MED ICA L PROGR ES S

Review Articles

Medical Progress

P REVENTION

OF

P REMATURE B IRTH

ROBERT L. GOLDENBERG, M.D.,

AND DWIGHT J. ROUSE, M.D.

RETERM birth, which occurs in 11 percent

of all pregnancies, is responsible for the majority of neonatal deaths and nearly one half of
all cases of congenital neurologic disability, including cerebral palsy.1 Although all births before 37
weeks of gestation are considered premature, births
before 32 weeks gestation (2 percent of all births)
account for most neonatal deaths and disorders.2
State and national vital statistics indicate that the incidence of preterm birth has risen over the past 15
years (Fig. 1), and it remains twice as high among
black women as among white women.3-5 Preterm
birth is commonly categorized as birth occurring after spontaneous premature labor (in approximately
50 percent of cases) or spontaneous rupture of the
membranes (in approximately 30 percent) or delivery of a premature infant as indicated for the benefit
of either the infant or the mother (in approximately
20 percent).6
Prevention of preterm birth is not an end in itself.
Preterm birth is consequential only because it results
in morbidity or death in some infants. If an infant
does not die or have any disorders and does not have
a prolonged hospitalization, preterm birth is of little
consequence. Moreover, a full-term infant may die
or have neurologic damage as a result of a problem
late in the pregnancy. Thus, although delaying birth
until term is desirable in most circumstances, in certain cases, preterm birth may be the lesser of two
evils.
There are two categories of strategies used to reduce adverse outcomes associated with prematurity:
those intended to prevent or delay preterm birth, and
those intended to reduce prematurity-associated morbidity and mortality.6 In this article, we do not review

From the Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 618 S. 20th St., OHB 560, Birmingham, AL 352947333, where reprint requests should be addressed to Dr. Goldenberg.
1998, Massachusetts Medical Society.

in detail the many interventions that ameliorate prematurity-associated morbidity and mortality. Among
them, however, the most successful is regionalization
of perinatal care, which ensures that most preterm infants are delivered at a newborn intensive care unit
with appropriate facilities and trained personnel. Effective neonatal interventions include improved methods
of mechanical ventilation, exogenous-surfactant therapy, liberal antibiotic treatment, and appropriate fluid
and electrolyte management. Effective obstetrical interventions include the use of prenatal corticosteroids
for fetal maturation and intrapartum antibiotics to reduce neonatal sepsis, as well as prevention and prompt
treatment of fetal hypoxia.7-10 Because of these interventions, among infants with a birth weight of 1000
to 1500 g, mortality has decreased from about 50 percent in 1960 to about 5 percent today, and among
those with a birth weight of 500 to 1000 g, mortality
has decreased from about 95 percent in 1960 to about
20 percent today.11 Despite these dramatically lower
mortality rates, approximately 50 to 60 percent of all
neonatal deaths occur in those few infants (1 percent)
who weigh less than 1000 g at birth.12 Moreover, the
improvement in survival has not been accompanied by
a substantial reduction, if any, in the risk of prematurity-associated neurologic handicaps.
SPONTANEOUS PRETERM BIRTH

Our definition of spontaneous preterm birth includes births that follow both spontaneous labor
and spontaneous rupture of the membranes. Although these events are often thought of as distinct,
there is considerable evidence that the risk factors
for them are similar and that the distinction is largely
artificial.13 Many interventions target both conditions.
Although there are many ways of characterizing the
interventions aimed at reducing spontaneous preterm birth, perhaps the most straightforward way is
to distinguish between the strategies used before labor and those designed to treat preterm labor once
it has become clinically manifest. The strategies discussed in this article are listed in Table 1.
Prenatal Care

Liberal provision of prenatal care is often advocated as an effective means of reducing preterm births.
Support for this approach comes from the observation that preterm birth is less likely among women
who seek prenatal care early or have more prenatal
visits than among those who seek care later or have
fewer visits. However, causality cannot be inferred
from this association. First, women at lower risk avail
themselves of prenatal care more often than those at
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Preterm Births2
(% of live births)

