Vaginal progesterone compared to intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent preterm birth in singleton gestations: a systematic review and meta-analysis

Objective: Randomized trials have found benefit for both vaginal progesterone and 17-hydroxy progesterone caproate (17-OHPC) in prevention of recurrent preterm birth. A prior meta-analysis directly comparing the two was limited by low quality evidence, and national and international society guidelines remain conflicting regarding progestin formulation recommended for prevention of recurrent preterm birth. The aim of this updated systematic review with meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB. Data sources: Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, Scielo, EMBASE and the Cochrane Central Register of Controlled Trials with the use of a combination of keywords and text words related to "preterm birth," "preterm delivery," "singleton," "cervical length," "progesterone," "progestogens," "vaginal," "17-alpha-hydroxy-progesterone caproate" and "intramuscular" from inception of each database to September 2021. No restrictions for language or geographic location were applied. Study eligibility criteria: We included all RCTs of asymptomatic singleton gestations with prior SPTB who were randomized to prophylactic treatment with either vaginal progesterone (i.e. intervention group) or intramuscular 17-OHPC (i.e. comparison group). Post hoc sensitivity analysis was performed for studies with low risk of bias, and studies with protocol registration. Study appraisal and synthesis methods: The primary outcome was PTB<34 weeks. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). Results: Seven RCTs, including 1,910 patients were included in the meta-analysis. Patients who received vaginal progesterone had a significantly lower rate of PTB<34 weeks (14.7% vs 19.9%; RR 0.74, 95% CI 0.57 to 0.96) as well as PTB<37 weeks (36.0% vs 46.6%; RR 0.76, 95% CI 0.69 to 0.85), and PTB<32 weeks (7.9% vs 13.6%, RR 0.58 95% CI 0.39-0.86), compared to women who received intramuscular 17-OHPC. There were no significant difference in the rate of PTB<28 weeks. Adverse drug reactions were significantly lower in the vaginal progesterone group compared to the 17-OHPC group (15.6% vs 22.2%; RR 0.71, 95% CI 0.54 to 0.92). Perinatal mortality was lower vaginal progesterone group compared to 17-OHPC (2.2% vs 4.4%, RR 0.51, 95% CI 0.25 to 1.01). In sensitivity analysis including trials with at least 4 Cochrane tools judged as 'low risk of bias', four trials were included (N=575), and there was no longer a significant difference in PTB<34 weeks with vaginal progesterone vs 17-OHPC (12.2% vs 13.9% (RR 0.87 95% CI 0.57 - 1.32). Conclusions: Overall vaginal progesterone was superior to 17-OHPC in prevention of preterm birth<34 weeks in singletons with prior spontaneous preterm birth, and although sensitivity analysis for high fidelity studies maintained the same trend, findings were no longer statistically significant.