女性不孕症与儿童神经发育障碍:丹麦女性不孕症与儿童神经发育障碍的关系及家族混杂的证据

khaoula Ben Messaoud, Vahe Khachadourian, Elias Arildskov, Stefan Hansen, Renee Gardner, Cecilia Ramlau-Hansen, Linda Kahn, Magdalena Janecka
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引用次数: 0

摘要

重要意义 现有研究表明,不孕症会对儿童神经发育障碍的风险产生影响,然而,迄今为止的研究都未能将男性和女性不孕症的影响区分开来,往往是用包含各种形式不孕症的代用指标来模糊界限。此外,虽然有人认为与不孕症同时存在的健康状况和上游遗传因素会影响不孕症与儿童结局之间的关联,但它们的作用以及对观察到的关联的潜在影响仍不清楚。目的 本研究的目的是调查女性不孕症与儿童自闭症之间的关系,并将其与男性不孕症和夫妇不孕症的影响区分开来;考虑各种母体因素和出生因素在这种关联中的作用;以及研究共同的家族混杂因素对这种关联的影响。该队列随访至 2016 年 12 月 31 日。暴露暴露为母亲及其姐妹的女性不孕史。我们根据丹麦全国患者登记册中的 ICD-10 编码,研究了女性不孕症的四种定义:任何女性不孕症;特定女性不孕症;女性唯一不孕症;女性或男性不孕症。主要结果和测量 结果是在丹麦精神病学中央研究登记册或全国患者登记册中诊断出自闭症谱系障碍(ASD)。在考虑儿童性别、出生年份、母亲年龄、教育水平、慢性合并症以及妊娠和分娩并发症的情况下,采用多变量考克斯回归模型来估计女性不孕症与自闭症之间的关系。结果 该队列包括 1,131,899 对母子,其中 18,374 名儿童确诊为 ASD。母亲的女性不孕史(所有定义)与儿童的自闭症显著相关,在对协变量进行调整后,相关性仍然很强(特定不孕症的 HRadj=1.14 (95% CI, 1.03-1.26))。在这项基于人群的出生队列研究中,我们发现有不孕不育史的母亲所生的孩子患自闭症的风险略高,这种关联在女性不孕不育的不同定义中保持一致,并且在调整了人口、儿童和母亲因素后仍很稳健。这项研究首次表明,共同的家族因素(可能是遗传因素,也可能是非遗传因素)可能会影响女性不孕症和儿童患自闭症的风险,这表明有必要进一步调查这些家族效应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Female Infertility and Neurodevelopmental Disorders in Children: associations and evidence for familial confounding in Denmark
IMPORTANCE Existing research suggests the impact of infertility on the risk of neurodevelopmental disorders in children, however, studies to date have failed to separate the impact of male and female infertility, often blurring the lines with proxies that encompass all forms of infertility. Moreover, while both health conditions co-occurring with infertility and genetic factors operating upstream have been suggested to influence the association between infertility and child outcomes, their roles and potential impact on observed associations remain unclear. OBJECTIVE The objectives of this study are to investigate the relationship between female infertility and autism in the child, differentiating it from the effects of male and the couple infertility; consider the role of various maternal and birth factors in the association; and examine the effects of shared familial confounders on the association. DESIGN SETTING AND PARTICIPANTS Danish population-based cohort study, including all singleton live births in Denmark 1998-2015, their parents and parents' siblings. The cohort was followed up until December 31, 2016. EXPOSURES The exposure was a history of female infertility in the mother and the mother's sister. We examined four definitions of female infertility based on the ICD-10 codes derived from the Danish National Patient Register - any female infertility; specified female infertility; female exclusive infertility; and female or male infertility. MAIN OUTCOME AND MEASURES The outcome was diagnosis of autism spectrum disorder (ASD) in the Danish Psychiatric Central Research Register or the national patient register. A multivariable Cox regression model was used to estimate the associations between female infertility and autism, accounting for child's sex, year of birth, maternal age, education level, chronic comorbidities, and pregnancy and birth complications. The effects of shared familial factors on the association were analyzed using exposure information from the child's maternal aunt. RESULTS The cohort included 1,131,899 mother-child pairs, among which 18,374 children with ASD diagnosis. History of female infertility in the mother (all definitions) was significantly associated with autism in the child, with the association remaining robust after adjustment for covariates (HRadj=1.14 (95% CI, 1.03-1.26) for specified infertility). The diagnosis of infertility in a child's maternal aunt was also significantly linked to the child's autism risk, even after adjustment for maternal infertility (HRadj=1.10 (95% CI, 1.00-1.20). CONCLUSIONS AND RELEVANCE in This population-based birth cohort study, we found a slightly higher risk of autism in children born to mothers with a history of infertility, with the association remaining consistent across various definitions of female infertility and robust to adjustments for demographic, child, and maternal factors. The study suggests for the first time that shared familial factors, possibly both genetic and non-genetic, could be influencing both female infertility and the risk of autism in children, indicating a need for further investigation into these familial effects.
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