Preterm birth: Risk factors and interventions for risk reduction

Authors
Julian N Robinson, MD
Errol R Norwitz, MD, PhD
Section Editor
Charles J Lockwood, MD, MHCM
Deputy Editor
Vanessa A Barss, MD, FACOG
Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2016. | This topic last updated: May 18, 2016.

INTRODUCTION — Most preterm births (PTBs) are spontaneous: related to preterm labor or
preterm premature rupture of membranes. The remainder are iatrogenic: performed because of
medical or obstetrical complications that jeopardize the health of the mother or fetus.

There are many risk factors for PTB (table 1) and many pathways from these risk factors to the
terminal cascade of events resulting in labor. Preterm labor likely occurs when local uterine factors
prematurely stimulate this cascade or suppressive factors that inhibit the cascade and maintain
uterine quiescence are withdrawn prematurely. The four major factors leading to preterm labor are
intrauterine infection, decidual hemorrhage, excessive uterine stretch, and maternal or fetal stress.
Uteroplacental vascular insufficiency, exaggerated inflammatory response, hormonal factors,
cervical insufficiency, and genetic predisposition also play a role. (See "Pathogenesis of
spontaneous preterm birth".)

Ideally, identification of modifiable and nonmodifiable risk factors for PTB before conception or early
in pregnancy will lead to interventions that help prevent this complication. However, few
interventions have been proven to prolong pregnancy in women at risk. This goal has been elusive
for several reasons: Many PTBs occur among women with no risk factors, causality has been
difficult to prove (eg, a cofactor may be required thus complicating the chain of causality), and no
adequate animal model exists for study of spontaneous PTB (sPTB).

Risk factors for PTB and potential interventions to mitigate risk, when possible, will be reviewed
here. Pathogenesis of PTB and diagnosis and treatment of preterm labor are discussed separately:

●(See "Pathogenesis of spontaneous preterm birth".)

●(See "Inhibition of acute preterm labor".)
●(See "Diagnosis of preterm labor and overview of preterm birth".)

REPRODUCTIVE HISTORY

History of spontaneous preterm birth — A history of sPTB is the major risk factor for recurrence,
and recurrences often occur at the same gestational age [1-3]. Women at highest risk are those
with:

●No term pregnancy between the previous sPTB and the current pregnancy
●A history of multiple sPTBs
In large series, the frequency of recurrent sPTB was 15 to 30 percent after one sPTB and increased
after two sPTBs [4-8]. Term births decrease the risk of sPTB in subsequent pregnancies (table
2 and table 3).

The risk of recurrent early sPTB is of particular concern given its high morbidity and mortality. In a
large prospective series, approximately 5 percent of women who had an sPTB at 23 to 27 weeks in
their prior pregnancy delivered at <28 weeks in their subsequent pregnancy [4]. By comparison, if
there was no previous history of sPTB, then the risk of sPTB <28 weeks was only 0.2 percent.

Women who were born preterm are at modestly increased risk of having a sPTB compared with
women who were born at term. (See 'Genetic factors' below.).

A prior sPTB of twins, especially if before 34 weeks, is associated with an increased risk of sPTB in
a subsequent singleton pregnancy [9,10]. The overall risk of sPTB in twin pregnancy is significantly
higher in multiparous women whose previous singleton pregnancy was a sPTB: 67.3 percent versus
20.9 percent if the previous singleton delivery was at term (odds ratio 7.8, 95% CI 5.5-11.2) [11].

Intervention — Progesterone supplementation reduces the risk of PTB in women with a history of
PTB. A review of evidence and treatment approaches is available separately. (See "Progesterone
supplementation to reduce the risk of spontaneous preterm birth", section on 'Spontaneous
singleton preterm birth in prior pregnancy' and "Progesterone supplementation to reduce the risk of
spontaneous preterm birth", section on 'Progesterone preparations and doses'.)

Sonographic measurement of cervical length in women with a history of PTB can identify those with
a short cervix who may benefit from placement of a cerclage. A review of screening and treatment
approaches and supporting evidence is available separately.

●(See "Second-trimester evaluation of cervical length for prediction of spontaneous preterm

birth", section on 'Singleton pregnancy, prior preterm birth'.)
●(See "Cervical insufficiency", section on 'Women with prior pregnancy losses or preterm
births'.)

Although an increase in uterine activity is a prerequisite for labor, randomized trials and a meta-
analysis have shown that self-measurement of the frequency of uterine contractions by self-
palpation/detection of signs of labor or through use of a home uterine activity monitor does not lead
to a reduction in the rate of PTB [12,13]. Moreover, such an approach increases the frequency of
unscheduled antenatal visits. The American College of Obstetricians and Gynecologists
recommends not using home uterine activity monitoring as a screening strategy for prediction or
prevention of PTB [14].

Prophylactic tocolytic therapy for prevention of PTB in high-risk asymptomatic women is not
effective, although few randomized trials have been conducted [15,16]. (See "Management of
pregnant women after inhibition of acute preterm labor".)

History of indicated preterm birth — A large retrospective cohort study assessed the risk of
recurrent PTB by the type of PTB in the previous pregnancy [7]. The rate of recurrent PTB was 23
percent for women with a prior indicated PTB and 31.6 percent for women with a prior sPTB.
Women with a prior indicated PTB were at particularly high risk for recurrent indicated PTB (relative
risk [RR] 9.10, 95% CI 4.68-17.71) but also at increased risk of sPTB (RR 2.70, 95% CI 2.00-3.65).
Women with a prior sPTB were at five- to sixfold increased risk for recurrent sPTB, but also
appeared to be at slightly increased risk for indicated PTB (RR 1.61, 95% CI 0.98-2.67).

Intervention — Interventions to reduce the risk for recurrent indicated PTB depend on the
indication for PTB. For example, administration of low-dose aspirin to women with a history of early
delivery because of preeclampsia with severe features can reduce their risk for recurrent
preeclampsia and PTB. (See "Preeclampsia: Prevention", section on 'Antiplatelet agents'.)

History of abortion — In a 2015 systematic review of pregnancy outcome after uterine evacuation
including over one million women (31 studies involving termination of pregnancy, five studies
involving spontaneous abortion), women with a history of surgical uterine evacuation had a small
but statistical increase in risk for PTB in a subsequent pregnancy compared with controls [17].
Women who underwent medical termination of pregnancy had a similar future risk of PTB as
women with no history of pregnancy termination. Although surgical uterine evacuation appeared to
be a risk factor for subsequent PTB, observational studies are flawed because they are subject to
recall bias and inadequate adjustment of many of the other risk factors for adverse pregnancy
outcome. (See "Overview of pregnancy termination", section on 'Future
pregnancies' and"Spontaneous abortion: Management", section on 'Future reproductive outcomes'.)

SHORT INTERPREGNANCY INTERVAL — An interpregnancy interval ≤6 months has been

associated with an increased risk for PTB. In a study of 263 women with sPTBs and 299 women
with term consecutive births, an interpregnancy interval ≤6 months more than tripled the risk for
sPTB less than 34 weeks [18]. (See "Interpregnancy interval and obstetrical complications", section
on 'Preterm birth' and "Interpregnancy interval and obstetrical complications", section on 'Preterm
premature rupture of membranes'.)

Intervention — Increasing the interval between pregnancies to at least 12 months may reduce a
woman's risk for sPTB. In a large cohort study that examined the impact of postpartum
contraceptive coverage and use within 18 months of birth in preventing PTB, postpartum
contraceptive coverage was protective against PTB [19]. For every month of contraceptive
coverage, odds of PTB <37 weeks decreased by 1.1 percent.

GENETIC FACTORS — Genetic polymorphisms appear to contribute to a woman's likelihood of

sPTB. PTB susceptibility genes have been identified; however, epigenetic and gene-environmental
factors probably play a more important role in PTB than the maternal genotype.

PTBs are more prevalent in some family pedigrees and racial groups, in women who were born
preterm themselves, and in women with a first-degree female relative who had a PTB [20]. In
addition, concordance for timing of parturition is higher in women who are monozygotic twins than in
those who are dizygotic twins [3,21-31].

The paternal genotype does not have a significant effect on PTB. (See 'Paternal risk factors' below.)

NON-HISPANIC BLACK RACE — In the United States, non-Hispanic blacks consistently have a
higher rate of PTB than non-Hispanic whites [32]. In a systematic review and meta-analysis of eight
English language studies including over 26 million singleton births, the odds of PTB were lowest in
couples in which both parents were white and progressively increased with black parentage:
white mother/white father (odds ratio [OR] 1.0), white mother/black father (OR 1.17),
black mother/white father (OR 1.37), black mother/black father (OR 1.78) [33]. This may be related
to both genetic and environmental factors (eg, social, educational, occupational, economic).

A discrepancy between black and white populations in the risk of recurrent PTB has also been
observed. In black and white women whose first delivery was at 20 to 31 weeks of gestation, the
frequency of a second delivery at the same gestational age range was 13.4 and 8.2 percent,
respectively, in one study [4,34]. For the gestational age range 32 to 36 weeks, the frequency of a
second delivery at the same gestational age was 3.8 and 1.9 percent, respectively.

Differences in epidemiologic and environmental risk factors account for some of the increased risk
in PTB, but polymorphisms in genes for regulation of innate immunity also appear to play a role [35-
37]. A woman's race/ethnicity seems to influence her microbiome and the impact of vaginal bacteria
on PTB [38-41]. One mechanism may involve an enhanced proinflammatory response to normal or
altered vaginal microflora, leading to preterm labor or preterm premature rupture of membranes
(PPROM) [42]. Alternatively, immune hyporesponsiveness may create a permissive environment for
ascending infection and its sequelae (premature labor, PPROM) [43,44]. (See "An overview of the
innate immune system".)

AGE — The rate of PTB is higher at the extremes of maternal age [32].

CERVICAL SURGERY — Cold knife conization and loop electrosurgical excision procedures for
treatment of cervical intraepithelial neoplasia have been associated with increased risks for late
miscarriage and PTB. Possible mechanisms include loss of tensile strength from loss of cervical
stroma, increased susceptibility for infection from loss of cervical glands, and loss of cervical
plasticity from cervical scarring. (See "Cervical intraepithelial neoplasia: Reproductive effects of
treatment".)

Intervention — Women undergoing treatment of cervical intraepithelial neoplasia should have the
procedure that best diagnoses or prevents cervical cancer and also incurs the lowest risk of
reproductive effects.

Although women who have undergone cervical surgery may develop cervical insufficiency, the
pregnancy course and outcome need to be evaluated before making this diagnosis. We perform a
single transvaginal ultrasound measurement of cervical length measurement at 18 to 24 weeks in
women with no prior PTB but risk factors for cervical insufficiency and treat those with a short cervix
(≤20 mm) with vaginal progesterone supplementation. (See "Cervical insufficiency", section on
'Women with no prior preterm birth, but risk factors for cervical insufficiency'.)

UTERINE MALFORMATIONS

Congenital — In women with congenital uterine malformations, the magnitude of risk for PTB
depends upon the specific abnormality [45-47]. (See "Clinical manifestations and diagnosis of
congenital anomalies of the uterus", section on 'Recurrent pregnancy loss' and "Clinical
manifestations and diagnosis of congenital anomalies of the uterus", section on 'Preterm delivery'.)

Intervention — Surgical correction of the abnormality may reduce the risk for PTB. (See "Surgical
management of congenital uterine anomalies".)

Acquired — Women with fibroids may be at slightly increased risk for pregnancy loss and PTB. A
large fibroid (ie, ≥5 to 6 cm) or multiple fibroids appear to be the most important risk factors for PTB;
a submucosal location is the most important risk factor for pregnancy loss. (See "Pregnancy in
women with uterine leiomyomas (fibroids)", section on 'Preterm labor and birth'.)

Intervention — Myomectomy before pregnancy may be indicated in women with pregnancy loss or
early PTB (see"Reproductive issues in women with uterine leiomyomas (fibroids)"). Every effort
should be made to avoid surgical removal of fibroids during pregnancy because of the risk for
significant morbidity (hemorrhage). (See "Pregnancy in women with uterine leiomyomas (fibroids)".)

CHRONIC MEDICAL DISORDERS — Chronic maternal medical disorders can be associated with
maternal or fetal complications necessitating medically indicated PTB as well as an increased risk
for sPTB. Examples include women with hypertension, renal insufficiency, type 1 diabetes mellitus,
some autoimmune diseases, and nonphysiologic anemia.

PREVIOUS INFANT WITH SUDDEN INFANT DEATH SYNDROME — A history of delivery of an

infant who subsequently died from sudden infant death syndrome appears to be a risk factor for
PTB in the following pregnancy [48]. (See "Sudden infant death syndrome: Risk factors and risk
reduction strategies".)

ASSISTED REPRODUCTION — Pregnancies conceived by assisted reproduction are at higher risk

for sPTB, even in the absence of multifetal gestation. The increased risk may be related to baseline
maternal factors related to subfertility and/orfactors related to assisted reproduction procedures.
(See "Pregnancy outcome after assisted reproductive technology", section on 'Preterm birth, LBW,
and SGA'.)

MULTIFETAL GESTATION — Multifetal gestation accounts for only 2 to 3 percent of all births but
17 percent of births before 37 weeks of gestation and 23 percent of births before 32 weeks. The
widespread availability of assisted reproductive technology has resulted in a large increase in the
incidence of multiple gestation; this increase, in turn, has led to an increase in spontaneous and
indicated PTB [49].

The mechanism for sPTB in multifetal gestations, and particularly higher-order multifetal gestations,
may be related to sequelae of increased uterine distension (see "Pathogenesis of spontaneous
preterm birth", section on 'Pathologic uterine distention'). The endocrine environment produced by
superovulation or the multiple pregnancy may also play a role. As an example, multifetal gestations
produce increased amounts of estrogen, progesterone, and sex steroids compared with singleton
pregnancies [50,51]. Increased steroid production may be a factor in initiation of labor
(see "Physiology of parturition"). Higher circulating levels of relaxin associated with super-ovulation
may cause cervical insufficiency with subsequent sPTB [52].

Intervention — Prevention and reduction of multifetal gestations, particularly high-order multifetal

gestations, appear to improve neonatal outcome. (See "Strategies to control the rate of high order
multiple gestation" and "Multifetal pregnancy reduction and selective termination".)

In unselected twin pregnancies, progesterone supplementation or use of a pessary does not

prolong gestation. In women with a twin pregnancy and a prior singleton sPTB or a short cervix, the
use of supplemental progesterone or a pessary is controversial and reviewed separately.
(See "Twin pregnancy: Prenatal issues", section on 'Preterm labor and delivery' and"Progesterone
supplementation to reduce the risk of spontaneous preterm birth", section on 'Twin pregnancy'.)
VAGINAL BLEEDING IN EARLY PREGNANCY — Early pregnancy bleeding is often due to
decidual hemorrhage and associated with an increased risk for both subsequent spontaneous and
indicated PTB. In a large study based on registry data, pregnancies with first-trimester bleeding
were at increased risk for preterm premature rupture of membranes (PPROM) (odds ratio [OR]
1.18, 95% CI 1.01-1.37), placental abruption (OR 1.48, 95% CI 1.30-1.68), and severe
preeclampsia (OR 1.25, 95% CI 1.09-1.43) [53]. In this and other studies, the association was
stronger for PTB before 34 weeks than late PTB [53,54]. Women with persistent vaginal bleeding
and bleeding in the second trimester are at higher risk of these complications than those with an
isolated first-trimester event. (See "Spontaneous abortion: Risk factors, etiology, clinical
manifestations, and diagnostic evaluation", section on 'Threatened abortion'.)

Decidual hemorrhage results in release of tissue factor, which can trigger local thrombin formation.
Decidual thrombin production has been associated with increased expression of soluble fms-like
tyrosine kinase-1 (sFlt-1) and monocyte-recruiting chemokines, factors also associated with
subsequent indicated PTB due to preeclampsia, abruption, or fetal growth restriction as well as
subsequent sPTB [55]. Later in pregnancy, decidual cell-derived thrombin can inhibit decidual cell
progesterone receptor expression, possibly resulting in PTB related to abruption or PPROM [56-58].
(See "Pathogenesis of spontaneous preterm birth", section on 'Decidual hemorrhage'.)

Intervention — Women with a history of PTB may be treated with progesterone to prevent
recurrence in a subsequent pregnancy. Those who have vaginal bleeding/abruption in the
subsequent pregnancy still appear to respond tohydroxyprogesterone caproate prophylaxis in that
pregnancy [59].

SHORT CERVIX — There is an inverse relationship between cervical length measured by

transvaginal ultrasound at 16 to 28 weeks of gestation and gestational age at delivery (table 4). A
high Bishop or cervical score on digital examination is also associated with increased odds of PTB
[60]. (See "Second-trimester evaluation of cervical length for prediction of spontaneous preterm
birth".)

Intervention — For women with singleton pregnancies and no history of prior PTB, we suggest
screening for a short cervix (≤20 mm) with a single examination at 18 to 24 weeks. Progesterone
supplementation in this population reduces the risk for PTB. A review of evidence and treatment
approaches are discussed in detail separately. (See "Progesterone supplementation to reduce the
risk of spontaneous preterm birth", section on 'Short cervix in current pregnancy' and "Progesterone
supplementation to reduce the risk of spontaneous preterm birth", section on 'Progesterone
preparations and doses'.)