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Year
Figure 1. Preterm Births in the United States, 1981 through
1994.
Data are from the National Center for Health Statistics.3

TABLE 1. INTERVENTIONS TO PREVENT

PREMATURE BIRTH.
Prenatal care (routine or enhanced)
Risk-scoring systems
Cervical cerclage
Progestin supplementation
Programs for cessation of tobacco, drug, and alcohol
use
Psychological support
Nutritional interventions
Counseling
Caloric supplementation
Protein supplementation
Vitamin or mineral supplementation
Patient education (to detect signs of preterm labor)
Home uterine-activity monitoring
Frequent contact with a nurse
Tocolytic therapy
Bed rest
Hydration
Screening for and treatment of infection (urinary
tract infection or bacterial vaginosis)
Antibiotics for preterm labor or premature rupture
of membranes
Low-dose aspirin
Calcium supplementation

higher risk. Furthermore, women who deliver early

often have fewer prenatal visits, simply because routine prenatal visits are scheduled at shorter intervals
in late pregnancy.
Interventions designed to reduce preterm births
include the introduction of standard prenatal care in
an area where there was previously little or no care
and the use of enhanced rather than routine prenatal
care. Our review of the literature and reviews by
others suggest that making prenatal care available to
more women or making more visits available to the
same number of women has generally not reduced
preterm births.14-17 Enhancing prenatal care by adding
combinations of patient education, case management,
home visiting, and nutrition counseling appeared to
314

be effective in reducing preterm births in a few randomized trials but not in most.18-23
An example of a study of enhanced prenatal care
is the March of Dimes multicenter trial.24 In this
study, women considered to be at high risk for preterm birth were randomly assigned to either standard or enhanced prenatal care. Enhanced care included patient education, weekly evaluation for signs
of preterm labor, and earlier use of tocolytic (laborinhibiting) therapy. Despite evidence from an observational study that this intervention held promise, it
was not effective in this or other randomized trials.24,25 Overall, because the enhancements to prenatal care have varied from study to study and because
the associated reductions in preterm birth have been
inconsistent, it is not clear which specific additions
to prenatal care, if any, are likely to result in a reduction in preterm births.
Risk scoring, with the use of a standardized questionnaire to gauge the intensity of prenatal care, has
been a component of several prematurity-prevention
strategies.26-29 In general, each of these scoring systems has been able to identify women with a risk of
preterm birth that was twice the normal risk, predominantly on the basis of a prior preterm birth.
However, the use of these scoring systems has resulted not in significant reductions in preterm births but
rather in an increased use of interventions with unproved effectiveness.29
An incompetent, or structurally weak, cervix is
diagnosed in 1 in 200 to 1 in 1000 pregnant women
on the basis of a history of spontaneous second-trimester preterm birth in the absence of recognizable
uterine contractions. The traditional treatment has
been the placement of one or several circumferential
stitches (cerclage) in the cervix. Whether women
with histories of second-trimester birth in the absence
of recognizable contractions benefit from cerclage
has not been tested prospectively, but comparisons
with historical controls suggest a benefit. However,
most women with suspected incompetent cervix have
histories that make it difficult to differentiate between an incompetent cervix and unrecognized preterm labor. In a randomized study involving women
with such histories, cerclage resulted in a statistically
significant reduction in the rate of preterm birth
before 33 weeks, but cerclage was required in 25
women to prevent 1 preterm birth.30,31
Studies in animals and some studies in humans
provide evidence that maternal progesterone concentrations decline before labor. Therefore, several
randomized studies have evaluated the effect of supplementation with a progestin, including weekly injections of hydroxyprogesterone caproate, in women
at risk for preterm birth.32,33 A meta-analysis suggests that progestin supplementation is associated
with a significant reduction in the rate of premature
birth.34 Nevertheless, because the most widely studied

