Concurrent progestogen and cerclage to reduce preterm birth: a multicenter international retrospective cohort

Objective : We aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth (sPTB) in singleton pregnancies Methods : This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016-June 2020. Exclusion criteria were: lack of documentation regarding whether progestogen was or was not prescribed, delivery outcome unavailable, and pregnancy termination (spontaneous or induced) prior to 16 weeks' gestation. Exposure of interest was progestogen use with cerclage placement, which included those who were continued on progestogen or who started progestogen after cerclage. Comparator was those without progestogen use after cerclage placement, which included those who had no progestogen use the whole pregnancy, or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. Primary outcome was sPTB <37 weeks. Secondary outcomes were sPTB <34 weeks, gestational age at delivery, composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, Grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, bronchopulmonary dysplasia. There was planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate (17-OHPC)), preterm birth history, and site. Continuous variables compared in adjusted analyses with ANCOVA and categorical variables compared with multivariable logistic regression adjusting for potential confounders with adjusted odds ratio (aOR). Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks. Results : During the study period, a total of 699 singletons met inclusion, N=561 in the progestogen with cerclage group, and N=138 with cerclage alone. Baseline characteristics were similar, except those in the progestogen group were more likely to have had a prior sPTB (61% vs 41%, p<0.001). Within the progestogen group, 52% were on 17-OHPC weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of sPTB<37 (31% vs 39% aOR 0.59 (0.39 - 0.89), p=0.01) and <34 weeks (19% vs 27%, aOR 0.55 (0.35 - 0.87), p=0.01), increased latency to spontaneous delivery (Hazard ratio to sPTB <37wk, 0.66 (0.49-0.90), p=0.009), and lower frequency of perinatal death (7% vs 16%, aOR 0.37 (0.20-0.67), p=0.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a prior preterm birth, those with ultrasound or exam-indicated cerclage, those that started progestogen therapy prior to cerclage, and in sites restricted to the United States. Conclusion : Use of progestogen with cerclage was associated with reduced rates of sPTB and early sPTB compared to cerclage alone. Although not powered for subgroups, the strength of evidence for benefit appeared greatest for those with ultrasound or exam-indicated cerclage, and with vaginal progesterone.