• Jodie M Dodd, Rosalie M Grivell, Cecelia M OBrien, Therese Dowswell, and Andrea R Deussen.
• The University of Adelaide, Women's and Children's Hospital, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, 72 King William Road, Adelaide, South Australia, Australia, 5006.
• Cochrane Db Syst Rev. 2019 Nov 20; 2019 (11).

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 this new review in Issue 10, 2017, we have now moved one study (El-Refaie 2016) from included to studies awaiting classification, pending clarification about the study data.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 CriteriaWe 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 AnalysisTwo 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 or intramuscular (IM) progesterone 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 progesterone versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM progesterone 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 progesterone 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; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by dose There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.90, 95% CI 0.66 to 1.23; women = 1503; studies = 5; I2 = 36%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; 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 (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.53, 95% CI 0.79 to 2.97; women = 1345; studies = 3; low-quality evidence); infant birthweight less than 2500 g (average RR 0.95, 95% CI 0.84 to 1.07; infants = 2640; studies = 3; I2 = 66%, moderate-quality evidence)). No childhood outcomes were reported in the trials. For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (8%) (RR 0.92, 95% CI 0.86 to 0.98; women = 1919; studies = 5; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.70, 95% CI 0.52 to 0.94; infants = 2695; studies = 4).Authors' ConclusionsOverall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) 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 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).Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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