Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Spontaneous preterm birth: Overview of risk factors and

prognosis
�������: Julian N Robinson, MD, Errol R Norwitz, MD, PhD, MBA
������� ������: Charles J Lockwood, MD, MHCM
������ ������: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2023.

This topic last updated: Jul 14, 2023.

INTRODUCTION

Preterm birth (PTB) is defined as a birth (ie, live born or stillborn ≥20+0 weeks of gestation)
that occurs at <37+0 weeks of gestation ( table 1). Seventy to 80 percent are spontaneous
(sPTB), resulting from preterm labor (40 to 50 percent), preterm prelabor rupture of
membranes (PPROM; 20 to 30 percent), or, rarely, cervical insufficiency or placental abruption.
The remaining 20 to 30 percent of PTBs are initiated by the health care provider because of
maternal or fetal conditions jeopardizing maternal or fetal health; however, such conditions
can also lead to sPTB.

An overview of risk factors for PTB and long-term maternal prognosis will be reviewed here.
Potential interventions to mitigate the risk for PTB, the pathogenesis of PTB, and the diagnosis
and treatment of preterm labor are discussed separately:

● (See "Spontaneous preterm birth: Overview of interventions for risk reduction".)

● (See "Spontaneous preterm birth: Pathogenesis".)
● (See "Inhibition of acute preterm labor".)
● (See "Preterm labor: Clinical findings, diagnostic evaluation, and initial treatment".)

RISK FACTORS

There are many risk factors for sPTB and many pathways from these risk factors to the

1 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

terminal cascade of events resulting in preterm labor. sPTB likely occurs when local uterine
factors prematurely stimulate this cascade, suppressive factors that inhibit the cascade and
maintain uterine quiescence are withdrawn prematurely, or both. (See "Preterm birth:
Definitions of prematurity, epidemiology, and risk factors for infant mortality", section on
'Incidence of prematurity' and "Spontaneous preterm birth: Pathogenesis".)

Obstetric history

Past history of preterm birth

● A history of sPTB is the major risk factor for recurrence [1-10]. In the Preterm Prediction
Study, individuals with any prior sPTB carried a 2.5-fold increase in risk of sPTB <37
weeks in the current gestation compared with those with no such history (21.7 versus 8.8
percent) [4].

The magnitude of the risk depends on the cause of the prior PTB, gestational age of the
prior PTB, and the number of prior PTBs. Earlier prior sPTB increases the risk compared
with later prior sPTB ( table 2), and recurrent sPTBs tend to occur at a similar
gestational age. A history of two sPTBs and no prior term birth also substantially
increases risk ( table 3).

● A history of painless advanced cervical dilation before sPTB increases risk compared with
a history of PPROM or preterm labor before sPTB.

● A maternal history of being born preterm increases risk compared with maternal history
of term birth. (See 'Genetic variants' below.)

● A history of prior indicated PTB is a major risk factor for recurrent indicated PTB (relative
risk [RR] 9.10, 95% CI 4.68-17.71) but also a risk factor for subsequent sPTB (RR 2.70, 95%
CI 2.00-3.65) [7].

● A prior twin sPTB is associated with an increased risk of sPTB in a subsequent singleton
pregnancy [11]. A prior singleton sPTB is associated with an increased risk of sPTB in a
subsequent twin gestation [12].

Use of assisted reproduction in the current pregnancy — 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/or
factors related to assisted reproduction procedures. This risk and possible interventions are
discussed separately. (See "Assisted reproductive technology: Pregnancy and maternal

2 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

outcomes", section on 'Spontaneous preterm birth' and "Assisted reproductive technology:

Pregnancy and maternal outcomes", section on 'Low birth weight'.)

Multifetal gestation in the current pregnancy — 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 (see "Twin pregnancy: Management of pregnancy complications",
section on 'Preterm labor and birth'). The widespread availability of assisted reproductive
technology initially resulted in a large increase in the incidence of multiple gestation; this
increase, in turn, led to an increase in sPTB and indicated PTB [13]. Subsequently, policies to
promote the transfer of only a single embryo into the uterus and other interventions have
reduced the frequency of multifetal gestations.

