Age-related uterine changes and its association with poor reproductive outcomes: a systematic review and meta-analysis

Background: The decline in women's fertility becomes clinically relevant between 35-40 years old, when there is insufficient ovarian activity, and it becomes more difficult to achieve pregnancy naturally and through artificial reproductive technologies. A competent endometrium is required for establishing and maintaining a pregnancy to term, however, experts in the field underestimate the contribution of endometrial age and its impact on reproductive outcomes remains unclear.

Study design: A systematic search of full-text articles available in PubMed was conducted to retrieve relevant studies published until March 2023. Search terms included: endometrium, uterus, age, aging, pregnancy, and oocyte donation. Terms related to reproductive pathologies were excluded. Eligibility criteria included original, rigorous, and accessible peer-reviewed work, published in English on the effect of age on the uterus and endometrium.

Results: From 11,354 records identified, 142 studies were included for systematic review, and 59 were eligible for meta-analysis of endometrial thickness (n = 7), pregnancy rate (n = 22), implantation rate (n = 10), live birth rate (n = 10) and pregnancy loss rate (n = 11). Studies for the meta-analysis of reproductive outcomes only included transfers of embryos from ovum donation (ovum donors < 36 years old). Age shrinks the uterus; depletes endometrial blood supply through narrow uterine veins and a progressive loss of uterine spiral arteries; disrupts endometrial architecture and cellular composition; alters hormone production, shortening menstrual cycle length and impeding endometrial progression to the secretory stage; and dysregulates key endometrial functions such as adhesion, proliferation, apoptosis, and receptivity, among others. Women over 35-40 years old had significantly thinner endometrium (MD 0.52 mm). Advanced maternal age is associated with lower odds of achieving implantation (27%) and clinical pregnancy (20%), or higher odds of experiencing pregnancy loss (44%).

Conclusion: Due to the effect of age on endometrium reported in this review, managing patients with advanced maternal age may require considering the endometrial factor as a potential tissue to treat with anti-aging strategies. This review provides researchers and clinicians with an updated and in-depth summary of this topic, encouraging the development of new tailored anti-aging and preventive strategies for precision medicine in endometrial factor in infertility.

Trial registration: PROSPERO 2023 (CRD42023416947).