Modified natural cycle versus hormone replacement therapy embryo transfer in women over 40 years old: a retrospective analysis.

OBJECTIVE: To compare live birth rate (LBR) and other reproductive outcomes between modified natural cycle (mNC-ET) and hormone replacement therapy embryo transfer (HRT-ET) cycles in women aged ≥40 years old undergoing single embryo transfer (SET). DESIGN: Observational, retrospective, multicentric cohort study. SUBJECT: A total of 26,039 SETs performed in 16,579 women aged 40-49 y.o. between January 2019 and December 2023 across 21 clinics in Spain and Italy. Only euploid frozen ETs were considered for autologous cycles, while both fresh and frozen ETs were included for egg donor cycles. EXPOSURE: Endometrial preparation with mNC-ET or HRT-ET protocols. MAIN OUTCOMES MEASURES: The primary outcome was LBR. Secondary outcomes included biochemical (BPR), clinical (CPR), and ongoing pregnancy (OPR) rates, and biochemical (BMR) and clinical miscarriage (CMR) rates. RESULTS: The study analyzed 26,039 SET(Fs (2,694 mNC-ETs vs. 23,345 HRT-ETs) in 16,579 patients (43.1±2.4 y.o.). Multivariate analysis adjusted for confounders demonstrated comparable LBR (aOR 1.11, 95% CI 0.99-1.24; p=0.06) between mNC and HRT-ET, while mNC-ET was associated with lower risk of clinical miscarriage (aOR 0.58, 95% CI 0.46-0.73 ; p<0.001) and higher OPR (aOR 1.14, 95% CI 1.02-1.26; p=0.02). Subgroup analyses indicated that mNC-ET was associated with a lower risk of clinical miscarriage (aOR 0.47, 95% CI 0.32-0.68; p<0.001) and a higher likelihood of OPR (aOR 1.24, 95% CI 1.05-1.47; p=0.01) and live birth (aOR 1.21, 95% CI 1.02-1.44; p=0.03) among autologous cycles. In donor oocyte cycles, it was associated with a reduced risk of clinical miscarriage (aOR 0.66, 95% CI 0.49-0.88; p=0.005), and comparable live birth (aOR 1.06 , 95% CI 0.93-1.22; p=0.37). CONCLUSIONS: mNC-ET was associated with comparable LBR compared to HRT-ET in women over 40 y.o., supporting its feasibility as an endometrial preparation method in this population. Further research should confirm the impact on reproductive outcomes and evaluate potential obstetric benefits in this population.