk. Prescription errors are common in medicine as alluded earlier.
Inappropriate drugs, wrong dosage, inadequate attention to sensitivity
and cross-reaction contribute adverse outcomes. Surgeons have
performed procedures on the wrong organ or indeed the wrong patient.
Errors occur because of poor documentation and poor communication.
A patient might be put at risk because the doctor may undertake a
procedure they are not competent to perform. They may have been
trained but have not performed enough of the procedures to maintain
their competence. Certain complex clinical procedures are more safely
performed by someone who has a sufficient caseload to maintain their
expertise and competence. When faced with such a situation by not
seeking assistance from a more competent colleague one increases the
patient’s risks of having an adverse outcome.
Harm due to omission is also common. Here, a doctor fails to be
conscientious in assessing and managing a patient’s needs adequately.
Errors due to omissions are more likely to happen when clinicians are
under stress, are sleep deprived are overworked and rushing to meet
deadlines. They are also more common after hours when peer support
is suboptimal. Examples of omission errors include misreading
investigation results or not reading them at all. In a recent review of
adverse outcomes in one Sydney hospital it was found that not one but
many clinicians involved in the care of the patients had missed on

important clinical clues that might have altered management and
outcomes. Even though there were measures put in place to highlight or
‘flag’ the abnormal results the errors were made not by one but by
several clinicians.
As alluded earlier clinician errors can occur because of many factors.
The clinician’s competence can be impaired because of over tiredness,
pressure of work, rushing, domestic and personal stress, ill health, etc.
The issue of lack of competence due to inadequate training will be
addressed later. The clinician would be aware of some of these factors
and has the responsibility to ensure that their patients are not put at
risk. Peers and supervisors also need to be vigilant that their colleagues
are providing safe patient care. This notion has challenged the profession
under the guise of professional ethical behavior. Understandably one
needs to be careful about how one pursues this responsibility. It is helpful
if there are clear definition of expected standards of competence and
clinical outcomes. If one’s practice does not meet these standards then
there must be appropriate strategies to assist one’s colleague improve
their clinical performance. The Bristol report from the United Kingdom
and the King Edward Enquiry report from Australia have both charged
the profession to view this responsibility seriously. This responsibility
includes having to prevent a colleague from practicing medicine in a
manner, which could cause patients harm. Thus, if one is concerned that
a colleague is performing below their usual level of competence or that
they are undertaking tasks beyond their competence then one needs to
take action
CREDENTIALING AND CLINICAL PRIVILEGES AS A STRATEGY TO

ENSURE COMPETENCE
There are some formal strategies to ensure that health professionals are
competent to perform tasks assigned to them. These include credentialing
and granting of clinical privileges. Credentialing is a formal process to
verify and evaluate the qualifications and experience of health care
professionals prior to appointment and reappointment. In other words,
the employer seeks evidence that the professional has the skills necessary
to undertake the duties allocated. At other times credentialing may be
necessary when the competence of a practitioner may be in question.
In assessing the credentials of a practitioner one reviews
documentation such as university degrees, fellowships/memberships
of professional colleges, registration by professional bodies, certificates

of service, completion of formal training and validated competence.
Reviewing an individual’s performance and claims with a reliable referee
is an effective way to confirm one’s credentials. A distinction should be
made between credentialing and certification, licensing or registration.
These are legal processes that bestow recognition of minimum standard
of training in a particular field. An example would be that one needs to
have a medical degree to practice as a doctor. However, the fact that
one has a medical degree does not mean one has the credentials to
undertake certain clinical tasks.
Clinical privileges are granted once one is offered an appointment
after the credentials for the position have been verified. These privileges
define the scope of work one can undertake within an institution. For
example, one could be allowed to perform diagnostic laparoscopies but
not advanced laparoscopic surgery.
Credentialing identifies the most suitable applicant for a position.
The granting of privileges defines the boundaries for one’s work. An
example of this would be to appoint a postgraduate trainee because
they have the necessary qualifications or credentials for the position.
The trainee may be privileged to perform an elective routine cesarean
section without direct supervision but not be allowed to undertake the
same procedure for an anterior placenta praevia without a senior assisting
him.
There are initiatives being developed to ensure that all clinicians are
credentialed to undertake their clinical tasks. However, many issues
need to be debated. These include who should be credentialed, by what
criteria and by whom? How often should credentialing be done? How
can individual rights be protected and what mechanisms can be placed
to prevent potential abuse of the process? Similarly there is a strong
view that clinical privileges should be reviewed periodically to ensure
that the doctor has maintained the required level of competence. Airline
pilots have to undergo regular health and proficiency assessments.
RISK MANAGEMENT AS A STRATEGY FOR

