Effectiveness of oral dydrogesterone compared to placebo in reducing the risk of preterm birth: a systematic review and meta-analysis

Preterm birth remains a major contributor to neonatal morbidity and mortality worldwide. Oral dydrogesterone is used in some clinical settings for preterm birth prevention, despite uncertainty regarding its effectiveness. This systematic review aimed to evaluate the efficacy and safety of oral dydrogesterone compared with placebo in women at risk of preterm birth. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. Randomized controlled trials comparing oral dydrogesterone with placebo in pregnant women at risk of preterm birth were included; non-randomized, observational, and animal studies were excluded. We searched PubMed, Cochrane Library, Web of Science, and Scopus from inception to December 2024. Risk of bias was assessed using the Cochrane Risk of Bias tool. Random-effects meta-analyses were performed where appropriate. We evaluated Certainty of evidence using the GRADE approach, and trial sequential analysis (TSA) was conducted to assess the conclusiveness of the evidence. The review was registered in PROSPERO (CRD42025639288). Five randomized controlled trials involving 436 participants were included. Compared with the placebo, dydrogesterone showed a non-significant trend toward increased gestational age at delivery (mean difference, 0.42 weeks; 95% CI -0.70 to 1.55) and a reduced risk of neonatal intensive care unit admission (risk ratio, 0.74; 95% CI 0.47 to 1.18). No statistically significant differences were observed for other maternal or neonatal outcomes. The certainty of evidence was rated as low or very low for most outcomes using GRADE. TSA demonstrated that the accumulated evidence remains underpowered and insufficient to draw firm conclusions. Current randomized evidence does not demonstrate a statistically or clinically meaningful benefit of oral dydrogesterone over placebo in preventing preterm birth or improving maternal or neonatal outcomes. The low to very low certainty of evidence and inconclusive TSA findings indicate that the existing evidence base is insufficient to support clinical recommendations. Larger, high-quality randomized trials are required before oral dydrogesterone can be considered for routine clinical use.