The mechanism for sPTB in multifetal gestations, and particularly higher-order multifetal
gestations (triplets and above), may be related to sequelae of increased uterine distension
(see "Spontaneous preterm birth: Pathogenesis", section on '#4 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 gestations
[14,15], and this increase in steroids may be a factor in initiation of labor (see "Physiology of
parturition at term"). Superovulation can result in higher circulating levels of a polypeptide
hormone relaxin, which may promote cervical insufficiency with subsequent sPTB [16].

Preterm labor in the current pregnancy — Spontaneous preterm labor precedes sPTB;
however, mild irregular uterine 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 or prodromal labor (contractions that do not result in cervical
change [called Braxton-Hicks contractions]). Only 13 percent of patients <34 weeks of
gestation who meet explicit contraction criteria for preterm labor go on to give birth within
one week and approximately 50 percent of patients diagnosed with preterm labor go to give
birth at term [17,18]. Data are reviewed separately. (See "Preterm labor: Clinical findings,
diagnostic evaluation, and initial treatment".)

Obstetric complications in the current pregnancy — Obstetric complications often require

an indicated PTB to protect the health of the pregnant person and/or fetus. Such
complications include placenta previa, placenta accreta spectrum, vasa previa, prior fundal
hysterotomy, PPROM, oligohydramnios or polyhydramnios, preeclampsia with severe features,
gestational diabetes with poorly controlled glucose levels, and intrahepatic cholestasis of
pregnancy with high total bile acid levels [19]. (See individual topic reviews on each condition).

3 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

Past history of surgical management of abortion — In a meta-analysis of pregnancy

outcome after uterine evacuation including over one million participants (31 studies involving
termination of pregnancy, five studies involving spontaneous abortion), those with a history of
surgical uterine evacuation had a small but statistically significant increase in risk for PTB in a
subsequent pregnancy compared with controls without a history of uterine evacuation [20].
Individuals who underwent medical termination of pregnancy had a similar future risk of PTB
as those 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. These issues are
reviewed separately. (See "Overview of pregnancy termination", section on 'Future
pregnancies'.)

Demographic factors

Non-Hispanic Black or American Indian/Alaska Native race — PTB and recurrent PTB
rates are higher for non-Hispanic Black and American Indian/Alaska Native females than for
White, Asian, or Hispanic females in the United States [4,21,22]. Lower educational attainment,
residence in a disadvantaged area, structural racism, stress/lack of social support, and lack of
access to prenatal care can lead to PTB through multiple pathways [23-25].

Although differences in environmental risk factors account for some of this increased risk in
PTB, some investigators have suggested that biologic factors may also have a role [26-29].
Polymorphisms in genes for regulation of innate immunity may be more prevalent is some
racial groups and may affect the vaginal microbiome [30-33]. One mechanism may involve an
enhanced proinflammatory response to normal or altered vaginal microflora, leading to
preterm labor or PPROM [34]. Alternatively, immune hyporesponsiveness may create a
permissive environment for ascending infection and its sequelae (premature labor, PPROM)
[35,36]. (See "An overview of the innate immune system".)

Extremes of maternal age — The rate of PTB appears to be higher at the extremes of
maternal age. Physiologic immaturity and socioeconomic factors may increase risk for
adolescent females; a higher prevalence of preexisting chronic disease and obesity may
increase risk for older females. Both groups have high rates of unplanned pregnancy, which is
a risk factor for PTB [37]. (See "Pregnancy in adolescents", section on 'Pregnancy outcome' and
"Effects of advanced maternal age on pregnancy".)

Cervical and uterine factors

4 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

● Short or dilated cervix in the midtrimester – There is an inverse relationship between

cervical length measured by transvaginal ultrasound at 16 to 28 weeks of gestation
( table 4) and gestational age at delivery ( table 4). A Bishop score ≥5 ( table 5) on
digital examination in the midtrimester has also been also associated with increased
odds of PTB [38]. A gradual decline in cervical length after 32 weeks can be normal and
much less predictive of sPTB. Data are reviewed separately. (See "Short cervix before 24
weeks: Screening and management in singleton pregnancies".)

The corollary (ie, a long midtrimester cervical length is associated with postterm birth [39])
further supports the hypothesis that cervical length is a critical determinant of gestational
length.

● Prior cold knife conization and loop electrosurgical excision – 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. Data are reviewed separately. (See "Reproductive effects
of cervical excisional and ablative procedures".)

● Prior dilation and curettage – In a meta-analysis of observational studies, patients with

a history of dilation and curettage (D&C) were at higher risk for PTB compared with those
with no such history: PTB <37 weeks (odds ratio [OR] 1.29, 95% CI 1.17-1.42); PTB <32
weeks (OR 1.69, 95% CI 1.20-2.38); PTB <28 weeks (OR 1.68, 95% CI 1.47-1.92) [40]. The
risk remained increased when the control group was limited to participants with a
medically managed miscarriage or induced abortion and when only sPTBs were
considered, and was highest for individuals with a history of multiple D&Cs.

● Cervical polyps – In small studies, both the presence of cervical polyps and their removal
during pregnancy have been associated with an increased risk for PTB [41-45]. It has
been hypothesized that cervical polyps may induce intrauterine infection and/or
inflammation leading to PTB, and this process may not be resolved by polypectomy. The
authors of this topic do not remove cervical polyps in pregnant patients unless they are
symptomatic (actively bleeding) or suspicious for malignancy.

● Congenital uterine anomalies – The magnitude of risk for PTB depends upon the
specific uterine abnormality (septate, bicornuate, unicornuate, uterus didelphys). Data
on risk are available separately. (See "Congenital uterine anomalies: Clinical
manifestations and diagnosis".)

5 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

● Uterine leiomyoma – Patients with fibroids may be at slightly increased risk for
pregnancy loss and PTB. The risk appears to be associated with fibroid size and location.
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. Data are available separately. (See "Uterine fibroids (leiomyomas): Issues in
pregnancy", section on 'Preterm labor and birth'.)

● Vaginal (uterine) bleeding in early pregnancy – Early pregnancy bleeding is often due
to decidual hemorrhage and associated with an increased risk for both subsequent sPTB
and indicated PTB. In a large study based on registry data, pregnancies with first-
trimester bleeding were at increased risk for PPROM (OR 1.18, 95% CI 1.01-1.37),
placental abruption (OR 1.48, 95% CI 1.30-1.68), and preeclampsia with severe features
(OR 1.25, 95% CI 1.09-1.43) [46]. In this and other studies, the association was stronger
for PTB before 34 weeks than late PTB [46,47]. Patients 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.

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 [48]. Later in pregnancy, decidual cell-
derived thrombin can inhibit decidual cell progesterone receptor expression, possibly
resulting in PTB related to abruption or PPROM [49-51]. (See "Spontaneous preterm
birth: Pathogenesis", section on '#3 Decidual hemorrhage'.)

Chronic medical disorders — Chronic maternal medical disorders can be associated with
maternal or fetal complications that necessitate medically indicated PTB as well as increase
the risk for sPTB. Examples include chronic hypertension, chronic kidney disease, type 1
diabetes mellitus, some autoimmune diseases, and chronic anemia. (See individual topic
reviews on each condition).

Both depression and exposure to selective serotonin reuptake inhibitors have been associated
with an increased risk of PTB. (See "Antenatal depression: Pregnancy and neonatal outcomes",
section on 'Preterm birth' and "Antenatal use of antidepressants and the potential risk of
teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors",
section on 'Preterm birth'.)

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

6 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

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 were reported by placental pathologists who have described
histologic 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 [52-55]. In the Collaborative
Perinatal Project, chorioamnionitis was detected in 6 percent of the nearly 44,000 deliveries
evaluated, and the rate decreased with increasing gestational age: 15 percent at 28 to 32
weeks, 8 percent at 33 to 36 weeks, and 5 percent after 36 weeks of gestation [56].

● Asymptomatic bacteriuria – Most clinical and epidemiologic evidence suggests a

strong association between untreated asymptomatic bacteriuria and low birth
weight/PTB, but it is unclear whether asymptomatic bacteriuria is an independent risk
factor for PTB [57-60]. 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 statistically significant increase in the overall rate of
PTB (adjusted odds ratio [aOR] 1.21, 95% CI 0.96-1.53) [58] or sPTB (aOR 1.07, 95% CI
0.78-1.46) [59] when the data were adjusted for demographic and social factors. (See
"Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on
'Pregnancy outcomes'.)

● 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 [61,62]. 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 [63-65].

Several hypotheses have been proposed to explain the association between periodontal
disease and sPTB [66-69]. 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

7 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

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. This may
explain why studies focused on aggressively treating periodontal disease in pregnant
patients have, in general, failed to abrogate the risk of PTB.