IMPROVING CLINICAL CARE
Implicit in the concept of clinical risk management is recognition that
health care is a risky business. However, there is also an admission that
adverse events are often preventable.
Concepts such as continuous clinical improvement and clinical quality
improvement have been popular for over a decade. In health care there
has been the old adage “first do no harm”. Iatrogenic causation of disease
however has been a reality. An example of this is the prevalence of
neonatal respiratory distress syndrome in the 1970s and 80s. At that
time, pregnancy dating was problematic and induction of labor rates
were high. Another example would be the relationship between
phocomelia and the use of thalidomide for the management of morning
sickness in pregnancy. The speciality of obstetrics and gynecology needs
to be commended for its insistence on audit. It was perhaps the first to
embrace the concepts of morbidity and mortality meetings. Clinical
outcomes were benchmarked at a local, national and international level.
This commitment to clinical audit alerted us to teratogenic risk of drugs
in pregnancy and the negative consequences of interventions such as
social inductions of labor without accurate determination of gestational
age.
Are there lessons from other industries that can contribute to making
health services safer for patients? Patients come to us trusting that we
will safeguard their health interests and in no way endanger them. After
an adverse event how often have we had a patient say “but we trusted
you”. The Japanese car industry is an example of an industry, which
reviewed errors and learnt the benefit of “doing it right the first time”.
This adherence to quality was not motivated by altruism but purely
commercial considerations. Doing it right the first time contributes to
profit margins, correcting errors was expensive to remedy and worse
still, bad advertisement. Here concept was to ensure a good quality
product first up. To use this analogy in health care the avoidance of
complications is ‘getting it right the first time’.
Another useful concept is the ‘near miss’ concept of the airline
industry. Commercial air travel is remarkably safe. This safety record
has been ensured by developing a range of risk minimization strategies.
These strategies are informed by an elaborate process of monitoring all
their activities in order to identify any process, which might put a flight
at risk of an accident. Once a risk is identified a decision is taken as to
how to deal with the problem. The airline industry has recognized that
every serious mishap was preceded by near miss situations. In health,
the anesthetists have used a similar approach to reduce the risks of
anesthesia. When one looks at our business, we can see the opportunities
for error-complex problems, time constraints, limited facilities, human
factors etc. Our business is one of trust, but our business is also very
risky. We need to learn to manage the risk. We need a mechanism to
recognize those elements in our business, which put patients at risk.
As mentioned earlier leape reported medication errors in 2-14% of

patients admitted to hospital. He also observed that in 35-40% of deaths,
at postmortem were associated with missed diagnosis. Andrews reported
inappropriate decisions in 45% of patients admitted to surgical units. It
has been reported that junior doctors miss 35% of fractures in Emergency
Departments. The Douglas enquiry in Australia reviewed 372 high-risk
cases and reported that in 47% of the cases there were one or more
clinical errors. Half of these errors were serious and most involved junior
doctors who were not appropriately supervised.
When an error in clinical practice is identified one must immediately
respond to it. The response should not be to seek out an individual to
blame but rather to look at how future occurrence of the error can be
minimized or eradicated. In any case most errors occur because of a
series of flaws in the system. Humans are fallible. Therefore, one should
focus on factors contributing to the error and find ways to reduce this
occurring. As pointed out earlier the ‘blame’ model is not helpful. The
individual who erred may be someone else the next time. It is important
to develop mechanisms to prevent the individual for erring in the future.
Risk management is reducing the probability of adverse events
occurring by recognizing that health care is a risky business but that it
can be made safer. In order to do this one needs to identify the risks
and then put strategies in place to minimize or avoid the potential risks.
A risk management approach requires an analysis of contributing factors
including issues relating to the patient, the task, the clinicians, the team,
the working conditions and the organizational and management
structures. Each of these contributes to patient safety and quality of
care. There are many factors, which contribute to error and place a patient
at risk. These include factors associated with the patient. Her health
problems might be complex, she may not be a good historian, there
might be other communication factors and she might deliberately conceal
important information. The task being undertaken may be complicated.
The clinician may be unfamiliar with the task. An example is someone
attempting a procedure for the first time with equipment they have
never used before. Then there are individual staff factors, which include
tiredness, feeling stressed, health problems, personal family problems,
etc. The health care team might be dysfunctional. The junior doctor feels
intimidated by the seniors; the nurses don’t have confidence in the junior
doctor who already feels insecure. There is inadequate skill mix in the
team. The work is being inadequately supervised by appropriately
trained and experienced clinicians. All this could be happening in a work

