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

Autores de IIS La Fe

• Antonio Pellicer Martínez

  Autor

• Juan Antonio García Velasco

  Autor

• Mauro Cozzolino

  Autor

Participantes ajenos a IIS La Fe

• Molinaro P
• Napoleoni E
• Alonso-Mayo C

Grupos

• Endocrinología Reproductiva e Infertilidad

• Medicina Fetal y Reproductiva

Abstract

OBJECTIVE: To compare live birth rate (LBR) and other reproductive outcomes between modified natural cycle embryo transfer (mNC-ET) and hormone replacement therapy embryo transfer (HRT-ET) cycles in women aged =40 years undergoing single embryo transfer (SET). DESIGN: Observational, retrospective, multicentric cohort study. SUBJECTS: A total of 26,039 SETs performed in 16,579 women aged 40-49 years between January 2019 and December 2023 across 21 clinics in Spain and Italy. Only euploid frozen ETs were considered for autologous cycles, whereas 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 pregnancy rate (BPR), clinical pregnancy rate (CPR), and ongoing pregnancy rate (OPR), and biochemical miscarriage rate (BMR) and clinical miscarriage rate (CMR). RESULTS: The study analyzed 26,039 SETs (2,694 mNC-ETs vs. 23,345 HRT-ETs) in 16,579 patients (43.1 ± 2.4 years). Multivariate analysis adjusted for confounders demonstrated comparable LBR (adjusted odds ratio [aOR] 1.11, 95% confidence interval [CI]: 0.99-1.24) 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) and higher OPR (aOR 1.14, 95% CI: 1.02-1.26). Subgroup analyses indicated that mNC-ET was associated with a lower risk of clinical miscarriage (aOR 0.47, 95% CI: 0.32-0.68) and a higher likelihood of OPR (aOR 1.24, 95% CI: 1.05-1.47) and live birth (aOR 1.21, 95% CI: 1.02-1.44) 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), and comparable live birth (aOR 1.06 , 95% CI: 0.93-1.22). CONCLUSION: Modified natural cycle embryo transfer was associated with a comparable LBR to that of HRT-ET in women over 40 years old, 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.

Copyright © 2026 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Keywords

• HRT-ET; advanced maternal age (AMA); hormone replacement therapy (HRT); mNC-ET; natural cycle