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MED IC A L PROGR ES S

regimen required weekly injections and the improvements, although significant, were at times not substantial, treatment with progestins is now rarely
used. Since the previous studies were relatively small
and had dissimilar designs, the Maternal Fetal Medicine Units Network of the National Institute of
Child Health and Human Development has initiated
a prospective, randomized trial of this intervention.
Programs for cessation of tobacco, drug, and alcohol use have been recommended as part of a strategy to reduce spontaneous preterm births. The use
of these substances, however, is more closely linked
to restricted fetal growth than to preterm birth.35,36
Moreover, these programs all achieve, at best, relatively low rates of cessation. For these reasons, such
programs have limited potential to reduce the overall rate of preterm birth.
Data on the association between various maternal
psychological characteristics (including stress, anxiety, and depression) and spontaneous preterm birth
are inconsistent,36,37 and when an association has
been observed, the relative risk of premature birth
among women with specific psychological characteristics has usually not been substantially increased.38
The few randomized studies in which psychosocial
support or counseling was provided did not demonstrate that the intervention reduced preterm births,
although it may have had other benefits for pregnant
women.39,40
Nutritional Interventions

In developed countries, women who are underweight before pregnancy and those who gain little
weight during pregnancy are at increased risk for
preterm birth.41 Whether these associations suggest
causality is unknown, because the mediators have
not been elucidated. For example, low weight gain
during pregnancy may reflect limited expansion of
blood and amniotic fluid volume or suboptimal fetal
growth, as well as inadequate nutritional intake.41
Four types of nutritional interventions have been
studied: counseling, protein supplementation, caloric
supplementation, and vitamin or mineral supplementation. There is little evidence that nutritional counseling changes the eating habits of pregnant women,
let alone the outcome of pregnancy.42 Interestingly,
the provision of protein supplementation has consistently been associated with adverse outcomes.43 The
Special Supplementation Program for Women, Infants, and Children, which provides a calorically enriched diet to low-income pregnant women, has
been in operation in the United States for more than
20 years. Studies of this and other caloric-supplementation programs in developed countries suggest
that they result in small increases in birth weight.42,44
However, in areas of relative famine, much greater increases in birth weight have been achieved with caloric
supplementation.45 In all likelihood, much of the in-

crease in birth weight is attributable to improved fetal

growth rather than the prolongation of pregnancy.42
Thus, those studies do not provide compelling evidence that caloric supplementation is associated with
a reduction in preterm births.
The relation between maternal vitamin or mineral
status and prematurity is complicated. For example,
many studies suggest that women with anemia are at
increased risk for preterm birth.46 However, because
of unequal rates of expansion of plasma volume and
red-cell mass during pregnancy, women in the second or early third trimester routinely have lower
hematocrits than those at term. Failure to correct for
gestational age has therefore resulted in a misleading
association between anemia and prematurity. More
appropriate studies, which controlled for gestational
age, showed little correlation between anemia and
preterm birth.47,48 Interventional studies have demonstrated that iron supplementation raises the hematocrit; however, there is no consistent evidence that
the rate of preterm birth is reduced with iron supplementation, and it may even be increased.49-51
Low maternal zinc levels have been associated
with an increased risk of restricted fetal growth and
possibly preterm birth.52 Several, but not most, trials
of zinc supplementation have shown an increase in
birth weight, and some, including our recent study,53
suggested that zinc supplementation may reduce the
rate of preterm birth, especially among thin women.
We studied a low-income minority population of
women with moderately low serum zinc values. In
contrast, a study of middle-class Scandinavian women
showed no effect of zinc supplementation on the
outcome of pregnancy.54 Studies of folate supplementation to reduce the rate of preterm birth have
likewise had conflicting results.
The efficacy of combined vitamin and mineral supplementation, used in many Western countries, in
lowering the risk of premature birth has not been rigorously evaluated. A recent study of an inner-city
population found that women who used a vitamin
mineral supplement had significantly fewer preterm
births than those who did not.55 Since this was not a
randomized trial, factors other than supplementation,
such as self-selection, may have accounted for the
observed differences in the outcome of pregnancy.
In summary, women with an adequate nutritional
status and a normal body-mass index have better
pregnancy outcomes than other women. Despite the
large number of studies that have been performed
and the variations in institutional practices, it remains
unclear whether any nutritional intervention is associated with a reduction in the rate of preterm birth.42
Early Identification of Preterm Labor

On the premise that labor-inhibiting drugs are effective only if administered before preterm labor has
been fully established, a number of strategies have
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evolved to identify women in early preterm labor.

