Abstract: We 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). Overall, 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).

Plain-language summary: We searched for evidence on 1 November 2016 and identified 16 randomised controlled trials involving 4548 women for inclusion in the review. In studies where women received progesterone by injection into the muscle compared with placebo (dummy treatment) more women gave birth before the 34th week of pregnancy in the progesterone group (low-quality evidence). There was no clear difference between the groups in the likelihood of the baby dying before or soon after the birth (low-quality evidence). No studies reported whether any women died or whether any babies had longer-term developmental problems or disability. There seems to be little or no difference between women receiving progesterone or placebo for other important outcomes, such as preterm birth before 37 weeks (high-quality evidence); preterm birth before 28 weeks (moderate-quality evidence) or infant birthweight less than 2500 grams (moderate-quality evidence). No childhood outcomes were reported in the trials. In studies where women received vaginal progesterone there may be little or no difference between women receiving progesterone or placebo in preterm birth before 34 weeks (low-quality evidence); although fewer births before 34 weeks occurred in the progesterone group, this finding may have occurred by chance. The number of infant deaths before or soon after birth was similar in both groups (low-quality evidence). No studies reported maternal death or longer-term outcomes for babies. There may be little or no difference between groups receiving vaginal progesterone versus placebo in any other important outcomes (preterm birth before 37 weeks (moderate-quality evidence); preterm birth before 28 weeks (low-quality evidence); or infant birthweight less than 2500 grams (moderate-quality evidence)). No childhood outcomes were reported in the trials. For other outcomes, we found no clear group differences, 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%)). Fewer infants whose mothers had received the vaginal progesterone needed mechanical help with breathing. We did not find any studies looking at progesterone taken by mouth. Overall, for women with a multiple pregnancy, treatment with progesterone (either intramuscular or vaginal) does not appear to reduce the likelihood of preterm birth or improve outcomes for babies. Future research could focus on looking at information about individual women taking part in studies, so that everything available about both intramuscular and vaginal progesterone treatments in women with a multiple pregnancy can be considered together.