For women with singleton pregnancies and a history of prior PTB who develop a short cervix during
pregnancy, cerclage may be indicated. (See "Cervical insufficiency", section on 'Candidates for
ultrasound surveillance and possible ultrasound-indicated cerclage'.)

INFECTION — Multiple unrelated studies from varied disciplines (epidemiology, histopathology,

microbiology, biochemistry, and maternal-fetal medicine) have reported an association
between infection/inflammation and PTB, likely mediated by prostaglandins. The most consistent of
these observations come from placental pathologists who have described histological evidence of
chorioamnionitis in the placentas of 20 to 75 percent of PTBs and positive membrane cultures in 30
to 60 percent of such patients [61-64]. In the Collaborative Perinatal Project, chorioamnionitis was
detected in 6 percent of 43,940 deliveries evaluated [65]. The rate increased with decreasing
gestational age: 15 percent at 28 to 32 weeks, 8 percent at 33 to 36 weeks, and 5 percent after 36
weeks of gestation. (See "Pathogenesis of spontaneous preterm birth", section on 'Bacteria'.)

Asymptomatic bacteriuria — It is unclear whether asymptomatic bacteriuria is an independent risk

factor for PTB [66]. In one of the largest studies, the Cardiff Birth Survey, which prospectively
studied over 25,000 births between 1970 and 1979, asymptomatic bacteriuria was not associated
with a significant increase in the overall rate of PTB (odds ratio [OR] 1.21, 95% CI 0.96-1.53) [67],
or sPTB (OR 1.07, 95% CI 0.78-1.46) [68] when the data were adjusted for demographic and social
factors.

Intervention — A first-trimester urine culture should be performed on all pregnant women [69,70],
and regular antenatal screening is recommended for women at high risk for asymptomatic
bacteriuria (eg, women with sickle cell trait, recurrent urinary tract infections, diabetes mellitus,
underlying renal disease). Reliance on symptoms to prompt screening is inadequate because
symptoms such as frequency and nocturia are often attributed to the state of pregnancy. Pregnant
women with asymptomatic bacteriuria should be treated with antibiotics to reduce their risk of
developing pyelonephritis, and possibly to reduce the risk of PTB. (See "Urinary tract infections and
asymptomatic bacteriuria in pregnancy", section on 'Asymptomatic bacteriuria'.)

In a systematic review and meta-analysis (14 randomized trials, overall poor quality), treatment of
asymptomatic bacteriuria clearly and substantially decreased the incidence of asymptomatic
bacteriuria (relative risk [RR] 0.25, 95% CI 0.14-0.48), pyelonephritis (relative risk [RR] 0.23, 95%
CI 0.13-0.41) [71], and low birth weight (RR 0.66, 95% CI 0.49-0.89), but a difference in PTB was
not established.

Periodontal disease — Periodontal disease is common in adults. Two systematic reviews have
reported an association between periodontal disease and adverse pregnancy outcome, such as
sPTB, but did not provide conclusive evidence that pregnancy complications, including sPTB, result
from periodontal disease [72,73]. The included studies had different designs and used different
criteria to diagnose periodontal disease and to define adverse outcome. Moreover, they generally
did not adequately adjust for confounders or have adequate sample size to detect significant
differences in pregnancy outcome. Oral bacteria that have been associated with both periodontal
disease and PTB include Tannerella forsythia, Porphyromonas gingivalis, Actinobacillus
actinomycetemcomitans, Treponema denticola, and Fusobacterium nucleatum [74-76].

Several hypotheses have been proposed to explain the association between periodontal disease
and sPTB [77-80]. Periodontal flora may seed the fetoplacental unit and cause local inflammation,
or inflammatory mediators of periodontal origin may cause systemic inflammation. An alternative,
but equally reasonable, explanation is that periodontal disease is a marker of individuals who have
a genetic predisposition towards an exaggerated local or systemic inflammatory response to a given
stimulus (eg, bacteria), which leads to two separate adverse clinical events: periodontal disease
and sPTB. Such individuals may also hyperrespond to vaginal bacteria with enhanced production of
cytokines that lead to preterm labor or rupture of membranes. Thus, periodontal disease and
preterm labor can be epidemiologically linked but not causally related.

Intervention — There is no strong evidence that treatment of periodontal disease improves

pregnancy outcome. A joint consensus report of the European Federation of Periodontology and
the American Academy of Periodontology in 2013 concluded that, although periodontal therapy is
safe and leads to improved periodontal health in pregnant women, periodontal therapy does not
reduce overall rates of PTB and low birth weight [81]. This conclusion was based on meta-analyses
limited to higher-quality randomized trials that demonstrated no significant effect of nonsurgical
periodontal treatment on rates of PTB or low birth weight [82-85]. Subsequent meta-analyses have
reported similar findings [86].

Several hypotheses have been proposed in an attempt to explain why periodontal treatment has not
been shown to reduce risk for adverse pregnancy outcomes. Possibilities include [87]:

●Lack of causality. Periodontitis may not be a direct or indirect cause of PTB or low birth
weight.
●Shared risk factors may mitigate the effect of treatment. Some risk factors for both
periodontitis and poor pregnancy outcome (eg, smoking) are not affected by periodontal
treatment. Furthermore, PTB is likely the end result of a variety of environmental, behavioral,
social, biological, and possibly genetic factors so periodontal treatment alone is unlikely to
have a major impact on reducing risk.
●Underpowered trials. Very large trials would be required to detect significant reductions in
very or extreme PTB rates since these are much less common than late PTBs.
●Lack of a consistent definition of periodontal disease. This has led to inclusion of women with
mild disease whose pregnancies may not benefit from treatment.
●Treatment of periodontal disease in the trials was inadequate to affect pregnancy outcome.
To demonstrate a beneficial effect, treatment may have to start before pregnancy or very early
in pregnancy, continue longer, or be more intense. If PTB is related to changes in the genital
tract microbiome induced by changes in the oral microbiome, local treatment of oral
inflammation may not reverse genital tract changes.

Genital tract infection — Multiple studies have reported an association between

preterm labor/delivery and various genital tract infections (table 5), including group B streptococci
(GBS) [88], Chlamydia trachomatis [89-92], bacterial vaginosis [93-95],Neisseria gonorrhea [96],
syphilis [97], Trichomonas vaginalis [98], Ureaplasma species [99], and
unencapsulatedHaemophilus influenzae [100]. A positive culture correlates with the presence of
histologic chorioamnionitis; however, causal relationships for most of these infections and PTB have
not been proven and are controversial [88,101,102].

Intervention

●Role of routine screening – Some treatment trials have reported a reduction in PTB with
routine screening and treatment for infection in the early second trimester, while others have
reported no benefit. Discordant findings may be due to confounding by recolonization or
reinfection after therapy, intercurrent use of nonprotocol antibiotics, and failure to culture
fastidious bacteria (eg, Mycoplasma hominis, Ureaplasma urealyticum) leading to
misclassifications of women as noninfected.
●Role of empiric antibiotic therapy – Empiric antibiotic therapy does not reduce PTB. A
2007 meta-analysis of 17 randomized trials evaluated use of prophylactic antibiotics for
prevention of PTB based on abnormal vaginal flora, three that selected women at risk based
on a previous PTB, and two that recruited women with a positive fetal fibronectin test result
 [103]. There was no significant association between antibiotic treatment and reduction in PTB
regardless of the criteria used to assess risk, the antimicrobial drug administered, or
gestational age at time of treatment (overall combined random effect for delivery at less than
37 weeks RR 1.03, 95% CI 0.86-1.24). A 2015 systematic review of randomized trials also
concluded that antibiotic prophylaxis in the second or third trimester did not reduce the risk of
preterm prelabor rupture of membranes (RR 0.31, 95% CI 0.06-1.49, one trial 229 women) or
PTB (RR 0.85, 95% CI 0.64-1.14, five trials, 1480 women); however, the included studies
were of low methodological quality [104].
●Chlamydia, gonorrhea, syphilis – There is no evidence that treatment of chlamydia,
gonorrhea, or syphilis prolongs gestation. The only controlled trial that evaluated the effect of
treatment of chlamydia on gestational duration did not show a reduction in PTB [105].
However, screening for and treatment of these infections is recommended to prevent other
maternal and neonatal sequelae. (See "Clinical manifestations and diagnosis of Neisseria
gonorrhoeae infection in adults and adolescents" and "Treatment of uncomplicated
gonococcal infections" and "Syphilis in pregnancy" and"Treatment of Chlamydia trachomatis
infection".)
●Bacterial vaginosis, Ureaplasma, GBS – Prospective controlled trials and meta-analyses
have reported either a modest or no effect of antibiotic treatment on prolonging gestation in
asymptomatic women who screened positive for bacterial vaginosis [106-110], Ureaplasma
urealyticum [111,112], or GBS [113], although these studies are undoubtedly confounded by
recolonization or reinfection after therapy and intercurrent use of nonprotocol antibiotics. GBS
screening in late pregnancy and chemoprophylaxis for prevention of early-onset neonatal GBS
infection is recommended. (See"Neonatal group B streptococcal disease: Prevention".)
Women with bacterial vaginosis and a previous PTB may benefit from bacterial vaginosis
screening and treatment, but there are insufficient data to recommend this as a routine
practice. This subject is discussed in detail separately. (See"Bacterial vaginosis", section on
'Pregnant women'.)
●Trichomonas – Screening and treatment of asymptomatic Trichomonas infection in HIV-
negative women is not recommended during pregnancy because there is no convincing
evidence that it reduces the risk for PTB [114-119]. In contrast, screening and treatment are
recommended for HIV-positive women to reduce the risks for pelvic inflammatory disease and
vertical transmission of HIV [120]. (See "Trichomoniasis", section on 'Pregnant women'.)

Malaria — Malaria is associated with PTB, low birth weight, and other maternal and neonatal
morbidities [121]. (See"Overview of malaria in pregnancy".)

Intervention — Prevention of malaria infection and treatment of established malaria infection can
reduce the risk for PTB [122-124]. (See "Prevention and treatment of malaria in pregnant women".)

BEHAVIOR

Occupational activity — A relationship between maternal physical activity related to working

during pregnancy and PTB has not been clearly established. A meta-analysis of 21 studies
including a total of 146,457 women identified a high cumulative work fatigue score as the strongest
work-related risk factor for PTB (odds ratio 1.63, 95% CI 1.33-1.98) [125]. The results of this
analysis are summarized in the table (table 6). Similar findings were reported in a subsequent large
European case-control study that noted employed women were at higher risk of PTB if they worked
longer than 42 hours/week, stood more than sixhours/day, or had low job satisfaction [126].

It is probably important to quantitate all of the factors involved in work-related exertion, as well as
the mother's ability to handle stress and fatigue, to gain insight into this controversy. In addition, a
"healthy worker" effect is likely present in many studies whereby healthier workers are more likely to
continue to work, work longer hours, and work in more demanding jobs, thus biasing outcomes.
(See "Working during pregnancy", section on 'The effect of work on pregnancy and child
outcomes'.)

Intervention — Women with uncomplicated pregnancies who are employed where there are no
greater potential hazards than those encountered in routine daily life may continue to work without
interruption until the onset of labor. Nevertheless, the physical demands of the woman's job should
be considered, especially in women at high risk of PTB.

The effects of reducing occupational fatigue have not been evaluated in randomized trials.
Maternity legislation in many European countries has regulated work schedules and working
conditions for pregnant women; however, none of the European countries except France have
experienced a reduction in PTB rates [127]. Nevertheless, paid maternity leave, guaranteed job
protection, and regulation of hazardous working conditions remain desirable societal goals.

Bed rest is often recommended for women at increased risk for PTB [128]. While bed rest improves
uteroplacental blood flow and can lead to a slight increase in birth weight, there is no evidence that
it decreases the incidence of PTB [129-131], even in women with a short cervix [132,133]. Although
underpowered, the only randomized trial attempting to determine whether hospitalization of women
with arrested preterm labor improved outcome found hospitalized women had similar outcomes to
those discharged home [134]. Moreover, exercise does not appear to increase the risk of PTB in
healthy women. Bedrest appears to increase the risk of thromboembolic events and has clear
negative psychosocial effects [135-137].

Exercise — In multiple cohort studies and randomized trials, exercise during pregnancy did not
appear to increase the risk for PTB. As discussed above, a "healthy exerciser" effect likely exists
whereby healthier women and those at low risk of PTB are more likely to continue to exercise
during pregnancy. (See "Exercise during pregnancy and the postpartum period: Practical
recommendations".)

Coitus — Sexual intercourse is not a risk factor for PTB; therefore, abstinence after pregnancy has
been achieved has no role in strategies for prevention of PTB. [138-141].

Smoking — Cigarette smoking has a modest dose-dependent relationship with the risk for PTB
[3,67,142-148]. This effect may be explained by increased rates of smoking-related complications of
pregnancy, such as placental abruption, placenta previa, premature rupture of membranes, and
intrauterine growth restriction. However, the association still exists when adjustment is made for
these possible confounding factors, suggesting that there may be a direct effect of cigarette
smoking on spontaneous preterm labor and delivery [148]. (See "Cigarette smoking: Impact on
pregnancy and the neonate".)

Intervention — Smoking cessation should always be encouraged for its general health benefits. It
is likely that smokers who decrease or stop cigarette smoking will reduce their risk for PTB, but this
has not been proven. (See "Cigarette smoking: Impact on pregnancy and the neonate", section on
'Smoking cessation'.)

Substance use — Maternal substance use increases the risk of PTB, but it is difficult to separate
the risk attributable to the substance from other risk factors, which are common in these patients
[67,145-153]. In one study, women with cocaine-positive urine samples were at fourfold increased
risk of developing preterm labor [151]. Another series found positive urine toxicology in 24 of 141
(17 percent) of women with preterm labor compared with 3 of 108 (2.8 percent) controls with
uncomplicated labor at term [150]. Cocaine was the most common substance identified and was
detected in approximately 60 percent of women in preterm labor with positive toxicology tests.
Alcohol [152] and toluene [153] are additional substances associated with an increased risk of
preterm labor. In women who use multiple drugs, risk of PTB has been reported to range from 25 to
63 percent [154,155]. (See "Overview of substance misuse in pregnant women" and "Alcohol intake
and pregnancy".)

Intervention — Healthcare providers should attempt to identify maternal substance use, provide
information on the maternal and fetal risks associated with this practice, and help patients to stop
using these drugs. It is likely that this will reduce their risk for PTB, but this has not been proven.
(See "Overview of substance misuse in pregnant women" and "Methadone maintenance therapy
during pregnancy" and "Buprenorphine substitution therapy in pregnancy".)

DIET — Women with adequate nutrition and a normal body mass index have better pregnancy
outcomes than other women, which suggests that nutritional interventions may have a role in
preventing PTB in selected populations.

There is some evidence supporting the hypothesis that maternal undernutrition in pregnancy results
in PTB [156]. In sheep, moderate maternal undernutrition around the time of conception results in
accelerated maturation of the fetal hypothalamic-pituitary-adrenal axis, a precocious fetal cortisol
surge, and PTB [157,158]. In Gambian women, pregnancies conceived during the rainy season
when food is scarce were significantly shorter than those conceived when food was more plentiful
[159]. Observations of shorter gestational length with early pregnancy exposure to the Dutch famine
also support this hypothesis [160]. Thus, focusing on dietary events around the time of conception
may be important in prevention of some cases of PTB.

Intervention — In systematic reviews, isocaloric protein supplements [161],

balanced protein/energy supplements [162], and high protein supplements [162] did not reduce the
rate of PTB. Most studies show that vitamin supplements during pregnancy do not reduce the risk of
PTB [163-170], although they have other benefits. There may be potential benefits of micronutrient
supplementation in specific subpopulations of pregnant women, such as those who are
undernourished or HIV-infected [171].

The effect of fish oil supplements on PTB has been studied in randomized trials and no benefit was
found. The effect of fish consumption on length of gestation has only been evaluated in
observational studies, which have reported discordant results. In these studies, the benefits of fish
consumption may be confounded by socioeconomic level, avoidance of more harmful foods that
fish replaces, beneficial effects of nutrients in fish other than n-3 long-chain polyunsaturated fatty
acids, and/or other attributes that are discordant between fish consumers and non-consumers. If
there is a true reduction, it is likely to be modest. (See "Fish consumption and omega-3 long-chain
polyunsaturated fatty acid supplementation during pregnancy".)

WEIGHT AND WEIGHT CHANGES — Extremes of prepregnancy weight and/or body mass index
have been associated with increased rates of PTB [172,173]. The strength of this association is not
well-defined because the effect is bimodal as opposed to linear and because of interdependent
variables [174]. For example, low prepregnancy weight may be confounded by socioeconomic
status, race/ethnicity, and even weight gain in pregnancy.

Obese gravida are at increased risk of iatrogenic PTB resulting from medical complications. Obesity
also appears to increase the risk for preterm premature rupture of membranes (PPROM) and
decrease the risk of sPTB without PPROM (See "The impact of obesity on female fertility and
pregnancy", section on 'Indicated and spontaneous preterm birth'.)

Low and high weight gain during pregnancy have also been associated with PTB [175,176]. These
issues are discussed in detail separately. (See "Weight gain and loss in pregnancy".)