environment which is crowded, noisy and the lighting is poor. The
workers feel unsupported by the organization and management.
Equipment failure or non-availability is common, supplies are consistently
short. Overall the organization is under resourced with chronic staff
shortage due to difficulty in recruiting, retaining staff and high
absenteeism. Poor management morale has percolated down through
out the system, which is not geared to deliver its core business of safe
health care. Budgetary constraints rather than safety drive business.
Many of the issues alluded to here were raised by the ‘Inquiry into
Obstetrics and Gynaecological Services’ at the King Edward Memorial
Hospital in Perth, Australia.
A powerful tool for identifying risks in the health system is to review
adverse outcomes systematically. The purpose of the review is not to
identify someone to blame but rather to identify factors, which
contributed to the adverse outcome. Almost always there will be a series
of systems issues, which contributed to the outcome. For example, there
was a recent case of a late intrapartum fetal death in utero. The patient
issues were that she was an intelligent woman who wished to have a
normal vaginal delivery. The primary carer was a midwife who was
respected by her colleagues and loved by her patients. The baby was
born after hours when supervision was suboptimal. The medical officer
was busy dealing with a series of cases in the operating theatre. The
junior doctor on duty in delivery suite was inexperienced and unfamiliar
with interpreting cardiotocograph recordings. The midwife thought that
it was appropriate to discontinue continuous fetal monitoring because
the patient was uncomfortable with the monitor belts.
Review of the stillbirth confirmed that the intrapartum management
had been suboptimal. The clinical decisions made by the midwife were
not correct, her reliance on the support of the junior doctor was
inappropriate, there was inadequate supervision, protocols had been
violated and the doctor responsible was busy in the operating theatre.
The analogy for this series of events is the alignment of holes in a series
of slices of Swiss cheese. A slice of Swiss cheese has several holes in it. If
one places a series of slices of Swiss cheese in parallel and the holes are
aligned one could place a rod through the holes. Thus, in the clinical
situation if a series of risks are aligned then one has an adverse outcome.
In the stillbirth reported earlier the holes were firstly the strong desire
for a natural birth by the patient, a midwife who was committed to
vaginal deliveries, her relative unfamiliarity with protocols for

monitoring and her inability to recognize signs of fetal distress, a junior
doctor unfamiliar with her responsibilities, a supervisor who did not
supervise and a busy work context. All this little risks were aligned to
cause a serious adverse outcome. The lessons for the organization is to
ensure staff know their roles and can do the tasks they are assigned to
do, that staff are aware of management protocols and that all shifts are
appropriately supervised. There are also issues of continuing education
for staff and of more rigorous credentialing.
THE QUALITY CYCLE AS A STRATEGY TO IMPROVE CLINICAL CARE

The concept of the Quality Cycle has much to commend it. Clinical audit
provides information about performance. Performance is then measured
against defined outcome measures. This informs the organization of
problems requiring fixing. The activity needing improvement is studied
and strategies are put in place to improve. The results of the interventions
are measured. If the interventions have had the desired effects then
they become the new way of doing things. If on the other hand the
problems persist or have become worse then the quality cycle is
commenced again. Sustainable, beneficial improvement strategies often
require many small steps. If one sees a task as impossible then no
improvement will occur. However, if several small gains are made by
many people then major improvements are possible.
An example of how clinical care in obstetrics can be improved would
be to cease those obstetrical practices, which have no proven value. Some
examples of these are routine vulval shaves and enemas for women
presenting in labor. Another is the use of routine episiotomies for all
primiparas. There are several practices, which are supported by good
evidence in improving pregnancy outcomes. These include observance
of good hygiene practices during childbirth to reduce sepsis and the
active management of the third stage of labor to reduce postpartum
hemorrhage. The audit of clinical practice would inform the organization
of clinical outcomes. Those outcomes which are at variance from good
practice standards need reviewing.
WHOSE RESPONSIBILITY IS IT?

Clinical governance is a concept used to define responsibility for patient
care. It is argued that the individual clinician is responsible to ensure
the best outcome for the patient. Therefore, improving the quality of
clinical care is the responsibility of every clinician. Many of the obstacles

