P-435 Superiority of modified natural cycle vs hormonal replacement therapy in non-menopausal egg recipients of advanced maternal age: clinical outcomes from 1273 single blastocyst transfer cycles
Authors: Moffa F , Moreno A , Novo S , Mancini F , Andrade P , Rovira S , Lolicato F , Antich M 
Published: July 2024

Study question

Is the modified natural cycle (mNC) better than hormonal replacement therapy (HRT) for endometrial preparation in non-menopausal egg recipients of advanced maternal age?

Summary answer

In women above 40 years, mNC shows better reproductive and obstetrical outcomes compared to hormonal replacement therapy, especially in the subgroup 45-50 years old.

What is known already

There is extensive evidence showing the superiority of mNC over HRT in terms of live birth rates, miscarriages, and even obstetric complications. Apparently, the presence of the corpus luteum plays a major role in endometrial receptivity and embryo implantation, probably allowing for better placentation. Nevertheless, there is a general belief that the ovulatory cycle of older women is not the best choice for endometrial preparation, although paradoxically they are the group of patients who could benefit most from the reduction of obstetric complications. An increase in cancellation rates for mNC is claimed, without consistent data available.

Study design, size, duration

Retrospective single-centre comparative clinical study, including 1273 endometrial preparation cycles for frozen single-blastocyst transfer between January 2020 and December 2022: 892 (70,2%) on HRT protocol and 381 (29,8%) on mNC protocol. The two groups were homogeneous for donor’s age (25,7 years HRT vs 25,3 years mNC), recipient’s age (42,2 years HRT vs 42,1 years mNC), severe male factor (6% HRT vs 5% mNC), and the need for a sperm donor (28% HRT vs 26% mNC).

Participants/materials, setting, methods

Among 1273 started non-menopausal recipient’s cycles, we compared cancellation rates between HRT and mNC due to either medical reasons (inadequate endometrium, bleeding, premature ovulation) or other issues (no embryo survival, COVID-19, etc).

We studied the outcomes of the 1096 elective frozen single-blastocyst transfers performed, comparing HRT and mNC cycles for: pregnancy, clinical pregnancy, miscarriage, live birth and &lt;35weeks preterm birth rates.

We stratified the results by age and used Chi-square test to compare groups (p &lt; 0,05).

Main results and the role of chance

The overall cancellation rate was 13.9%. No significant differences in cancellation for medical reasons were found between HRT (7%) and mNC (6.8%), p = 0.93.

When we analyse results stratified by age, patients aged 39 or less (270 cycles: HRT 75.9%, mNC 24.1%) showed no statistically significant differences in pregnancy (58% vs 64.6%, p = 0.35), clinical pregnancy (50.7% vs 56.9%, p = 0.34), miscarriage (18.3% vs 18.9%, p = 0.93), and live birth rates (41.5% vs 46.2%, p = 0.5).

In the 40-44 age group (494 cycles: HRT 64.2%, mNC 35.8%), no statistically significant differences were found between HRT and mNC in pregnancy (58.2% vs 61.5%, p = 0.47), clinical pregnancy (50.8% vs 51.1%, p = 0.96), and live birth rates (40.4% vs 45.8%, p = 0.25). The HRT group had a significantly higher miscarriage rate (21%) compared to mNC (10%), p = 0.03.

For patients aged 45-50 years (332 cycles: HRT 72%, mNC 28%), no statistically significant differences were observed in pregnancy (56.5% vs 62.4%, p = 0.33) and miscarriage rates (24.3% vs 15.1%, p = 0.18). Clinical pregnancy (44.8% Vs 57%, p = 0.04) and live birth rates (33.9% vs 48.4%, p = 0.01) were significantly higher in the mNC group compared to HRT.

No significant differences were found between HRT and mNC in preterm birth rates &lt;35 weeks (3.6% vs 4.6%, p = 0.75).

Limitations, reasons for caution

This study is a single-centre retrospective comparative trial. Our homogeneity study included several confounding variables, however other bias such as severe uterine factor, embryo quality or repeated implantation failure cases were not taken into account.

Wider implications of the findings

Modified natural cycle should be encouraged as the first option for endometrial preparation in non-menopausal egg recipients of advanced maternal age, having shown superiority over hormonal replacement therapy in patients aged 45-50 years. Moreover, modified natural cycles are more patient friendly and cost-effective, with no increase in the cancellation rates.

Trial registration number

not applicable