CHAPTER 37 Joses A. Jain and Cynthia Gyamfi‐Bannerman Columbia University Medical Center, New York, NY, USA Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, the sequelae of which result in over one million infant deaths each year. Spontaneous preterm labor is the result of multiple pathophysiologic processes, and contributes to approximately 70% of all cases of preterm birth [1]. The resultant burden is the leading cause of neonatal morbidity and mortality, accounting for 36.5% of infant deaths and 25–50% of cases of long‐term neurologic impairment in children [2]. The incidence of preterm‐related complications is inversely proportional to the gestational age at the time of delivery [3]. Thus, both pharmacologic and non‐pharmacologic strategies that have been developed to improve the outcomes in pregnancies complicated by preterm labor have targeted two goals: the prolongation of pregnancy and the optimization of the preterm neonate’s transition to extrauterine life. Table 37.1 Risk factors for spontaneous preterm birth with corresponding references to the literature The diagnosis of spontaneous preterm labor has been given multiple definitions by various authors. The classic definition requires the clinical criteria of uterine contractions and documented cervical change (in dilatation, effacement, or both) with intact membranes at 20–36 6/7 weeks gestation. An alternative definition requires an initial presentation with regular contractions and cervical dilatation of at least 2 cm between 20 and 36 6/7 weeks gestation. With this definition, however, only 10% of women diagnosed with preterm labor actually deliver within seven days of presentation [4]. A more recently proposed definition consists of uterine contractions (more than 4 in 20 minutes or more than 8 in 60 minutes) with a transvaginal ultrasound‐determined cervical length of less than 20 mm, or 20–29 mm with a positive fetal fibronectin (FFN) test, at 20–36 6/7 weeks gestation [5]. Regardless of the definition used, the identification of a woman who will actually deliver a premature infant remains a challenge. This chapter will consider the quality of evidence pertaining to the diagnostic tools available in the identification and risk‐stratification of a women at risk for having a preterm birth, including elements of clinical history, transvaginal ultrasound, and fetal fibronectin. The evidence in the literature regarding the management of these patients will then be evaluated. Historically proposed non‐pharmacologic interventions such as bed rest, hydration, and relaxation techniques, in addition to pharmacologic interventions such as tocolysis, antibiotics, antenatal corticosteroids, and magnesium sulfate will also be examined. Many potential risk factors can lead to multiple possible pathways that culminate in the end result of spontaneous preterm birth. Table 37.1 lists some of these risk factors with corresponding references to the literature. Although many of these have been identified, the inherent challenge in successful primary prevention is that many women who have a spontaneous preterm birth have no identifiable risk factors [25]. Of the risk factors that have been identified, a history of a prior preterm birth is the most significant, with subsequent preterm births often occurring at the same gestational age. In a large prospective study by Mercer et al. involving 1711 multiparous women with singleton gestations, those with a prior preterm delivery carried a 2.5‐fold increase in the risk of spontaneous preterm delivery compared to those without a prior preterm delivery (21.7% vs. 8.8%, relative risk (RR) 2.5). An early prior spontaneous preterm delivery (23–27 weeks gestation) was most highly associated with early spontaneous preterm delivery less than 28 weeks gestation (RR 22.1) [26]. The finding of a shortened cervical length as measured by transvaginal ultrasound has been established as a known independent risk factor for preterm birth [4]. As a result, cervical length screening by transvaginal ultrasonography in women with a prior preterm birth has been shown to be a useful predictive tool for the risk of a subsequent preterm birth. In a blinded observational study by Owen et al., a cervical length assessment between 16 weeks and 18 weeks 6 days’ gestation, augmented by serial evaluations up to 23 weeks 6 days’ gestation, was able to predict spontaneous preterm birth prior to 35 weeks’ gestation in women with a history of a prior spontaneous preterm birth [27]. Multiple studies have also demonstrated the predictive value of cervical length screening, including a systematic review by Crane and Hutchens in 2008 [28]. However, the utility of transvaginal ultrasound is limited in that it carries a sensitivity of approximately 70% with a 20% false‐positive rate [27]. The optimal timing and identification of appropriate candidates for cervical length screening also remains a source of controversy. A Cochrane review from 2013 demonstrated insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with transvaginal sonography, identifying a non‐significant association between knowledge of cervical