Abstract
BackgroundPreterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.Methods/designWe propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.DiscussionCombining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.
Highlights
Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies
Progestogens to prevent preterm birth Randomized trials in singleton pregnancies have suggested that antenatal progestogens prevents preterm delivery in women who are at high risk of preterm delivery because of a previous preterm delivery [4,5] or a short cervix [6]
Criteria for inclusion of studies in Individual participant data (IPD) We propose an IPD meta-analysis of randomized controlled trials of 17- OHPC or vaginal progesterone versus placebo in women with twin pregnancies
Summary
Preterm birth in twins Preterm birth in multiple pregnancies is a major public health concern. Rationale for an IPD meta-analysis Aggregated data meta-analysis involves synthesis of estimates from clinical trials This allows for a more robust estimate of the overall treatment effect of progestogen on multiple pregnancies as well as a more conclusive evaluation of any harmful effects. Criteria for inclusion of studies in IPD We propose an IPD meta-analysis of randomized controlled trials of 17- OHPC or vaginal progesterone versus placebo in women with twin pregnancies. Identification of studies We will perform an electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE and ClinicalTrials.gov for published or registered randomized controlled trials including women with twin pregnancy that were randomly allocated to treatment with progestogens (including vaginal progesterone and 17-hydroxyprogesterone caproate) or placebo in the second or third trimester with the intention to prevent preterm birth. To ensure that subgroup effects are not confounded by between-trial differences, dependency between data originating from the same trial will be taken into account using a random intercept for every study in the regression model [18]
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