Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy.

backgroundMultiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe. Since publication of the review update in 2019 readers are alerted that the study awaiting classification El-Refaie 2016, has been retracted [El-Refaie 2021]. The study has been moved to Excluded Studies table and the review amended accordingly.

objectivesTo assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy. SEARCH

methodsWe searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi-randomised or cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence. MAIN

resultsWe included 16 trials, which all compared either vaginal progesterone or intramuscular (IM) 17‐hydroxyprogesterone caproate (17‐OHPC) with a placebo or no treatment, and involved a total of 4548 women. The risk of bias for the majority of included studies was low, with the exception of three studies that had inadequate blinding, or significant loss to follow‐up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM 17‐OHPC versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM 17‐OHPC group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low‐quality evidence). Although the incidence of perinatal death in the 17‐OHPC group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low‐quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow‐up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I AUTHORS'

conclusionsOverall, for women with a multiple pregnancy, the administration of progestogens (either IM 17‐OHPC or vaginal progesterone) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes. Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM 17‐OHPC and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).