clinical practice
Caren G. Solomon, M.D., M.P.H., Editor
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.
A woman presents for prenatal care in the first trimester of her third pregnancy. Her
first child was born at 30 weeks of gestation after preterm labor. Her second preg-
nancy ended in delivery at 19 weeks of gestation. How would you recommend reduc-
ing the risk of preterm birth in this pregnancy?
From the Division of Maternal Fetal Med- In the United States, the annual rate of preterm births (before 37 weeks of gesta-
icine, Ohio State University Wexner Med- tion) reached a peak of 12.8% in 2006 and was 11.7% in 2011.1 The rate in the
ical Center, Columbus. Address reprint
requests to Dr. Iams at the Division of United States remains nearly twice the rate in European nations.2
Maternal Fetal Medicine, Ohio State Uni- Premature birth in the United States accounts for 35% of deaths in the first year
versity Wexner Medical Center, 395 W. of life3,4 and estimated annual costs exceeding $26 billion.5 Rates of death in the
12th Ave., Columbus, OH 43210-1267, or
at stefanie.palmer@osumc.edu. first year of life and long-term morbidity such as neurobehavioral impairment are
inversely related to gestational age at birth. Neonates born before 24 weeks of
N Engl J Med 2014;370:254-61.
DOI: 10.1056/NEJMcp1103640 gestation rarely survive without serious handicaps. Among neonates born at or after
Copyright © 2014 Massachusetts Medical Society. 24 weeks of gestation, mortality and morbidity decline with advancing weeks of
gestation. Serious neurodevelopmental complications are uncommon after 32 weeks
of gestation; however, neonates born before 36 weeks of gestation often have dif-
ficulties with respiration, thermoregulation, and feeding, as well as increased risks
of health problems and death in childhood.6
Approximately 25% of preterm births in developed nations are iatrogenic, re-
flecting cases in which maternal or fetal conditions make early delivery a safer
An audio version choice than continued pregnancy, for the mother, the fetus, or both. Multifetal
of this article is pregnancies account for about one fifth of all preterm births; 50% of twin births
available at and more than 90% of triplet births are preterm. Most singleton preterm births
NEJM.org
occur after the spontaneous early onset of the parturitional process. This article
focuses on strategies to prevent preterm birth.
Risk Factors
Factors associated with a risk of preterm birth may be identified before pregnancy,
at conception, or during pregnancy. Major risk factors for spontaneous preterm
birth in cases of singleton pregnancies include black maternal race, previous preg-
nancy with an adverse outcome, genitourinary infection, smoking, extremes of
body weight, and social disadvantage. Maternal depression, prepregnancy stress,
poor diet, assisted fertility, and periodontal disease are also associated with pre-
term birth.5
Black women have a higher risk of preterm birth than do women of any other
racial or ethnic background. In 2011, rates of birth before 37 weeks of gestation
were 1.6 times as high among non-Hispanic black women as among non-Hispanic
white women (16.8% vs. 10.5%), and rates of birth before 32 weeks of gestation
were 2.5 times as high among non-Hispanic black women as among non-Hispanic
• Previous preterm birth and a short cervix (≤20 mm, as measured by transvaginal ultrasonography) are major
risk factors for preterm birth.
• The use of progesterone supplementation in women with a previous preterm birth, a short cervix, or both was
shown in randomized trials to reduce the frequency of preterm birth and is recommended for women with
these risk factors.
• Cervical cerclage reduces the risk of recurrent preterm birth among women with a short cervix.
