Preterm birth (PTB) is traditionally defined as delivery of a fetus between 20 0/7 and 36 6/7 weeks’ gestation. PTB affects 5%–18% of pregnancies. It is the leading cause of neonatal death and the second leading cause of childhood death below the age of 5 years.1 The rate of all-cause preterm deliveries in the United States decreased from 10.4% in 2007 to 9.6% in 2015. In 2014, preterm deliveries occurred in 7.7% of single gestation pregnancies.2 Multiple gestation pregnancies are associated with increased rates of preterm delivery (50% of twins and 90% of triplets are delivered before 37 weeks’ gestation).3 PTB can be medically-indicated or spontaneous. In this article, we refer to spontaneous PTB (sPTB) only. Most of spontaneous preterm deliveries are preceded by early onset of the parturitional process. Spontaneous preterm delivery is the most common reason for hospitalization during pregnancy in the United States.
Preterm parturition is the consequence of pathological signals that activate the common pathway of parturition. The most well-known components of the common pathway of parturition are the uterine components including: (1) increased myometrial contractility; (2) cervical ripening/dilatation and effacement; (3) membrane/decidual activation.4
Preterm parturition is considered as a syndrome with multiple etiologies and there would not be a single treatment, diagnostic method or preventive strategy that will work for all PTBs. The same concept applies to methods for risk assessment or preventive strategies.5,6
Many risk factors for sPTB have been identified such as black maternal race, previous pregnancy with an adverse outcome, genitourinary infection, smoking, extremes of body weight, social disadvantage, maternal depression, pregnancy stress, poor diet, assisted fertility, periodontal disease, history of cervical surgery, and so on. In as many as half of PTBs, the mother has no evident risk factors.
Although many risk scoring systems have been developed, their ability to identify women at risk and subsequently prevent a preterm delivery has not been evaluated.7 Currently risk recognition and subsequent management of contributing factors are still the practical strategy to prevent preterm delivery.
Two of the strongest clinical risk factors for sPTB are prior sPTB and short cervical length (CL). Women with a prior preterm delivery have a 1.5-fold to 2-fold increased risk of a subsequent preterm delivery. Importantly, the number of prior sPTBs and the gestational age at the prior delivery significantly affect the recurrence risk of sPTB. A PTB followed by delivery at term confers lower risk than the opposite sequence. A patient with history of two very early sPTB (<32 weeks) has a risk of about 57% for recurrent sPTB in subsequent pregnancies.8 sPTB are also more common among women with a history of giving birth between 16 weeks and 20 weeks of gestation or with a history of stillbirth before 24 weeks of gestation.9,10
Short CL is most commonly defined as less than 25 mm, usually before 24 weeks of gestation, but up to 28 weeks of gestation in some series. It is a cut-off that has been associated with an increased risk of sPTB in screened populations. Clinically, the shorter the CL, the greater the risk of sPTB. The relative risks (RR) of preterm delivery among the women with shorter cervixes were 6.19 for lengths at or below the 10th percentile (26 mm), 9.49 for lengths at or below the 5th percentile (22 mm).11 Transvaginal cervical ultrasonography has been shown to be a reliable and reproducible way to assess the length of the cervix.12 This is in contrast to transabdominal ultrasound evaluation of the cervix which can be affected by maternal obesity, position of the cervix, and shadowing from the fetal presenting part.
Adequately powered randomized controlled trials (RCTs) of interventions aimed at nutritional deficiencies (vitamins C and E, calcium, and n-3 fatty acids), genital tract microorganisms (bacterial vaginosis and Trichomonas vaginalis), or treatment of periodontal disease have not shown reductions in PTBs among women with risk factors.13
Historically, studies have recognized that progesterone plays crucial roles in pregnancy.14 These findings inspired basic science and clinical research to determine how progesterone maintains pregnancy. It is now generally accepted that progesterone is essential for the establishment and maintenance of pregnancy and that labor is triggered by its withdrawal. Progesterone causes inhibition of cervical ripening, reduction of myometrial contractility through suppression of oxytocin-receptor synthesis and function, and modulation of inflammation.15 Lars Bengtsson in 1962 found that progesterone treatment did not prevent infection-induced parturition. However, progesterone prevented formalin-induced (and presumably infection-free) parturition.16 Thus, progesterone therapy sustained human pregnancy only in the absence of infection and in the context of endogenous progesterone deficiency. Importantly, the data suggest that endogenous or exogenous progesterone activity can be overridden by intrauterine infection.
