Hum Reprod. 2026 Apr 11:deag058. doi: 10.1093/humrep/deag058. Online ahead of print.
ABSTRACT
STUDY QUESTION: Can natural cycles (NC) be effectively utilized in advanced maternal age (AMA) undergoing oocyte donation, without compromising live birth rates (LBRs) and miscarriage outcomes, when compared to artificial cycles (ACs)?
SUMMARY ANSWER: In donor oocyte embryo transfer cycles, NC demonstrated superior outcomes in reproductive efficacy and obstetrical safety compared to AC, independent of the recipient’s age.
WHAT IS KNOWN ALREADY: Previous studies have posited that NC may result in better outcomes when compared to AC embryo transfer, including a lower risk of miscarriage and hypertensive disorders of pregnancy. Recent studies support that NC-frozen embryo transfer (FET) decreases obstetrical and neonatal complications compared to AC-FET, even if LBR differences remain controversial in some general populations. There is limited research on the use of NCs in women of AMA.
STUDY DESIGN, SIZE, DURATION: This retrospective, multicentre, cohort study included all single blastocyst embryo transfers following oocyte donation performed between January 2010 and December 2023, subdivided according to the type of endometrial preparation performed (NC or AC). The oocyte donation model was chosen to minimize the potential confounding effect related to poor oocyte competence in older women and the influence of ovarian stimulation performed during autologous IVF on endometrial receptivity prior to a fresh embryo transfer.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The main objective of the study was to compare LBR. Secondary outcomes included hCG-positive pregnancy rate, clinical pregnancy rate, miscarriage rate, obstetric, and perinatal outcomes. Confounder-adjustment was performed using a multivariable generalized estimating equations model regression analysis, adjusting for multiple confounders. A sub-analysis compared results when the AC protocol was optimized with progesterone (P4) monitoring and rescue therapy. Additionally, an interaction variable was added to the final multivariable model to assess whether female recipient age may modify the effect of each type of endometrial preparation on LBRs.
MAIN RESULTS AND THE ROLE OF CHANCE: In total, 67 048 embryo transfers were analysed, including NC (n = 6922) and AC (n = 60 126). The NC group demonstrated consistent superiority over AC after adjustment for confounders across all transfers. NC was associated with a higher LBR (aOR 1.38, 95% CI 1.29-1.47; P < 0.01) and significantly lower miscarriage rate per hCG-positive pregnancy (aOR 0.68, 95% CI 0.61-0.76; P < 0.01). This superiority persisted even in optimized AC cycles with P4 monitoring and rescue therapy (LBR aOR 1.42, 95% CI 1.31-1.54; P < 0.01). Furthermore, NC was associated with significantly lower obstetrical risks in singleton pregnancies, including hypertensive disorders of pregnancy (aOR 0.72, 95% CI 0.56-0.94; P = 0.01), Caesarean delivery (aOR 0.86, 95% CI 0.77-0.96; P < 0.01), and large for gestational age (aOR 0.77, 95% CI 0.67-0.89; P < 0.01). The interaction between endometrial preparation method and female recipient age was not statistically significant (aOR 1.02, 95% CI 0.99-1.03).
LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and the inherent risk of bias related to unmeasured confounding factors may have impacted the results. Another limitation is the low percentage of NC included in the study (10.32% of all cycles), which could be related to the low uptake to this treatment modality in real-life practice.
WIDER IMPLICATIONS OF THE FINDINGS: NC may offer superior reproductive outcomes and is associated with lower obstetrical risks, with differences unlikely to be modified by female age. Therefore, it seems reasonable to suggest NC for older women, as they could benefit from the decreased risk of miscarriage and hypertension during pregnancy.
STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. A.R.N. has received research grants (to institution) from Theramex; Consulting and Speakers’ fees and travel support from Organon and Merck KgaA; S.S.-R. has received consulting fees from Organon, IBSA, and Besins; Speakers’ fees and travel support from Organon, Ferring Pharmaceuticals, Theramex, IBSA, Gedeon Richter, Abbott, and Besins. He has also received travel support from Organon, Ferring, Theramex, IBSA, Gedeon-Richter, Abbott, and Besins. He holds stocks/shares with IVIRMA Lisboa. He is a member of the ESHRE Executive Committee and was the Senior Deputy of Safety and Quality for ESHRE.
TRIAL REGISTRATION NUMBER: N/A.
PMID:41968377 | DOI:10.1093/humrep/deag058