to improvement have been defined. Many of the strategies required to
improve clinical outcomes require a new way of thinking. In this new
way eminence has given way to evidence. Outcomes are more important
than reputation. Competence should replace ego. Mistakes should be an
opportunity for learning rather then blame. Above all caring for the
patient should be the priority. Those things the individual clinician can
control he must. These include ethical, evidence-based practice,
undertaking tasks within once competence, and ensuring that one’s
colleagues are doing the same. Those factors which are beyond the
individual’s control must be passed on to the appropriate authorities.
These may include senior colleagues, administrators or health regulatory
bodies. The clinician must actively promote quality in health care and
not be passive when ‘things do not appear right’. A useful motto may be
‘help ever, harm never’.
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Index 335
Index
A B
Abdominal sacrocolpopexy 125 Bacterial vaginosis 35
Acosta’s classification 222 Barusiban 47
Acute pyelonephritis 39 Beta-thalassemia 111
Administration of letrozole 150 Body mass index 141
advantages letrozole in COH 154 Bone marrow transplantation 110
dose and timing 151 Bone mineral density measurements (BMD)
effects on endometrium 151 215
for superovulation before IUI 153 BRCA1 or BRCA2 mutations, breast and
letrozole and h-FSH in poor responders ovarian cancer 119
153 Breast cancers 178
letrozole versus CC 151
Advantages of MVA over D & C 67
Advantages of presurgical GnRH-a C
treatment 229 CA-125 116, 227
Advantages, MVA technique 66 CA15-3 116
Advantages/disadvantages of medical Cancer 177
therapy, endometriosis 228 Cancer predisposition in children born 178
Algorithm for evaluating adolescent Cannula insertion-1 60
hypermorrhea 201 Cannula insertion-2 60
American fertility society revised Carbonyl iron (Fefol-Z, anofer) 106
classification of endometriosis Carcinoembryonic antigen 116
223 Causes, vomiting during pregnancy 83
Analgesia/anesthesia during labor 74 CC plus hMG, induced ovulation 162
Anemia 106 Classification of endometrial hyperplasia
anemia associated with chronic diseases and risk of cancer 246
107 Clinical guidelines for the management of
causes of anemia 107 postmenopausal bleeding 261
causes of refractory anemia in Clomiphene citrate (CC) 136,142
pregnancy 107 antiestrogenic effect of CC on
hypoplastic and aplastic anemia during endometrium 145
pregnancy 109 clomiphene administration 143
management 110 clomiphene citrate in unexplained
Anemia of protein starvation and liver fertility problems 147
disease 111 clomiphene resistance 146
Anencephaly 4, 16 dose 143
Antepartum features, ultrasonically 71 duration of therapy 144
Antiestrogens 142 monitoring 144
Apgar scores, episiotomies 100 outcome 145
Apgar scores, neonatal intensive care 80 side effects 144
Aplastic anemia 110 time of therapy 143
Aromatase 219 Clomiphene citrate versus tamoxifen 148
Aromatase expression in mullerian-derived Clostridial myonecrosis 101
tissues 221 Collagen sponge (e.g. helistat) 131
Aromatase inhibitor letrozole 147 Colpectomy 125
Aromatase inhibitors (AI) 149 Colpocleisis 125
mechanism of action 150 Colpopexy 123
Assisted reproductive technologies (ART) Colporrhaphy 124
137 Combination of CC and tamoxifen 148
Atosiban 46 Combined oral contraceptives 205, 229
Common symptoms associated with Encephalocele 4
endometriosis 224 Endometrial ablation techniques 286
Comparison with other procedures, cavaterm thermal device 290
sacrospinous fixation 124 coaxial bipolar electrodes-versapoint
Competitive inhibitors (anastrozole and system 292
letrozole) 149 cryoablation of endometrium 292
Complications, ovulation induction 175 endometrial electrosurgical vaporization
multiple pregnancy 177 287
ovarian hyperstimulation syndrome endometrial laser ablation 287
(OHSS) 175 endometrial laser intrauterine thermo
prevention 175 therapy (ELITT) 288
RCOG recommendation 177 hydrothermal ablation (HTA) 293
treatment 176 microwave endometrial ablation (MEA)
Corpus luteum 139 288
Corticosteroids 110 photodynamic endometrial ablation
Cranial defects 14 (PDT) 293
anencephaly 14,16 radiofrequency-induced thermal
encephalocele 16,17 endometrial ablation 294
exencephaly 18 thermal balloon ablation 290
iniencephaly 18 three dimensional bipolar ablation
Creutzfeldt-Jacob disease 179 (novasure system) 291
Cytokines 219 transcervical resection of endometrium
286
vesta system, unipolar electrodes 291
D Endometrial destruction 283
Endometrial hyperplasia 243
Danazol 230
appearance, endometrial hyperplasia by
Deep calf vein thrombosis 179
endovaginal sonography 262
Delivery of the preterm fetus 48
echogenic fluid in endometrial cavity
Delivery route for women with twins 71
265
Depo-provera 205
endometrial hyperplasia 263
Desmopressin 203, 204