Intervention — Although some evidence suggests that weight loss in obese women before
pregnancy and appropriate weight gain in pregnancy can reduce the risk for PTB, the evidence is
not definitive. In a systematic review of randomized trials of the effects of dietary and lifestyle
interventions in pregnancy on maternal weight and obstetric outcomes, PTB was not statistically
reduced (relative risk 0.78, 95% CI 0.60-1.02, 13 trials, 2652 women) [177]. However, these trials
had significant heterogeneity and were of low quality. (See "The impact of obesity on female fertility
and pregnancy" and "Weight gain and loss in pregnancy".)

Regardless of its effect on pregnancy, weight loss before pregnancy should be recommended for
obese women because of general health benefits. (See "Obesity in adults: Health hazards".)

Women with eating disorders can also benefit from intervention. (See "Eating disorders in
pregnancy".)

HEIGHT — Women with shorter stature appear to be at increased risk for preterm birth and taller
women appear to be decreased risk [178-180].

STRESS — Most women report experiencing at least one stressful life event in the year before
giving birth [181]. An association between stress (including posttraumatic stress disorder) and PTB
is biologically plausible. There is evidence that maternal and fetal stress activates cells in the
placenta, decidua, and fetal membranes to produce corticotropin-releasing hormone (CRH) [182].
CRH can enhance local prostaglandin production, which initiates contractions. However, studies
have not consistently demonstrated a relationship between maternal stress, CRH concentration,
and PTB [183-185]. (See"Pathogenesis of spontaneous preterm birth", section on 'Activation of the
HPA axis'.)

When maternal psychosocial stress has been associated with an increased risk of PTB, the risk
was modest: approximately 1.5- to twofold in large prospective studies [185-190]. Analysis of data is
complicated by difficulty defining and measuring maternal stress, assessments at different times
during pregnancy, variations in adjustment of confounders, lack of differentiation between acute and
chronic stressors, and discordant baseline characteristics of the populations studied [191].
Intervention — Although social support during pregnancy has resulted in improvements in
immediate psychosocial outcome, it has not been shown to significantly reduce the rate of PTB in
stressed gravida. A 2003 systematic review concluded that social support was not sufficiently
powerful to improve the obstetrical outcome of the pregnancy in which it was provided, possibly
because of the immense social deprivation experienced by most of the women in the trials
examined [192].

There are limited data on other interventions for reducing stress in pregnant women (eg, relaxation
or mind-body therapies [eg, meditation, massage, yoga, breathing exercises, music therapy,
aromatherapy]). Available trials are small and of poor quality; clear effects on birth outcome have
not been proven [193].

SUBOPTIMAL PRENATAL CARE — The absence of prenatal care has been consistently identified
as a risk factor for preterm labor and delivery, but it is less clear whether this association is causal
or a marker for other factors that contribute to PTB. (See "Initial prenatal assessment and first-
trimester prenatal care" and "Prenatal care (second and third trimesters)".)

Intervention — Retrospective studies cannot be adequately controlled to adjust for confounding

factors, while randomized trials (no prenatal care versus standard care) would be unethical.
Therefore, the only well-designed studies on the effect of prenatal care on PTB compare standard
with enhanced care (ie, some combination of patient education, case management, home visits,
nutrition counseling, and extra prenatal visits and cervical examinations).

Regular prenatal care should be encouraged and improves perinatal outcome in women with
underlying medical disorders (eg, diabetes, chronic hypertension, thyroid disease) or pregnancy-
related conditions (eg, preeclampsia); however, the March of Dimes trial discussed below suggests
enhanced care is unlikely to decrease the incidence of PTB.

The March of Dimes Multicenter Prematurity Prevention Trial assigned 2395 women with singleton
or multiple gestations at high risk for PTB to either standard of care or an enhanced care
intervention (more frequent prenatal visits, improved patient education regarding symptoms and
signs of preterm labor, and weekly pelvic examinations after 20 to 24 weeks of gestation) [12].
There was no significant difference between the two groups in sPTB rates. A meta-analysis that
included three trials of women with singleton pregnancies also found no clear evidence that
specialized antenatal clinics reduced PTB [194].

PRETERM LABOR — Uterine contractions are an essential component of labor, but mild irregular
contractions are a normal finding at all stages of pregnancy, thereby adding to the challenge of
distinguishing true labor (contractions that result in cervical change) from false labor (contractions
that do not result in cervical change, ie, Braxton-Hicks contractions). Only 13 percent of women
presenting at <34 weeks of gestation and meeting explicit contraction criteria for preterm labor
deliver within one week. (See "Diagnosis of preterm labor and overview of preterm birth".)

Intervention — Tocolytic therapy of an acute episode of idiopathic preterm labor often abolishes
contractions temporarily but does not remove the underlying stimulus that initiated the process of
parturition or reverse parturitional changes in the uterus. The net effect is that tocolytics are unlikely
to prolong pregnancy by weeks or months. However, delivery can often be delayed for at least 48
hours so that glucocorticoids given to the mother can achieve their maximum effect. (See "Inhibition
of acute preterm labor".)
FETAL FACTORS — Male sex is a risk factor for sPTB [195-198]. Certain congenital anomalies
[199,200] and growth restriction [201-206] are risk factors for spontaneous and indicated PTB. For
example, congenital anomalies may lead to polyhydramnios, which increases the risk for preterm
labor and PPROM.

PATERNAL RISK FACTORS — No paternal risk factors for development of PTB in their partners
have been identified [207]. PTB risk does not appear to be affected by the father's history of
preterm children with other women or PTBs to members of the father's family [208].

PREDICTING RISK FOR PRETERM BIRTH

Risk scoring systems — Risk scoring is a quantitative method used to identify women at
increased risk for PTB. Proposed systems typically calculate an additive score based on points
assigned to arbitrarily selected or weighted epidemiological, historical, and clinical risk factors
[67,147,148].

A systematic review concluded that there were no effective risk scoring systems for prediction of
PTB [149]. This is due to our lack of knowledge regarding the cause(s) of PTB in most women and
because the most powerful risk factor is previous PTB, which is not applicable to nulliparous
women. The positive predictive value (the percent of women defined as high risk that actually go on
to have a PTB) of most risk scoring systems is low, 20 to 30 percent, and varies according to the
population studied [150].

Biomarkers — Fetal fibronectin is a useful biomarker for predicting PTB in women with
contractions but minimal cervical change. It is most useful when combined with ultrasound
assessment of cervical length and when a quantitative measurement is available. (See "Diagnosis
of preterm labor and overview of preterm birth", section on 'Ultrasound ± fetal fibronectin
examination'.)

Over 30 other biomarkers have been studied for identification of women at high risk of PTB. A
systematic review of these biomarkers included 72 observational studies involving almost 90,000
women and concluded that none of these other biomarkers was clinically useful for predicting sPTB
in asymptomatic women [209]. The markers included inflammation-related biomarkers,
placental protein/hormone-related biomarkers, angiogenesis-related biomarkers, coagulation-
related biomarkers, genetic-biomarkers, and proteomic-related biomarkers. There is no clinical role
for assessing levels of single or combinations of biomarkers (other than fetal fibronectin) for
prediction of PTB.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
 Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient information: Preterm labor (The Basics)")

●Beyond the Basics topics (see "Patient information: Preterm labor (Beyond the
Basics)" and "Patient information: Bacterial vaginosis (Beyond the Basics)" and "Patient
information: Management of a cervical biopsy with precancerous cells (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●There are many risk factors for preterm labor and delivery (table 1). Some are reversible,
others are permanent. Identification of risk factors for spontaneous preterm birth (sPTB)
before conception or early in pregnancy ideally would lead to interventions that could help
prevent this complication (refer above)
●Prior PTB is the strongest risk factor for future PTB, and recurrences often occur at the same
gestational age. The frequency of recurrent PTB is 15 to 30 percent after one PTB and up to
60 percent after two PTBs. Term births decrease the risk of PTB in subsequent pregnancies
(table 2 and table 3). (See 'History of spontaneous preterm birth' above.)
●Short cervical length on ultrasound examination between 16 and 24 weeks of gestation in the
current pregnancy is a well-established risk factor for PTB. Progesterone supplementation can
prolong gestation. (See 'Short cervix' above.)
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Topic 6761 Version 48.0

Diagnosis of preterm labor and overview of preterm birth
Author
Charles J Lockwood, MD, MHCM
Section Editor
Susan M Ramin, MD
Deputy Editor
Vanessa A Barss, MD, FACOG
Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2016. | This topic last updated: Feb 29, 2016.

INTRODUCTION — Identifying women with preterm contractions who will actually deliver preterm is
an inexact process, even though preterm labor is one of the most common reasons for
hospitalization of pregnant women. Accurate identification of women truly in preterm labor allows
appropriate application of interventions that can improve neonatal outcome: antenatal corticosteroid
therapy, group B streptococcal infection prophylaxis, magnesium sulfate for neuroprotection, and
transfer to a facility with an appropriate level nursery (if necessary). On the other hand, accurate
triage of women not actually in preterm labor can avoid performance of unnecessary interventions
and associated costs for the 20 to 50 percent of patients with suspected preterm labor who will go
on to deliver at term without tocolytic therapy [1].

This topic will describe our approach to the diagnostic evaluation of women who present with
possible preterm labor and provide an overview of issues related to preterm birth. Treatment of
preterm labor is discussed separately. (See "Inhibition of acute preterm labor".)

PRETERM LABOR

Pathogenesis — The pathophysiology of preterm labor involves four primary pathogenic processes
that result in a final common pathway ending in spontaneous preterm labor and delivery:

●Activation of the maternal or fetal hypothalamic-pituitary-adrenal axis associated with either

maternal anxiety and depression or fetal stress
●Infection
●Decidual hemorrhage
●Pathological uterine distention

These processes and the pathophysiology of normal labor are discussed in detail separately.
(See "Pathogenesis of spontaneous preterm birth" and "Physiology of parturition".)

Clinical findings — The clinical findings of true labor (ie, contractions plus cervical change) are the
same whether labor occurs preterm or at term. The following are early signs and symptoms of labor;
however, they are non-specific and can be present for several hours in women who do not exhibit
cervical change:

●Menstrual-like cramping
●Mild, irregular contractions
●Low back ache
●Pressure sensation in the vagina
 ●Vaginal discharge of mucus, which may be clear, pink, or slightly bloody (ie, mucus plug,
bloody show)

Uterine contractions are the sine qua non of labor, but mild irregular contractions are a normal
finding at all stages of pregnancy, thereby adding to the challenge of distinguishing true labor
(contractions that result in cervical change) from false labor (contractions that do not result in
cervical change, ie, Braxton Hicks contractions). True labor is more likely when an increasing
frequency of contractions is accompanied by increasing intensity and duration of contractions as an
increase in the frequency of contractions alone may occur transiently, especially at night and with
increasing gestational age. Although many investigators have tried, no one has been able to identify
a threshold contraction frequency that effectively identifies women who will progress to true labor.
Only 13 percent of women presenting at <34 weeks of gestation with explicit contraction criteria for
preterm labor deliver within one week [2].

Cervical changes on physical examination that precede or accompany true labor include dilation,
effacement, softening, and movement to a more anterior position. A short or a dilated cervix may be
the first clinical manifestation of a parturition process triggered by subclinical inflammation [3]. The
rate of cervical change distinguishes cervical ripening, which occurs over days to weeks, from true
labor, in which cervical change occurs over minutes to hours.

Diagnostic evaluation

History and initial examinations — Our initial evaluation of women with suspected preterm labor
includes:

●Review of the patient's past and present obstetrical and medical history, and assessment of
gestational age.
●Evaluation of signs and symptoms of preterm labor (see 'Clinical findings' above) and risk
factors for preterm birth (table 1).
●Maternal vital signs (temperature, blood pressure, heart rate, respiratory rate).
●Review of the fetal heart rate pattern. (See "Intrapartum fetal heart rate assessment".)
●Assessment of contraction frequency, duration, and intensity. (See "Management of normal
labor and delivery", section on 'Uterine contractions'.)
●Examination of the uterus to assess firmness, tenderness, fetal size, and fetal position.

Speculum examination — We perform a speculum examination using a wet non-lubricated

speculum. Lubricants may interfere with tests on vaginal samples. The goals of this examination are
to:

●Estimate cervical dilation. Cervical dilation >3 cm supports the diagnosis of preterm labor.
●Assess the presence and amount of uterine bleeding. Bleeding from abruptio placenta or
placenta previa can trigger preterm labor. (See "Placental abruption: Clinical features and
diagnosis" and "Clinical features, diagnosis, and course of placenta previa".)
●Evaluate fetal membrane status (intact or ruptured) by standard methods. Preterm premature
rupture of membranes (PPROM) often precedes or occurs during preterm labor. Diagnosis
and management of PPROM are reviewed separately. (See "Preterm premature (prelabor)
rupture of membranes".)
 ●Obtain a cervicovaginal fluid specimen in case fetal fibronectin (fFN) testing is desired after
transabdominal ultrasound examination. "Blind" sampling is acceptable if a speculum
examination cannot be performed. In one method, the posterior vaginal wall is depressed with
an unlubricated, gloved finger and then the polyester swab is slowly passed along the finger
toward the posterior fornix until resistance is felt [4]. In another method, the labia are held
apart and then the swab is blindly inserted into the vagina and directed slowly toward the
posterior fornix until meeting resistance [5]. The swab is rotated in the posterior fornix for 10
seconds. In both methods, it is important to stop at the first sign of resistance to avoid
rupturing exposed membranes, if present. (See 'Fetal fibronectin' below.)

Cervical examination — In most patients, cervical dilation and effacement are assessed by digital
examination after speculum examination and after placenta previa and rupture of membranes have
been excluded by history and physical, laboratory, and ultrasound examinations, as appropriate. A
digital examination should be performed sooner if the information is urgently needed to care for the
patient (eg, abnormal fetal heart rate, probable advanced phase of active labor) and placenta previa
is unlikely. As discussed above, cervical dilation >3 cm supports the diagnosis of preterm labor and
inhibition of acute preterm labor is less likely to be successful as the cervix dilates beyond 3 cm.

When assessing cervical dilation and effacement in the second trimester, it is important to
distinguish between patients whose membranes have hour-glassed (prolapsed) through a mildly
dilated and effaced cervix (suggestive of cervical insufficiency) and those who are in active labor
with advanced cervical dilation and effacement. Transvaginal ultrasound assessment of the cervical
length in the second trimester can be used to make the diagnosis of cervical insufficiency in women
with risk factors. Only a digital cervical examination is needed in patients with advanced cervical
dilation. (See "Cervical insufficiency", section on 'Physical examination reveals a dilated cervix and
visible membranes before 24 weeks' and "Transvaginal cervical cerclage", section on 'Replacement
of prolapsed membranes'.)

Laboratory evaluation — We order the following laboratory tests:

●Rectovaginal group B streptococcal culture if not done within the previous five weeks;
antibiotic prophylaxis depends on the results. (See "Neonatal group B streptococcal disease:
Prevention", section on 'Approach to threatened preterm delivery'.)
●Urine culture, since asymptomatic bacteriuria is associated with an increased risk of preterm
labor and birth. (See"Urinary tract infections and asymptomatic bacteriuria in pregnancy".)
●Drug testing in patients with risk factors for substance abuse, given the link between cocaine
use and placental abruption. (See "Overview of substance misuse in pregnant women".)
●Fetal fibronectin (fFN) in women <34 weeks of gestation with cervical dilation <3 cm and
cervical length 20 to 30 mm on transvaginal ultrasound examination. (See 'Cervical length 20
to 30 mm' below.)

Fetal fibronectin — Fetal fibronectin (fFN) is an extracellular matrix protein present at the decidual-
chorionic interface. Disruption of this interface due to subclinical infection or inflammation, abruption
or uterine contractions releases fFN into cervicovaginal secretions, which is the basis for its use as
a marker for predicting spontaneous preterm birth [6]. A positive fFN test (fFN concentration
≥50 ng/mL in cervicovaginal fluid between 220/7ths and 346/7ths weeks of gestation) in women with
intact membranes, cervical dilation <3 cm, and no gross vaginal bleeding correlates with an
increased risk of preterm delivery within seven days.

Measurement of fFN is performed to distinguish women in true preterm labor from those with false
labor. Accurate identification of women in true preterm labor provides an opportunity for
interventions that can improve neonatal outcome (eg, antenatal corticosteroid therapy, group B
streptococcal infection prophylaxis, magnesium sulfate for neuroprotection, transfer to a facility with
an appropriate level nursery, if necessary). It would also avoid unnecessary intervention and
associated costs for the 20 to 50 percent who will go on to deliver at term without tocolytic therapy
[1]. Evidence from randomized trials suggests that fFN testing results in a modest cost benefit,
which is largely dependent on a reduction in hospital admission for women with a negative test [7].

In women with signs and symptoms of preterm labor, a 2013 systematic review of five randomized
trials and 15 diagnostic test accuracy studies evaluating cervicovaginal fFN for predicting preterm
birth reported the following pooled estimates [7]:

●Delivery within 7 to 10 days of testing: sensitivity and specificity 76.7 and 82.7 percent,
respectively
●Delivery <34 weeks of gestation: sensitivity and specificity 69.1 and 84.4 percent,
respectively
●Delivery <37 weeks of gestation: sensitivity and specificity 60.8 and 82.3 percent,
respectively

Positive and negative predictive values depend on the prevalence of preterm birth in the population.
In a systematic review in which the prevalence of preterm birth within seven days of sampling varied
from 2 to 30 percent among the included studies, the overall pretest probability of delivery within
seven days of testing was 7.7 percent, and based on positive or negative fFN results, the post-test
probabilities were 25.9 and 2.4 percent, respectively [8].