Typically, pregnant women receive instruction in detecting contractions or other signs of labor, such as
pelvic pressure, vaginal discharge, and back pain.56
The March of Dimes prematurity-prevention program, which included instruction in uterine selfpalpation and detection of signs of labor, did not result
in a reduction in preterm births when tested prospectively in a number of settings.24,25
One method of detecting uterine contractions before the onset of active preterm labor is home uterineactivity monitoring, in which a contraction monitor
records data on uterine activity and transfers the information electronically to a central site for analysis.57 The monitor was approved by the Food and
Drug Administration primarily because it can detect
contractions, the data can be transmitted to a central
location, and contractions are associated with an increased risk of preterm birth. In most randomized
trials, however, this approach has failed to prevent
preterm births.58-61 In the most recent study, home
monitoring not only failed to reduce preterm births,
but its use was also associated with an increased
number of unscheduled hospital visits and increased
use of tocolytic drugs.61 Strategies using home uterine-activity monitoring have often included daily
contact with a nurse, and several authors have suggested that this interaction may result in a reduced
rate of preterm birth. The data are, at best, conflicting, and there is little evidence that daily contact
with a nurse, as compared with routine prenatal care,
reduces preterm births.60-62
Tocolytic Drugs

Tocolytic drugs interrupt or stop uterine contractions. Some of these drugs, such as beta-mimetic
agents, have been thoroughly evaluated, whereas others, including magnesium sulfate, calcium-channel
blockers, oxytocin antagonists, and nonsteroidal antiinflammatory agents, have not. In general, data from
randomized trials suggest that tocolytic drugs prolong
pregnancy for up to 48 hours.63-65 However, if a benefit is defined as a reduction in preterm delivery or
even a delay in delivery for more than a week, the
effect of tocolytic therapy appears to be minimal. Furthermore, the use of tocolytic agents alone has not
been associated with a reduction in neonatal mortality
or the respiratory distress syndrome, which is the most
common neonatal disorder. In addition, use of betamimetic agents has been associated with an increased
risk of neonatal intraventricular hemorrhage.66,67
Nevertheless, the delay in delivery afforded by
tocolytic drugs may have a substantial benefit. Antenatal administration of corticosteroid drugs for as
few as 12 to 24 hours before delivery is associated
with significant reductions in neonatal respiratory
distress syndrome, intraventricular hemorrhage, and
mortality.8 Since the apparent benefit of tocolytic
316

drugs is to delay delivery for 48 hours, the combined

use of tocolytic drugs and corticosteroids has become
widespread. Even though this approach has not been
adequately tested in randomized studies, several
retrospective studies suggest that it improves the
outcome.68
Bed Rest and Hydration

Although bed rest and hydration are widely used

in women in preterm labor, there is no convincing
evidence of a reduction in preterm delivery with
either approach.69,70 In fact, in two randomized trials
involving twins, hospitalization with bed rest was
associated with increased rates of preterm birth.69 In
addition, there are other possible adverse outcomes
associated with these interventions, including venous
thrombosis and pulmonary edema.71
Treatment of Infection