In the late 1940s, researchers found that in animal models 17α-substituted derivatives of progesterone had higher progestin activity than progesterone. One of the most potent compounds was the caproic acid ester of 17α-hydroxyprogesterone.17 Clinical trials conducted between 1960 and 1990 of 17α-hydroxyprogesterone-caproate (17OHPC) prophylaxis to prevent sPTB produced mixed outcomes. However, a meta-analysis of the pre-1990 placebo-controlled trials showed that 17OHPC prophylaxis reduced sPTB risk by 50% in women with existing increased risk for sPTB.18
Meis trial which is a large multicenter random placebo-controlled trial of weekly 250 mg injections of 17OHPC in women with a singleton gestation and a history of sPTB showed a 34% reduction in the risk of birth before 37 weeks of gestation among women who received active treatment as compared with those who received placebo (36.3% for 17OHPC vs. 54.9% for placebo).19 The result of this study lead to Food and Drug Administration (FDA) conditional approval of 17OHPC as treatment for prevention of sPTB in patients with a history of sPTB. There were several concerns about this study including unusually high sPTB rate in control group, castor oil being used as vehicle for the medicine, most of data came from a single medical center and higher but not significantly increased pregnancy loss rate at midtrimester in treatment group. American College of Obstetricians and Gynecologists (ACOG) adopted the study result from Meis trial and recommended 17OHPC 250 mg injection starting from 16 weeks to 20 weeks until 37 weeks for prevention of sPTB in patient with a history of sPTB in previous pregnancies.20
The mechanism by which 17OHPC decreases the risk for sPTB is uncertain. Some studies reported that progesterone suppresses myometrial contractility; however, 17OHPC did not have this effect and, at high concentrations, it stimulated myometrial contractility.21,22 A second RCT was requested by FDA in order to fully approve 17OHPC use. Progestin's Role in Optimizing Neonatal Gestation (PROLONG) study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway. The results of the PROLONG study are now available. The authors conclude that in this study population, 250 mg 17OHPC did not decrease recurrent sPTB before 35 weeks and 0 day (RR: 0.95, 95% confidence interval (CI): 0.71–1.26) and was not associated with increased fetal/early infant death (RR: 1.12, 95% CI: 0.70–1.66).23 On October 29, 2019, the FDA advisory committee recommended the drug to be withdrawn from the market (9 to 7 vote). Although the recommendation is not binding, it does become part of the overall assessment process when the FDA makes its final decision. ACOG notes that while eligibility criteria were similar between the Meis trial and PROLONG, the populations are different and PTB rate in PROLONG study is approximately 50% lower than the earlier study. Society for Maternal-Fetal Medicine (SMFM) statement said that “it is reasonable for providers to use 17OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit”.
Meis trial did not provide patients’ information of CL. Whether 17OHPC is effective in preventing PTB in women with a short cervix needs to be examined. A multicenter RCT was conducted in nulliparous women with a singleton gestation between 16 and 22 3/7 weeks of gestation, and a CL <30 mm to examine this question and showed no benefit from 17OHPC (RR: 1.03, 95% CI: 0.79–1.35).24 Subgroup analysis yielded negative results too in women with either a CL of <15 mm, or at 10–20 mm.
The efficacy of vaginal progesterone in preventing sPTB has also been examined. Several clinical trials have been conducted on vaginal progesterone in preventing of sPTB in patients at risk especially with short cervix or history of sPTB. De Fonseca et al. found that daily vaginal progesterone suppository prophylaxis (100 mg) decreased the incidence of PTB in women at risk for sPTB (at least one previous sPTB, prophylactic cervical cerclage, and uterine malformation) compared with placebo. More women were delivered before 34 weeks in the placebo group (18.5%) than in the progesterone group (2.7%) (P < 0.05).25 O’Brien et al. trial was larger and found that vaginal progesterone did not reduce the rate of sPTB (≤32 weeks) in women with a history of sPTB. In this trial, not many patients with short CL (<25 mm) were included. A planned sub-investigation of short CL showed that progesterone may prevent early PTB (≤32 weeks of gestation) and improve neonatal outcome in women with CL <28 mm.26
