Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials

OBJECTIVE: To investigate whether treatment with progestogens in the first trimester of pregnancy would decrease the incidence of miscarriage in women with a history of unexplained recurrent miscarriage. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women with a history of unexplained recurrent miscarriage. INTERVENTION(S): Randomized, controlled trials were identified by searching electronic databases. We included randomized, controlled trials comparing supplementation with progestogens (i.e., intervention group) in the first trimester of pregnancy with control (either placebo or no treatment) in women with a history of recurrent miscarriage. All types of progestogens, including natural P and synthetic progestins, were analyzed. MAIN OUTCOME MEASURE(S): The primary outcome was the incidence of miscarriage. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). RESULT(S): Ten trials including 1,586 women with recurrent miscarriage were analyzed. Eight studies used placebo as control and were double-blind. Regarding the intervention, two RCTs used natural P, whereas the other eight studies used progestins: medroxyprogesterone, cyclopentylenol ether of progesterone, dydrogesterone, or 17-hydroxyprogesterone caproate. Pooled data from the 10 trials showed that women with a history of unexplained recurrent miscarriage who were randomized to the progestogens group in the first trimester and before 16 weeks had a lower risk of recurrent miscarriage (RR 0.72, 95% CI 0.53-0.97) and higher live birth rate (RR 1.07, 95% CI 1.02-1.15) compared with those who did not. No statistically significant differences were found in the other secondary outcomes, including preterm birth (RR 1.09, 95% CI 0.71-1.66), neonatal mortality (RR 1.80, 95% CI 0.44-7.34), and fetal genital abnormalities (RR 1.68, 95% CI 0.22-12.62). CONCLUSION(S): Our findings provide evidence that supplementation with progestogens may reduce the incidence of recurrent miscarriages and seem to be safe for the fetuses. Synthetic progestogens, including weekly IM 17-hydroxyprogesterone caproate, but not natural P, were associated with a lower risk of recurrent miscarriage. Given the limitations of the studies included in our meta-analysis, it is difficult to recommend route and dose of progestogen therapy. Further head-to-head trials of P types, dosing, and route of administration are required