Abstract / Summary
Abstract Background Conventional ovarian stimulation for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment begins in the early follicular phase and requires gonadotrophin-releasing hormone (GnRH) analogs to prevent premature LH surges. Late follicular phase ovarian stimulation has emerged as an alternative in freeze‑all IVF/ICSI cycles, but still depends on exogenous pituitary modulators. To date, robust evidence from randomized controlled trials (RCTs) regarding whether late follicular phase ovarian stimulation could be performed without an exogenous pituitary modulator remains lacking. Methods This prospective randomized non-inferiority trial included 300 normo-ovulatory infertile women who were randomized between February 2022 and October 2023. Participants were assigned (1:1) to either the GnRH antagonist protocol or the GnRH antagonist-free late follicular phase ovarian stimulation (LS) protocol. The primary outcome was the number of usable embryos. Secondary outcomes included number of oocytes retrieved, number of mature oocytes, clinical pregnancy rate, implantation rate and early miscarriage rate. Results The number of usable embryos did not differ significantly between the LS group (median 3 [IQR 1–5]) and the GnRH antagonist group (median 3 [IQR 1–4]), with a median difference of 0 (95% CI: −1 to 0). The lower bound of the 95% CI (− 1) met the prespecified non‑inferiority margin, establishing non‑inferiority. The number of oocytes retrieved did not differ significantly between groups ( P = 0.105), but the LS group yielded significantly more mature oocytes (median 7 [IQR 4–10.25] vs. 5.5 [IQR 3–8], P = 0.018). The implantation rate was higher in the LS group (68.15% vs. 54.86%; P = 0.013), while the clinical pregnancy rate (66.01% vs. 55.36%; P = 0.051) and early miscarriage rate (14.85% vs. 12.9%; P = 0.695) were comparable between groups. Conclusion Our study demonstrated that the LS protocol is non‑inferior to the GnRH antagonist protocol with respect to usable embryo yield in normo‑ovulatory women undergoing IVF/ICSI with a freeze‑all strategy, suggesting that the LS protocol may represent a viable alternative to the antagonist regimen. Larger multicenter trials are warranted to confirm these findings. Trial number This trial was registered with the Chinese Clinical Trial Registry (ChiCTR2200055972) on 30 January 2022.