False positive results can occur due to ejaculate from coitus within the previous 24 hours, a grossly
bloody specimen, or digital cervical examination [9-11]. Digital cervical examination can also cause
a false positive result [9]. Theoretically, transvaginal ultrasound examination may cause a false
positive result, but in one study all 25 women with a negative baseline fFN test had a second
negative fFN test post-ultrasound [12]. Administration of intravaginal substances, such as
lubricants, medications, or douching may interfere with the assay [13]

Quantitative measurement of fFN appears to improve predictive value compared with use of the
qualitative test using a 50ng/mL threshold [14-16]. In symptomatic women, the positive predictive
values of fFN thresholds of 10, 50, 200, and 500 ng/mLfor preterm birth within 14 days were 11, 20,
37, and 46 percent, respectively, in one prospective blinded study [14]. For preterm birth <34 weeks
of gestation, positive predictive values for the same thresholds were 19, 32, 61, and 75 percent,
respectively. Instrumentation for quantitative measurement of fFN is not commercially available in
the United States.

An algorithm combining quantitative fFN and cervical length, demographic information, and obstetric
history (previous spontaneous preterm birth/preterm premature rupture of membranes) has been
incorporated into an App (QUiPP) for prediction of spontaneous preterm birth in Europe [17,18].
Diagnosis — We make the diagnosis of preterm labor based upon clinical criteria of regular painful
uterine contractions accompanied by cervical change (dilation and/or effacement). Vaginal
bleeding and/or ruptured membranes in this setting increase diagnostic certainty [19]. Because the
clinical findings of early labor are poorly predictive of the diagnosis, over-diagnosis is common until
labor is well established.

Specific clinical criteria that have been used for selecting subjects in research settings include
persistent uterine contractions (4 every 20 minutes or 8 every 60 minutes) with documented cervical
change or cervical effacement ≥80 percent or cervical dilation >2 cm. These criteria were chosen
because women who do not meet these criteria are often ultimately diagnosed with false labor and
go on to have a late preterm or term delivery [20].

Triage

Pregnancies ≥34 weeks of gestation — The 34th week of gestation is the threshold at which
perinatal morbidity and mortality are too low to justify the potential maternal and fetal complications
and costs associated with inhibition of preterm labor, which only results in short term delay in
delivery. (See "Inhibition of acute preterm labor", section on 'Lower and upper gestational age
limits'.)

Furthermore, antenatal corticosteroids are not administered after 34 weeks of gestation because of
the low risk of severe respiratory morbidity after 34 weeks, the lack of consistent evidence of
corticosteroid efficacy at this age, and the theoretic potential for long-term harm following late
exposure. (See "Antenatal corticosteroid therapy for reduction of neonatal morbidity and mortality
from preterm delivery", section on 'After 34 weeks'.)

Therefore, women in preterm labor ≥34 weeks are admitted for delivery. After an observation period
of four to six hours, women without progressive cervical dilation and effacement are discharged to
home, as long as fetal well-being is confirmed (eg, reactive nonstress test) and obstetrical
complications associated with preterm labor, such as abruptio placenta, chorioamnionitis, and
preterm rupture of membranes, have been excluded. We arrange follow-up in one to two weeks and
give the patient instructions to call if she experiences additional signs or symptoms of preterm labor,
or has other pregnancy concerns (eg, bleeding, rupture of membranes, decreased fetal activity).
(See "Patient information: Preterm labor (Beyond the Basics)".)

Pregnancies <34 weeks of gestation — In women <34 weeks with uterine contractions, cervical
dilation ≥3 cm supports the diagnosis of preterm labor; further diagnostic evaluation with
sonographic measurement of cervical length or laboratory assessment of fetal fibronectin does not
enhance diagnostic accuracy. Treatment of preterm labor is initiated. (See 'Treatment of women
<34 weeks with suspected preterm labor' below.)

The diagnosis of preterm labor is less clear in women with contractions, cervical dilation <3 cm, and
intact membranes. Our approach is based upon clinical experience and available data that the
frequency of preterm birth is low in symptomatic women <34 weeks with cervical length >30 mm
[19,21-23], unless abruption is the cause of their symptoms; the frequency of preterm birth is
increased but still relatively low in symptomatic women with cervical length 20 to 30 mm; and the
frequency of preterm birth is high in symptomatic women with cervical length <20 mm (algorithm 1)
[2,19,21,24-26].
Ultrasound ± fetal fibronectin examination — Measurement of cervical length is useful for
supporting or excluding the diagnosis of preterm labor when the diagnosis is unclear. A short cervix
before 32 weeks of gestation is predictive of preterm birth in all populations. (See "Second-trimester
evaluation of cervical length for prediction of spontaneous preterm birth".)

We also perform an obstetrical ultrasound examination to look for fetal, placental, and maternal
structural abnormalities; confirm the fetal presentation; assess amniotic fluid volume; and estimate
fetal weight. This information can be useful for counseling the patient about the potential causes
and outcomes of preterm birth and determining the best route of delivery, if required.

Cervical length 20 to 30 mm — Symptomatic women with cervical dilation <3 cm and cervical
length 20 to 30 mm are at increased risk of preterm birth compared with women with longer cervical
lengths, but most of these women do not deliver preterm. Therefore, for this subgroup of women,
we send a cervicovaginal sample for fFN testing (see 'Fetal fibronectin'above). Selective testing
helps reduce diagnostic uncertainty and, in turn, unnecessary intervention, by identifying the
significant proportion of patients in this group who are at low (<5 percent) risk of preterm delivery
within seven days [27]. Since the test is expensive, reducing the number of women tested by one-
third is advantageous [28,29].

If the fFN test is positive, we begin interventions to reduce morbidity associated with preterm birth
(see 'Treatment of women <34 weeks with suspected preterm labor' below). If the fFN test is
negative, we discharge the patient after 6 to 12 hours of observation, given its high negative
predictive value (98 to 100 percent for delivery within 7 or 14 days [30]) [7].

Use of sonographic cervical length and fFN determinations to differentiate true labor from false
labor in preterm symptomatic women are supported by the American College of Obstetricians and
Gynecologists [31].

Cervical length <20 mm — Symptomatic women with cervical length <20 mm are at high risk (>25
percent) of delivery within seven days; the addition of fFN testing does not significantly improve the
predictive value of cervical length measurement alone [27-29,32,33]. Therefore, we do not send
their cervicovaginal samples to the laboratory for fFN testing and we begin interventions to reduce
morbidity associated with preterm birth. (See 'Treatment of women <34 weeks with suspected
preterm labor' below.)

Cervical length >30 mm — Symptomatic women with cervical length >30 mm are at low risk (<5
percent) of delivery within seven days, regardless of fFN result; the addition of fFN testing does not
significantly improve the predictive value of cervical length measurement alone [27,28,32,33].
Therefore, we do not send their cervicovaginal samples to the laboratory for fFN testing.

After an observation period of four to six hours, women without progressive cervical dilation and
effacement are discharged to home, as long as fetal well-being is confirmed (eg, reactive nonstress
test) and obstetrical complications associated with preterm labor, such as abruptio placenta,
chorioamnionitis, and preterm rupture of membranes, have been excluded. We arrange follow-up in
one to two weeks and give the patient instructions to call if she experiences additional signs or
symptoms of preterm labor, or has other pregnancy concerns (eg, bleeding, rupture of membranes,
decreased fetal activity). (See "Patient information: Preterm labor (Beyond the Basics)".)
Treatment of women <34 weeks with suspected preterm labor — We hospitalize women
diagnosed with preterm labor <34 weeks of gestation and initiate the following treatments [34]:

●A course of betamethasone to reduce neonatal morbidity and mortality associated with

preterm birth. (See "Antenatal corticosteroid therapy for reduction of neonatal morbidity and
mortality from preterm delivery".)
●Tocolytic drugs for up to 48 hours to delay delivery so that betamethasone given to the
mother can achieve its maximum fetal effect. Inhibition of acute preterm labor and
management of pregnancies after successful inhibition are reviewed separately.
(See "Inhibition of acute preterm labor" and "Management of pregnant women after inhibition
of acute preterm labor".)
●Antibiotics for GBS chemoprophylaxis. (See "Neonatal group B streptococcal disease:
Prevention", section on 'Approach to threatened preterm delivery'.)
●Magnesium sulfate for pregnancies at 24 to 32 weeks of gestation. In utero exposure to
magnesium sulfate provides neuroprotection against cerebral palsy and other types of severe
motor dysfunction in offspring born preterm. (See"Neuroprotective effects of in utero exposure
to magnesium sulfate".)

Antibiotic therapy has no role in the treatment of acute preterm labor in the absence of a
documented infection or GBS prophylaxis [35]. (See "Inhibition of acute preterm labor", section on
'Antibiotic therapy'.)

Progesterone supplementation has no role in the treatment of acute preterm labor.

(See "Progesterone supplementation to reduce the risk of spontaneous preterm birth", section on
'Threatened preterm labor'.)

OVERVIEW OF PRETERM BIRTH — Preterm birth refers to a delivery that occurs before 37 weeks
of gestation. It may or may not be preceded by preterm labor. Although term pregnancy has been
defined as 370/7ths to 416/7ths weeks of gestation, the period 370/7ths to 386/7ths weeks is considered
“early term” because neonates born in this gestational age range have higher neonatal morbidity
and mortality than infants born at “full term” from 390/7ths to 406/7ths weeks [36,37].

Classification — Preterm births are described by gestational age, birth weight, and initiating factor.

●Gestational age criteria:

World Health Organization [38]:
•Moderate to late preterm: 32 to <37 weeks
•Very preterm: 28 to <32 weeks
•Extremely preterm: <28 weeks
Centers for Disease Control and Prevention [39]
•Preterm: <37 weeks
•Late preterm: 34 to 36 weeks
•Early preterm: <34 weeks
●Birth weight criteria [40]:
•Low birth weight (LBW): <2500 grams
•Very low birth weight (VLBW): <1500 grams
•Extremely low birth weight (ELBW): <1000 grams
 ●Initiating factor: spontaneous or iatrogenic (ie, indicated, provider-initiated)
•Spontaneous: 70 to 80 percent, due to preterm labor (40 to 50 percent) or preterm
premature rupture of membranes (20 to 30 percent).
•Provider-initiated: 20 to 30 percent, due maternal or fetal issues (eg, preeclampsia,
placenta previa, abruptio placenta, fetal growth restriction, multiple gestation).
Complications of pregnancy can lead to both spontaneous and provider-initiated preterm
births.

Prevalence — Few countries are able to provide reliable national preterm birth prevalence data.
Worldwide, the preterm birth rate is estimated to be about 11 percent (range 5 percent [parts of
Europe] to 18 percent [parts of Africa]), and about 15 million children are born preterm each year
(range 12 to 18 million) [41,42]. Of these preterm births, 84 percent occurred at 32 to 36 weeks, 10
percent occurred at 28 to <32 weeks, and 5 percent occurred at <28 weeks.

In the United States in 2013, 11.4 percent of births were <37 weeks (8 percent at 34 to 36 weeks
and 3.4 percent <34 weeks [1.9 percent <32 weeks]) [43].

An increase in multiple gestations due to assisted reproductive technology is one reason for the
increasing prevalence of preterm birth in some countries. (See "Pregnancy outcome after assisted
reproductive technology", section on 'Proportion of singleton and multiple gestation'.)

Epidemiology — Preterm birth rates in the United States are highest among women <20 and >35
years of age and among non-Hispanic black mothers, followed by American Indian or Alaskan
Natives, Hispanics, non-Hispanic whites, and Asian or Pacific Islanders
[44]. Racial/ethnic disparities in preterm birth rates may reflect biological (genetic)
differences and/orvariations in socioeconomic, lifestyle, and cultural factors; access to medical care;
and environmental/occupational exposures.

Risk factors — When trying to assess the probability of preterm labor, it can be helpful to assess
the presence or absence of clinical risk factors. Numerous risk factors for spontaneous preterm birth
have been reported (table 1). Causal associations between most of these risk factors and preterm
birth have been difficult to prove because (1) many preterm births occur among women with no risk
factors, (2) some obstetrical complications resulting in preterm birth require cofactors to exert their
effect, making the chain of causality difficult to document, and (3) an adequate animal model for
study of preterm birth does not exist. Risk factors for preterm birth are discussed in detail
separately. (See "Preterm birth: Risk factors and interventions for risk reduction".)

Significance

Child — Preterm birth is the leading direct cause of neonatal death (death in the first 28 days of
life), and is responsible for 27 percent of neonatal deaths worldwide [41,45]. The risk of neonatal
mortality decreases as gestational age at birth increases, but the relationship is nonlinear (figure 1).
The risk of neonatal mortality is also significantly impacted by the cause of preterm birth. In a
prospective population-based cohort study, live born neonates <34 weeks of gestation delivered
because of suspected growth restriction had two- to threefold higher mortality than those born after
preterm labor [46]. Preterm birth is the second most common cause of death (after pneumonia) in
children younger than five years. (See "Perinatal mortality", section on 'Causes of infant death'.)
Preterm birth is also a major determinant of short- and long-term morbidity in infants and children.
The burden of preterm birth includes neonatal morbidity and long-term sequelae, including
neurodevelopmental deficits (eg, cerebral palsy, impaired learning, visual disorders) and an
increased risk of a spectrum of diseases in adulthood [47]. (See "Short-term complications of the
preterm infant" and "Long-term complications of the preterm infant".)

Maternal — Spontaneous preterm birth has been associated with an increased risk of maternal
cardiovascular morbidity and mortality years after the delivery. In a 2015 systematic review and
meta-analysis of 10 cohort studies, women who had a spontaneous preterm delivery were at higher
risk for the following cardiovascular events when compared with women who delivered at term and
followed for 12 to 35 years postpartum [48]:

●Fatal and nonfatal ischemic heart disease (hazard ratio [HR] 1.38, 95% CI 1.22-1.57)
●Fatal and nonfatal stroke (HR 1.71, 95% CI 1.53-1.91)
●Fatal and nonfatal overall cardiovascular disease (HR 2.01, 95% CI: 1.52-2.65)

It is unclear why spontaneous preterm delivery appears to be a marker for later cardiovascular
disease or whether women who delivered preterm should be identified by primary care providers
and encouraged to optimize modifiable risk factors for cardiovascular disease more than women
without this history. (See "Overview of primary prevention of coronary heart disease and stroke".)

Prevention — Interventions with proven efficacy for prevention of preterm birth include [49]:

●Smoking cessation. (See "Cigarette smoking: Impact on pregnancy and the neonate".)
●Progesterone supplementation in asymptomatic women with previous spontaneous preterm
birth or in asymptomatic women with no history of spontaneous preterm birth but a short cervix
(ie, ≤20 mm) in the current pregnancy. (See"Progesterone supplementation to reduce the risk
of spontaneous preterm birth".)
●Reduction of multiple gestation by limiting the number of embryo transfers in women
undergoing assisted reproductive technology (see "Strategies to control the rate of high order
multiple gestation") or multifetal pregnancy reduction. (See"Multifetal pregnancy reduction and
selective termination".)
●Avoidance of induction of labor and scheduled cesarean delivery in the absence of medical
indications. (See "Induction of labor", section on 'Elective or marginally indicated induction at
term' and "Cesarean delivery: Preoperative issues", section on 'Indications and
contraindications'.)
●Cerclage in women with previous spontaneous preterm birth and a short cervix in current
pregnancy. (See "Cervical insufficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient information: Preterm labor (The Basics)" and "Patient information:
How to tell when labor starts (The Basics)")
●Beyond the Basics topics (see "Patient information: Preterm labor (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Preterm labor

●Early signs and symptoms of labor are non-specific and include: menstrual-like cramping;
mild, irregular contractions; low back ache; pressure sensation in the vagina; vaginal
discharge of mucus, which may be clear, pink, or slightly bloody (ie, mucus plug, bloody
show). (See 'Clinical findings' above.)
●The diagnosis of preterm labor is based on clinical criteria of regular painful uterine
contractions accompanied by cervical dilation and/or effacement. (See 'Diagnosis' above.)
●Thirty-four to 35 weeks of gestation is the threshold at which perinatal morbidity and mortality
are too low to justify the potential maternal and fetal complications and costs associated with
inhibition of preterm labor, which only results in short-term delay in delivery. (See 'Pregnancies
≥34 weeks of gestation' above.)
●For pregnancies ≥34 weeks of gestation, women without progressive cervical dilation and
effacement after an observation period of four to six hours can be discharged to home, as long
as fetal well-being is confirmed (eg, reactive nonstress test) and obstetrical complications
associated with preterm labor, such as abruptio placenta, chorioamnionitis, and preterm
rupture of membranes, have been excluded. Women in preterm labor are admitted for
delivery. (See'Pregnancies ≥34 weeks of gestation' above.)
●For pregnancies <34 weeks of gestation and cervical length <3 cm, transvaginal ultrasound
measurement of cervical length and laboratory analysis of cervicovaginal fetal fibronectin level
help to support or exclude the diagnosis of preterm labor, as described in the algorithm
(algorithm 1). (See 'Pregnancies <34 weeks of gestation' above.)
●For pregnancies <34 weeks and cervical length ≥3 cm, we administer tocolytic drugs for up
to 48 hours, antibiotics for group B streptococcal chemoprophylaxis (when appropriate), and
antenatal betamethasone. Magnesium sulfate is administered for neuroprotection to
pregnancies at 24 to 32 weeks of gestation. (See 'Treatment of women <34 weeks with
suspected preterm labor' above.)

Preterm birth

●Obstetricians classify preterm births as early (<34 week) or late (34 to 36 weeks) and
spontaneous or initiated by a clinician for medical or obstetrical indications. Seventy to 80
percent of preterm births are spontaneous and due to preterm labor (40 to 50 percent) or
preterm premature rupture of membranes (20 to 30 percent). (See 'Classification'above.)
●In the United States, 11.4 percent of births were <37 weeks (8 percent at 34 to 36 weeks and
3.4 percent <34 weeks [1.9 percent <32 weeks]) in 2013. (See 'Prevalence' above.)
 ●Preterm birth rates in the United States are highest among women <20 and >35 years of age
and among non-Hispanic black mothers. Numerous risk factors for spontaneous preterm birth
have been reported (table 1). (See 'Epidemiology'above and 'Risk factors' above.)
●Preterm birth is the leading direct cause of neonatal death (death in the first 28 days of life),
and is responsible for 27 percent of neonatal deaths worldwide. The risk of neonatal mortality
decreases as gestational age at birth increases, but the relationship is nonlinear (figure 1).
Preterm birth is also a major determinant of short- and long-term morbidity.
(See'Significance' above.)
●Spontaneous preterm birth has been associated with an increased risk of maternal
cardiovascular morbidity and mortality years after the delivery. It is unclear why spontaneous
preterm delivery is a marker for later cardiovascular disease or whether women who delivered
preterm should be identified by primary care providers and encouraged to optimize modifiable
risk factors for cardiovascular disease more than women without this history.
(See 'Maternal' above.)
Use of UpToDate is subject to the Subscription and License Agreement.

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381:223.

Topic 6798 Version 46.0

Antenatal corticosteroid therapy for reduction of neonatal morbidity and mortality from
preterm delivery
Authors
Men-Jean Lee, MD
Debra Guinn, MD, FACOG
Section Editor
Charles J Lockwood, MD, MHCM
Deputy Editor
Vanessa A Barss, MD, FACOG
Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2016. | This topic last updated: Apr 08, 2016.

INTRODUCTION — In a landmark paper, Liggins and Howie showed that a single course of
antenatal corticosteroid therapy administered to women at risk for preterm delivery (PTD) reduced
the incidence and severity of respiratory distress syndrome (RDS) and mortality in offspring [1].
More than a dozen randomized trials have confirmed these findings [2]. Subsequent trials have also
shown that antenatal corticosteroid therapy improves circulatory stability in preterm neonates,
resulting in lower rates of intraventricular hemorrhage (IVH) and necrotizing enterocolitis compared
with unexposed preterm neonates.

This topic will review evidence supporting the use of antenatal corticosteroids to improve neonatal
outcomes in women at risk for preterm delivery, pharmacological issues, and clinical concerns
about administration of this therapy.

BACKGROUND

Mechanism of action — Corticosteroid stimulation of developmentally regulated gene expression

and physiologic functions result in maturation of the lungs and some other tissues [3]. Antenatal
steroids accelerate development of type 1 and type 2 pneumocytes, leading to structural and
biochemical changes that improve both lung mechanics (maximal lung volume, compliance) and
gas exchange [4-8]. Induction of type 2 pneumocytes increases surfactant production by inducing
production of surfactant proteins and enzymes necessary for phospholipid synthesis. Other effects
of antenatal corticosteroids include induction of pulmonary beta-receptors, which play a role in
surfactant release and absorption of alveolar fluid when stimulated [5]; induction of fetal lung
antioxidant enzymes [9]; and upregulation of gene expression for the epithelial Na+ channel, which
is important for absorption of lung fluid after birth [10]. For these changes to occur, however, the
lungs need to have reached a stage of development that is biologically responsive to
corticosteroids. (See 'Gestational age at administration' below.)

The biologic rationale for repeating antenatal corticosteroid therapy is based upon the observation
that biochemical stimulation of surfactant production appears to be reversible in cell culture models
(eg, surfactant protein mRNA levels decline to control levels after cortisol is removed) [5,11].
However, other beneficial effects, such as cytostructural maturation, persist (in rhesus monkeys)
after steroid exposure is withdrawn [12]. (See 'Use of repeated courses of therapy' below.)

Evidence of short-term clinical efficacy

Reduction of RDS — Randomized trials performed worldwide have consistently reported a
significant reduction in the incidence of RDS among infants exposed to antenatal corticosteroid
therapy. In a 2006 systematic review of randomized trials comparing antenatal corticosteroid
therapy versus placebo/no treatment in women at risk for preterm birth, antenatal corticosteroid
therapy resulted in a [2]:

●Reduction in RDS (relative risk [RR] 0.66, 95% CI 0.59-0.73; 21 studies, 4038 infants)
●Reduction in moderate to severe RDS (RR 0.55, 95% CI 0.43-0.71; 6 studies, 1686 infants)

A statistical benefit was observed among infants born between one and seven days after the first
treatment dose (RR 0.46, 95% CI 0.35-0.60; 9 trials, 1110 infants), but not for those born less than
24 hours or more than seven days after the first dose. The benefits of corticosteroids were not
affected by fetal gender or race [13]; however, these conclusions were based on analysis of
subgroups defined after randomization and intervention, which may have biased the results [14].

Reduction of IVH, NEC, NNM, infection — Other benefits of antenatal corticosteroid therapy
demonstrated by a 2006 systematic review of randomized trials include reductions in the risk of [2]:

●Intraventricular hemorrhage (IVH) (RR 0.54, 95% CI 0.43-0.69; 13 studies, 2872 infants)
●Necrotizing enterocolitis (NEC) (RR 0.46, 95% CI 0.29-0.74; 8 studies, 1675 infants)
●Neonatal mortality (NNM) (RR 0.69, 95% CI 0.58-0.81; 18 studies, 3956 infants)
●Systemic infection in the first 48 hours of life (RR 0.56, 95% CI 0.38-0.85; 5 studies, 1319
infants)

Some of these benefits derive from the beneficial effect on respiratory morbidity; however,
maturational effects in numerous tissues due to corticosteroid stimulation of developmentally
regulated genes and physiological function suggest an independent effect, as well [15,16].

GESTATIONAL AGE AT ADMINISTRATION

23 to 34 weeks — We recommend administration of antenatal corticosteroids for all pregnant

women at 23 to 34 weeks who are at increased risk of preterm delivery within the next seven days.
Selection of pregnancies at increased risk of preterm delivery within the next seven days is a clinical
judgment based on high probability of induction/cesarean for obstetrical or medical indications (eg,
preeclampsia) or high probability of spontaneous preterm labor and delivery (eg, preterm premature
rupture of membranes, tocolysis for active preterm labor).

A 2006 meta-analysis of randomized trials of antenatal corticosteroids in women at risk of preterm

birth provided strong evidence that respiratory distress syndrome (RDS), intraventricular
hemorrhage (IVH), and neonatal death are significantly reduced when corticosteroids are given at
26 to 34 weeks of gestation [2].

A 2016 meta-analysis of randomized trials of antenatal corticosteroid therapy before 24 weeks of

gestation demonstrated a reduction in perinatal mortality at 23 weeks of gestation (OR 0.45, 95% CI
0.33-0.60), and a possible reduction at 22 weeks (OR 0.66, 95% CI 0.40-1.07) [17]. No statistical
reductions were observed for respiratory distress syndrome, severe intraventricular hemorrhage, or
necrotizing enterocolitis at <24 weeks. The possibility of a modest reduction cannot be definitively
excluded since the number of exposed newborns and events were small.
22 weeks or less — Administration of antenatal steroids in the 22nd week of gestation is
reasonable if delivery in the next seven days is anticipated and the family desires aggressive
neonatal intervention after thorough consultation with maternal-fetal medicine and neonatology
specialists [18]. Parents should be informed that antenatal corticosteroids may provide a survival
benefit while increasing the risk for survival with severe impairment. Also, if the pregnancy is not
delivered, then a single repeat course of antenatal corticosteroids may be needed later in gestation.
(See "Limit of viability" and 'Use of repeated courses of therapy' below.).

Administration of antenatal corticosteroids before 22 weeks of gestation is unlikely to significantly

improve lung function, as there are only a few primitive alveoli at this gestational age on which the
drug can exert an effect (see 'Mechanism of action'above) [19].

After 34 weeks — The use of antenatal corticosteroids after 34 weeks of gestation is controversial
because of inconsistent data about its efficacy and virtually no data about long-term safety.
Limitations of available data are largely related to the low risk for severe respiratory morbidity after
34 weeks of gestation and lack of information on long-term outcomes after exposure to
corticosteroids in late gestation [20-25]. (See 'Potential adverse effects on infants' below
and 'Potential long-term effects in children and adults' below.)

37 to 39 weeks of gestation — Empiric use of steroids has been recommended prior to cesarean
delivery at 37 to 39 weeks of gestation [20] based on the following lines of evidence. The Antenatal
Steroids for Term Caesarean Section trial (ASTECS) randomly assigned almost 1000 women to
receive a course of betamethasone or no betamethasone 48 hours before planned cesarean
delivery at ≥37 weeks and reported a reduction in the overall incidence of respiratory problems in
the treated group (composite of transient tachypnea of the newborn and respiratory distress
syndrome 2.4 versus 5.1 percent; relative risk 0.46, 95% CI 0.23-0.93) [21]. A similar trial
of dexamethasone administration 48 hours before scheduled cesarean delivery in the 38 th week of
gestation also reported a significant reduction in neonatal intensive care unit admission for
respiratory morbidity (10/616 [1.6 percent] versus 24/211 [3.9 percent]), which was primarily related
to a reduction in transient tachypnea of the newborn (1.3 versus 3.4 percent; RR 0.38, 95% CI 0.17-
0.85) [26]. There was no statistical difference between groups in respiratory distress syndrome (0.6
versus 1.6 percent; RR 0.4, 95% CI 0.13-1.26) or need for mechanical ventilation (0.8 versus 1.8
percent; RR 0.45, 95% CI 0.16-1.29).

34 to 36 weeks of gestation — The Antenatal Late Preterm Steroids Trial (ALPS) was designed to
investigate the efficacy of steroid administration after 34 weeks and before term [27]. Women at
340/7ths to 365/7ths weeks of gestation at high risk for late preterm birth were randomly assigned to
receive a first course of antenatal corticosteroids (two injections ofbetamethasone 24 hours apart)
or placebo. No tocolytics were administered. The primary outcome was a composite of neonatal
respiratory treatment in the first 72 hours (continuous positive airway pressure [CPAP], high-flow
nasal cannula for ≥2 hours, supplemental oxygen with FIO2 ≥0.30 for at least 4 hours,
extracorporeal membrane oxygenation, or mechanical ventilation), stillbirth, or neonatal death within
72 hours of delivery. Major findings were:

●The primary outcome occurred less often in the treatment group (11.6 versus 14.4 percent;
relative risk [RR] 0.80; 95% CI 0.66-0.97), and was primarily driven by reductions in CPAP
and high flow nasal cannula use.
 ●Severe respiratory complications (CPAP or high flow nasal cannula for ≥12 hours,
FIO2 ≥0.30 for at least 24 hours), transient tachypnea of the newborn, surfactant use, and
bronchopulmonary dysplasia, while infrequent in absolute terms, also occurred significantly
less frequently in the treatment group.
●Neonatal hypoglycemia occurred more frequently in the treatment group (24 versus 15
percent; RR 1.60; 95% CI 1.37-1.87).
●The rates of respiratory distress syndrome (RDS) and mechanical ventilation were similar in
both groups (RDS: 5.5 versus 6.4 percent with placebo; mechanical ventilation: 2.4 versus 3.1
percent with placebo).

No data are available about the long-term neurodevelopmental outcomes of children exposed to
corticosteroids between 340/7ths and 365/7ths weeks of gestation. This is a significant concern
because active brain growth through cell division is occurring at this time and might be inhibited by
administration of corticosteroids, which might affect neurodevelopment adversely (see 'Potential
long-term effects in children and adults' below). In newborns, postnatal systemic glucocorticoid
therapy contributes to neurodevelopmental impairment, especially cerebral palsy. (See "Postnatal
use of glucocorticoids in bronchopulmonary dysplasia", section on 'Long-term outcome'.)

Our approach — Based on the data described above, the authors take the following approach,
which limits late preterm in utero steroid exposure to pregnancies certain to deliver preterm and with
neonates at most risk for experiencing serious respiratory problems from transient tachypnea of the
newborn.

●For women scheduled for cesarean delivery at 340/7ths to 366/7ths weeks, we believe offering a
first course of antenatal corticosteroids to reduce neonatal respiratory morbidity is reasonable.
While there may be short-term advantages to receiving steroids prior to cesarean at this
gestational age, the risk-to-benefit ratio is unknown. Families should be informed and
participate in the decision-making.
We would not administer a second course of steroids at this gestational age to women who
received steroids before 34 weeks as the benefits and risks have not been studied in this
population. We also would not administer steroids to women undergoing scheduled cesarean
delivery at ≥37 weeks: The overall risk of neonatal respiratory illness at this gestational age is
low and rarely serious.
●For women in whom vaginal delivery at ≥340/7ths weeks is expected, we would not administer
a first course of steroids as transient tachypnea of the newborn is less common after labor and
vaginal birth [28-30].
●For women in whom delivery at 340/7ths to 366/7ths is uncertain (eg, threatened preterm labor),
we would not administer a course of steroids because of the potential for long-term harm with
no benefit if the patient does not deliver preterm.

Other approaches

●The Society for Maternal-Fetal Medicine Specialists recommends a two-dose course of

antenatal betamethasone for women at 340/7ths to 366/7ths weeks of gestation at high risk for
preterm birth within seven days, with the following caveats [31]:
 •For women with symptoms of preterm labor, cervical dilation should be ≥3 cm or
effacement ≥75 percent before treatment and tocolysis should not be used to delay
delivery for completion of the course of steroids.
•For women with potential medical/obstetric indications for early delivery, steroids should
not be administered until a definite plan for delivery has been made.
●The American College of Obstetricians and Gynecologists states administration
of betamethasone may be considered in women with a singleton pregnancy at 34 0/7ths to
366/7ths weeks of gestation at imminent risk of preterm birth within 7 days, with the following
caveats [32]:
•Antenatal corticosteroid administration should not be administered to women with
chorioamnionitis.
•Tocolysis should not be used to delay delivery in women with symptoms of preterm
labor to allow administration of antenatal corticosteroids. Medically/obstetrically indicated
preterm delivery should not be postponed for steroid administration.
•Antenatal corticosteroids should not be administered if the patient has already received
a course antenatal corticosteroids.
•Newborns should be monitored for hypoglycemia.
●The Royal College of Obstetricians and Gynaecologists (RCOG) recommends routine
administration of antenatal glucocorticoids for (1) all women at risk of preterm birth up to and
including 346/7ths weeks of gestation and (2) all women who must undergo scheduled cesarean
delivery before 39/07ths weeks of gestation [20].

TIMING BEFORE DELIVERY — Antenatal corticosteroid therapy should be administered when

indicated unless impending delivery is anticipated [15]. Therapy should not be withheld if delivery is
anticipated prior to completion of the two-dose course of medication. We suggest this liberal
approach to treatment because the minimal interval between drug administration and delivery
required to achieve neonatal benefits has not been clearly defined and the hour of delivery cannot
be predicted accurately. In one study, only one-quarter of women delivered within the optimal
window of after steroid administration: 24 hours to 7 days after the second dose [1,33].

Observational data suggest neonatal benefits begin to accrue within a few hours of corticosteroid
administration. Infants who received one dose of betamethasone in utero, but delivered before the
second dose was given, had better outcomes than infants who did not receive any antenatal
corticosteroids [34]. Laboratory data also support an early physiologic effect [35,36]. One study,
however, observed that a betamethasone booster appeared to increase the risk of respiratory
distress syndrome and decrease intact survival rates among infants who were delivered within 1 to
24 hours [37]; this finding warrants further study.

CHOICE OF DRUG AND INITIAL DOSE — Both betamethasone and dexamethasone are effective
for accelerating fetal lung maturity; either drug is acceptable for antenatal corticosteroid therapy. We
prefer betamethasone because long-term follow-up data of fetuses exposed only to dexamethasone
are limited and do not clearly demonstrate equivalence or superiority of dexamethasone over
betamethasone for both short- and long-term outcomes. In a 2013 Cochrane review of 12 trials
comparing use of different corticosteroids in women at risk of preterm birth (n = 1557 women and
1661 infants), no statistical differences between dexamethasone and betamethasone were
observed for respiratory distress syndrome (RDS) (relative risk [RR] 1.06, 95% CI 0.88-1.27; 5
trials, 753 infants) or neonatal death (RR 1.41, 95% CI 0.54-3.67; 4 trials, 596 infants) [38].
Although a statistical reduction in all intraventricular hemorrhage (IVH) favored dexamethasone use,
no significant differences in severe IVH or periventricular leukomalacia were noted. Use of
betamethasone also requires fewer injections than use of dexamethasone.

A course of therapy consists of:

●Betamethasone two doses of 12 mg given intramuscularly 24 hours apart OR

●Dexamethasone four doses of 6 mg given intramuscularly 12 hours apart. A non-sulfite
containing preparation should be used as the sulfite preservative (NNF60211) commonly used
in dexamethasone preparations may be directly neurotoxic in newborns [39-42].