CL is the best predictor of PTB.11,27,28 Fonseca et al.29 found that vaginal progesterone appeared to have beneficial effects in women with a short cervix (≤15 mm) detected by vaginal ultrasound at around 20 weeks of gestation and this effect was confirmed by Hassan et al.30 in patients with CL of 10–20 mm. Hassan trial also demonstrated significant benefit of vaginal progesterone in reducing neonatal morbidity or mortality event (7.7% vs. 13.5%, RR: 0.57, 95% CI: 0.33–0.99, P = 0.04). Subsequently, a large multi-center placebo controlled trial, OPPTIMUM (does progesterone prophylaxis to prevent preterm labour improve outcome?) study, in the UK was conducted to test the effect of daily vaginal progesterone administered between 22 weeks and 34 weeks of gestation in women with a singleton pregnancy who were at risk for sPTB based on a previous sPTB at ≤34 weeks or a CL ≤25 mm. No significant beneficial effect of vaginal progesterone prophylaxis on the rate of sPTB (<34 weeks) was detected regardless of PTB risk factor.31 Nevertheless, OPPTIMUM trial confirmed the safety of vaginal progesterone use in pregnancy. With the data from OPPTIMUM study incorporated, Romero et al. published several meta-analysis studies which confirmed the beneficial effect of vaginal progesterone in prevention of sPTB in pregnant women with short cervix (<25 mm).32-34
Because of the current availability of a treatment strategy for women with a short cervix (vaginal progesterone), the question arises regarding universal CL screening of women without risk factors for sPTB. ACOG statement about this issue is published in ACOG practice bulletin: “The ACOG recognizes that both sides of this debate raise valid issues. Although this document does not mandate universal CL screening in women without a prior PTB, this screening strategy may be considered. Practitioners who decide to implement universal CL screening should follow one of the protocols for transvaginal measurement of CL from the clinical trials on this subject.”20
Cervical cerclage is traditionally used to treat cervical insufficiency. The term cervical insufficiency is used to describe the inability of the uterine cervix to retain a pregnancy in absence of the signs and symptoms of clinical contractions, or labor, or both in the second trimester.35 The working mechanism of cerclage is still poorly understood.
Emerging evidence suggests that premature ripening of the uterine cervix plays a significant role in premature parturition syndrome. Owen et al. studied singleton gestation women with CL <25 mm and prior sPTB at less than 34 weeks of gestation.36 If the CL was less than 25 mm before 24 weeks, placement of a cerclage was associated with significant reductions in deliveries before 24 weeks of gestation (RR: 0.44, 95% CI: 0.21–0.92) and before 37 weeks of gestation (RR: 0.75, 95% CI: 0.60–0.93) as well as in perinatal death (RR: 0.54, 95% CI: 0.29–0.99) when compared with the group that did not undergo cerclage. In a planned secondary analysis, cerclage for CL less than 15 mm was associated with a significant decrease in PTB at less than 35 weeks of gestation (RR: 0.23, 95% CI: 0.08–0.66). Based on the pooled results of five clinical trials, in a singleton pregnancy with prior sPTB at less than 34 weeks of gestation and CL less than 25 mm before 24 weeks of gestation, cerclage was associated with a 30% reduction in the risk of PTB at less than 35 weeks of gestation and a 36% reduction in composite perinatal mortality and morbidity.37,38
Currently for pregnant women with short cervix in second trimester without prior history of sPTB, vaginal progesterone is the choice of treatment. Cerclage placement in this patient population with CL less than 25 mm detected between 16 weeks and 24 weeks of gestation has not been associated with a significant reduction in PTB.39 A meta-analysis study by Berghella et al. found cerclage significantly reduced sPTB in women with CL <10 mm and without prior sPTB.40 However, the quality of evidence in this study is low. Most studies regarding the role of cerclage in preventing sPTB in women with short cervix showed that cerclage is most beneficial when the CLs were in the lowest centiles. A great portion of women with short cervix in midtrimester would not respond to progesterone treatment. Moreover, insufficient evidence exists to assess if progesterone and cerclage together have additive effect in reducing the risk of sPTB.20 It is unclear whether cerclage can decrease risk for sPTB in women with the CL becoming progressively shortened (<10 mm) despite treatment with vaginal progesterone. A recent retrospective cohort study in this patient group showed cerclage plus vaginal progesterone significantly decreased overall sPTB rates, prolonged pregnancy latency by two-fold, and decreased the overall neonatal morbidity and mortality.41
However, cervical cerclage is a surgical procedure and may have a number of complications, such as rupture of the cervix, trauma of the maternal urinary tract, stimulation of labor activity, cervical stenosis, eruption of sutures, intrauterine infection, and complications of anesthesia. Also, surgeons’ skill and experience play important roles in the quality and outcome of cerclage placement.
