Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol

Abstract

BackgroundPreterm birth is the most common cause of death and harm to newborn babies. Babies that are born early may have difficulties at birth and experience health problems during early childhood. Despite extensive study, there is still uncertainty about the effectiveness of progestogen (medications that are similar to the natural hormone progesterone) in preventing or delaying preterm birth, and in improving birth outcomes. The Evaluating Progestogen for Prevention of Preterm birth International Collaborative (EPPPIC) project aims to reduce uncertainty about the specific conditions in which progestogen may (or may not) be effective in preventing or delaying preterm birth and improving birth outcomes.MethodsThe design of the study involves international collaborative individual participant data meta-analysis comprising systematic review, re-analysis, and synthesis of trial datasets.Inclusion criteria are as follows: randomized controlled trials comparing progestogen versus placebo or non-intervention, or comparing different types of progestogen, in asymptomatic women at risk of preterm birth. Main outcomes are as follows; fetal/infant death, preterm birth or fetal death (<=37 weeks, <=34 weeks, <= 28 weeks), serious neonatal complications or fetal/infant death, neurosensory disability (measured at 18 months or later) or infant/child death, important maternal morbidity, or maternal death. In statistical methods, IPD will be synthesized across trials using meta-analysis. Both ‘two-stage’ models (where effect estimates are calculated for each trial and subsequently pooled in a meta-analysis) and ‘one-stage’ models (where all IPD from all trials are analyzed in one step, while accounting for the clustering of participants within trials) will be used. If sufficient suitable data are available, a network meta-analysis will compare all types of progesterone and routes of administration extending the one-stage models to include multiple treatment arms.DiscussionEPPPIC is an international collaborative project being conducted by the forming EPPPIC group, which includes trial investigators, an international secretariat, and the research project team. Results, which are intended to contribute to improvements in maternal and child health, are expected to be publicly available in mid 2018.Systematic review registrationPROSPERO CRD42017068299

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

“…18 How best to adjudicate the findings of the PROLONG trial, given it was underpowered and inconclusive regarding assessment of treatment efficacy, will be challenging for clinicians, patients, and policy makers. Combining data in systematic reviews and/or meta-analyses 19,20 to attempt to differentiate a population with the most optimal benefit/risk ratio will be important. The absence of other evidence-based interventions to offer this orphan population (women with prior SPTB) combined with the reality that 17-OHPC has been widely used for over 15 years adds to the complexity.…”

The long‐term effect of prenatal progesterone treatment on child development, behaviour and health: a systematic review

“…Neurodevelopmental impairments are common after preterm birth 41,42 . Even though there is still considerable heterogeneity between progesterone trials, a large recent IPD‐MA showed a reduction of preterm birth after progesterone in singleton pregnancies at high risk for preterm birth 43 . Therefore, we anticipated improvements in neurodevelopmental outcomes among prenatally progesterone exposed children.…”

“…41,42 Even though there is still considerable heterogeneity between progesterone trials, a large recent IPD-MA showed a reduction of preterm birth after progesterone in singleton pregnancies at high risk for preterm birth. 43 Therefore, we anticipated improvements in neurodevelopmental outcomes among prenatally progesterone exposed children. However, in four 32,34,37,38 of five studies, preterm birth rate was comparable between the progesterone and the placebo group.…”

Effect of QUiPP prediction algorithm on treatment decisions in women with a previous preterm birth: a prospective cohort study

“…Vaginal administration of natural progesterone could be an alternative strategy but the Cochrane review and OPPTIMUM study did not find evidence for reduction in PTB risk with this strategy . It is hoped that soon to be published individual patient data analysis by the EPPPIC group will provide definitive evidence in this respect …”