These steroids are preferred over other steroids because they are less extensively metabolized by
the placental enzyme 11 beta-hydroxysteroid dehydrogenase type 2. At the above doses, 75 to 80
percent of available corticosteroid receptors are occupied, which should provide near-maximal
induction of corticosteroid receptor-mediated response in fetal target tissues [43]. These doses
result in cord blood glucocorticoid levels in the range seen with physiologic stress in the preterm
neonate.

There is no convincing evidence that the beneficial fetal effects of standard doses of antenatal
corticosteroids are significantly reduced in overweight women (body mass index [BMI]
≥25 kg/m2), but further study is needed [44]. In a randomized trial, maternal and cord
blood betamethasone levels were similar for obese (BMI ≥30 kg/m2) and non-obese women;
however, this trial did not evaluate clinical outcomes [45].

The efficacy of alternative dosing regimens is unproven and discussed below. (See 'Nonstandard
dosing regimens' below.)

Betamethasone — One milliliter of the betamethasone suspension commonly used in clinical

practice is a combination of 3 mg of betamethasone sodium phosphate and 3 mg of betamethasone
acetate. Betamethasone sodium phosphate is soluble so it is rapidly absorbed, while
betamethasone acetate is only slightly soluble and, therefore, provides sustained activity. It is only
available for intramuscular injection.

The biological half-life is 35 to 54 hours [15]. The onset and duration of action is affected by the
vascularity at the injection site. Drug concentrations in cord blood are approximately 20 percent of
maternal levels one hour following maternal injection [43].

Dexamethasone — Dexamethasone is available as dexamethasone sodium phosphate, which has

a rapid onset and short duration of action. Therefore, the dosing frequency for dexamethasone is
shorter than that for betamethasone. It is less costly and more widely available than
betamethasone; only sulfite-free dexamethasone preparations should be used.

Although dexamethasone is well absorbed from the gastrointestinal tract, safety and efficacy of the
oral route for fetal maturation has not been established. (See 'Oral administration of
dexamethasone' below.)

Hydrocortisone — Hydrocortisone is extensively metabolized by placental enzymes so relatively

little active drug crosses into the fetal compartment; therefore, beneficial fetal effects may not occur.
However, if both betamethasone and dexamethasoneare unavailable due to drug shortages,
hydrocortisone 500 mg intravenously every 12 hours for four doses has been proposed as a last
resort [46,47].

In women incidentally receiving high-dose hydrocortisone for treatment of a medical disorder, a

standard course ofbetamethasone or dexamethasone, when indicated for fetal lung maturation, is
recommended.

Other drugs — Use of thyrotropin-releasing hormones (TRH) provides no additional benefits. In a

2013 systematic review including 15 randomized trials and over 4600 pregnancies, adding
thyrotropin-releasing hormones (TRH) to antenatal corticosteroids did not further reduce neonatal
breathing problems and lung disease after preterm birth [48].

SAFETY AND SIDE EFFECTS OF A SINGLE COURSE THERAPY — Administration of a single

course of antenatal corticosteroid therapy (ie, two doses of betamethasone or four doses
of dexamethasone) before 34 weeks of gestation appears to be safe for the fetus/infant and mother,
but has some side effects. The safety of administration later in pregnancy is unclear. (See 'After 34
weeks' above and 'Potential long-term effects in children and adults' below.)

Potential fetal side effects

●Fetal heart rate and biophysical parameters – Administration of antenatal corticosteroids

may be associated with transient fetal heart rate (FHR) and behavioral changes that typically
return to baseline by four to seven days after treatment [49]. When a nonreassuring fetal
evaluation (eg, nonreactive nonstress test [NR-NST] or low biophysical profile [BPP] score)
occurs within two or three days of corticosteroid administration, the possibility of transient
drug-related changes should be considered. Whether continued close fetal monitoring or
delivery is preferable in this setting depends on assessment of the total clinical scenario and
clinical judgment. (See "Nonstress test and contraction stress test" and"The fetal biophysical
profile".)
The most consistent FHR finding is a decrease in variability on days two and three after
administration [50-54]. Reduced fetal breathing and body movements can result in a lower
BPP score or NR-NST [54-57]. However, this is not a consistent finding; a placebo-controlled
randomized trial in humans did not report a decrease in maternal perception of fetal
movements in patients who received antenatal corticosteroids [58].
FHR and behavioral changes may reflect a direct physiologic response of the brain to
corticosteroids or they may be an indirect result of a transient increase in fetal vascular
resistance and blood pressure, which has been demonstrated in some animal studies [59-63].
●Doppler flow studies – A transient improvement in umbilical artery end-diastolic flow (EDF)
after antenatal corticosteroid administration has been described in 63 to 71 percent of patients
participating in three studies [64-66]. The improvement began about eight hours after the first
dose of betamethasone and lasted a median of three days (range 1 to 10 days). However,
other studies have not observed effects on fetal blood flow velocity waveform patterns in the
umbilical artery, middle cerebral artery, or ductus venosus [56,67].
However, preterm fetuses with severe early-onset growth restriction and absent or reversed
EDF do not have a consistent cardiovascular response to
maternal betamethasone administration. Some exhibit transient improvement of EDF, while
others do not. The latter group appears to be at higher risk of severe intrauterine acidosis or
death. However, these observations are based on a small number of events in two studies
 and need to be confirmed before a change in management of this subgroup of fetuses is
considered [66,68]. (See "Doppler ultrasound of the umbilical artery for fetal surveillance".)

Potential adverse effects on infants — In a 2006 systematic review of randomized trials, a single
course of antenatal corticosteroids before 34 weeks did not increase the risk of any adverse infant
outcome, including neonatal sepsis, small for gestational age infant, hypothalamic-pituitary-adrenal
(HPA) suppression, or air leak syndrome [2]. However, further research is needed, as several
studies of infants exposed to antenatal corticosteroids have observed reduced basal and stress-
induced cortisol secretion in these infants [69-73].

The safety and effectiveness of steroid administration after 34 weeks is less clear. In a multifaceted
intervention trial (ACT) designed to increase the use of antenatal corticosteroids in low-income and
middle-income countries, increased use of steroids increased neonatal and perinatal mortality in the
overall population, which was an unexpected and unexplained finding that may have been related,
in part, to increased in utero steroid exposure among neonates born at term [23].

Potential long-term effects in children and adults — Most studies of children/adults exposed to
a single course of antenatal corticosteroids before 34 weeks of gestation have not reported adverse
effects on growth; lung function; or psychosexual, motor, cognitive, neurologic, and ophthalmologic
outcomes compared with unexposed controls [4,74,75]. Some potentially adverse cardiovascular
and metabolic effects have been reported and require further study (eg, increased cortisol reactivity,
increased aortic arch stiffness, increased insulin resistance, increased risk of adult hypertension)
[75-81].

However, concerns remain regarding potential adverse effects on neurodevelopmental outcome,

particularly with in utero exposure late in gestation. Early in gestation, antenatal steroid exposure
may delay myelination; however, nearer to term, as the brain becomes much more mitotically
active, steroid exposure may result in cell death, which would have a more serious impact on brain
growth and function. Evidence from animal studies shows that corticosteroids can have an adverse
effect on the growth and development of the immature brain [82-84]. Few human data are available.
A study that attempted to distinguish the direct effects of antenatal steroid treatment on general
cognitive functioning from confounding influences of preterm delivery found that children born at
term of women without pregnancy complication scored on average 6 to 7 IQ points higher than
children born at term of women hospitalized for threatened preterm delivery, whether or not they
were exposed to corticosteroids in utero [85]. This suggests that factors related to risk for preterm
birth may have adverse effects.

In the ASTECS trial [21], which administered betamethasone 48 hours before planned cesarean
delivery at ≥37 weeks, at 8 to 15 years of age schools were more likely to perceive steroid-exposed
children to be in the lowest achievement group compared with the control group [25]. However,
objective testing of academic ability was not performed as part of the trial and results from national
standardized assessments did not show statistical differences between the scores for each group.

Multiple courses of steroids could accentuate potential adverse effects. (See 'Use of repeated
courses of therapy' below.)

Maternal side effects — Most pregnant women tolerate a single course of antenatal corticosteroids
without difficulty. In a 2006 systematic review of randomized trials, treatment did not increase the
risk of maternal death, chorioamnionitis, or puerperal sepsis [2]. Case reports have described
pulmonary edema, primarily associated with combination treatment with tocolytics, especially in the
setting of chorioamnionitis, fluid overload, or multiple gestation [86-88]. Betamethasone itself has
low mineralocorticoid activity compared with other corticosteroids; therefore, hypertension is not a
contraindication to therapy [89].

Transient hyperglycemia occurs in many women; the steroid effect begins approximately 12 hours
after the first dose and may last for five days. Screening for gestational diabetes, if indicated, should
be performed either before corticosteroid administration or at least five days after the first dose
[90,91]. In women with diabetes, hyperglycemia can be severe if not closely monitored and treated.
(See "Pregestational diabetes mellitus: Obstetrical issues and management", section on 'Antenatal
glucocorticoids'.)

The total leukocyte count increases by about 30 percent within 24 hours

after betamethasone injection, and the lymphocyte count significantly decreases [92,93]. These
changes return to baseline within three days, but may complicate the diagnosis of infection.

USE OF REPEATED COURSES OF THERAPY — We administer a single repeat dose

of betamethasone 12 mg to pregnancies up to 34 weeks of gestation with all of the following
characteristics, as we feel the benefit-to-risk ratio is most favorable in this setting:

●Clinically estimated to be at high risk of delivery within the next seven days.
●Initial course of antenatal corticosteroids at <28 weeks of gestation [94].
●Prior exposure to antenatal corticosteroids at least two weeks earlier (the American College
of Obstetricians and Gynecologists recommends considering a repeat course if the prior
course was at least seven days earlier [95]).

We use a single dose rather than a two-dose course of betamethasone for repeat therapy based on
indirect evidence from the Australasian Collaborative Trial of Repeat Doses of Steroids
(ACTORDS), which demonstrated that weekly repeat dosing with a single injection of
betamethasone was effective after initial standard therapy [96]. However, a single repeat course of
therapy using the two-dose betamethasone or four-dose dexamethasone regimen is also
reasonable [95] and commonly used [97,98].

Evidence of effects from repeated courses of therapy — Evidence for repeating steroid therapy
was provided by a 2015 systematic review of randomized trials that assessed the effectiveness and
safety of repeated doses of antenatalbetamethasone versus no repeat courses for women who
remain at risk of preterm birth ≥7 days after an initial course of therapy [99]. Compared with a single
course of therapy, repeated courses of betamethasone resulted in:

For the neonate:

●Reduced risk of respiratory distress syndrome (RDS) (relative risk [RR] 0.83, 95% CI 0.75-
0.91, 8 trials, 3206 infants, numbers needed to treat [NNT] 17, 95% CI 11-32).
●Reduced risk of composite serious infant outcomes (RR 0.84, 95% CI 0.75-0.94, 7 trials,
5094 infants, NNT 30, 95% CI 19-79). Serious infant outcomes were variably defined in each
trial and included perinatal death, bronchopulmonary dysplasia, severe intraventricular
hemorrhage, necrotizing enterocolitis, sepsis, periventricular leukomalacia, and/orretinopathy
of prematurity.
 However, repeated dosing did not result in statistically significant reductions in risk for
individual outcomes of severe lung disease (RR 0.80, 95% CI 0.56-1.14, 6 trials, 4826),
perinatal mortality (RR 0.94, 95% CI 0.71-1.23, 9 trials, 5554 infants), chronic lung disease
(RR 1.06, 95% CI 0.87-1.30, 8 trials, 5393 infants), or intraventricular hemorrhage (RR 0.94,
95% CI 0.75-1.18, 6 trials, 3065 infants).
●Reduction in mean birthweight (mean difference -75.79 g, 95% CI -117.63 to -33.96, 9 trials,
5626 infants), which was not statistically significant when birthweight was adjusted for
gestational age.

For the mother:

●No significant increase in chorioamnionitis (RR 1.16, 95% CI 0.92-1.46, 6 trials, 4261
women)
●No significant increase in puerperal sepsis (RR 1.15, 95% CI 0.83-1.60, 5 trials, 3091
women)

For the young child:

●No significant harm or benefit. At follow-up in early childhood (18 months to 2 years
corrected age), there were no statistically significant differences in total deaths; survival free of
any disability or major disability; major disability; composite serious outcome; growth
assessment (weight, height); developmental delay; blindness; deafness; or cerebral palsy.

However, we and others [73] remain concerned about administering multiple repeat courses of
steroid therapy because the systematic review did not evaluate whether there was an increased risk
of harm as the number of repeat courses ofbetamethasone increased. Individual trials suggest
increasing exposure to steroids is associated with increasing risk of adverse effect:

●In the Maternal Fetal Medicine Units network (MFMU) trial, 63 percent of patients received
≥4 courses of therapy. The percentage of small for gestational age (SGA) fetuses below the
10th percentile and below the 5th percentile was significantly higher in the repeated steroid
course group compared with the single course group (for the 10th percentile: 19.3 versus 8.4
percent; for the 5th percentile 10.4 versus 4.7 percent) [100]. After 32 weeks of gestation,
placental weight was significantly less in the repeat corticosteroid group and was related
inversely to the number of steroid courses [101]. Although statistically nonsignificant, repeat
courses were associated with an increased incidence of cerebral palsy (one case of cerebral
palsy in the control group and five in the weekly steroid group; RR 5.68, 95% CI 0.69-46.7);
five of the six children with cerebral palsy were delivered near term or term and five of the six
were exposed to ≥4 courses of antenatal corticosteroids [100].
●A secondary analysis of data from the Multiple Courses of Antenatal Corticosteroids for
Preterm Birth Study, a randomized trial of single versus multiple course steroid therapy,
reported a dose-response relationship between the number of corticosteroid courses and a
decrease in fetal growth [102]. Multiple courses of therapy were not associated with an
increased risk of maternal side effects [103] or the composite outcome of death/survival with a
neurodevelopmental disability at five years of age [104].
●In a small prospective cohort study, exposure to repeat courses of antenatal corticosteroids
appeared to impact some aspects of executive functioning, but was not associated with
 general deficits in higher cognitive functions, self-reported attention, adaptability, or overall
psychological function [105].

Evidence for salvage, rescue, booster therapy — Use of a single repeat course of antenatal
corticosteroids has been termed salvage, rescue, or booster therapy. Salvage (rescue, booster)
therapy is an attractive alternative to routinely repeating weekly courses of antenatal corticosteroids
once an initial course has been given. Salvage (rescue, booster) therapy is limited to pregnancies
estimated to be at high risk of delivering within seven days. In theory, this would allow a single
booster or rescue course of therapy to those pregnancies most likely to benefit. This could result in
a reduction in RDS without increasing the risk of potentially adverse outcomes.

Three placebo-controlled randomized trials of salvage (rescue, booster) therapy have been
published. One trial (n = 249 pregnancies) did not show a reduction in the incidence of RDS with
salvage therapy (52 percent with betamethasone versus 48 percent with placebo) [37], while the
other (n = 437 pregnancies) reported a significant reduction in RDS (41.4 percent[67/162] with
betamethasone versus 61.6 percent [101/164] with placebo; OR 0.45, 95% CI 0.27-0.75) [97]. A
higher proportion of subjects that actually received the intervention in the second trial compared
with the first trial likely accounted for the significant reduction in RDS. A third placebo-controlled
randomized trial (n = 85 pregnancies) also suggested a benefit: a rescue course of betamethasone
significantly increased respiratory compliance (primary outcome) and, in deliveries less than 34
weeks, significantly decreased the incidence of RDS (15/44 [34 percent] versus 22/39 [56 percent]
in the placebo group) [98]. When deliveries at all gestational ages were included, the reduction in
RDS remained but was not statistically significant(15/56 [27 percent] versus 23/56 [41 percent]).

Although none of these trials reported a statistical increased risk of adverse effects, no firm
conclusions can be made since the number of subjects and events was small and the infants were
followed for only a short time after birth.

The American College of Obstetricians and Gynecologists (ACOG) endorses the concept of a single
course of salvage (rescue, booster) steroids in women who remain at risk of preterm delivery before
34 weeks of gestation and whose prior course was administered at least 7 days previously [106].

The Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) demonstrated that
weekly repeat dosing with a single injection of betamethasone was effective after initial standard
therapy [96]. Based on this indirect evidence and our concerns about potential adverse effects of
repeat corticosteroid injections, we give a single dose of betamethasone
forsalvage/rescue/booster therapy rather than two doses 24 hours apart. However, a two-dose
course of therapy is also reasonable and commonly used [97,98].

NONSTANDARD DOSING REGIMENS — There is no convincing evidence of the safety and

efficacy of increasing the steroid dose, accelerating the dosing interval, or using an intravenous or
oral route of administration.

Higher dose — In a clinical study, doubling the dose of betamethasone to 24 mg per day was not
associated with increased efficacy [107].

Pharmacokinetic studies demonstrated that the standard dosing intervals of two 12 mg doses
of betamethasone administered 24 hours apart provide maximum glucocorticoid receptor
occupancy and near-maximal stimulation of glucocorticoid receptor target genes in fetal tissues
[5,108,109]. If receptors are not available for activation, then a higher daily dose of glucocorticoid
would not be expected to increase efficacy and the excess drug would likely be excreted. In
addition, supraphysiological doses of glucocorticoids suppress glucocorticoid receptor levels by
“homologous down-regulation” [110]. Thus, administration of a higher dose of steroid would
probably result in no more than a negligible increase in fetal lung maturation.

