Late follicular phase progesterone levels and in vitro fertilization and intracytoplasmic sperm injection outcomes

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Objective: fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. Methods: This single-center, retrospective cohort study was conducted from January 2014 to December 2024 and included 24,868 women undergoing their first fresh embryo transfer following an IVF or ICSI cycle at a university-affiliated fertility center. The exposure was serum progesterone level measured on the day of hCG administration. Primary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR) and live birth rate (LBR). Results: In women aged <35 years, progesterone was inversely associated with CPR (fully adjusted aOR=0.868, 95% CI 0.812-0.927, P<0.001) but positively associated with LBR after adjustment (aOR=1.090, 95% CI 1.019-1.167, P = 0.013). No significant effects were observed in patients aged ≥35 years. The progesterone-outcome relationship was significantly modified by protocol, with a nonlinear inverted U-shaped curve in GnRH-agonist protocols (interaction P<0.001 for CPR, P = 0.005 for LBR). In protocol-stratified analyses, progesterone was independently associated with reduced CPR in ultra-long GnRH-agonist (aOR=0.814, 95% CI 0.718-0.922, P = 0.001) and GnRH-antagonist protocols (aOR=0.849, 95% CI 0.771-0.936, P = 0.001), but not in the long GnRH-agonist protocol. The effect on LBR was positive in the long GnRH-agonist protocol (aOR=1.105, 95% CI 1.013-1.205, P = 0.024) and negative in the GnRH-antagonist protocol (aOR=0.884, 95% CI 0.788-0.991, P = 0.035). Sensitivity analyses confirmed the superiority of GnRH-agonist protocols across all progesterone levels (all adjusted P<0.01). Conclusion: The association between late follicular progesterone elevation and reproductive outcomes differs across ovarian stimulation protocols, demonstrating a nonlinear relationship with both clinical pregnancy and live birth. These results suggest that late follicular progesterone elevation should be interpreted with protocol-specific considerations.

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