Impact of endometrial preparation protocols on pregnancy outcomes in patients with unexplained recurrent implantation failure undergoing frozen embryo transfer

ABSTRACT Objectives To evaluate the impact of different endometrial preparation protocols on pregnancy outcomes in patients with unexplained recurrent implantation failure (uRIF) undergoing frozen embryo transfer (FET). Methods This retrospective cohort study reviewed 110 372 FET cycles from three fertility centers in China between January 2014 and July 2021. Among them, 4346 cycles were performed in patients with uRIF, including 557 who had the natural cycle (NC) protocol, 1310 who had the stimulated cycle (SC) protocol and 2479 who had the artificial cycle (AC) protocol. The primary outcome measure was live birth rate. For singleton live births, the main obstetric outcomes (hypertensive disorders of pregnancy, gestational diabetes mellitus, abnormal placentation and prelabor rupture of membranes) and neonatal outcomes (Cesarean delivery, preterm birth, post‐term birth, low birth weight, macrosomia, small‐for‐gestational age, large‐for‐gestational age and major birth defect) were collected through standardized questionnaire interviews. Potential confounders were controlled by 1:1:1 propensity score matching and multivariable logistic regression analysis using prematched data. Results There were 397 cycles in each group after matching and all baseline characteristics were balanced with no significant differences between the groups. The live birth rate was comparable among the NC, SC and AC groups (29.5% vs 35.3% vs 33.0%, respectively; P = 0.21), as were the rates of clinical pregnancy, embryo implantation and miscarriage. The three groups differed significantly in Cesarean delivery rate (65.6% vs 71.1% vs 81.1%, respectively; P = 0.04), with post‐hoc statistical significance identified between the NC and AC groups ( P = 0.01). No significant associations were observed between endometrial preparation protocols and other pregnancy, obstetric and neonatal outcomes. The results after matching were in good agreement with the multivariable‐adjusted outcomes before matching. Conclusions Our findings do not prioritize one specific endometrial preparation protocol over another for improving pregnancy rates among patients with uRIF; however, the increased risk of Cesarean delivery in the AC group necessitates careful consideration to optimize delivery outcomes. Nonetheless, given the overall high rate of Cesarean delivery in all three groups, further clarification is required on whether medical indication or personal preference influenced the decision on the mode of delivery. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.