Modified letrozole vs GnRH antagonist protocols in ovarian aging women for IVF: an open-label, multicenter, randomized controlled trial

For women with diminished ovarian reserve or of advanced age, controlled ovarian stimulation presents a significant challenge during in vitro fertilization cycles. This multi-center, open-label, randomized controlled trial enrolled 318 women with diminished ovarian reserve (defined as an antral follicle count < 5 or anti-Müllerian hormone level of 0.1-1.1 ng/mL) or advanced age (40-45 years) between 2020 and 2023. Participants were assigned to either a modified letrozole protocol (mLP, n = 159) or a gonadotropin-releasing hormone antagonist protocol (n = 159). Primary outcomes, cumulative clinical pregnancy rate and cumulative live birth rate, were analyzed using both the full analysis set and the per-protocol set. Secondary outcomes, including live birth rate, clinical pregnancy rate, and pregnancy loss rate, were analyzed using the per-protocol set. Results from the full analysis set showed comparable cumulative clinical pregnancy rates (32.1% vs 34.0%; RR 0.94, 95% CI: 0.69-1.29) and cumulative live birth rates (24.5% vs 22.6%; RR 1.08, 95% CI: 0.73-1.61) between the two groups. The per-protocol analysis also demonstrated comparable cumulative clinical pregnancy rates (33.3% vs 36.0%; RR 0.93, 95% CI: 0.68-1.27). Notably, the mLP was associated with a significantly higher clinical pregnancy rate among patients with diminished ovarian reserve who underwent dual cleavage-stage fresh embryo transfers (65.8% vs 36.4%; RR 1.81, 95% CI: 1.15-2.85). Although primary outcomes were similar between protocols, the mLP improved clinical pregnancy rates in fresh embryo transfers for women with diminished ovarian reserve, suggesting its potential to enhance in vitro fertilization efficacy in this population. Fresh transfers demonstrated non-significant difference of mLP for live birth rate (34.0% vs 22.2%; RR 1.53, 95% CI: 0.96-2.43), non-significant reduced biochemical pregnancy loss rate (22.0% vs 34.3%; RR 0.59, 95% CI: 0.29-1.21) and miscarriage rate (20.0% vs 26.7%; RR 0.75, 95% CI: 0.32-1.77). Trial registration: ChiCTR2000029272.