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Spontaneous preterm birth: Overview of risk factors and prognosis

Spontaneous preterm birth: Overview of risk factors and prognosis
Literature review current through: Jan 2024.
This topic last updated: Dec 07, 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). Approximately 10 percent of all births occur preterm, most (85 percent) between 32+0 and 36+6 weeks of gestation [1]. Seventy to 80 percent of PTBs 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 are medically indicated (ie, 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 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prematurely stimulate this cascade, suppressive factors that inhibit the cascade and maintain uterine quiescence are withdrawn prematurely, or both.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 [2-11]. 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) [5].

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) [8].

A prior twin sPTB is associated with an increased risk of sPTB in a subsequent singleton pregnancy [12]. A prior singleton sPTB is associated with an increased risk of sPTB in a subsequent twin gestation [13].

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 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 [14]. 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 [15,16], 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 [17].

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 [18,19]. 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 [20]. (See individual topic reviews on each condition).

Past history of procedural 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 procedural abortion had a small but statistically significant increase in risk for PTB in a subsequent pregnancy compared with controls without a history of uterine evacuation [21]. Individuals who underwent medication abortion had a similar future risk of PTB as those with no history of pregnancy termination.

Although procedural abortion 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 [5,22,23]. 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 [24-26].

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 [27-30]. Polymorphisms in genes for regulation of innate immunity may be more prevalent is some racial groups and may affect the vaginal microbiome [31-34]. One mechanism may involve an enhanced proinflammatory response to normal or altered vaginal microflora, leading to preterm labor or PPROM [35]. Alternatively, immune hyporesponsiveness may create a permissive environment for ascending infection and its sequelae (premature labor, PPROM) [36,37]. (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 [38]. (See "Pregnancy in adolescents", section on 'Pregnancy outcome' and "Effects of advanced maternal age on pregnancy".)

Cervical and uterine factors

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 [39]. 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 [40]) 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) [41]. 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 [42-46]. 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".)

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) [47]. In this and other studies, the association was stronger for PTB before 34 weeks than late PTB [47,48]. 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 [49]. Later in pregnancy, decidual cell-derived thrombin can inhibit decidual cell progesterone receptor expression, possibly resulting in PTB related to abruption or PPROM [50-52]. (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, 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 [53-56]. 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 [57].

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 [58-61]. 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) [59] or sPTB (aOR 1.07, 95% CI 0.78-1.46) [60] 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 [62,63]. 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 [64-66].

Several hypotheses have been proposed to explain the association between periodontal disease and sPTB [67-70]. 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. 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) [71], Chlamydia trachomatis [72-75], bacterial vaginosis (BV) [76], Neisseria gonorrhea [77], syphilis [78], Trichomonas vaginalis [79], Ureaplasma species [80], unencapsulated Haemophilus influenzae [81], and possibly persistent human papillomavirus 16/18 [82-85]. Mycoplasma hominis in cervicovaginal fluid does not appear to be a risk factor for sPTB [86-89].

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 [90]. 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 [71,91,92].

Candida species colonization is not a risk factor for PTB [93].

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 [94]. 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 [95-97]. 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 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 [95]. 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 [98-100].

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 [101,102]. Concordance for timing of parturition is higher in females who are monozygotic twins than in those who are dizygotic twins [4,103-113]. 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 [114]. 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 [115]. 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 and the neonate".)

Substance use — Maternal substance use (eg, cocaine, alcohol, toluene) increases the risk of PTB [116-120]. Among individuals who use multiple drugs, the risk of PTB ranges from 25 to 63 percent [121,122]. 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 [123]. 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 [124,125]. In Gambian females, pregnancies conceived during the rainy season when food is scarce were significantly shorter than those conceived when food was more plentiful [126]. Observations of shorter gestational length with early pregnancy exposure to the Dutch famine also support this hypothesis [127].

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 [128-132]. The strength of this association is not well-defined because the effect is bimodal as opposed to linear and because of interdependent variables [133]. 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 [134-136]. 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 [137-140]. 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 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 [141]. 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 [142]. 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 [143]. (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 [144-147].

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 [148]. 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) [149]. CRH can enhance local prostaglandin production, which initiates contractions. However, studies have not consistently demonstrated a relationship between maternal stress, CRH concentration, and PTB [150-152]. (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 [153]. 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 [154].

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 [155-163]. 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 [164-167].

Fetal conditions associated with sPTB and/or indicated PTB include certain congenital anomalies [168,169], growth restriction [170-175], 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 [176]. (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 [177]. 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 [178].

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 [59,179-182].

Systematic reviews have concluded that there is no effective risk scoring system for prediction of PTB [183,184]. 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 [116].

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 [185]. 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 [186,187]. 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 [188].

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 30 weeks of gestation for PTB <32 weeks was 32.1 and 3.1 percent, respectively [189]. 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 [190]. 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 [191]. 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 [192] or the cervix [193-195], 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 [196]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

Premature all-cause mortality was also increased in a national cohort and cosibling study [197]. 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 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 [198]. The association between spontaneous PTB and noncardiovascular causes of death in some studies may reflect unmeasured confounding [199].

Offspring prognosis

(See "Overview of short-term complications in preterm infants".)

(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 "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.)

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Topic 6761 Version 141.0

References

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