Progesterone levels on hCG trigger day and neonatal outcomes in fresh embryo transfers: a retrospective threshold analysis of GnRH antagonist versus agonist long protocols

Background Elevated progesterone levels on the day of human chorionic gonadotropin (hCG) trigger are known to adversely affect pregnancy outcomes in fresh embryo transfer (fET) cycles, but their impact on neonatal outcomes remains poorly understood. This study aimed to investigate the association between progesterone levels on hCG trigger day and neonatal outcomes, and to explore the progesterone threshold, so as to provide reference for clinical decision-making. Methods This retrospective cohort study included 2, 201 patients who achieved singleton live births following fET between April 1, 2021 and December 31, 2024. All patients were ≤ 42 years of age and underwent either a GnRH antagonist protocol or an agonist long protocol. A multivariable regression analysis was performed to detect the relationship between progesterone level and neonatal outcomes. Smooth curve fitting and threshold effect analysis were used to evaluate the cutoff value of progesterone level. Results In the overall population, higher progesterone levels were significantly associated with increased risks of preterm delivery (PTD) (adjusted OR: 1.89, 95% CI: 1.03 to 3.47, P = 0.0399) and low birthweight (LBW) (adjusted OR: 2.67, 95% CI: 1.14 to 6.24, P = 0.0231). These associations were observed only in the GnRH antagonist protocol, particularly with progesterone ≥ 1.0 ng/mL significantly elevating the risks of PTD (adjusted OR: 4.54, 95% CI: 2.16 to 9.56, P = 0.0021) and LBW (adjusted OR: 4.16, 95% CI: 1.15 to 15.07, P = 0.0378). Threshold analysis further identified progesterone > 0.90 ng/mL as the inflection point for PTD (adjusted OR: 6.60, 95% CI: 2.52 to 14.56, P = 0.0131) and progesterone > 0.98 ng/mL for LBW (adjusted OR: 7.50, 95% CI: 3.71 to 15.87, P = 0.0038) in antagonist cycles. No such associations were found in the GnRH agonist long protocol. Conclusions Our findings suggest that in GnRH antagonist cycles, a serum progesterone level exceeding 0.90 ng/mL on hCG trigger day may serve as an independent predictor of an increased risk of PTD in singletons born after fET. These results highlight the need for enhanced perinatal surveillance in this population, and call for further validation in larger prospective multicenter studies.