Shadows Cast Before Birth: In Utero and Perinatal Origins of Premature Ovarian Insufficiency—A Multi-Generational Cohort Study
DOI:
https://doi.org/10.64229/zx5n7p63Keywords:
Premature ovarian insufficiency, Fetal programming, Ovarian reserve, Developmental origins of health and disease, Anti-Müllerian hormone, Environmental exposures, Maternal nutrition, Multi-generational cohortAbstract
Background: Premature ovarian insufficiency (POI) affects 1%-3.7% of women under 40, causing infertility and long-term health morbidities. While genetic, autoimmune, and iatrogenic factors are well-established, emerging evidence suggests that ovarian reserve, established entirely during fetal life, may be profoundly shaped by intrauterine exposures. This study investigates whether maternal nutritional status, metabolic dysfunction, and environmental toxin exposure during pregnancy predict reduced ovarian reserve in female offspring. Methods: This prospective multi-generational cohort study enrolled 1,248 mother-daughter dyads from Fatima Memorial Hospital, Lahore, Pakistan (2008-2012). Maternal data included dietary diversity scores (MDD-W), serum micronutrients, heavy metal profiles (lead, cadmium, mercury), glycaemic indices, and obstetric records. Daughters were followed through age 14-18 years, when ovarian reserve was assessed using serum anti-Müllerian hormone (AMH) and antral follicle count (AFC). Multivariate regression and structural equation modelling were applied. Results: Of 1,248 enrolled dyads, 1,024 (82.1%) completed follow-up. Daughters of mothers in the lowest MDD-W quartile had significantly lower AMH (1.42 vs. 2.87 ng/mL; p < 0.001). Maternal gestational diabetes was associated with 34.7% reduction in daughter's AFC (β = −2.3, p < 0.001). Blood lead > 5 μg/dL predicted AMH reduction of 0.84 ng/mL (p < 0.001). Intrauterine growth restriction mediated 38.2% of the undernutrition-AMH pathway. Cumulative exposures produced additive effects, with triple-exposed daughters showing 1.96 ng/mL lower AMH. Conclusions: Maternal nutritional deficiency, environmental toxins, and metabolic dysfunction during pregnancy represent modifiable determinants of daughter's ovarian reserve. These findings support fetal programming of POI and argue for antenatal health optimization and targeted screening in high-risk pregnancies.
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