normal postmenopausal
Diabetic embryopathy 6
endometrium 263
Diagnosis of endometriosis 224
clinical profile 250
Diamond-blackfan syndrome 109, 110
pap test and endometrial
Different types of electrode tips of
hyperplasia 251
versapoint system 292
current understanding of the molecular
Disadvantages of MVA over D & C 68
biology of 249
Dopamine agonists 155
bcl-2 oncogene and fas/fasl gene 249
bromocriptine 155
PTEN tumor suppressor gene 249
cabergoline 155
current views on definition and
cabergoline versus bromocriptine 155
classification of 243
Drugs, trigger ovulation and oocyte
diagnosis 260
maturation 165
endometrial hyperplasia and selective
GnRH agonist 166
estrogen receptor modulators 252
human chorionic gonadotropin 165
hormone replacement therapy and
RCOG recommendation 167
recombinant hCG (r-hCG) versus
hydrosonography 265
urinary hCG (u-hCG) 166
hysteroscopy 270
recombinant human LH (rh-LH) 166
pathologic criteria 246
atypical hyperplasia 248
complex hyperplasia 248
E progression from hyperplasia to
Effectiveness of treatments, cancer 248
age-related infertility 173 simple hyperplasia 247
unexplained infertility 172 saline infusion sonohysterography 265
Electronic fetal heart rate monitoring 74 hydrosonography 266
Emesis gravidarum 84 hydrosonography in perimenopausal
Index 337
bleeding 268 Fetal survey for NTD 13
hydrosonography in Fibroids 119
postmenopausal bleeding 268 Flexible plastic cannulae 58
procedure of hydrosonography 266 Folic acid 7
SIS focal endometrial lesion 267 Follicle-stimulating hormone (FSH) 136
SIS showing endometrial polyp Frontal encephaloceles 17
sonohysterography 265 FSH 139, 149, 150
treatment 272 FSH receptors 150
ultrasonography 260 FSH threshold 139
Endometrial sampling 268 FSH window 139
dilatation and curettage 269
pipelle endometrial sampling 270
Endometriosis 149, 219 G
Endometriosis-associated infertility 234
Gaucher’s disease 110
controlled ovarian hyperstimulation 236
Gelatin sponge (e.g. gelfoam) 131
minimal and mild endometriosis-
Gene therapy 183
associated infertility 235
Genetic treatments for OI 183
moderate and severe endometriosis-
Genetically engineered gonadotropin
associated infertility 235
preparations 182
Epidural anesthesia 74
Gestrinone 231
Episiotomy 95
Gonadotropin receptor hormone (GnRH)
anal incontinence 99
agonists 138, 163
association of episiotomy and delivery
Gonadotropin-releasing hormone
position with deep perineal
antagonists 138, 164
laceration 101
Gonadotropin-releasing hormone-analogues
current recommendations 102
129, 162
do not heal better than tears 99
Gonadotropins (GN) 136, 138, 158
do not prevent fetal brain damage 100
hMG versus urinary FSH (u-FSH) 159
downside of episiotomies 100
purified FSH versus hMG 159
episiotomies benefits 97
recombinant FSH (r-FSH) versus urinary
episiotomies do not prevent pelvic floor
FSH (u-FSH) 160
muscle relaxation 99
Growth hormone (GH), as an adjunct to
episiotomy and incidence of perineal
ovulation induction 165
lacerations 98
Guidelines, female tubal sterilization
episiotomy types 95
procedure 302
increases blood loss 100
aftermath of sterilization death 316
is it really necessary 97
anesthetics, analgesics and
obstetric myths versus research realities 98
premedication 305
pain and dyspareunia 100
contraindication to surgery 304
should be used judiciously 102
discharge card 308
side effects of the episiotomy 97
eligibility criteria 304
situations needing episiotomy 102
fallacies in the guidelines 308
Erythropoietin therapy 111
general anesthesia 306
Estimated fetal weights 73
monitoring of patient 307
Estradiol 139, 148
morbidity of the procedure 310
Estrogen receptor modulators (SERM) 142
mortality of the procedure 311
Evacuation of uterine contents 61
place for sterilization 302
Evidence-based medicine 30
places where mistakes are made and
their preventions 313
postoperative care and safety 307
F
procedural details 306
Factors affecting growth, survival of qualified practitioner 302
endometriotic implants 222 responsibility in death 312
Fanconi’s anemia 110 sedative and analgesics 305
Female tubal sterilization 301 timing of the procedure 306
Fetal complications 73 types of procedures 306
Fetal fibronectin 34 when patient dies 314
H I
HCG 149 Iliococcygeus hitch 125
Hematocrit 106, 110 Improving, quality of clinical care and
Hemoglobin 106 reducing risks to the patient 321
Highly purified FSH (hp-FSH) 137 credentialing and clinical privileges as a
Hormone replacement therapy 210 strategy to ensure competence 326
bisphosphonates 216 quality cycle as a strategy to improve
calcitonin 217 clinical care 331
cardiovascular disease 212 risk management as a strategy for
controversial issues 211 improving clinical care 327
osteoporosis 214 whose responsibility is it 331
phytoestrogens 217 In vitro fertilization 137
selective estrogen receptor modulators Induction of labor 73