In recent years, substantial progress has been made

in understanding the relation between maternal infection and preterm birth. Up to 80 percent of early
preterm births are associated with an intrauterine infection that precedes the rupture of membranes.72,73
There have been many trials of antibiotic therapy in
women with preterm labor, most of which have
found that such therapy does not prevent premature
birth.73 Whether this failure is due to the selection
of inappropriate antibiotics, the initiation of treatment too late in the cascade of events leading to
spontaneous preterm delivery, or other factors is unknown.
If treatment with antibiotics in women with established preterm labor is ineffective, it remains possible
that antibiotic therapy before labor in selected women may prevent spontaneous preterm birth. In fact,
in the 1970s, it was demonstrated that women randomly assigned to tetracycline treatment for asymptomatic urinary tract infections had fewer spontaneous
preterm deliveries than those assigned to a control
group. However, because tetracycline adversely affects the development of fetal teeth and bones, its
use during pregnancy declined. More recently, both
symptomatic and asymptomatic urinary tract infections have been associated with an increased risk of
preterm delivery, and several randomized trials have
provided confirmation that treating asymptomatic
bacteriuria not only reduces the risk of maternal
pyelonephritis but may also reduce the risk of preterm birth.74
Identification of other infections that may have a
causal role in spontaneous preterm birth is the focus
of much of the current research. For example, nearly
every sexually transmitted disease, including syphilis,
gonorrhea, and infection with chlamydia, has been
associated with increased preterm births.75 However,
women with sexually transmitted diseases often have
other risk factors for preterm birth, which have rarely

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MED IC A L PROGR ES S

been evaluated as confounding factors. Furthermore,

because of the inconsistency of the association between infection and preterm birth and the relatively
low prevalence of most infections, their elimination
in pregnant women, although otherwise beneficial,
is not likely to have a major effect on the overall rate
of preterm birth.75
We are therefore left with the question of how to
prevent preterm birth associated with an intrauterine
infection. Bacterial vaginosis, a polymicrobial overgrowth of predominantly anaerobic bacteria, has
been consistently associated with a risk of spontaneous preterm birth that is increased by a factor of 1.5
to 3.76 Furthermore, in two randomized trials involving women at high risk for preterm birth (predominantly because of prior preterm birth), treatment of bacterial vaginosis with metronidazole
either alone or in combination with erythromycin
resulted in substantial reductions in rates of spontaneous preterm birth.77,78 How generalizable these
findings are to women at lower risk remains to be
established. However, since so many premature births
are related to infection, antibiotic treatment has
great promise in reducing early spontaneous preterm births, especially among black women, who
have significantly higher rates of bacterial vaginosis
than other women (30 percent vs. 10 percent).79-81
PRETERM RUPTURE OF THE MEMBRANES

In the absence of intervention, the majority of

women with preterm rupture of the membranes have
spontaneous labor and deliver within a week. Thus,
most pregnancies complicated by preterm rupture of
the membranes end in preterm birth. Interventions in
these pregnancies have generally not been intended to
reduce the rate of preterm delivery but instead have
had more pragmatic goals, such as increasing the time
from preterm rupture of the membranes to delivery
or reducing morbidity and mortality in mothers and
infants.
Because of concern about the increased risk of
maternal and fetal infection associated with preterm
rupture of the membranes, until two decades ago
preterm rupture of the membranes was nearly always
considered an indication for expeditious delivery, regardless of gestational age. With the availability of
more potent antibiotics and a better understanding
of the risk of infection as compared with the risk of
complications of prematurity, management of preterm rupture of the membranes at less than 32 or 34
weeks of gestation has evolved into a policy of watchful waiting, with delivery at any sign of infection. This
strategy appears to benefit the minority of infants
who are not delivered for a substantial period of time.
Prophylactic antibiotic therapy has been found to
be effective in prolonging the period between preterm
rupture of the membranes and delivery.82,83 The largest
study to date, as well as meta-analyses of studies, has

also demonstrated that antibiotic treatment reduces

the risks of maternal chorioamnionitis, neonatal respiratory distress syndrome, and neonatal sepsis.82,83
There is considerable controversy over the use of corticosteroid treatment in women with preterm rupture
of the membranes. Meta-analyses have produced conflicting data on the efficacy of this approach.8,84 Nevertheless, a National Institutes of Health consensus
conference recommended the use of corticosteroids
in women with preterm rupture of the membranes at
less than 30 to 32 weeks of gestation in order to
reduce the risk of intraventricular hemorrhage.85 Because there were few randomized trials restricted to
women with preterm rupture of the membranes,
however, the American College of Obstetrics and
Gynecology did not make a similar recommendation.
The combined use of corticosteroids and antibiotics
has been associated with a reduced risk of the respiratory distress syndrome, as compared with the use of
corticosteroids alone.86 Thus, antibiotics are beneficial in prolonging the interval between preterm rupture of the membranes and delivery and in reducing
neonatal morbidity. Corticosteroids may augment
this benefit. Tocolytic drugs used independently or in
conjunction with corticosteroids or antibiotics have
not consistently been shown to provide further improvement in the outcome. No strategy has resulted
in a reduction in preterm birth after preterm rupture
of the membranes.
CONDITIONS THAT REQUIRE
PREMATURE DELIVERY

Two conditions account for the majority of nonspontaneous preterm births: preeclampsia and presumed fetal growth restriction. In most cases, the
infant is delivered prematurely because of the presence of preeclampsia and the judgment that either
the mother or the infant is at unacceptable risk should
the pregnancy continue.6,87 Since the pathway leading
to preeclampsia involves a relative overproduction of
thromboxane, low-dose aspirin has been used to
inhibit its production selectively, and early studies
suggested that aspirin reduced the risk of preeclampsia.88 In recent years, however, several large, multicenter, randomized trials have shown that low-dose
aspirin confers little, if any, protection against preeclampsia.89-91 Like aspirin, calcium supplementation, which lowers blood pressure, was associated
with a reduction in preeclampsia in several early trials.92,93 In the largest randomized, multicenter study,
however, calcium supplementation did not reduce
the risk of preeclampsia.94 There are also no data in
support of the many other interventions, including
bed rest, use of antihypertensive medications, use of
diuretics, and salt restriction, that have been used in
the hope of preventing preeclampsia.
Infants with presumed fetal growth restriction are
often delivered prematurely because of the physicians
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belief that they are at increased risk for stillbirth or

neurologic impairment if left undelivered. Many strategies have evolved to reduce maternal risk factors associated with fetal growth restriction or at least mitigate its consequences. These include programs for
smoking, alcohol, and drug cessation, bed rest, administration of oxygen, and nutritional supplementation. These types of interventions may have a positive, albeit marginal, effect on fetal growth, but they
have not been associated with a reduction in premature delivery.42,69,95-97 Although the use of ultrasonography to determine gestational age and the use of various amniotic fluid tests to assess fetal pulmonary
maturity have greatly reduced the number of iatrogenic preterm births associated with elective induction of labor and cesarean delivery, there are no specific interventions that reliably prevent the clinical
conditions that require indicated preterm delivery.
Therefore, the current strategy to reduce the risk
of death or disability associated with preeclampsia
and fetal growth restriction is to identify at-risk fetuses
through fetal-movement counting, fetal-heart-rate
monitoring, fetal ultrasonography, or Doppler bloodflow measurements.98 If the fetus is considered to be
at high risk for death or neurologic damage, an early
delivery is effected. Although this approach does not
prevent premature birth, the substantial reduction in
third-trimester stillbirths over the past two decades
suggests that it is effective in reducing the number
of stillbirths.99
SUMMARY

The available data on the effectiveness of various

interventions aimed at reducing premature births
provide an explanation for the epidemiologic observation that the rate of preterm birth is not declining.
Most interventions designed to prevent preterm birth
do not work, and the few that do, including treatment of urinary tract infection, cerclage, and treatment of bacterial vaginosis in high-risk women, are
not universally effective and are applicable to only a
small percentage of women at risk for preterm birth.
A more rational approach to intervention will require
a better understanding of the mechanisms leading to
preterm birth. In the meantime, substantial reductions in preterm delivery are unlikely to be achieved.
Supported in part by a contract with the Agency for Health Care Policy
and Research (290-92-0055).

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