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

Abstract

Background: PTB (PTB) remains a leading cause of neonatal morbidity and mortality. Cerclage for short cervical length (CL) ≤25mm in singletons with a history of spontaneous PTB is associated with decreased neonatal morbidity/mortality. Both vaginal progesterone and cerclage individually have level 1 evidence supporting benefit in prevention of PTB in pregnancies complicated by short CL, however there is a paucity of level 1 evidence regarding the potential benefit of cerclage with progesterone compared to progesterone alone for short CL ≤25mm in singletons without a history of spontaneous PTB.

Objective: We aimed to conduct a pragmatic randomized controlled trial to evaluate the additional benefit of cerclage with vaginal progesterone compared to vaginal progesterone alone in singletons without prior spontaneous PTB and with a current mid-trimester transvaginal ultrasound (TVU) CL ≤25mm STUDY DESIGN: This is a multicenter international randomized controlled trial from 09/2017-09/2023 with four sites in the United States and Italy. Singleton pregnancies without prior spontaneous PTB received TVUCL (universal) screening during mid-trimester anatomy ultrasound as part of routine care. Inclusion criteria was TVUCL≤25mm at 18 0/7 - 23 6/7 weeks. Exclusion criteria included current or planned cerclage, cervical dilation, symptoms of labor, infection, bleeding, rupture of membranes at screening. Participants were randomized 1:1 to cerclage with vaginal progesterone (200mg vaginal progesterone daily) or vaginal progesterone alone; randomization was stratified by study site and TVUCL≤15mm. Primary outcome was PTB<35 weeks by intention to treat analysis. Secondary outcomes included PTB <37,32,28,24 weeks, gestational age at delivery, latency to delivery, and neonatal outcomes. Categorical variables were compared with Pearson Chi-Square and relative risk (RR) estimate and 95% confidence interval (CI). Continuous variables compared with Mann Whitney U test. Latency to delivery and gestational age at delivery were also compared with Kaplan Meier Survival Curve. Planned enrollment was N=206 based on an estimated 0.54 relative risk with cerclage and a 34% incidence of PTB with standard care. The trial was registered on clinicaltrials.gov (NCT03251729) on June 22, 2017.

Results: Enrollment ran from September 22^nd, 2017- October 31^st, 2023, and it was halted early due to lagging enrollment. Ninety-three participants were randomized, three were excluded due to withdrawal (n=1) and loss to follow up (n=2). Of the 90 included in the intention to treat analysis, 43 to cerclage and progesterone, and 47 to progesterone alone. Overall, 40 (40.4%) had a TVUCL≤15mm. There was no significant difference in primary outcome PTB<35 weeks in those randomized to cerclage with progesterone vs progesterone alone: 16.3% vs 23.4%, RR 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=0.01), and a significantly later gestational age at delivery, median difference 1.0 (0.2-1.7) weeks (p=0.035). Kaplan Meier Survival curve also demonstrated increased latency to delivery and gestational age at delivery for cerclage with progesterone compared to progesterone alone, Mantel Cox Log Rank p<0.001 and p=0.003 respectively. These findings persisted within both subgroups of ≤15mm and at 16-25mm.

Conclusion: In singleton gestations without a prior spontaneous PTB, and a TVU CL ≤25mm before 24 weeks, cerclage with progesterone was not found to significantly reduce PTB rate, but 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 for benefit with cerclage and progesterone compared to progesterone alone in singletons without a prior spontaneous PTB and a short cervical length ≤25mm before 24 weeks. This trial was halted early and these findings should be confirmed in larger trial or meta-analysis.

Tweetable abstract: In singletons with short cervix and no prior spontaneous PTB cerclage with progesterone compared to progesterone alone did not reduce incidence of PTB; but those with cerclage and progesterone had increased latency to delivery and gestational age of delivery. This trial was halted early, and larger clinical trials or meta-analyses are necessary.