● Genital tract infection/colonization – Multiple studies have reported an association

between preterm labor/birth and various genital tract infections/colonizations
( table 6), including Group B Streptococcus (GBS; Streptococcus agalactiae) [70],
Chlamydia trachomatis [71-74], bacterial vaginosis (BV) [75-77], Neisseria gonorrhea [78],
syphilis [79], Trichomonas vaginalis [80], Ureaplasma species [81], unencapsulated
Haemophilus influenzae [82], and possibly persistent human papillomavirus 16/18 [83-86].
Mycoplasma hominis in cervicovaginal fluid does not appear to be a risk factor for sPTB
[87-90].

In a population-based retrospective cohort study including over 14 million singleton live

births in the United States, the PTB rate associated with chlamydia, gonorrhea, and
syphilis infection was 9.9, 12.2, and 13.3 percent, respectively [91]. Compared with
pregnancies without these infections, the odds of PTB were: chlamydia OR 1.03 (95% CI
1.02-1.04), gonorrhea OR 1.11 (95% CI 1.08-1.15), syphilis OR 1.17 (95% CI 1.11-1.22), and
any of these sexually transmitted infections OR 1.06 (95% CI 1.05-1.07), after adjustment
for sociodemographic, medical, and/or health factors. Limitations of the study included
lack of information about gestational age at diagnosis, treatment, type of PTB
(spontaneous, indicated, or after PPROM), and misclassification bias.

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 [70,92,93].

Candida species colonization is not a risk factor for PTB [94].

• Vaginal microbiome – Emerging research has found that pregnancy alters the vaginal
microbiome profile to be more hospitable to Lactobacillus and less favorable to G.
vaginalis and other taxa associated with BV, with the exception of BV-associated
bacterium 1 (BVAB1), which tends to remain stable [95]. In addition, there is
increasing evidence that some vaginal microbiomes are associated with an increased
risk for sPTB, and the prevalence of these microbiomes varies across populations
[96-98]. As an example, carriage of BVAB1 is positively associated with PTB and more
prevalent in pregnant people of African ancestry, who are known to have an increased

8 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

risk of PTB compared with those of European ancestry, whereas carriage of L.

crispatus is protective against PTB and more prevalent in pregnant people of
European ancestry [96]. Whether interventions designed to favorably alter the vaginal
microbiome will abrogate the risk of PTB is not known.

● Malaria – Malaria is associated with PTB, low birth weight, and other maternal and
neonatal morbidities. The complications of malaria in pregnancy are discussed
separately. (See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis,
and outcome".)

Physical and genetic factors

Short stature — Females with shorter stature appear to be at increased risk for PTB and
taller females appear to be decreased risk [99-101].

Genetic variants — Genetic variants appear to contribute to length of gestation and

likelihood of sPTB. PTBs are more prevalent in individuals with a first-degree female relative
who had a PTB [102,103]. Concordance for timing of parturition is higher in females who are
monozygotic twins than in those who are dizygotic twins [3,104-114]. In a genome-wide
association study of a large cohort of females of European ancestry, maternal variants at the
EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration
and maternal variants at the EBF1, EEFSEC, and AGTR2 loci were associated with PTB; however,
birth outcomes were self-reported [115]. A subsequent maternal genome-wide meta-analysis
of gestational duration found seven loci associated with PTB (in WNT4, EEFSEC, KCNAB1,
HAND2, EBF1, HLA-DQA1, and LRP5 genes [>18,000 PTB cases, >260,000 controls]) and large
genetic similarities with gestational duration [116]. Although PTB susceptibility genes have
been identified, epigenetic and gene-environmental factors probably play a more important
role in PTB than the maternal genotype.

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

Behavioral factors

Cigarette smoking — Cigarette smoking has a modest dose-dependent relationship with the
risk for PTB. This effect may be explained by increased rates of smoking-related complications
of pregnancy, such as placental abruption, placenta previa, PROM, and fetal growth
restriction. However, the association still exists after adjusting for these possible confounding
factors, suggesting that there may be a direct effect of cigarette smoking on sPTB. Data are
reviewed separately. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy

9 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

and the neonate".)