Shorter dosing interval — Shortening the dosing interval has been proposed to increase the
probability of completing the steroid course before delivery. The safety and effectiveness of this
approach are unclear as it is supported by limited low-quality evidence [111,112], and one of these
studies reported a possible increased risk of necrotizing enterocolitis with a shorter dosing interval,
which is concerning [111]. Therefore, a shortened dosing interval should be avoided until data from
appropriately powered randomized trials demonstrate efficacy and safety.

Intravenous administration — The clinical efficacy of intravenous antenatal corticosteroids has

not been studied in human pregnancy. Intravenous administration results in rapid peaks and
troughs in maternal and fetal steroid concentrations. This produces less sustained fetal exposure to
corticosteroid stimulation and thus may not be as effective as intramuscular administration.

Oral administration of dexamethasone — In the absence of adequate data establishing the

safety and efficacy of oraldexamethasone therapy for fetal maturation, we recommend using only
intramuscular therapy.

Outpatient oral administration of dexamethasone has been used to facilitate completion of full
courses of corticosteroids in ambulatory women at increased risk of preterm delivery. In the only
randomized trial of this approach, 170 women between 24 and 33 weeks of gestation at high risk of
preterm delivery were randomly assigned to receive either 6 mg intramuscular dexamethasone or 8
mg oral dexamethasone every 12 hours for 4 doses, repeated weekly until 34 weeks [113]. There
was no statistical difference between groups in the frequency of RDS, but the oral dexamethasone
group had significantly higher rates of intraventricular hemorrhage (IVH) and neonatal sepsis,
leading to premature discontinuation of the trial after 39 percent enrollment.

TESTING FOR FETAL LUNG MATURITY AFTER ANTENATAL CORTICOSTEROID

THERAPY — We recommend not performing tests for fetal lung maturation following antenatal
corticosteroid therapy because these tests may not be sufficiently sensitive to detect subtle
changes in the surfactant concentration of amniotic fluid. In addition, they cannot assess the effects
of steroid-induced architectural changes of the fetal lung.

Although some studies have reported an increased lecithin-sphingomyelin ratio or TDx-FLM II five
days to two weeks after corticosteroid therapy [114-116], several other series found no change in
this ratio [1,117,118]. (See "Assessment of fetal lung maturity".)

SPECIAL POPULATIONS

Multiple gestation — We use a standard dosing schedule for both singleton and multiple
gestations.

In a 2006 systematic review, the small number of multiple gestations included in the antenatal
corticosteroid trials precluded a definite conclusion about the effectiveness of the therapy or the
optimum dose (respiratory distress syndrome [RDS] in multiple gestations exposed to antenatal
steroids: relative risk [RR] 0.85, 95% CI 0.60-1.20) [2]. In theory, multiple gestations may require
higher doses of antenatal corticosteroids to maximize fetal exposure. However, maternal and cord
bloodbetamethasone levels were similar in singleton and multiple gestations in a randomized trial
[45]. This trial did not compare clinical outcomes. A prospective pharmacokinetic study also
reported pharmacokinetics were the same for singleton and multiple gestations [119].

Observational data suggest benefits in multiple gestations exposed to antenatal corticosteroids,

although these have not consistently approached the benefits achieved in singletons [120-122].

Hypertension — Betamethasone has low mineralocorticoid activity compared with other

corticosteroids and does not aggravate hypertension. A randomized trial supported both the safety
and efficacy of antenatal corticosteroid therapy in pregnancies complicated by severe preeclampsia
[89].

Diabetes — Antenatal corticosteroid therapy should be administered to women with diabetes when
indicated; however, hyperglycemia related to corticosteroid administration can be severe in this
population if not closely monitored and treated. The steroid effect on glucose levels begins
approximately 12 hours after the first dose and may last for five days. Women with diabetes
generally have been excluded from randomized trials of antenatal corticosteroid therapy because of
the adverse effects of steroids on glycemic control, thus efficacy in this population is inferred [123].
(See "Pregestational diabetes mellitus: Obstetrical issues and management", section on 'Antenatal
glucocorticoids'.)

Preterm premature rupture of membranes — Antenatal corticosteroid administration improves

neonatal outcome in pregnancies complicated by preterm premature rupture of membranes and
does not increase the risk of neonatal or maternal infection. (See "Preterm premature (prelabor)
rupture of membranes", section on 'Administration of antenatal corticosteroids'.)

POSTNATAL SURFACTANT THERAPY — Postnatal surfactant administration is not a substitute

for antenatal corticosteroid therapy. The combination of antenatal corticosteroid therapy and
postnatal exogenous surfactant reduces neonatal morbidity and mortality more than use of
exogenous surfactant alone [124].

SUMMARY AND RECOMMENDATIONS

●Antenatal corticosteroid therapy leads to improvement in neonatal lung function by

enhancing maturational changes in lung architecture and by inducing lung enzymes involved
in respiratory function. (See 'Mechanism of action' above.)
●Antenatal corticosteroid therapy reduces the incidence of respiratory distress syndrome,
intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and neonatal mortality by
approximately 50 percent. These effects are not limited by gender or race; efficacy in multiple
gestations is unclear, as high-quality data are sparse. (See 'Evidence of short-term clinical
efficacy' above and 'Multiple gestation' above.)
●Given these benefits, we recommend administration of antenatal corticosteroids to pregnant
woman who are at 23 to 34 weeks of gestation and at increased risk of preterm delivery within
the next seven days (Grade 1A). In our practice, we restrict administration of the first course
of antenatal corticosteroids to women who rupture membranes or are receiving tocolysis for
active preterm labor, or in whom delivery for maternal or fetal indications is anticipated within
the next seven days. This approach minimizes the need for salvage (rescue, booster) therapy
while allowing most patients to receive a course of antenatal corticosteroids prior to preterm
delivery.
A course of antenatal corticosteroids consists of betamethasone suspension 12 mg
intramuscularly every 24 hours for two doses or four doses of 6
mg dexamethasone intramuscularly 12 hours apart. We prefer betamethasone over
dexamethasone. (See 'Choice of drug and initial dose' above and 'Timing before
delivery' above.)
●We consider approximately 230/7ths weeks of gestation the lower limit for administration of
antenatal corticosteroids since only a few primitive alveoli are present below this gestational
age. Earlier administration in the 22nd week is reasonable if aggressive neonatal intervention is
planned after thorough counseling about the limit of viability. (See '22 weeks or less'above
and '23 to 34 weeks' above.)
●In contemporary obstetric practice in the United States, women delivered at 34 0/7ths to
386/7ths weeks of gestation for an obstetric indication are increasingly delivered without
amniocentesis to test for fetal lung maturity. The following approach reflects our concern that
widespread use of antenatal steroids after 34 weeks will result in treatment of many
pregnancies that will not benefit or will derive only a modest clinical benefit, while exposing
them to the theoretical long-term hazards of steroid administration, particularly adverse
neurodevelopment outcome in offspring (see 'After 34 weeks' above and'Potential long-term
effects in children and adults' above).
•For women scheduled for cesarean delivery at 340/7ths to 366/7ths weeks, we suggest a
first course of antenatal corticosteroids (Grade 2C). Some clinicians and patients may
choose not to use steroids after 34 weeks of gestation, given uncertainly in the balance
between benefits and risks after 34 weeks.
•For women at 340/7ths to 366/7ths weeks who have already received a course of antenatal
corticosteroids, or who are expected to deliver vaginally, or whose likelihood of delivery
within the next seven days is uncertain, we suggest not administering a course of
antenatal corticosteroids (Grade 2C). Repeat courses of steroids have not be studied
after 34 weeks, transient tachypnea of the newborn is less common after labor and
vaginal birth, and most women with threatened preterm labor do not deliver preterm.
•We also suggest not administering steroids to women undergoing scheduled cesarean
delivery at ≥37 weeks (Grade 2C). The overall risk of neonatal respiratory problems at
this gestational age is low and illness is rarely serious.
●The absence of consistent and long-term data precludes making a strong recommendation
for the number of courses that are safe for the fetus, the appropriate time interval between
courses, the optimal dose for repeated courses of therapy, or the full ramifications of the
single course approach to therapy. Given the potential for harm from repeated courses of
antenatal corticosteroid therapy:
•We suggest a single course of salvage (rescue, booster) therapy only if the patient is
clinically estimated to be at high risk of delivery within the next seven days, more than
two weeks have elapsed since the initial course of antenatal corticosteroid therapy, and
the gestational age at administration of the initial course was <28 weeks of gestation
(Grade 2C).
•We also suggest that providers who elect to give salvage (rescue, booster) therapy use
one dose of 12 mgbetamethasone and limit treatment to this one additional dose (Grade
 2C). One dose appears to be effective and may minimize complications related to steroid
use; however, a two dose course is also reasonable. Patients should be informed of
potential adverse effects. (See 'Use of repeated courses of therapy' above.)
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Topic 6796 Version 61.0

Pathogenesis of spontaneous preterm birth
Author
Charles J Lockwood, MD, MHCM
Section Editor
Susan M Ramin, MD
Deputy Editor
Vanessa A Barss, MD, FACOG
Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2016. | This topic last updated: Jan 07, 2016.

INTRODUCTION — Preterm birth (PTB) is the leading cause of infant morbidity and mortality in the
industrialized world (table 1). While rates in the United States have fallen for four consecutive years,
the overall rate remains just under 12 percent [1]. Moreover, the incidence of very early preterm
birth and of low birthweight remains unchanged. Given that low and very low birthweight newborns
are at the highest risk of early death or disability, major focuses of obstetrical research justifiably
include the pathogenic processes leading to PTB and development of preventive interventions.

ETIOLOGY — Approximately 70 percent of preterm deliveries occur spontaneously as a result of

preterm labor (PTL, 45 percent) or preterm premature rupture of membranes (PPROM, 25 percent);
intervention for maternal or fetal problems account for the remaining 30 percent (table 2). Many
epidemiologic and clinical risk factors have been associated with spontaneous PTB (table 3).
Genetic factors are increasingly recognized as important determinants of PTB. However, the
magnitude of effect and the degree to which genetic factors contribute to racial differences in PTB
risk across populations remain largely unknown [2].

Compelling clinical and research evidence suggest that a number of pathogenic processes can lead
to a final common pathway that results in spontaneous PTB. The four primary processes are:

●Premature activation of the maternal or fetal hypothalamic-pituitary-adrenal axis

●Exaggerated inflammatory response/infection
●Abruption (decidual hemorrhage)
●Pathological uterine distention

These processes may lead to cervical shortening [3] and may be initiated long before PTL or
PPROM are diagnosed clinically.

Activation of the HPA axis — Stress is a common element activating a series of physiologic
adaptive responses in the maternal and fetal compartment. From this perspective, premature
activation of the hypothalamic-pituitary-adrenal (HPA) axis can initiate PTB (algorithm 1). Major
maternal physical or psychological stressors, including anxiety and depression, can activate the
maternal HPA axis and have been associated with a slightly higher rate of PTB [4-11]. As an
example, a prospective cohort study of women with depressive symptoms early in pregnancy found
that these women had almost twice the PTB risk of women without such symptoms [12]. The risk of
PTB increased with increasing severity of depression, suggesting a "dose-response" effect. In
addition, data derived from a large New York database provided evidence that mothers with
posttraumatic stress disorder were more likely to deliver preterm (OR 2.48, 95% CI 1.05–5.84) [13].
Premature fetal HPA activation can result from the stress of uteroplacental vasculopathy and has a
higher correlation with subsequent PTB than maternal stress [14-16]. In one study, spontaneous
PTB ≤35 to 36 weeks of gestation was associated with a four- to seven-fold increased risk of
placental pathological evidence of vascular damage, bleeding, fetal vascular disruption, or lack of
normal physiologic conversion of maternal spiral arteries [17]. In another report, severe
preeclampsia was associated with a threefold increase in the risk of spontaneous PTB [18]. In
contrast to women with uncomplicated first pregnancies, a third study found that women whose first
pregnancy ended in spontaneous PTB were at increased risk of PTB, preeclampsia, and fetal
growth restriction in their second pregnancy [19]. The earlier the PTB, the higher the risk of one of
these complications in the second pregnancy.

The mechanisms by which HPA activation are thought to cause spontaneous PTB include:

●Increased placental production and release of corticotropin-releasing hormone (CRH), which

appears to program a "placental clock" [20,21].
●Increased release of fetal pituitary adrenocorticotropic hormone (ACTH) secretion, which
stimulates production of placental estrogenic compounds and prostaglandins that may activate
the myometrium and initiate labor [22].

Corticotropin-releasing hormone — Corticotropin-releasing hormone (CRH) appears to play a

role in both term and preterm birth. CRH is released by the hypothalamus but, during pregnancy, is
also expressed by placental and chorionic trophoblast, amniochorion, and decidual cells [23-25]. It
stimulates the secretion of ACTH from the pituitary, which then promotes the release of cortisol from
the adrenal. In the maternal HPA axis, cortisol inhibits hypothalamic CRH and pituitary ACTH
release, creating a negative feedback loop. In contrast, cortisol stimulates CRH release in the
decidua-trophoblast-membrane compartment [25,26]. CRH, in turn, further drives maternal and fetal
HPA activation, establishing a potent positive feedback loop.

CRH also enhances prostaglandin production by amnion, chorion, and decidua [27]. In turn,
prostaglandins stimulate CRH release from the placenta [26], creating a second positive feedback
loop for CRH secretion.

In a normal pregnancy, it is hypothesized that maturation of the fetal HPA axis and development of
the fetal zone of the fetal adrenal gland beginning in midgestation cause a physiologic increase in
fetal cortisol secretion and enhancing CRH release from the placenta [28]. The effects of CRH are
augmented near term by a reduction in maternal plasma CRH-binding protein [29]. As noted above,
the CRH-induced increases in maternal and fetal adrenal cortisol synthesis and placental
prostaglandin production promote positive feedback loops that lead to even higher levels of CRH,
cortisol, and prostaglandins [30]. There is also some evidence that CRH can directly augment
myometrial activation [31].

The rise in prostaglandins ultimately results in parturition via the elaboration of genital tract
proteases (eg, matrix metalloproteinases [MMPs]) and enhanced myometrial contractility [32]. In
vitro studies in human myometrial cells suggest that prostaglandins act to increase the
progesterone receptor (PR)-A to B expression ratio [33]. Since the PR-A isoform can antagonize the
antiparturition effects of the PR-B isoform, these findings suggest that prostaglandins can induce
functional progesterone withdrawal. Indeed, since prostaglandins can induce labor at virtually any
point in gestation, their generation is an integral part of the common final pathway of PTB.
If the sequence of events outlined above occurs too early in gestation, PTL and PTB may result.
This was illustrated in a prospective cohort study that measured serum CRH concentrations
between 17 and 30 weeks of gestation in 860 unselected pregnant women [34]. The median serum
CRH in pregnancies that subsequently spontaneously delivered preterm (37 women) was twice the
median value of women of the same gestational age who went on to deliver at term.

Increased fetal adrenal zone size correlates with enhanced adrenal activity and increased fetal
adrenal gland volume, as measured by three-dimensional ultrasound, is a potential predictor of
stress associated prematurity [35]. However, since the fetal adrenal zone is not well developed until
the third trimester, fetal stress-associated PTB is more likely to account for later PTBs.

Maternal and/or fetal stress may also enhance steroid-induced immunophilin cochaperone FKBP51
expression, which may lead to functional progesterone withdrawal from inhibition of progesterone
receptor and/or glucocorticoid receptor mediated transcription [36].

Estrogens — Activation of the fetal HPA axis also leads to PTB through a pathway involving
estrogens. Fetal pituitary ACTH secretion stimulates adrenal synthesis of dehydroepiandrosterone
sulfate (DHEA), which is converted to 16-hydroxy-DHEA-S in the fetal liver. Placental CRH can also
augment fetal adrenal DHEA production directly [37]. The placenta converts these androgen
precursors to estrone (E1), estradiol (E2), and estriol (E3), which, in the presence of estrogen
receptor-alpha (ER-alpha), activate the myometrium by increasing gap junction formation, oxytocin
receptors, prostaglandin activity, and enzymes responsible for muscle contraction (myosin light
chain kinase, calmodulin) [38-42]. Moreover, the functional progesterone withdrawal noted above is
expected to be accompanied by rising concentrations of myometrial ER-alpha, thereby mediating
this estrogen-induced myometrial activation.

In the setting of infection-induced fetal stress, the fetal cortisol-to-DHEA ratio remains low, with no
direct correlation between the fetal adrenal gland volume and either cortisol or DHEA levels [35].
This suggests that infection-mediated PTB may act via alternative pathways.

The potential predictive value of estrogenic compounds was suggested by a prospective study in
which serial measurements of salivary E3 were obtained [43]. Mean salivary estriol was higher from
24 to 34 weeks of gestation in women with singleton pregnancies delivering preterm than in those
delivering at term. A surge in salivary E3 occurred three to four weeks before the onset of labor in
both groups. The predictive value of salivary estriol measurements was greatest for later PTBs (≥34
weeks). The precise mechanism for this limitation remains unknown; however, it likely reflects the
requirement for development of the fetal zone of the fetal adrenal, which is responsible for the bulk
of DHEA production and enlarges rapidly in the last six weeks of gestation [44]. In turn, sonographic
measurement of fetal adrenal size appears to be predictive of PTB risk, with relatively high
sensitivity and specificity [45].

