Reproductive outcome after frozen embryo transfer with hormone replacement therapy according to luteal-phase support protocol: systematic review and network meta-analysis of randomized controlled trials.

objectiveTo compare reproductive outcome between luteal-phase support (LPS) protocols for frozen embryo transfer (FET) cycles with hormone replacement therapy (HRT).

methodsA search was conducted in MEDLINE, Scopus, LILACS, EMBASE, Scielo.br, PROSPERO, CINAHL, PsycINFO, AMED, ClinicalTrials.gov, ICTRP, the Cochrane Library and conference proceedings, with no restrictions on date, geography or language. We included all randomized controlled trials (RCTs) that allocated infertile women to at least two different hormone-based LPS protocols for HRT-FET, with similar baseline characteristics between groups. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension statement for network meta-analyses (PRISMA-NMA) was followed. A random-effects network meta-analysis was performed for direct and indirect pairwise comparisons to rank available LPS protocols by the surface under the cumulative ranking curve area (SUCRA). Risk of bias was assessed using the Cochrane risk-of-bias tool version 1. Certainty of evidence was evaluated using the Confidence in Network Meta-Analysis (CINeMA) criteria. The primary outcomes were the live birth rate and the combined rate of ongoing pregnancy and live birth; the secondary outcomes were the clinical pregnancy rate and the pregnancy loss rate.

resultsTen RCTs assigned a total of 4216 patients to nine different LPS approaches. Regarding the combined outcome of ongoing pregnancy and live birth, oral dydrogesterone (DYD) combined with gonadotropin-releasing hormone agonist (GnRHa) was significantly more efficacious compared with all other LPS protocols (very low to low certainty of evidence), with SUCRA analysis ranking it as the treatment of choice (SUCRA = 97.3%). When the analysis was restricted to live birth only, vaginal suppository progesterone showed a higher likelihood of being the treatment of choice (SUCRA = 89.7%), but only exhibited a significant difference on pairwise analysis when compared with intramuscular progesterone (odds ratio (OR), 0.53 (95% CI, 0.33-0.84); low certainty of evidence) and intramuscular progesterone + vaginal suppository progesterone (OR, 0.47 (95% CI, 0.32-0.69); low certainty of evidence). For the clinical pregnancy rate, no significant differences between treatments were found (very low to low certainty of evidence), with vaginal suppository progesterone + human chorionic gonadotropin being the highest-ranked treatment (SUCRA = 33.7%). For pregnancy loss rate, intramuscular progesterone + vaginal suppository progesterone was significantly more efficacious compared with either treatment alone (low certainty of evidence), and had the highest chance of being the top-ranked treatment (SUCRA = 51.4%).

conclusionsThere is very-low-to-low-certainty evidence that oral DYD + GnRHa and vaginal suppository progesterone alone could be the most promising LPS approaches to increase the rates of live birth and ongoing pregnancy in women undergoing HRT-FET. However, the low certainty of evidence and the lack of a clear first-ranked treatment, due to inconsistencies in the analysis for some outcomes, stress the need for further RCTs on this subject. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.