Vaginal Progesterone in Pregnancies with a Short Cervix: Reassessment of Aggregate Trial Data and Methodological Limitations

Abstract

Introduction: Cervical shortening increases spontaneous preterm birth risk, while vaginal progesterone may provide preventive benefits. Objective: To assess whether aggregate evidence supports singleton-specific estimates of vaginal progesterone effectiveness. Method: This critical reassessment examined searches of PubMed and Google Scholar, identifying 49 records, three quantitatively synthesized reports, and OPPTIMUM for qualitative assessment. The retracted Cetingoz trial was excluded. Results and Discussion: Random-effects analyses reported reduced risks of preterm birth at approximately ≤35 weeks (RR 0.65; 95% CI 0.46–0.92), spontaneous birth before 34 weeks (RR 0.56; 0.36–0.86), respiratory distress syndrome (RR 0.50; 0.29–0.86), and birth weight below 1,500 g (RR 0.57; 0.38–0.85). Neonatal intensive care admission was not significantly reduced (RR 0.80; 0.54–1.18). However, mixed-plurality populations, inconsistent outcomes, uncertain denominators, and nonreproducible extraction limited validity. Conclusion: Favorable estimates cannot establish singleton-specific effectiveness without dataset reconciliation. Clinical interpretation should prioritize broader participant-level evidence