Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Abstract

BackgroundPreterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce PTB and adverse neonatal outcomes. MethodsSystematic review of randomised trials comparing vaginal progesterone, intramuscular 17hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016 (12 months before data collection began) by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. FindingsInitial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11,644 women and 16,185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 769 women; relative risk [RR] 0•78, 95% CI 0•68-0•90), 17-OHPC (five trials, 3,053 women; 0•83, 0•68-1•01), and oral progesterone (two trials, 183 women; 0•60, 0•41-0•90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1•01, 95% CI 0•84-1•20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1•04, 0•92-1•18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1•59, 95% CI 1•15-2•22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC InterpretationVaginal progesterone and 17...

Prevention of Preterm Birth with Progesterone

“…The authors considered trials of both singleton and multifetal pregnancies comparing vaginal, intramuscular and oral progesterone administration with control, or with each other. Compared with controls, both the vaginal route and the intramuscular 17-OHPC reduced the risk of PTB before 34 weeks for singleton pregnancies in high risk women, with a 22% reduction in the relative risk (RR) for participants who received vaginal progesterone (nine trials, 3769 women), and 17% reduction for those received 17-OHPC (five trials, 3053 women) [ 57 ]. Importantly, given that the upper confidence limit crosses the line of no effect, the reported implication that 17-hydroxyprogesterone caproate (17-OHPC) “reduced birth before 34 week in high-risk singleton pregnancies” is not justified in light of its lack of statistical significance.…”

“…Regarding the utility of oral progesterone administration as preventive strategy in high risk patients, evidence to support its use in clinical routine practice is still inconsistent [ 57 ].…”

Vaginal microbial profiling in a preterm birth high-risk cohort using shallow shotgun metagenomics

“…A meta-analysis from 2018 with large high-risk pregnancies cohorts report that vaginal progesterone (VP) use resulted in a pooled relative risk ratio (RR) of 0.29-0.68, while cervical cerclage had a RR of 0.64-0.70 11 . The effectiveness of VP appears to be particularly robust in high-risk women with short cervical length (<25 mm), as has been recently demonstrated in the EPPPIC meta-analysis 12 .…”

Contemporary Issues in Women’s Health

“…A recent meta‐analysis and systemic review published in the Lancet 2 examines the efficacy of different formulations of progesterone to prevent sPTB in women at high risk of a preterm birth either because of a short cervix or a prior preterm birth, or both. Members of the EPPPIC team, ‘Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC)’, obtained individual‐level participant data from 31/47 identified eligible trials, which included 11 644 women and 16 185 infants.…”