Vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials

OBJECTIVE: Randomized controlled trials (RCTs) have recently compared intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB. METHODS: Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17-OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB < 34 weeks. Secondary outcomes were SPTB < 37 weeks, < 32 weeks, < 28 weeks and < 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed. RESULTS: Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17-OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB < 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53-0.95); low quality of evidence) and < 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40-0.94); low quality of evidence) compared with women who received 17-OHPC. There were no significant differences in the rates of SPTB < 37 weeks, < 28 weeks and < 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17-OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31-0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17-OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47-0.83); low quality of evidence). For the comparison of 17-OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions). CONCLUSIONS: Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect