Oral Dydrogesterone Versus Vaginal Progesterone for Luteal Phase Support in Frozen-Thawed Embryo Transfer Cycles: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background/Objectives: Until recently, oral dydrogesterone has only been established in fresh in vitro fertilization (IVF) cycles, whereas its role in luteal phase support (LPS) for frozen embryo transfer (FET) cycles remains unclear. The aim of this study is to determine whether oral dydrogesterone as LPS in FET cycles results in pregnancy rates comparable to vaginal progesterone, focusing primarily on ongoing pregnancy rates, but also on clinical pregnancy, miscarriage, and live birth rates. Methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Five databases (Embase, MEDLINE®, APA PsycInfo, Global Health, and HMIC) and two additional sources were searched from inception to November 28, 2024. Only randomized controlled trials (RCTs) were included. A common effects model combined risk estimates, and heterogeneity was assessed using I2. Study quality was evaluated with Risk of Bias 2 (RoB2), and evidence certainty was graded using GRADE. Results: Overall, five RCTs with a total of 636 women were included in the meta-analysis. The comparison between oral dydrogesterone and vaginal progesterone for LPS did not yield significant differences for any of the outcomes studied. For ongoing pregnancies, the pooled odds ratio (OR) was 0.90 (95% CI: 0.59-1.35), with no heterogeneity (I2 = 8.7%). For miscarriage events, the OR was 1.41 (95% CI: 0.63-3.13, I2 = 0). For clinical pregnancies, the OR was 0.94 (95% CI: 0.62-1.42, I2 = 49.2%), with heterogeneity attributed to dosage. For live births, the pooled OR was 1.08 (95% CI: 0.67-1.75, I2 = 0%). Two studies were assessed as high risk of bias, two as low risk, and one as moderate. The GRADE assessment indicated low to moderate certainty of evidence. Conclusions: Oral dydrogesterone and vaginal progesterone yield comparable reproductive outcomes for LPS in FET cycles. Given its ease of administration, dydrogesterone may serve as a viable alternative in future FET protocols. However, further RCTs are needed to assess its efficacy against other progesterone administration routes.