Feng Wanbing, Ren Yujia, Zhou Jiayi, Zhu Hanbing, Zhao Han, Qin Yingying, Li Jing, Xia Mingdi, Xu Lihong, Li Mei, Wang Huidan, Cui Linlin, Chen Zi-Jiang
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
Hum Reprod Open. 2025 Mar 28;2025(2):hoaf019. doi: 10.1093/hropen/hoaf019. eCollection 2025.
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?
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.
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.
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.
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.
The offspring were aged 2-6 years, limiting the ability to assess comprehensive reproductive phenotypic changes. Longer follow-up studies are necessary.
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.
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与卵巢反应正常的母亲所生子女相比，卵巢反应不良（POR）的母亲所生子女在2至6岁时其生殖内分泌特征是否存在改变？
预期存在POR的年轻母亲（<35岁）所生的女性后代在儿童期更有可能血清抗苗勒管激素（AMH）水平较低。
POR影响不孕不育诊所中32%至43%的女性。遗传易感性和潜在的不良子宫内环境对下一代构成威胁。然而，目前尚无与POR相关的代际生殖影响的直接证据。
研究设计、规模、持续时间：我们进行了一项前瞻性队列研究，以调查母亲POR对后代生殖内分泌健康的代际影响。数据来自“辅助生殖技术出生儿童（ARTKID）”，这是2013年在中国一家三级医疗中心建立的一个出生队列。共招募了2013年至2019年间出生的3103名2至6岁的后代，并将其纳入我们的研究直至2021年。通过辅助生殖技术受孕的暴露组后代根据其母亲使用以患者为导向的策略个体化卵母细胞数量标准（POSEIDON）的分类分为四组。未暴露组后代是辅助生殖技术后卵巢反应正常的母亲所生。
参与者/材料、设置、方法：通过辅助生殖技术受孕的后代在2至6岁时提供血样以评估生殖内分泌参数。基于线性混合模型获得均值差异和95%置信区间。调整后的模型考虑了父亲年龄、母亲年龄、后代年龄、父亲吸烟情况、卵胞浆内单精子注射（ICSI）的使用以及冷冻胚胎移植情况。
预期存在POR的年轻母亲（POSEIDON第3组）所生的女性后代在儿童期的AMH和催乳素（PRL）水平低于对照组（AMH：调整后均值差异[AMD]=-0.64，95%置信区间=-1.10，-0.18；PRL：AMD=-1.59，95%置信区间=-2.97，-0.21）。预期存在POR的年长母亲（≥35岁）（POSEIDON第4组）所生的女性后代的AMH水平呈下降趋势，尽管与对照组相比该差异无统计学意义[AMD=-0.60，95%置信区间=-1.31，-0.12]。预期存在POR的年轻母亲（POSEIDON第1组）所生的女性后代的硫酸脱氢表雄酮（DHEA-S）水平低于对照组[AMD=-1.38，95%置信区间=-2.58，-0.17]。相比之下，POR母亲所生的男性后代的生殖内分泌特征与对照组相似。
局限性、谨慎理由：后代年龄为2至6岁，限制了评估全面生殖表型变化的能力。有必要进行更长时间的随访研究。
母亲POR对后代生殖内分泌特征的潜在影响可能主要与卵巢储备有关。遗传易感性、雄激素缺乏症和其他子宫内环境因素可能是预期存在POR的年轻母亲所生女性后代AMH水平降低的可能原因。
研究资金/利益冲突：本研究得到中国国家重点研发计划（2022YFC2703000、2022YFC2704404、2024YFC2706902、2022YFC2702905、2024YFC2706700）、中国医学科学院医学与健康科技创新工程（2021-I2M-5-001）、山东省自然科学基金（ZR2022JQ33）、山东大学基本科研业务费（2023QNTD004）、国家高层次人才特殊支持计划、山东省卫生科技创新团队建设项目以及山东省泰山学者青年专家计划（tsqn201909195）的支持。作者声明他们没有利益冲突。
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