Uterine Aging May Reduce Donor Egg Pregnancy Success After Age 49, Landmark Study Finds

A major new study presented at the 42nd Annual Meeting of the European Society of Human Reproduction and Embryology (search)Search company (ESHRE) has provided some of the strongest clinical evidence to date that age-related changes in the uterus independently contribute to poorer pregnancy outcomes—even when egg quality is controlled through donor oocytes.

Researchers from the IVIRMA Global Research Alliance (search)Search term at IVI Roma (search)Search term, Italy, analyzed 2,760 single blastocyst transfers performed in 1,774 women undergoing donor-oocyte treatment between March 2021 and December 2024. The study design allowed the team to examine uterine factors while largely controlling for the effects of egg aging.

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 and over, 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, those 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 and over who transferred all available embryos.

Endometrial changes point to uterine aging

The study also found age-related changes in 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 receptive to embryo implantation—declined significantly with age, from 94.7% among women aged 35–40 to 81.0% among women aged 49 and over.

"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," said Dr. Beatrice Crestani, lead author of the study.

"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.

Clinical implications and expert perspectives

Dr. Crestani emphasized that the findings should not discourage women from pursuing donor-oocyte treatment, as 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."

Professor Borut Kovacic, Chair-elect of ESHRE, commented: "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."

Independent expert reactions highlight strengths and limitations

Several independent experts provided reaction to the study through the Science Media Centre. Dr. Priya Bhide, Clinical Reader in Obstetrics and Gynaecology at Queen Mary University of London, noted: "This study provides very useful information for patients and those seeking treatment with donor eggs. Comparable data have been reported in the literature. The findings are consistent with previous studies, provide external validation, and support the generalisability of these results."

Professor Ying Cheong, Professor of Reproductive Medicine at the University of Southampton, described the study as "well-designed because it uses donor eggs to strip out egg quality and isolate the uterus itself as a factor in age-related infertility (search)Search disease." However, she cautioned: "It's retrospective, so it shows an association between age and outcome, not proof that uterine ageing is the cause; other differences between older and younger patients could be playing a role."

Dr. Norah Fogarty, Group Leader and Lecturer at King's College London, raised methodological concerns regarding the cumulative live birth rate calculation, noting that restricting the analysis "to only patients who used all their available embryos introduces several specific problems." She explained that patients who get pregnant early usually stop before using all their embryos, potentially making the "completers-only" group unrepresentative. Dr. Fogarty suggested that an intention-to-treat cohort with survival analysis using Kaplan-Meier methods would allow researchers to "separate true uterine-aging effects from potential artifacts of the cumulative live birth rate calculation method."

Dr. Emma Lucas, Lecturer in Reproductive Medicine at the University of Sheffield, highlighted that all participants were over 35 years old, meaning no comparison to younger patients was available. She also noted that the use of hormone replacement therapy cycles increased with age in the study and that paternal age also increased in the older female groups—factors that may require further scrutiny in the full paper.

Future research directions

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.

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