To assess the efficacy and safety of vaginal progesterone to prevent recurrent preterm birth and adverse perinatal outcomes in singleton gestations with a history of spontaneous preterm birth.

MEDLINE, Embase, LILACS, and CINAHL (from their inception to February 28, 2022), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.

Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a singleton gestation and a history of spontaneous preterm birth.

The primary outcomes were preterm birth <37 and <34 weeks of gestation. The secondary outcomes included adverse maternal and perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in the included studies, heterogeneity (I² test), small-study effects, publication bias, and quality of evidence; performed subgroup and sensitivity analyses; and calculated 95% prediction intervals and adjusted relative risks.

Ten studies (2958 women) met the inclusion criteria: 7 with a sample size <150 (small studies) and 3 with a sample size >600 (large studies). Among the 7 small studies, 4 were at high risk of bias, 2 were at some concerns of bias, and only 1 was at low risk of bias. All the large studies were at low risk of bias. Vaginal progesterone significantly decreased the risk of preterm birth <37 weeks (relative risk, 0.64; 95% confidence interval, 0.50–0.81; I²=75%; 95% prediction interval, 0.31–1.32; very low-quality evidence) and <34 weeks (relative risk, 0.62; 95% confidence interval, 0.42–0.92; I²=66%; 95% prediction interval, 0.23–1.68; very low-quality evidence), and the risk of admission to the neonatal intensive care unit (relative risk, 0.53; 95% confidence interval, 0.33–0.85; I²=67%; 95% prediction interval, 0.16–1.79; low-quality evidence). There were no significant differences between the vaginal progesterone and the placebo or no treatment groups in other adverse perinatal and maternal outcomes. Subgroup analyses revealed that vaginal progesterone decreased the risk of preterm birth <37 weeks (relative risk, 0.43; 95% confidence interval, 0.33–0.55; I²=0%) and <34 weeks (relative risk, 0.27; 95% confidence interval, 0.15–0.49; I²=0%) in the small but not in the large studies (relative risk, 0.98; 95% confidence interval, 0.88–1.09; I²=0% for preterm birth <37 weeks; and relative risk, 0.94; 95% confidence interval, 0.78–1.13; I²=0% for preterm birth <34 weeks). Sensitivity analyses restricted to studies at low risk of bias indicated that vaginal progesterone did not reduce the risk of preterm birth <37 weeks (relative risk, 0.96; 95% confidence interval, 0.84–1.09) and <34 weeks (relative risk, 0.90; 95% confidence interval, 0.71–1.15). There was clear evidence of substantial small-study effects in the meta-analyses of preterm birth <37 and <34 weeks of gestation because of funnel plot asymmetry and the marked differences in the pooled relative risks obtained from fixed-effect and random-effects models. The adjustment for small-study effects resulted in a markedly reduced and nonsignificant effect of vaginal progesterone on preterm birth <37 weeks (relative risk, 0.86; 95% confidence interval, 0.68–1.10) and <34 weeks (relative risk, 0.92; 95% confidence interval, 0.60–1.42).

There is no convincing evidence supporting the use of vaginal progesterone to prevent recurrent preterm birth or to improve perinatal outcomes in singleton gestations with a history of spontaneous preterm birth.