(SERMS) 216 Inhibition of preterm labor 41
Human menopausal gonadotropins (hMG) aims of inhibition of 41
136 beta agonists (sympathomimetics) 43
Human urinary gonadotropins 136 calcium channel blockers for inhibiting 45
Hydrocephalus with banana sign 22 contraindications to inhibition of 41
Hyperemesis gravidarum 74,84,90 first-line tocolytic therapy 42
alternative therapies 92
hydration therapy for inhibition of 47
amorphous antagonists 91
indomethacin for tocolysis 46
antihistaminics 91
magnesium sulfate for tocolysis 45
clinical course 87
maintenance tocolytics 43
clinical features 88
modalities of treatment 41
complications 88
nitric oxide donors 46
corticosteroids 92
oxytocin antagonists for tocolysis 46
dopamine agonists 91
supportive measures 47
drugs used in the management of
Initial intrapartum evaluation of twin
hyperemesis gravidarum 90
gestations 70
etiology 85
Injection epofer (emcure) 108
fluid management 90
Insulin sensitizers 167
incidence 84
adverse effects 170
investigations 89
during pregnancy 171
management 90
effects of metformin on insulin sensitivity
pathology 86
and endocrine profile 168
phenothiazine derivatives 91
mechanism of action 167
piperazine derivatives 91
metformin 167
Hypermenorrhea 195
metformin plus CC 169
case situations 207
metformin plus CC or FSH 170
clinical approach 201
metformin versus meformin plus CC
evaluation 196
versus CC 169
history 196
outcome 170
hormonal forms of treatment 205
investigations 197 RCOG recommendations 171
management 203 Insulin-dependent diabetes mellitus 9
management based on hemoglobin level, Insulin-like growth factor (IGF) 150
hemodynamic status, 206 Interferons 231
physical examination 197 Interleukin-10 35
treatment of 200 International projects assistance services 53
17β-hydroxydehydrogenase 219 Intrapartum fetal monitoring 74
Hyperprolactinemia 154 Intrapartum management 70
Hypoferric anemia 111 Intravaginal slingplasty 125
Hypoproliferative anemias 111 Investigations in endometriosis 225
Hysterectomy 128, 283 Iron deficiency anemia 106
Index 339
L Menorrhagia 283
Menstrual regulation (MR) versus MVA
Laparometformin 141 67
Laparoscopic ovarian diathermy (LOD) 156 Metalloproteinases 219
Laparoscopic ovarian drilling 156 Modified McCall’s culdoplasty 125
Laparoscopic ovarian surgery 157 Monitoring, stimulated cycles 174
Laparotomy 135 Multiple of median (MoM), AFP results 9
Lemon sign, ultrasound 13 MVA double valve syringe and cannulae 57
Letrozole 141, 149 MVA syringe 56,57
LH 149, 150 MVA versus electric vacuum aspiration 67
LH surge 139
Lipid-associated sialic acid 116
LOD versus gonadotropins 157 N
Luteinizing hormone (LH) 136
National family welfare programme 301
National Nutritional Anemia Control
M Programme 106
NB/70K, tumor marker 116
Management of twin pregnancies 77 Necrotizing fasciitis 101
Management of vaginal delivery 75 Neonatal mortality rates 100
of first twin 75 Neural tube defect (NTD) 3
cephalic presentation 75 anomalies 5
non-vertex twin A 75 diagnostic methods 8
of second twin 76 amniotic fluid acetylcholinesterase
external cephalic version 78 test 10
internal podalic version (IPV) 79 amniotic fluid AFP (AFAFP) 10
second twin breech 77 maternal serum alpha fetoprotein 9
second twin cephalic 77 prenatal diagnosis by biochemical
third stage of labor 80 tests 8
time interval between vaginal ultrasonography 11
delivery of twins 80 embryology 6
Management, endometriosis-associated incidence 4
pain 234 pathogenesis 5
Management, problems during the prevention 7
procedure, MVA 62 Neuroblastoma 178
advice on discharge 63 New drug-delivery techniques 180
causes of failure of uterine evacuation New reproductive drugs 180
by MVA 64 Nifedipine 45
client care after procedure 63 Nongonadotropin agents in OI 182
clinical problem during the procedure 63 Nonsteroidal anti-inflammatory drugs
complications 64 (NSAID) 203, 228
follow up 64
remote complications 65
sterilization and maintenance of O
equipment 65
Obstetric indications for cesarean section in
storage and reassurance 66
twin gestation 71
technical problems with the MVA 62
Occipital encephalocele 17
Manual vacuum aspiration (MVA) 53
Occipital meningocele 17
care before performing MVA 55
Oligohydramnios 46
client assessment 55
Optimal route of delivery in multiple
contraindications 54
gestations 71
counseling of a client 54
Origin of endometriotic implants 220
equipment and instruments needed 56
coelomic metaplasia theory 220
indications for use of MVA 53
embryonic rest theory 220
objective of introducing MVA technique 53
induction theory 220
requirement for procedure 56
lymphatic and vascular metastasis
Meckel-Gruber syndrome 17
theory 221
Medical therapy, endometriosis 228
Sampson’s theory of retrograde management 130
menstruation 220 intraperitoneal hemorrhage
Ovarian cancer 115, 178 relaparotomy 133
annulal pelvic examination 116 invasive radiologic embolization for