Substance use — Maternal substance use (eg, cocaine, alcohol, toluene) increases the risk of
PTB [117-121]. Among individuals who use multiple drugs, the risk of PTB ranges from 25 to
63 percent [122,123]. However, it is difficult to separate the risk attributable to the substance
from other risk factors, which are common in these patients. Data are reviewed separately.
(See "Substance use during pregnancy: Screening and prenatal care" and "Alcohol intake and
pregnancy".)

Diet, weight, physical activity

Undernutrition — Maternal undernutrition in pregnancy appears to increase the risk of PTB

[124]. 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 [125,126]. In Gambian females, pregnancies conceived during the
rainy season when food is scarce were significantly shorter than those conceived when food
was more plentiful [127]. Observations of shorter gestational length with early pregnancy
exposure to the Dutch famine also support this hypothesis [128].

Low and high prepregnancy weight and gestational weight gain — Extremes of
prepregnancy weight and/or body mass index have been associated with increased rates of
PTB [129-133]. The strength of this association is not well-defined because the effect is
bimodal as opposed to linear and because of interdependent variables [134]. For example, low
prepregnancy weight may be confounded by socioeconomic status, race/ethnicity, and even
weight gain in pregnancy.

Pregnant people with obesity are at increased risk of medically-indicated PTB. Obesity also
appears to increase the risk for PPROM and may increase the risk of sPTB without PPROM. A
potential effect on sPTB is hypothesized to be mediated by the inflammatory state, but data
are weak and reviewed separately. (See "Obesity in pregnancy: Complications and maternal
management", section on 'Indicated and spontaneous preterm birth'.)

Low and high weight gain during pregnancy have also been associated with PTB [135-137].
These issues are discussed in detail separately. (See "Gestational weight gain".)

Occupational physical activity — A relationship between maternal physical activity related

to working during pregnancy and PTB has been consistently noted in meta-analyses, but has
not been clearly established because available evidence is generally of low quality [138-141].
Factors that have been evaluated include a high cumulative work fatigue score; standing and
walking at work for more than three or four hours per day; lifting and carrying >5 kg or ≥11

10 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

kg; lifting objects for a combined weight of ≥100 kg per day; lifting and carrying in the third
trimester; having a job that required physical effort or physical exertion; and working rotating
shifts, fixed night shifts, or longer hours (>40/week). The ORs ranged from 1.1 to 1.6 for all of
these associations, and some dose-response patterns were observed.

It is probably important to quantitate all of the factors involved in work-related exertion, as

well as the pregnant person'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. Data are reviewed separately. (See "Working during
pregnancy", section on 'Work on pregnancy and child development'.)

Role of exercise — In randomized trials of individuals with uncomplicated pregnancies,

exercise during pregnancy did not increase the risk for PTB [142]. A systematic review of
prospective cohort, case-cohort, nested case-control, or randomized study design found that
exercise (leisure time physical activity) was not associated with an increased risk of PTB, and
may decrease the risk by 10 to 14 percent compared with physical inactivity [143]. The
optimum time appeared to be two to four hours of physical activity/week. As discussed above,
a "healthy exerciser" effect likely exists whereby healthier individuals and those at low risk of
PTB are more likely to continue to exercise during pregnancy. However, it has also been
hypothesized that exercise may reduce the risk of PTB by reducing oxidative stress or
increasing placental vascularization [144]. (See "Exercise during pregnancy and the
postpartum period".)

Role of coitus — Sexual intercourse during pregnancy does not appear to be a risk factor for
PTB [145-148].

Additional factors

Short interpregnancy interval — A short interpregnancy interval (<6 months) has been
associated with an increased risk for PTB, even if the previous birth was at term; however, the
risk is highest when the previous birth was preterm. Data are reviewed separately. (See
"Interpregnancy interval: Optimizing time between pregnancies".)

Excessive stress — Most pregnant people report experiencing at least one stressful life
event in the year before giving birth [149]. An association between stress (including
posttraumatic stress disorder [PTSD]) 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) [150]. CRH can enhance local prostaglandin

11 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

production, which initiates contractions. However, studies have not consistently demonstrated
a relationship between maternal stress, CRH concentration, and PTB [151-153]. (See
"Spontaneous preterm birth: Pathogenesis", section on '#1 Stress-induced premature
activation of the HPA axis'.)