Infection and inflammation — Inflammation is a highly coordinated process set in place to protect
the host [46]. When properly controlled, inflammation is beneficial, but when dysregulated, it
becomes harmful [47].

Laboratory and clinical data show a link between spontaneous PTB and the presence of both
systemic and genitourinary tract pathogens [48-54]. For example,
 ●In a large retrospective population-based study of 199,093 deliveries, 2.5 percent of patients
had asymptomatic bacteriuria, which was independently associated with PTB (adjusted OR
1.6, 95% CI 1.5-1.7) [48]. Conversely, the diagnosis and treatment of asymptomatic
bacteriuria appears to reduce the risk of PTB [49].
●In another study of 759 women who underwent first trimester assessment of their vaginal
flora, those with normal vaginal flora had a 75 percent lower risk of delivery before 35 weeks
than women with abnormal vaginal flora [50]. Absence of lactobacilli and the presence of
bacterial vaginosis (BV) were both associated with a twofold increased risk of PTB, while gram
positive coccus-associated aerobic vaginitis was associated with a three-fold increase in risk
of PTB. Others have reported that Lactobacillus are the predominant flora of the microbial
community in normal pregnancy and the prevalence of a Lactobacillus-poor vaginal
community state type (CST 4) is inversely correlated with gestational age at delivery [55]. In
addition, the risk for PTB is more pronounced for women with CST 4 and
elevated Gardnerella orUreaplasma. However, treatment of BV does not appear to
consistently reduce PTB rates in low-risk patients [56]. (See"Bacterial vaginosis", section on
'Pregnant women'.)
●Similarly, periodontal disease and subsequent systemic inflammation may play a role in
triggering PTB [57]. Intervention studies have not consistently demonstrated a benefit to
treatment [51,52,58]. However, it remains possible that the putative beneficial effects of
periodontal treatment may be dependent on time of initiation and success of therapy [59].
(See "Preterm birth: Risk factors and interventions for risk reduction".)
●Lastly, both clinical and subclinical chorioamnionitis are much more common in preterm than
term deliveries, and may account for 50 percent of PTB before 30 weeks of gestation [60].
(See "Preterm birth: Risk factors and interventions for risk reduction", section on 'Infection'.)

These studies, and others, suggest that disorders of maternal innate or acquired immunity, rather
than the mere presence of certain genital tract bacteria, are the primary causes of inflammation-
associated PTB.

There is a significant racial disparity in inflammation-associated PTB, with African-Americans

disproportionately affected [61]. This may be explained by the observation that multiple maternal
and fetal inflammatory pathway genetic polymorphisms linked to inflammation-associated PTB have
been found in greater prevalence among African-American mothers and/or fetuses than among
Caucasians [62,63]. For example, African-American mothers harboring both a polymorphism of the
tumor necrosis factor-alpha (TNF) gene and bacterial vaginosis are at significantly greater risk of
PTB (OR 6.1; 95% CI 1.9–21.0) [64]. (See"Preterm birth: Risk factors and interventions for risk
reduction", section on 'Genetic factors'.)

Binding of bacterial ligands to toll-like receptors (TLRs) in decidual, amnion-chorion and cervical
and placental cells and resident leucocytes induce the transcription factor NFkappaB which, in turn,
triggers a maternal and/or fetal inflammatory response in susceptible individuals that is linked to
PTB (algorithm 2). Activation of the TLRs is dependent not only on the presence of bacterial
molecular wall motifs, but also on a palette of intracellular signaling adaptors (eg, MyD88), co-
receptor molecules (eg, CD14) [65], and soluble receptor modulators (soluble TLR2, soluble TNF
receptor-1, soluble IL-6 receptor, soluble gp130 and soluble RAGE) [66-69].
This TLR-mediated response is ultimately characterized by the presence of activated neutrophils
and, to a lesser extent, activated macrophages and various proinflammatory mediators (eg,
interleukins [IL] 1,6, and 8; TNF, granulocyte colony-stimulating factor (G-CSF), colony stimulating
factor-2 (CSF-2), and MMPs). The key initial mediators of this response are IL-1beta and TNF,
which enhance prostaglandin production by inducing COX-2 expression in the amnion and decidua
while inhibiting the prostaglandin metabolizing enzyme, 15-hydroxy-prostaglandin dehydrogenase
(PGDH) in the chorion [70,71]. Moreover, IL-1beta and/or TNF directly enhance the expression of
various MMPs in the amnio-chorion, decidua, and cervix to degrade the extracellular matrix of the
fetal membranes and cervix [72-74].

Furthermore, chorioamnionitis is associated with intense decidual immunostaining for IL-8 and CSF-
2, which recruit neutrophils capable of releasing additional PPROM-causing MMPs and IL-
1beta and/or TNF greatly augment the output of IL-8 and CSF-2 in term decidual cells [75,76]. TNF-
alpha plays an additional role, since it can induce apoptosis (physiologic cell death). Elevated levels
of TNF and increased apoptosis in amnion epithelial cells have been associated with PPROM [77].
Chorioamnionitis is also linked to increased decidual and membrane IL-6 production [78,79], which
further enhances decidual and fetal membrane prostaglandin production, and G-CSF expression,
which recruits and activates neutrophils [80,81]. Complement activation also appears to play a role
[82]. Thus, both maternal and fetal inflammatory responses to infection are processes that can lead
to PTL and PPROM. In contrast, the presence of bacteria, without a host response, does not
always cause an adverse outcome (see below) [83].

Immunohistochemical staining of placentas from patients with chorioamnionitis-associated PTB

demonstrated significantly lower PR levels in decidual cells [84]. Moreover, treatment of cultured
term decidual cells with IL-1beta decreased PR-B and A isoform expression as well as PR mRNA
levels and significantly increased PGE2 and PGF2alpha production and COX-2 expression. While
addition of PGF2alpha to these cultures also suppressed PR expression, indomethacin did not
reverse IL-1beta inhibition of PR levels, suggesting a direct inhibitory effect by this cytokine on PR
expression. Taken together these studies suggest that infection-associated PTB is, at least in part,
caused by IL-1beta-mediated functional progesterone withdrawal.

Elevated proinflammatory mediator levels have been demonstrated in the amniotic fluid of women
with PTL with intact membranes and these levels correlated well with positive results from culture of
the amniotic fluid and fetal membranes [85]. In a review of 17 primary studies compromising 6270
asymptomatic women, elevated cervicovaginal and amniotic fluid IL-6 levels at mid-gestation
predicted PTB with odds ratios (OR) of 3.05 (95% CI 2.00-4.67; number needed to treat = 7) and
4.52 (95% CI 2.67-7.65; number needed to treat = 7), respectively [86]. In addition, patients with
intraamniotic inflammation destined to deliver preterm appear to present unique amniotic fluid,
vaginal-cervical secretion, and serum proteomic profiles [87-91]. In one study, 104 amniotic fluid
samples of patients at risk for PTB were analyzed using surface-enhanced laser desorption
ionization (SELDI) proteomic profiling [87]. Patients with intraamniotic inflammation that delivered
preterm were found to display neutrophil defensins-1 and -2, and calgranulins A and C. The
presence of more than two of these proteins had greater than 90 percent sensitivity and specificity
for detection of intraamniotic inflammation. Although the measurement of proinflammatory
mediators is possible, these tests have not been sufficiently studied to be clinically useful at this
time.
Bacteria — In addition to inducing an inflammatory response, bacteria may also have a direct role
in the pathogenesis of PTB. Some organisms (eg, Pseudomonas, Staphylococcus, Streptococcus,
Bacteroides, and Enterobacter) produce proteases, collagenases, and elastases that can degrade
the fetal membranes [92,93]. Bacteria also produce phospholipase A2 (which leads to prostaglandin
synthesis) and endotoxin, substances that stimulate uterine contractions and can cause PTL [94].

Metagenomic techniques, including surveillance of the 16S-rRNA gene, have increased

understanding of the spectrum of cultivated and uncultivated human microbial agents involved in
the pathogenesis of PTB [95]. By using metagenomic tools, several groups of investigators reported
that in pregnancies complicated by PTB secondary to infection approximately two thirds of the
amniotic fluid bacteria detected by culture-independent methods were not isolated in cultures
[96,97]. These included both uncultivated and difficult-to-cultivate species, such as Fusobacterium
nucleatum, Leptotrichia (Sneathia), Bergeyella, Peptostreptococcus, Bacteroides, and a species of
the order Clostridials.

Proinflammatory mediators unrelated to infection — Noninfectious etiologies, such as placental

hypoperfusion, also appear to increase production of proinflammatory mediators [98]. This may be
another mechanism accounting for the slightly higher rate of spontaneous PTB among growth
restricted infants [99].

In addition, there is increasing evidence that psychological stress and distress (ie, depressive
symptoms) can cause dysregulation of inflammatory processes leading to elevations in circulating
inflammatory cytokines and exaggerated inflammatory responses [100].

Decidual hemorrhage — Vaginal bleeding from decidual hemorrhage is associated with a high risk
of PTL and PPROM [101-103]. Decidual hemorrhage (placental abruption) originates in damaged
decidual blood vessels and presents clinically as vaginal bleeding or retroplacental hematoma
formation [104]. In a case-control study of 341 patients, vaginal bleeding in more than one trimester
increased the risk of PPROM sevenfold [101]. In another series, occult decidual hemorrhage
(manifested by hemosiderin deposition and retro-chorionic hematoma formation) was present in 38
percent of patients with PTB between 22 and 32 weeks of gestation due to PPROM and 36 percent
of patients experiencing PTB after PTL; these placental findings were present in only 0.8 percent of
term deliveries (p <0.01) [103].

As noted above, PTB is strongly linked to histological evidence of maternal spiral artery hemorrhage
and damage [17]. In a prospective cohort analysis of maternal genotypes, pregnancy outcomes,
and placental pathology among 560 Caucasian and 399 black women, the factor V Leiden and
angiotensinogen-6G>A mutations were positively linked to abruption-associated PTBs (OR 4.8;
95% CI:1.6-14.2 and OR 3.8; 95% CI, 1.3-10.5, respectively), but not with other causes of preterm
delivery and only among Caucasians [105]. This suggests that polymorphisms predisposing to
decidual vasculopathy, thrombosis, and abruption also predispose to PTB. This finding helps
account for the predominance of abruption-associated PTB in European populations [106].

The development of PPROM in the setting of abruption may be related to the high decidual
concentration of tissue factor, the primary cellular mediator of hemostasis. Following intrauterine
hemorrhage from placental abruption, decidual tissue factor combines with factor Vlla to activate
factor Xa, which in turn complexes with its cofactor, Va, to generate thrombin (figure 1).
(See "Overview of hemostasis".) In addition to its hemostatic properties, thrombin binds to decidual
protease-activated receptors (PAR1 and 3) that regulate the expression of proteases such as
MMPs [107-109].

Abruption can be accompanied by an inflammatory process in the absence of infection [110].

Proteomics studies provided evidence that proteases and free hemoglobin chains activate innate
immunity and a feed-forward mechanism that reinforces the inflammatory process, leading to
PPROM and PTB. In addition, thrombin is a potent inducer of IL-8 in decidual cells, accounting for
the dense neutrophil infiltrate observed in abruption-associated PPROM in the absence of infection
[111]. The interactive effects of thrombin-enhanced MMPs with neutrophil-derived proteases
promote degradation of the fetal membrane extracellular matrix, which can result in PPROM
(algorithm 3).

Decidual hemorrhage results in intense local thrombin generation. Hormonal factors such as
progesterone play an important modulator role [112]. Thrombin also induces synthesis of elements
of the fibrinolytic system in decidual cells [113]. However, the primary effect of thrombin is to inhibit
fibrinolysis via generation of type-1 plasminogen inhibitor (PAI-1) to avoid hemorrhage in the setting
of abruption, suggesting that abruption-associated decidual proteolysis and PPROM are mediated
primarily by thrombin-enhanced MMP expression.

In laboratory studies, small quantities of thrombin produced during coagulation increased the
frequency, intensity, and tone of myometrial contractions; an effect that is suppressed by blood
containing thrombin inhibitors [114,115]. Interactions of thrombin with PARs lead to activation of the
phosphatidylinositol pathway. Abruption-associated generation of thrombin also appears to initiate
functional progestin withdrawal in the decidua by inhibiting expression of progesterone receptors in
decidual cells [116]. As with IL-1beta mediated inhibition of PR expression, thrombin inhibition of
PR protein and mRNA expression is also mediated by ERK1/2 MAPK signaling. This may be a
mechanism for PTL in pregnancies complicated by antepartum bleeding. However, the main effect
of thrombin released at the site of decidual hemorrhage is to maintain hemostasis, rather than to
stimulate uterine contractions [113].

Thrombin activation (measured by serum thrombin-antithrombin complex levels [TAT]) has been
noted in women with PTL and in asymptomatic women who subsequently delivered preterm. A pilot
study of 23 gravidas at 24.0 to 32.9 weeks of gestation hospitalized with PTL found significantly
higher blood TAT levels in those who subsequently delivered within three weeks compared to
gestational-age matched nonlaboring controls or PTL patients who did not deliver within three
weeks (TAT levels 7.8 ± 2.86 ng/mL, 5.77 ± 1.43 ng/mL, and 5.57 ± 1.69 ng/mL, respectively) [117].
A TAT level of greater than 8.0 ng/mL in symptomatic women had sensitivity, specificity, and
positive and negative predictive values of 50, 91, 80, and 71 percent, respectively, for delivery
within three weeks. A TAT level greater than 6.3 ng/mL had sensitivity, specificity, and positive and
negative predictive values of 75, 73, 67, and 73 percent, respectively. In another study of women
undergoing second trimester genetic amniocentesis, amniotic fluid TAT concentration was
statistically higher in women who subsequently had a spontaneous or indicated preterm birth
(median 87.6 and 117.7 mcg/L, respectively) than those who delivered at term (66.3mcg/L) [118].

These results should be validated before TAT levels are used to manage patients.

Pathologic uterine distention — Multiple gestation, polyhydramnios, and other causes of

excessive uterine distention are well described risk factors for PTB. Enhanced stretching of the
myometrium induces formation of gap junctions, upregulation of oxytocin receptors, and production
of inflammatory cytokines and prostaglandins, and myosin light chain kinase, which are critical
events preceding uterine contractions and cervical dilation (figure 2) [119-121]. Myometrial
distention also increases expression of genes with important roles in collagenolysis and
inflammation [122]. (See "Physiology of parturition".)

Distention of the fetal compartment also contributes to myometrial activation. Cytokines,

prostaglandins, and collagenase are produced from excess stretch of the fetal membranes [123-
125].

Pathologic cervical change — Cervical insufficiency refers to pathological

dilatation and/or effacement of the uterine cervix unrelated to labor and leading to previable
pregnancy loss, as well as PTB. It may occur with or without coexisting distention of the corpus, and
cerclage may be helpful in select instances [126]. (See "Cervical insufficiency".)

Cervical insufficiency due to intrinsic cervical factors is probably a rare event. It is more likely that
progressive cervical shortening prior to viability results from activation of the inflammatory of
hemorrhagic pathways at a point in gestation when both myometrial quiescence, as well as amniotic
fluid, fetal membrane, and decidual antiprotease activity are maximal. Thus, cervical change occurs
without apparent antecedent PTL and PPROM.

Genetic factors may also play a role in the PTB phenotype. For example, the enhancing G13 allele
in the anti-inflammatory IL-10.G microsatellite occurs more frequently in women with cervical
insufficiency compared with controls, suggesting that constitutively increased anti-inflammatory
modulators may produce cervical insufficiency rather than PTL or PPROM phenotype in the face of
inflammatory or hemorrhagic stimuli [127].

Even putative mechanical causes of cervical insufficiency may have other etiologies. In a
retrospective cohort study of 624 women who delivered after a loop electrosurgical excision
procedure (LEEP), the risk of PTB was increased two-fold and the risk was even higher following
repeated procedures or larger biopsies [128]. However, this apparent effect may reflect
ascertainment bias since another retrospective cohort analysis of women with CIN3 compared to
women with no record of CIN found the former were significantly more likely to have spontaneous
PTB (OR of 1.52; 95% CI: 1.29-1.80) and that LEEP did not alter these pregnancy complication
rates [129]. This suggests that immunological, clinical or social risk factors associated with the
development CIN rather than cervical surgery alone may increase PTB rates in women who have
undergone LEEP.

SUMMARY AND RECOMMENDATIONS

●Approximately 70 percent of preterm deliveries occur spontaneously as a result of preterm

labor (45 percent) or preterm premature rupture of membranes (25 percent); intervention for
maternal or fetal problems account for the remaining 30 percent (table 2).
(See 'Etiology' above.)
●There are four discrete mechanisms for the pathogenesis of preterm birth:
•Premature activation of the maternal or fetal hypothalamic-pituitary-adrenal axis
•Exaggerated inflammatory response/infection
•Decidual hemorrhage
 •Pathological uterine distention

These mechanisms share a final common pathway involving the formation of uterotonic
agents and proteases that weaken the fetal membranes and cervical stroma.
(See 'Etiology' above.)
●Although each mechanism has distinct epidemiological, genetic, and clinical characteristics,
they are not mutually exclusive. (See 'Etiology' above.)
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