Uterine aging may reduce donor egg pregnancy success after 49

A major new study suggests that age-related changes in the uterus may contribute to poorer pregnancy outcomes, with women aged 49 and over experiencing lower live birth rates and higher miscarriage risk despite donor-oocyte treatment.

Presented today at the 42nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), the findings challenge the assumption that donor eggs can fully 'reset' the reproductive clock by eliminating the effects of reproductive aging.

In recent decades, maternal age at childbirth has increased steadily due to social, economic and technological changes. While age-related fertility decline has traditionally been attributed largely to declining egg quality, growing evidence suggests that uterine and endometrial aging may also exert independent effects.

However, until now, clinical evidence quantifying the contribution of uterine aging to reproductive outcomes has remained limited.

To investigate this, researchers from the IVIRMA Global Research Alliance at IVI Roma, Italy, analysed 2,760 single blastocyst transfers performed in 1,774 women undergoing donor-oocyte treatment between March 2021 and December 2024, allowing them to examine uterine factors while largely controlling for the effects of egg aging.

Pregnancy outcomes were compared across four recipient age groups (35–40, 41–45, 46–49 and ≥49 years), with live birth rates, miscarriage rates and endometrial characteristics assessed while adjusting for embryo-, maternal- and paternal-related factors.

The analysis identified 49 years as a clinically meaningful threshold, after which reproductive outcomes declined despite the use of donor eggs. Clinical pregnancy rates fell from 54.0% in women aged 35–40 to 42.6% in those aged ≥49, while live birth rates declined from 46.2% to 31.7%. Miscarriage rates increased from 24.2% to 37.6%.

Compared with women aged 35–40, women aged 49 and over had significantly lower odds of achieving a live birth and more than double the odds of miscarriage. Cumulative live birth rates also declined substantially with age, from 80.0% among women aged 35–40 to 62.5% among women aged ≥49 who transferred all available embryos.

The study also found age-related changes in the lining of the uterus, known as the endometrium. While the thickness of the uterine lining remained similar across age groups, the proportion of women with a trilaminar endometrial pattern – a feature generally associated with a uterus that is receptive to embryo implantation – declined significantly with age, from 94.7% among women aged 35–40 to 81.0% among women aged ≥49.

For many years, reproductive aging has been seen primarily as an ovarian issue, meaning that if you replace older eggs with donor oocytes, you essentially 'reset' the reproductive clock. Our findings suggest the picture is more complex."

Dr. Beatrice Crestani, Lead Author

"Donor eggs clearly overcome the problem of egg quality, and outcomes remain very good for many women even into their late forties. However, beyond the age of 49 we observed lower live birth rates and higher miscarriage rates despite the use of donor eggs, suggesting that age-related changes in the uterine environment may also influence reproductive success," Dr Crestani explained.

Discussing the implications of the findings, Dr Crestani added: "These findings should not discourage women from pursuing donor-oocyte treatment, because success rates remain meaningful even at advanced ages. However, patients should be counselled that donor eggs cannot completely eliminate the effects of reproductive aging, particularly beyond 49 years."

Looking ahead, the researchers hope to better understand the biological mechanisms underlying uterine aging, including the potential roles of vascular, immune, hormonal and molecular changes. Future studies should focus on identifying biomarkers of 'uterine biological age' and exploring ways to predict, prevent or potentially improve age-related declines in uterine function.

Commenting on the study, Professor Borut Kovacic, Chair-elect of ESHRE, said: "In recent years, increasing research efforts have focused on understanding the processes that enable cross-talk between the embryo and the endometrium, marking the onset of implantation. This study identifies an age threshold associated with the beginning of loss of uterine function. While this threshold is unlikely to be absolute, it provides important information for patients and offers a valuable foundation for future research aimed at identifying novel biomarkers of uterine aging."

The study abstract will be published today in Human Reproduction, one of the world's leading reproductive medicine journals.