Reproductive outcomes after rescue luteal phase support for women with low serum progesterone in artificial cycles around frozen embryo transfer day: Systematic review and network meta‐analysis of over 7500 patients

BACKGROUND: Low serum progesterone levels around the time of frozen embryo transfer (FET) in artificially prepared cycles have been associated with reduced reproductive success. Rescue luteal phase support (LPS) has been proposed as a strategy to optimize outcomes in these cases. OBJECTIVES: This study assesses the effectiveness of rescue LPS in improving reproductive outcomes among women with suboptimal serum progesterone levels prior to FET. METHOD: A comprehensive literature search was conducted to identify randomized and non-randomized (prospective or retrospective) studies evaluating the impact of additional progesterone administration in women with low serum levels around FET in artificial cycles. Twelve observational studies comprising more than 7500 participants were included. Eligible studies assessed clinical outcomes following supplemental progesterone via various routes in patients with below-threshold serum levels. A network meta-analysis was performed to compare the effectiveness of different rescue LPS protocols. Routes of progesterone administration included intramuscular, vaginal, oral, subcutaneous, and rectal. Primary outcomes included clinical pregnancy rate, live birth rate, ongoing pregnancy rate, pregnancy loss rate, and biochemical pregnancy rate. RESULTS: Rescue LPS in women with low serum progesterone was associated with improved reproductive outcomes, approaching that observed in women with adequate progesterone levels. Intramuscular and vaginal administration were frequently ranked highest, although no protocol demonstrated clear superiority. Significant heterogeneity existed across studies, particularly regarding progesterone cutoff values. CONCLUSION: Rescue luteal phase support appears to be a promising approach for managing low serum progesterone before FET. However, randomized controlled trials with standardized thresholds and protocols are needed to confirm these findings and guide clinical practice.