When maternal psychosocial stress has been associated with an increased risk of PTB, the risk
was modest (OR 1.42, 95% CI 1.05-1.91) in cohort studies [154]. 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 [155].

Lack of prenatal care — The absence of prenatal care has been consistently identified as a
risk factor for preterm labor and birth, but it is unclear whether this association is causal or a
marker for other factors that contribute to PTB. Data are reviewed separately. (See "Prenatal
care: Initial assessment" and "Prenatal care: Second and third trimesters".)

Environmental risk factors — Systematic reviews have reported an association between

PTB and fine particulate matter and ozone in the air, high environmental temperature, and
phthalate exposure [156-164]. Although the effects were small and limited by differences in
study designs, particularly assessment of exposure, a causal effect is possible. Data are
reviewed separately. (See "Occupational and environmental risks to reproduction in females:
Specific exposures and impact".)

Fetal and infant risk factors

● Male sex is a risk factor for sPTB [165-168].

● Fetal conditions associated with sPTB and/or indicated PTB include certain congenital
anomalies [169,170], growth restriction [171-176], alloimmunization, and hydrops fetalis.
(See individual topic reviews on these conditions).

● A history of sudden infant death syndrome (SIDS) appears to be a risk factor for PTB in
the subsequent pregnancy [177]. (See "Sudden infant death syndrome: Risk factors and
risk reduction strategies".)

Paternal risk factors — No paternal risk factors for development of PTB in their partners
have been identified [178]. PTB risk does not appear to be affected by the father's history of
preterm children with other partners or PTBs to members of the father's family [179].

12 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

PREDICTING RISK FOR PRETERM BIRTH

Risk scoring systems — Risk scoring is a quantitative method used to identify pregnant
individuals at increased risk for PTB. Proposed systems typically calculate an additive score
based on points assigned to arbitrarily selected or weighted demographic, historical,
laboratory, and clinical risk factors [58,180-183].

Systematic reviews have concluded that there is no effective risk scoring system for prediction
of PTB [184,185]. This is due to our lack of knowledge regarding the cause(s) of PTB in most
pregnancies and because the most powerful risk factor is previous PTB, which is not applicable
to nulliparous patients. The positive predictive value (the percent of patients defined as high
risk that actually go on to have a PTB) of most risk scoring systems is low, approximately 20 to
30 percent, and varies according to the population studied and the trimester [117].

Biomarkers

● Fetal fibronectin – Cervicovaginal fetal fibronectin (fFN) can be a useful biomarker for
predicting PTB within 7 to 14 days in patients with contractions and mild cervical dilation
and effacement, particularly when combined with ultrasound assessment of cervical
length and when a quantitative measurement is available. The predictive value of fFN for
PTB more than 14 days after testing is poor. (See "Preterm labor: Clinical findings,
diagnostic evaluation, and initial treatment", section on '<34 weeks of gestation'.)

Fetal fibronectin may be useful for predicting risk of PTB in asymptomatic high-risk
pregnant people (eg, previous PTB). A fFN ≥50 ng/mL at 22 to 27+6 weeks of gestation
had sensitivity 55 percent and positive predictive value 27 percent for prediction of PTB
<34 weeks in one study [186]. An algorithm combining quantitative fFN (not available in
the United States) and cervical length, demographic information, and obstetric history
(whether previous sPTB/PPROM or current suspected preterm labor) has been
incorporated into an App (QUiPP) for prediction of sPTB in Europe [187,188]. In a
randomized multicenter trial involving nearly 1900 pregnant people between 23+0 and
34+6 weeks of gestation with symptoms of preterm labor, the QUiPP app did not reduce
unnecessary treatments compared with routine management [189].

By contrast, fFN is not useful as a screening test for predicting risk of PTB in
asymptomatic nulliparous people. In the largest prospective cohort study of use of fFN in
asymptomatic low-risk nulliparous people with singleton pregnancies and cervical length
>15 mm (n = 9410), the sensitivity and positive predictive value of fFN ≥50 ng/mL at 22 to

13 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

30 weeks of gestation for PTB <32 weeks was 32.1 and 3.1 percent, respectively [190].
Using a lower or higher threshold did not significantly improve overall test performance.