combined modalities 118 hemostasis 132
current recommendations 120 local hemostatic agents 131
genetic screening 119 non-surgical bleeding 130
pap smear 116 postoperative intraperitoneal
potential screening test 116 bleeding 131
serum tumor markers 116 reactionary hemorrhage 132
ultrasound 117 resuscitation 133
Ovarian cystadenocarcinoma antigen 116 retroperitoneal hemotoma 133
Ovarian drilling 156 surgical bleeding 130
Ovarian hyperstimulation syndrome prevention 129
(OHSS) 138 Prion disease 179
Ovulation induction (OI) 137 Procidentia 125
Ovulogens 136 Progesterone 139, 205
Oxidized cellulose 131 Progesterone preparations for treatment of
Progesterone receptor antagonists 230
P Progestogens 230
Prophylactic sacrospinous colpopexy at
Pax-3 mutation 6
vaginal hysterectomy 125
Perinatal mortality and morbidity 106
Protocols of administration, GN 160
Perineal lacerations 98
conventional (classical) step up dose
Phases of ovulation 139
regimen 160
Phenobarbital prior to preterm birth 48
low dose step down protocol 161
Physiology of ovulation, practical aspects 138
low dose step up protocol 160
Pituitary and hypothalamic causes of
RCOG recommendations 161
anovulation 158
sequential (step up-step down) low
Polycystic ovary syndrome (PCOS) 140
dose protocol 161
Polygenic multifactorial disorder 5
Pulsatile GnRH therapy 141
Polyhydramnios 15
Pulsatile gonadotropin-releasing hormone 164
Polymaltose 106
Purified FSH 137
Posterior colporrhaphy 123
Prediction of preterm labor 32
biological markers 34
R
high-risk factors 32
ultrasound markers 33 Raloxifene 142, 148, 258
Premarin 205 RCOG national evidence-based clinical
Preparation of vacuum in syringe-1 59 guidelines 272
Preparation of vacuum in syringe-2 59 of menorrhagia in secondary care 273
Presentations and position of twins 72 the initial management of menorrhagia
Preterm labor 31 272
Prevention of preterm labor 36 Recombinant human FSH (rh-FSH) 137
antenatal advice 36 Recommendations for intrapartum
antibiotics 37 management at vaginal delivery
asymptomatic bacteriuria 39 in twins 72
cervical cerclage 37 Recommended protocol for moderate and
preterm labor with an established severe endometriosis 237
infection 38 Rectal tears 99
preterm labor with intact membranes 37 Refractory anemias 111
preterm labor with ruptured membranes Releasing pinch valve 61
38 Respiratory distress syndrome (RDS) 39
prophylactic progesterones 39 Resuscitation, secondary hemorrhage 134
ureaplasma urealyticum 39 Reversible, nonsteroidal aromatase inhibitor
Primary hemorrhage, hysterectomy 128 149
causes 128 Risk factors for endometriosis 224
Index 341
Ritodrine hydrochloride, tocolytic 43 preparation of the client 58
Role of aromatase, expression in preparation of vacuum syringe and
endometriosis 221 cannulae 58
Role of cytokines, ovarian dysfunction 181 steps of procedure 58
Role of endometrial destruction 284 Terbutaline pump maintenance therapy 44
Role, maternal corticosteroid Thermachoice thermal balloon system 291
administration 39 Thiazolidinedione group of drugs 171
Rosiglitazone 171 Threatened preterm labor 46
Thromboembolic disease 180
Tocolytic therapy 43
S Tranexamic acid 203, 204
Transvaginal color-flow doppler
Sacrospinous colpopexy 122,125,126
ultrasound 117
Sacrospinous fixation procedure 122
Transvaginal sonography for the detection
Sacrospinous hysteropexy 125,126
of ovarian cancer 117
Sacrospinous ligament fixation advantages
Treatment options, endometriosis 227
124
Troglitazone 171
Sacrospinous ligament fixation with uterine
Tumor necrosis factor (TNF) 35
conservation at prolapse surgery 125
Type and incidence, twin presentations in
Sacrospinous ligament fixation, results 124
labor 72
Scopic ovarian diathermy (LOD) 141
Types of lesions seen on laparoscopy,
Secondary hemorrhage, postoperatively
endometriosis 225
vaginal bleeding 134
Sedative and analgesics 305
Selection criteria for endometrial ablation 285
U
Sonographic features, endometriosis 226
Spina bifida 5,7 Urofollitropin 137
Spinal defects 19 Use of amoxicillin-clavunic acid
management 23 (augmentin) 38
prognosis 23
spina bifida 19
Spontaneous preterm birth 35 V
Staging system for endometriosis 222
Vacuum release 60
Sterilization 301
Vaginal breech delivery of twin B, criteria
Surgical method, correct vaginal eversion 122
Vaginal eversion 122, 126
Surgical ovulation induction 156
Vaginal hysterectomy 126
Surgical technique, sacrospinous ligament
Vaginal ultrasound 33
fixation 123,126
Vaginal vault prolapse 123
Surgical treatment, endometriosis 231
Vault hematomas 134
aims of surgery 231
Vault suspension 125
major indications for surgery 232
ultrasound-guided aspiration 233
W
T Weight-related amenorrhea 141
TAG 72.3, tumor marker 116 WHO group II ovulation disorders, RCOH
Tamoxifen 142, 147, 252 recommendations 148
Technique of MVA 58 Women with a poor ovarian response,
precautions 62 management 172