white women (3.8% vs. 1.5%).1 The racial dispar- vical length below the 10th percentile (25 mm)
ity persists after adjustment for social, educa- is 25 to 30%, and the risk associated with a
tional, economic, and medical risk factors.5,7 cervical length at or below the 3rd percentile
A previous preterm birth is a strong and easily (15 mm) is 50%.11 Among women who have had
identified risk factor for future preterm births; a preterm birth, the risk of recurrence in a sub-
a preterm birth increases the risk of future pre- sequent pregnancy ranges from less than 10%
term births by a factor of 1.5 to 2. The number, when the cervical length at 22 or 24 weeks is
sequence, and weeks of gestation of previous above 35 mm to more than 35% when the cervi-
births all affect the risk of recurrence, which cal length is below 25 mm.14 A short cervix is
ranges from less than 15% among women with relatively uncommon among women who have no
one preterm birth after 32 weeks of gestation risk factors for preterm birth; however, a short
that was followed by a birth at term, to nearly cervix confers an increase in the relative risk of
60% among women with a history of two or more preterm birth that is similar among nulliparous
births before 32 weeks of gestation.8 Spontane- women and those with a previous birth at term.15
ous preterm births are also more common among
women with a history of giving birth between Natural History
16 weeks and 20 weeks of gestation9 or with a Cervical preparation for birth begins soon after
history of stillbirth before 24 weeks of gesta- conception.16 The two phases of cervical change
tion.10 However, most women who give birth be- that have been described are softening and ripen-
fore term do not have multifetal pregnancies or ing.16,17 Softening occurs slowly and is character-
major risk factors. Risk assessment in the gen- ized by an increase in cervical compliance (with
eral obstetrical population is limited by the high maintenance of tissue competence) in an environ-
prevalence and low relative risk of preterm deliv- ment that is high in progesterone and low in es-
ery associated with risk factors such as genito- trogen.17 Ripening, defined by loss of tissue com-
urinary infection, social disadvantage, depression, pliance and decreased tensile strength, occurs
stress, and poor nutrition. In as many as half of during the weeks or days preceding active labor.16
preterm births, the mother has no evident risk In normal parturition, these cervical changes are
factors.5 followed by decidual activation and myometrial
Short cervical length (i.e., values below the contractions.18 Decidual activation is paracrine
10th percentile for gestational age), as measured signaling from the fetus through the amniotic
with the use of transvaginal ultrasonography at fluid and across the membranes to the underly-
18 to 24 weeks of gestation (Fig. 1) is a consis- ing maternal decidua and myometrium, ultimate-
tent predictor of an increased risk of preterm ly causing contractions. This process normally
delivery,11,12 regardless of other factors.13 The occurs in late pregnancy as the fetal pituitary
risk increases as cervical length decreases in the adrenal axis achieves maturity. The steps in de-
second trimester; the risk associated with a cer- cidual activation can be activated prematurely in
Yes No
Yes No
Measure TVCL every 14 days
from 16–24 wk of gestation, Does the patient have signs or symptoms Progestogens are ineffective
every 7 days if CL <30 mm of parturition (e.g., persistent pelvic pressure, and cerclage may increase
cramps, or spotting or vaginal discharge)? the risk of preterm birth
In an analysis by Chang et al., compounded drug costs, questions about insurance coverage,
17OHPC from 15 pharmacies in the United States and limited availability of certain preparations
“did not raise safety concerns when assessed for often result in an interval of days or weeks be-
potency, sterility, pyrogen status, or impurities.”55 tween the writing of a prescription and receipt of
Uncertainty on the part of providers about what the medication. Nurse navigators with specialized
to prescribe (e.g., which formulation and route of training in progesterone treatment may be useful
administration) may delay treatment. Moreover, in overcoming these delays.
Side effects of progesterone are mainly local, lished guidelines agree on treatment, they leave
such as swelling at the injection site and vaginal open the question of how best to identify eligible
dryness. Women should be asked whether they women. Recommendations in this article are
have allergies to the yam, soy, or peanut base of generally concordant with these guidelines.
progestogens.
C onclusions a nd
A r e a s of Uncer ta in t y R ec om mendat ions
The pathophysiology of preterm parturition and The woman described in the vignette has had
the basis of its association with risk factors such two early preterm births. Her risk of recurrent
as black race are poorly understood. The mecha- preterm birth is at least 35% and is higher if she
nism of action of progestogens and the optimal is black. Her first prenatal visit should include
route of administration and dose of progestogen ultrasonography to determine the number of
supplementation for reducing the risk of preterm weeks of gestation, and a careful history taking
birth are also uncertain. More research is needed to identify other risk factors, such as cigarette
to identify women who give birth prematurely smoking, nutritional deficits, and genitourinary
but do not have a short cervix and to determine infections (even though trials have not shown the
the relative benefit of treatment with progesto- efficacy of nutritional supplementation and treat-
gens in women with a short cervix. ment of genitourinary infection in reducing pre-
term birth rates). She should receive supplemen-
Guidel ine s tal progestogen treatment, with either 17OHPC
injections or vaginal progesterone. She should
The Society for Maternal-Fetal Medicine53 and also undergo regular transvaginal ultrasono-
the American College of Obstetricians and Gyne- graphic surveillance of cervical length, beginning
cologists54 have issued guidelines recommending at 16 weeks of gestation, with consideration of
that women with a previous spontaneous pre- cerclage if the cervix measures less than 25 mm
term birth be offered treatment with weekly in- before 24 weeks of gestation. Finally, she should
jections of 17OHPC and that women with a short be educated about the signs and symptoms of
cervix (≤20 mm) be offered treatment with vagi- early cervical change that warrant prompt eval-
nal progesterone. The guidelines highlight the uation.
importance of obtaining a thorough obstetrical Dr. Iams reports receiving grant support from Sera Prognos-
history and the need for proper training to ob- tics and honoraria from the American College of Obstetricians
tain satisfactory ultrasonographic images. Uni- and Gynecologists. No other potential conflict of interest rele-
vant to this article was reported.
versal ultrasonographic screening is supported Disclosure forms provided by the author are available with the
but not considered mandatory. Although the pub- full text of this article at NEJM.org.
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