length result and a lower incidence of preterm birth [29]. On the other hand, limiting screening to women with historical risk factors for preterm birth would lead to approximately 40% of women with a short cervix being undiagnosed [30]. For this reason, economic analyses regarding universal screening have been published with results demonstrating that such an approach may be reasonable and cost‐effective [31, 32]. As will be discussed later in this chapter, vaginal progesterone has been shown to be an effective intervention to decrease the risk of spontaneous preterm birth in women with a short cervix; this may add further justification to the concept of universal screening, as this intervention has been included in decision analysis studies [31, 32]. The fetal fibronectin test is a commonly used diagnostic tool that detects the presence of the glycoprotein in vaginal and cervical secretions. This test has been incorporated into clinical practice as a stratification tool to identify those women who are at high risk of having a preterm birth after presenting with symptoms of preterm labor. A systematic review of five randomized controlled trials involving knowledge of FFN results versus no such knowledge in 474 pregnant women did not find enough evidence to support or refute the use of the fetal fibronectin test in the management of women with symptoms of preterm labor [33]. The review did find an association between the knowledge of FFN results and a lower incidence of preterm birth before 37 weeks. Another recent systematic review and meta‐analysis by Berghella et al. demonstrated that fetal fibronectin testing in singleton gestations with threatened preterm labor is not associated with the prevention of spontaneous preterm birth or an improvement in perinatal outcome, but is associated with higher costs [34]. Based on the results of these reviews, there is currently insufficient evidence to recommend the routine use of fetal fibronectin as a secondary screening tool. Progesterone is a steroid hormone that is essential for early pregnancy maintenance and appears to have a role in maintaining uterine quiescence in the latter half of pregnancy. Progesterone also appears to possess anti‐inflammatory properties that may protect against a precipitating elaboration of cytokines and matrix metalloproteinases that lead to preterm birth [35]. Two landmark studies published in 2003 by Meis et al. and da Fonseca et al. initially illustrated the utility of progesterone in the prevention of preterm birth. Meis et al. demonstrated the role of 17 alpha‐hydroxyprogesterone caproate in the prevention of recurrent preterm birth in the Maternal Fetal Medicine Units (MFMU) network trial [36]. In this study, 459 women with a history of a spontaneous singleton preterm delivery at less than 37 weeks’ gestation were randomly assigned to receive weekly intramuscular injections of hydroxyprogesterone caproate (250 mg) or placebo beginning at 16–20 weeks’ gestation and continuing until either 36 weeks’ gestation or until delivery if earlier. Women treated with progesterone had a reduced risk of delivery compared to women treated with placebo at all gestational ages studied: less than 37 weeks (RR 0.66, 95% CI 0.54–0.81), less than 35 weeks (RR 0.67, 95% CI 0.48–0.93), and less than 32 weeks (RR 0.58, 95% CI 0.37–0.91). Infants born to women who were treated with progesterone also experienced significant reductions in the rates of birth weight less than 2500 g, necrotizing enterocolitis, the need for supplemental oxygen, and intraventricular hemorrhage compared to infants born to women treated with placebo [36]. In the Brazilian trial by da Fonseca et al., 142 women at high risk for preterm delivery (based on at least one prior spontaneous preterm birth, prophylactic cervical cerclage, or uterine malformation) were randomized to receive daily progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks’ gestation [37]. Women in the treatment group had a decreased risk of delivery at less than 37 weeks (14% vs. 29%) and less than 34 weeks (3% vs. 19%) when compared to women in the placebo group [37]. A subsequent multi‐center, double‐blinded, randomized controlled trial by Hassan et al. also demonstrated evidence to support the use of vaginal progesterone for the prevention of preterm birth in women with a sonographic short cervix [38]. A Cochrane meta‐analysis from 2013 included 36 randomized controlled trials (8523 women and 12 515 infants) involving prenatal progesterone for the prevention of preterm birth. In women with a history of a prior preterm birth, progesterone administration was associated with a significant reduction in overall perinatal mortality (RR 0.5, 95% CI 0.33–0.75), preterm birth less than 34 weeks (RR 0.31, 95% CI 0.14–0.69), preterm birth less than 37 weeks (RR 0.55, 95% CI 0.42–0.74), infant birth weight less than 2500 g (RR 0.58, 95% CI 0.42–0.79), the use of assisted ventilation (RR 0.40, 95% CI 0.18–0.90), necrotizing enterocolitis (RR 0.30, 95% CI 0.10–0.89), neonatal death (RR 0.45, 95% CI 0.27–0.76), and admission to neonatal intensive care unit (NICU) (RR 