Abstract: Twelve trials (1,856 women) met the inclusion criteria. Eight of the included trials compared treatment with placebo and the remaining four trials compared progestogen administration with no treatment. The trials were a mix of multicenter and single-center trials, conducted in India, Jordan, UK and USA. In five trials women had had three or more consecutive miscarriages and in seven trials women had suffered two or more consecutive miscarriages. Routes, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Ten trials (1684 women) contributed data to the analyses. The meta-analysis of all women, suggests that there may be a reduction in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (average risk ratio (RR) 0.73, 95% confidence interval (CI) 0.54 to 1.00, 10 trials, 1684 women, moderate-quality evidence). A subgroup analysis comparing placebo-controlled versus non-placebo-controlled trials, trials of women with three or more prior miscarriages compared to women with two or more miscarriages and different routes of administration showed no clear differences between subgroups for miscarriage. None of the trials reported on any secondary maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility. There was probably a slight benefit for women receiving progestogen seen in the outcome of live birth rate (RR 1.07, 95% CI 1.00 to 1.13, 6 trials, 1411 women, moderate-quality evidence). We are uncertain about the effect on the rate of preterm birth because the evidence is very low-quality (RR 1.13, 95% CI 0.53 to 2.41, 4 trials, 256 women, very low-quality evidence). No clear differences were seen for women receiving progestogen for the other secondary outcomes including neonatal death, fetal genital abnormalities or stillbirth. There may be little or no difference in the rate of low birthweight and trials did not report on the secondary child outcomes of teratogenic effects or admission to a special care unit. For women with unexplained recurrent miscarriages, supplementation with progestogen therapy may reduce the rate of miscarriage in subsequent pregnancies.

Plain-language summary: We searched for evidence on 6 July 2017 and identified a total of 13 trials that enrolled a total of 2556 women with a history of recurrent miscarriages. These trials found that giving progestogen medication to women with recurrent miscarriages early in their pregnancy may help lower the rates of miscarriage in that pregnancy from 27.5% to 20.1%. We believe that these findings are based on evidence of only moderate quality, so we cannot be certain about the results. We did not find that giving the progestogen medication by mouth, as a shot (injection), or in the vagina, was any better than any of the other ways. We also found that the trials showed that giving progestogen to women with prior recurrent miscarriages made the chances of having a live baby in the current pregnancy slightly higher. We are uncertain about the effect on the rate of preterm birth because the evidence is very low-quality. We did not find evidence of improvement in other outcomes such as newborn death, stillbirth, low birthweight, or newborn birth defects for women given progestogens. We found evidence from randomized controlled trials that giving progestogen medication may prevent miscarriage for women with recurrent previous miscarriages.