Cerclage in singleton pregnancies with no prior spontaneous preterm birth and short cervix: a randomized controlled trial

BACKGROUND: Preterm birth remains a leading cause of neonatal morbidity and mortality. Cerclage for short cervical length <= 25 mm in patients with singleton pregnancies with a history of spontaneous preterm birth is associated with decreased neonatal morbidity/mortality. Both vaginal progesterone and cerclage individually have level 1 evidence supporting benefit in the prevention of preterm birth in pregnancies complicated by short cervical length. However, there is a paucity of level 1 evidence regarding the potential benefit of cerclage with progesterone relative to progesterone alone for short cervical length <= 25 mm in patients with singleton pregnancies without a history of spontaneous preterm birth. OBJECTIVE: This study aimed to conduct a pragmatic randomized controlled trial to evaluate the additional benefit of cerclage with vaginal progesterone relative to vaginal progesterone alone in patients with singleton pregnancies without prior spontaneous preterm birth and with a current midtrimester transvaginal ultrasound cervical length <= 25 mm. STUDY DESIGN: This was a multicenter international randomized controlled trial conducted from September 2017 to September 2023, involving 4 sites in the United States and Italy. Patients with singleton pregnancies without prior spontaneous preterm birth received transvaginal ultrasound cervical length (universal) screening during the midtrimester anatomy ultrasound examination as part of routine care. Inclusion criteria included transvaginal ultrasound cervical length <= 25 mm at 18 0/7 to 23 6/7 weeks. Exclusion criteria included current or planned cerclage, cervical dilation, symptoms of labor, infection, bleeding, and rupture of membranes at screening. Participants were randomized in a 1:1 ratio to cerclage with vaginal progesterone (200-mg vaginal progesterone daily) or vaginal progesterone alone. Randomization was stratified by study site and transvaginal ultrasound cervical length <= 15 mm. The primary outcome was preterm birth <35 weeks, assessed using intention-to-treat analysis. Secondary outcomes included preterm birth <37, 32, 28, and 24 weeks, gestational age at delivery, latency to delivery, and neonatal outcomes. Categorical variables were compared using the Pearson chi-square test and relative risk estimates with 95% confidence intervals. Continuous variables were compared using the Mann-Whitney U test. Latency to delivery and gestational age at delivery were also compared using Kaplan-Meier survival curves. Planned enrollment was set at N=206 on the basis of an estimated 0.54 relative risk with cerclage and a 34% incidence of preterm birth with standard care. The trial was registered on ClinicalTrials.gov (NCT03251729) on June 22, 2017. RESULTS: Enrollment ran from September 22, 2017 to October 31, 2023, and was halted early because of lagging enrollment. A total of 93 participants were randomized; 3 were excluded because of withdrawal (n=1) and loss to follow-up (n=2). Of the 90 participants included in the intention-to-treat analysis, 43 were assigned to cerclage and progesterone and 47 to progesterone alone. Overall, 40 participants (40.4%) had a transvaginal ultrasound cervical length <= 15 mm. There was no significant difference in the primary outcome of preterm birth <35 weeks between those randomized to cerclage with progesterone vs progesterone alone (16.3% vs 23.4%; relative risk, 0.70 [0.30-1.63]). Those randomized to cerclage with progesterone had significantly increased latency from randomization to delivery (median difference, 13 [5-20] days; P=. 01) and a significantly later gestational age at delivery (median difference, 1.0 [0.2-1.7] weeks; P=.035). A Kaplan-Meier survival curve also demonstrated increased latency to delivery and gestational age at delivery for cerclage with progesterone compared with progesterone alone (Mantel-Cox log-rank P<.001 and P=.003, respectively). These findings persisted within both subgroups of cervical length <= 15 mm and 16 to 25 mm. CONCLUSION: In singleton gestations without a prior spontaneous preterm birth and a transvaginal ultrasound cervical length <= 25 mm before 24 weeks, cerclage with progesterone was not found to significantly reduce the preterm birth rate compared with progesterone alone. However, cerclage and progesterone did result in a significantly longer latency from randomization to delivery and a significantly later gestational age at delivery, compared to progesterone alone. These results suggest the potential benefit of cerclage and progesterone relative to progesterone alone in patients with singleton pregnancies without a prior spontaneous preterm birth and a short cervical length <= 25 mm before 24 weeks. This trial was halted early, and these findings should be confirmed in a larger trial or meta-analysis.