0.24, 95% CI 0.14–0.40). Subgroup analyses did not identify a differential effect on the majority of outcomes examined when considering the route of administration (intramuscular vs. vaginal vs. oral) [39]. The above results contrast to those of the OPPTIMUM trial, which was published after the 2013 Cochrane meta‐analysis. The OPPTIMUM trial was a double‐blind, randomized, placebo‐controlled trial of vaginal progesterone 200 mg taken daily beginning at 22–24 weeks gestation, and ending at 34 weeks gestation. The trial consisted of women at high risk of preterm birth due to a history of previous spontaneous birth at ≤34 weeks gestation, cervical length ≤ 25 mm, or a positive fetal fibronectin test combined with other clinical risk factors for preterm birth (any one of a history of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure). Vaginal progesterone administration did not result in a significantly decreased incidence of the primary obstetric outcome (preterm birth before 34 weeks or fetal death), the primary neonatal outcome (a composite of neonatal death, brain injury, and bronchopulmonary dysplasia), or the primary childhood outcome (standardized cognitive score at two years of age) in comparison to placebo. However, there did appear to be a reduction in neonatal brain injury in the treatment group. Subgroup analysis indicated a possible treatment effect in women who had a history of a prior spontaneous preterm birth, but only for the composite neonatal outcome [40]. Although these results contrast the prior findings in the literature, it is important to note that the compliance rate in this study was 69%, far less than the 88.5% reported compliance rate in the study by Hassan et al. [38, 40]. Regardless, the OPPTIMUM study does raise new questions regarding the effectiveness of progesterone as an intervention for the prevention of preterm birth. Antenatal management of a woman with a history of a prior preterm birth is dependent on a number of factors involving both her prior pregnancy outcomes and her clinical status at the time of her assessment. A detailed history should be obtained, with attention paid to the circumstances and events surrounding the prior preterm delivery (i.e. bleeding, infection, contractions, ruptured membranes) any interventions employed, and the gestational age at delivery. Cervical length surveillance, as discussed above, has an important role in screening for the presence of a short cervix in high‐risk women; however the optimum timing and frequency of transvaginal sonography is not well established. Two randomized controlled trials have demonstrated that a measurement of cervical length at 18–24 weeks, followed by vaginal progesterone treatment of women in whom short cervix is identified, results in a 40% decrease in the incidence of preterm birth, and a significant reduction in composite neonatal morbidity and mortality [38, 41]. Although a systematic review demonstrated that changes in cervical length over two or more examinations were not more predictive of preterm birth than a single cervical length measurement at 18–24 weeks, several studies have demonstrated that in women with a short cervix, a change in cervical length on subsequent ultrasound examinations has been shown to impact the risk of preterm birth [42–44]. In a multi‐center, randomized controlled trial involving 1014 women with a history of a prior preterm birth, 302 were randomized to either undergo a cerclage or not undergo a cerclage after transvaginal ultrasound screening identified a cervical length less than 25 mm [45]. There was no significant difference in the primary study outcome of preterm birth at less than 35 weeks’ gestation. However, cerclage placement was associated with significant reductions in deliveries prior to 24 weeks’ gestation (RR 0.44, 95% CI 0.21–0.92), deliveries prior to 37 weeks’ gestation (RR 0.75, 95% CI 0.60–0.93), and in perinatal death (RR 0.54, 95% CI 0.29–0.99). In a secondary analysis of this study, cerclage placement for a cervical length of less than 15 mm was associated with a significant decrease in preterm birth at less than 35 weeks’ gestation (RR 0.23, 95% CI 0.08–0.66) [45]. Based on the pooled results of five clinical trials, in a singleton pregnancy with prior spontaneous preterm birth at less than 34 weeks’ gestation and cervical length less than 25 mm before 24 weeks’ gestation, cerclage was associated with a 30% reduction in the risk of preterm birth at less than 35 weeks’ gestation (RR 0.7, 95% CI 0.55–0.89) and a 36% reduction in composite perinatal mortality and morbidity (RR 0.64, 95% CI 0.45–0.91) [45–48]. There is currently insufficient evidence to support the notion of an additive effect of progesterone and cerclage together in reducing the risk of preterm birth. There is also currently no evidence to support the simultaneous use of multiple formulations of progesterone, or the changing of progesterone formulations (i.e. the addition of or changing to vaginal progesterone in a woman receiving intramuscular progesterone due to a history of a prior preterm birth, and in whom a short cervix is diagnosed).