Manual of Ultrasound in Obstetrics and Gynaecology, 2nd Edition - Jaypee Brothers Medical Publishers (P) Ltd. (2009)

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Manual of Ultrasound in Obstetrics and Gynaecology, 2nd Edition - Jaypee Brothers Medical Publishers (P) Ltd. (2009)

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Current Practice

Current Practice in Obstetrics and Gynecology—1

First Edition: 2005

Typeset at JPBMP typesetting unit

I would like to specially mention with a deep sense of my gratitude

Baroda Pankaj Desai

Ashish Kumar Bhattacharjee Sarbjeet Kaur

Rajat Gyaneshwar Arun H Nayak

Ankita Pasi Ashish N Shah

12. Current Approach to Abnormal Uterine Bleeding

Current Concepts in the

births.19 But population-based active surveillance programs that include

Maternal diabetes significantly increases the risk of congenital

Prenatal Diagnosis of NTD by Biochemical Tests

Maternal Serum Alphafetoprotein (MSAFP)

Amniotic Fluid AFP (AFAFP)

Amniotic Fluid Acetylcholinesterase (AChE) Test

confirmed this in Oxford. A positive AChE gel test in amniotic fluid

Ultrasonography in Detection of NTD

Abdominal vs Transvaginal Probes

Three-dimensional (3D) Ultrasonography

Magnetic Resonance Imaging (MRI)

FETAL SURVEY FOR NTD

Fig. 1.1: Lemon sign

This should be followed by the examination of the spine throughout

hemispheres are typical of anencephaly. The spine ends at the base of

Fig. 1.3A: Encephalocele with cervical meningomyelocele

Fig. 1.3B: Encephalocele

The usual sonographic finding includes a mass (cystic or solid) usually

with Dandy-Walker malformation (cyst in the posterior cranial fossa),

exposed brain tissue in the amniotic fluid undergoes trauma to produce

Fig. 1.4A: Spinal defects

in high-risk cases. The accuracy of referral centers (level III ultrasound)

Fig. 1.5A: Lemon sign

Fig. 1.5B: Spina bifida

Fig. 1.6: Hydrocephalus with banana sign

First, a defective dysraphic vertebra or vertebrae are noted. This can be

although isolated NTD may also show abnormal karyotype.77 Hence,

function, between those delivered vaginally compared to those delivered

Preterm Labor: Evidence-

Knowing the importance of the evidence-based medicine and practice,

PREDICTION OF PRETERM LABOR

High-Risk Factors from History

• Systemic infections of the mother like pneumonia, acute pyelobep-

The maternal salivary estriol has also been suggested as a useful

PREVENTION OF PRETERM LABOR

Preterm Labor with Intact Membranes

those who received antibiotics. This treatment can not therefore be

Preterm Labor with Ruptured Membranes

Preterm Labor with an Established Infection

is very little evidence that detection and treatment of bacterial vaginosis

ROLE OF MATERNAL CORTICOSTEROID ADMINISTRATION

It is very important to remember that the primary aim of using beta-

• Extremely rare complication of adrenal insufficiency should be

INHIBITION OF PRETERM LABOR

Contraindications to Inhibition of Preterm Labor

examination of the cervix to exclude rupture of membranes, digital

First-Line Tocolytic Therapy

channel blockers, and magnesium sulfate nearly doubled the odds of

of recurrent preterm labor, preterm birth, and its consequences.

• Hyperglycemia: Diabetic patients will need additional monitoring and

Indomethacin for tocolysis

Hydration Therapy for Inhibition of Preterm Labor