Cervical pessary is a silicone device that has been used in past 50 years to prevent sPTB. Cervical pessary is relatively noninvasive and easy to use. Growing interest has focused on pessary for prevention of sPTB. The leading hypotheses for its mechanisms in prevention of sPTB are two: that the pessary helps to keep the cervix closed, and that the pessary changes the inclination of the cervical canal so that the pregnancy weight is not directly above the internal os.42 Several trials had been conducted and the results were not consistent.43–45 A random controlled trial by Goya showed pessary insertion could significantly decrease preterm delivery before 34 weeks in pregnant women with CL of 25 mm or less.43 Another RCT by Nicolaides could not confirm this finding.45 A meta-analysis from Saccone et al. showed that in singleton pregnancies with a transvaginal ultrasound CL ≤25 mm at 20 0/7–24 6/7 weeks, the pessary does not reduce the rate of sPTB or improve perinatal outcome.42 More studies are needed to elucidate the efficacy of pessary in prevention of sPTB and currently several trials are being conducted. Currently the Arabin pessary has not been approved by FDA for prevention of sPTB and its use is limited in research settings in the USA.
Multiple gestation is a strong risk factor for PTB, and more than 50% of women with a twin pregnancy will give birth before 37 weeks gestation.2 The etiology of sPTB in multiple gestations is likely to be multifactorial, different from singletons, and remains not cleared. The possible pathophysiologic mechanisms include intrauterine infection, cervical insufficiency and increased uterine distension. There is also increased secretion of mediators including corticotrophin-releasing hormone from the larger placental mass, and factors produced by the maturing fetal lung such as surfactant protein-A, which stimulates myometrial contractility and may contribute to preterm parturition.46
No study looking at a single intervention for the prevention of sPTB in asymptomatic, unselected twin gestations has found a beneficial effect.47 Therefore, it's crucial to select twin pregnancies which may respond to treatment for prevention of sPTB. Transvaginal ultrasonographic CL, digital examination, fetal fibronectin screening, and home uterine monitoring have been used for screening asymptomatic women with multifetal gestations for the risk of sPTB. The use of these screening methods in asymptomatic women with multifetal pregnancies is not recommended by ACOG because “there are no interventions that have been shown to prevent spontaneous preterm delivery in asymptomatic women with multifetal gestations identified to be at risk based on these screening methods”.48
Nonetheless, in asymptomatic women with a twin pregnancy, there is some evidence supports the use of measuring CL from 18 weeks of gestation as a predictor of sPTB.49 A meta-analysis showed that in asymptomatic women with twins, a CL of <25 mm was associated with a 25% risk of delivery before 28 weeks of gestation.50 Twins with prior PTB have not been studied separately and sufficiently for interventions of progesterone, cerclage, and pessary.51 In twins with a short CL, vaginal progesterone seems to be for now the most promising intervention. Meta-analysis studies showed that administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix (<25 mm) in the midtrimester reduces the risk of PTB.52,53
Regarding ultrasound-indicated cerclage, some studies showed no benefit or even harm in patient with twin gestation and short CL (<25 mm).37,54,55 A retrospective cohort study involved 140 women with twin pregnancies showed that ultrasound-indicated cerclage with a CL of ≤25 mm did not reduce the risk of preterm delivery before 34 weeks of gestation (adjusted odds ratio (OR): 0.37, 95% CI: 0.16–1.1) nor was it associated with increased neonatal morbidity (adjusted OR: 0.7, 95% CI: 0.4–1.2). In the pre-specified subgroup analysis of women with a CL of ≤15 mm (n = 32), there was a significant reduction in the rate of PTB before 34 weeks of gestation (OR: 0.42, 95% CI: 0.24–0.81).56
In summary, current evidence doesn’t support cervical cerclage placement in reducing sPTB rates in multiple gestations. However, patients with multiple gestations and very short cervix (≤15 mm) or cervical dilation may benefit from cerclage placement for extending pregnancies. Further studies in this area are needed.
Evidence about the use of cervical pessary for prevention of sPTB in twins is also conflicting. Placement of pessary in unselected twin pregnancies showed no benefit.57 However, there is some encouraging evidence suggesting that the pessary may be useful in women with twin gestations and short CL.58,59
Preterm parturition is a syndrome with multiple etiologies and there would not be a single treatment, diagnostic method or preventive strategy that will work for all PTBs.5,6 Difference in patient populations contributes to the conflicting study results. History of sPTB and short CL are strong risk factors for sPTB. Vaginal progesterone, 17OHPC and cerclage can be used to prevent sPTB and the indications for these interventions are different (Fig. 1). Risk and benefits of different interventions should be discussed with at-risk patients and shared decision-making approach should be incorporated. Pessary use is still limited in research settings in the USA. No intervention is effective in preventing sPTB in unselected multiple gestations. CL screening can be used in multiple gestations. Further studies are needed to evaluate the benefit of progesterone, cervical cerclage and cervical pessary in preventing sPTB in multiple gestation.
Conflicts of Interest
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