Preterm labor
Background
Risk factor
Risk
References
Prior pregnancy history
Prior spontaneous preterm birth
RR 6.4 (95% CI 4.4–9.2)
Goldenberg et al. [6]
Prior surgical uterine evacuation
OR 1.44 (95% CI 1.09–1.90)
Saccone et al. [7]
Short interpregnancy interval (≤6 mo)
OR 3.6 (95% CI 1.41–8.98)
Rodrigues et al. [8]
Demographics
Non‐hispanic black race
OR 1.78 (95% CI 1.59–2.00)
Srinivasjois et al. [9]
Age ≥ 40 yr
OR 1.4 (95% CI 1.1–1.7)
Cleary‐Goldman et al. [10]
Uterine factors
Congenital Mullerian anomalies
OR 5.9 (95% CI 4.3–8.1)
Hua et al. [11]
Uterine fibroids (≥5–6 cm), or multiple fibroids
OR 1.5 (95% CI 1.3–1.7)
Klatsky et al. [12]
Cervical factors
Prior cervical conization
OR 4.7 (95% CI 2.22–7.10)
OR 1.99 (95% CI 1.81–2.20)
Klaritsch et al. [13]
Jakobsson et al. [14]
Prior LEEP
RR 2.61 (95% CI 2.02–3.20)
RR 1.61 (95% CI 1.35–1.92)
Jakobsson et al. [15]
Connor et al. [16]
Short cervix
RR inversely related to cervical length.
Iams et al. [17]
Assisted reproductive technology
In‐vitro fertilization
OR 2.0 (95% CI 1.7–2.2)
Jackson et al. [18]
Infection
Periodontal disease
OR 2.83 (95% CI 1.95–4.10)
OR 4.45 (95% CI 2.16–9.18)
Vergnes et al. [19]
Jeffcoat et al. [20]
Asymptomatic bacteriuria
OR 2.08 (95% CI 1.45–3.03)
Klein et al. [21]
Bacterial vaginosis before 16 wk
OR 7.55 (95% CI 1.8–31.7)
Klein et al. [21]
Gonorrhea
OR 5.31 (95% CI 1.57–17.9)
Klein et al. [21]
Chlamydia (at 24 wk)
OR 2.2 (95% CI 1.03–4.78)
Klein et al. [21]
Trichomonas vaginalis
OR 1.3 (95% CI 1.1–1.4)
Klein et al. [21]
Behavioral factors
Smoking (>10 cigarettes/day)
OR 1.7 (95% CI 1.4–2.0)
Kyrklund‐Blomberg et al. [22]
Underweight
RR 1.32 (95% CI 1.10–1.57)
Han et al. [23]
Maternal stress
OR 1.16 (95% CI 1.05–1.29)
Copper et al. [24]
Clinical questions
Transvaginal ultrasound
Fetal fibronectin (FFN)
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