Effects of maternal poor ovarian response on the reproductive endocrine profiles of the next generation: a prospective cohort study in China.

Study question: Do offspring born to mothers with poor ovarian response (POR) have alterations in their reproductive endocrine profile at 2-6 years of age compared to those born to mothers with normal ovarian response?

Summary answer: Female offspring born to young mothers (<35 years) with expected POR were more likely to have low serum anti-Müllerian hormone (AMH) levels in childhood.

What is known already: POR affects 32-43% of women in infertility clinics. Genetic susceptibility and potentially adverse intrauterine environments pose threats to the next generation. However, there is currently no direct evidence of intergenerational reproductive effects associated with POR.

Study design size duration: We conducted a prospective cohort study to investigate the intergenerational effects of maternal POR on reproductive endocrine health of offspring. Data were obtained from 'Assisted Reproductive Technology-born KIDs (ARTKID)', a birth cohort established in 2013 at a tertiary care center in China. A total of 3103 offspring, aged 2-6, born between 2013 and 2019, were recruited and included in our study until 2021. The exposed offspring conceived by ART were classified into four groups based on their mothers' categorization using the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. The unexposed offspring were born to mothers with normal ovarian response after ART.

Participants/materials setting methods: Offspring conceived by ART provided blood samples at 2-6 years for the assessment of reproductive endocrine parameters. Mean difference and 95% CI were obtained based on a linear mixed model. The adjusted model accounted for paternal age, maternal age, offspring age, paternal smoking, use of ICSI, and frozen embryo transfer.

Main results and the role of chance: Female offspring born to young mothers with expected POR (POSEIDON Group 3) had lower AMH and PRL (prolactin) levels in childhood compared to controls (AMH: adjusted mean difference [AMD] = -0.64, 95% CI = -1.10, -0.18; PRL: AMD = -1.59, 95% CI = -2.97, -0.21). Female offspring born to older mothers (≥35 years) with expected POR (POSEIDON Group 4) showed a decreasing trend in AMH levels, though this difference was not statistically significant compared to controls [AMD = -0.60, 95% CI = -1.31, -0.12]. Female offspring born to young mothers with unexpected POR (POSEIDON Group 1) had lower DHEA-S (dehydroepiandrosterone sulfate) levels than controls [AMD = -1.38, 95% CI = -2.58, -0.17]. In contrast, male offspring born to POR mothers showed similar reproductive endocrine profiles as controls.

Limitations reasons for caution: The offspring were aged 2-6 years, limiting the ability to assess comprehensive reproductive phenotypic changes. Longer follow-up studies are necessary.

Wider implications of the findings: The potential effects of maternal POR on reproductive endocrine profiles of offspring may be primarily linked to ovarian reserve. Genetic susceptibility, hypoandrogenism, and other intrauterine environmental factors may be probable explanations for reduction in AMH levels observed in female offspring born to young mothers with expected POR.

Study funding/competing interests: This study was supported by the National Key Research and Development Program of China (2022YFC2703000, 2022YFC2704404, 2024YFC2706902, 2022YFC2702905, 2024YFC2706700), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Shandong Provincial Natural Science Foundation (ZR2022JQ33), the Fundamental Research Funds of Shandong University (2023QNTD004), the National Special Support Program for High-level Talents, the Health Science and Technology Innovation Team Construction Project of Shandong Province, and the Taishan Scholars Program for Young Experts of Shandong Province (tsqn201909195). The authors declare that they have no competing interests.

Trial registration number: N/A.