● PreTRM – A test (PreTRM Test) for two serum proteins, insulin-like growth factor-binding
protein 4 and sex hormone-binding globulin, is available for clinical use to predict PTB. In
a study to develop and validate a mass spectrometry-based serum test to predict sPTB in
asymptomatic pregnant people, the test had sensitivity and specificity of 0.75 and 0.74,
respectively, for predicting PTB <37 weeks [191]. We recommend not moving forward
with serum screening for PTB until such screening has been adequately tested and
validated.

● Other biomarkers – Over 30 other biomarkers have been studied for identification of
asymptomatic pregnant people at high risk of PTB. A systematic review of these
biomarkers included 72 observational studies involving almost 90,000 participants and
concluded that none of these other biomarkers (alone or in combination) was clinically
useful for predicting sPTB in asymptomatic people [192]. The markers included
inflammation-related biomarkers, placental protein/hormone-related biomarkers,
angiogenesis-related biomarkers, coagulation-related biomarkers, genetic-biomarkers,
proteomic-related biomarkers, and markers of a dysfunctional vaginal microbiome.

Use of RNA profiling, either in the maternal circulation [193] or the cervix [194-196], is a
promising area of active investigation. Additional studies are needed to characterize the
specific RNA species and identities of the most predictive markers, and then to test them in
well-designed, prospective studies in both high- and average-risk populations.

PROGNOSIS AFTER A PRETERM BIRTH

Long-term maternal consequences — PTB is one of several pregnancy-related risk factors

for future maternal cardiovascular morbidity and mortality. In a meta-analysis of cohort
studies, individuals with a history of PTB were 63 percent more likely to experience
cardiovascular morbidity than those with no history of PTB (OR 1.63, 95% CI 1.39-1.93) and 93
percent more likely to experience a cardiovascular disease--related death (OR 1.93, 95% CI
1.83-2.03) at a median follow-up of 7.5 years postpartum, although the absolute risk is low
[197]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

Premature all-cause mortality was also increased in a national cohort and cosibling study
[198]. The risk was higher with early- versus late-PTB. Causes included cardiovascular and
respiratory disorders, diabetes, and cancer, and were independent of shared genetic or

14 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

environmental factors within families.

The mechanisms for the association between cardiovascular disease and spontaneous or
indicated PTB are unknown. One possibility is a proinflammatory maternal phenotype [199].

Offspring prognosis

● (See "Short-term complications of the preterm infant".)

● (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant
mortality".)
● (See "Late preterm infants".)
● (See "Overview of the long-term complications of preterm birth".)
● (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology
and risk factors".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Preterm labor and
birth".)

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 education: Preterm labor (The Basics)")

● Beyond the Basics topics (see "Patient education: Preterm labor (Beyond the Basics)" and

15 de 16 25/7/2023, 17:24
Spontaneous preterm birth: Overview of risk factors and prognosis - U... https://www.uptodate.com/contents/spontaneous-preterm-birth-overview...

"Patient education: Bacterial vaginosis (Beyond the Basics)" and "Patient education:
Management of a cervical biopsy with precancerous cells (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Risk factors for preterm birth (PTB) – There are many maternal risk factors for PTB
( table 7). Some are reversible, others are not. Identification of risk factors for PTB
before conception or early in pregnancy may lead to interventions that could help
prevent this complication. (See 'Risk factors' above.)

● Frequency of recurrent PTB – A history of spontaneous PTB (sPTB) is the major risk
factor for recurrence. Earlier prior sPTB increases the risk compared with later prior sPTB
( table 2), and recurrent sPTBs tend to occur at a similar gestational age. A history of
two sPTBs and no prior term also substantially increases risk ( table 3). (See 'Past
history of preterm birth' above.)

● Risk scoring systems for predicting PTB – No quantitative method for identifying
pregnant individuals at increased risk for PTB has been proven useful for clinical use.
Proposed systems typically calculate an additive score based on points assigned to
arbitrarily selected or weighted demographic, historical, laboratory, and clinical risk
factors. (See 'Predicting risk for preterm birth' above.)

● Long-term maternal prognosis after a PTB – Patients who give birth preterm are at
increased risk for premature cardiovascular morbidity and mortality and all-cause
mortality remote from delivery. (See 'Long-term maternal consequences' above.)

Use of UpToDate is subject to the Terms of Use.

Topic 6761 Version 137.0

16 de 16 25/7/2023, 17:24