Ben Messaoud Khaoula, Khachadourian Vahe, Arildskov Elias, Hansen Stefan N, Gardner Renee, Ramlau-Hansen Cecilia, Kahn Linda, Janecka Magdalena
Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
Department of Biomedecine, Aarhus University, Aarhus, Denmark.
medRxiv. 2024 Sep 18:2024.09.17.24313638. doi: 10.1101/2024.09.17.24313638.
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.
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.
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.
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.
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.
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 (HR=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 (HR=1.10 (95% CI, 1.00-1.20).
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.
现有研究表明不孕症对儿童神经发育障碍风险有影响，然而，迄今为止的研究未能区分男性和女性不孕症的影响，常常将所有形式不孕症的代理因素混为一谈。此外，虽然有人提出与不孕症同时出现的健康状况和上游运作的遗传因素会影响不孕症与儿童结局之间的关联，但其作用以及对观察到的关联的潜在影响仍不明确。
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，将其与男性不孕症和夫妻不孕症的影响区分开来；考虑各种母体因素和出生因素在该关联中的作用；并研究共同的家族混杂因素对该关联的影响。
设计、设置和参与者：基于丹麦人群的队列研究，包括1998年至2015年丹麦所有单胎活产及其父母和父母的兄弟姐妹。该队列随访至2016年12月31日。
暴露因素为母亲和母亲姐妹的女性不孕症史。我们根据从丹麦国家患者登记处获得的国际疾病分类第十版（ICD - 10）编码检查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；女性单纯性不孕症；以及女性或男性不孕症。
结局是丹麦精神病学中央研究登记处或国家患者登记处的自闭症谱系障碍（ASD）诊断。使用多变量Cox回归模型估计女性不孕症与自闭症之间的关联，并考虑儿童性别、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。使用来自儿童母亲姨妈的暴露信息分析共同家族因素对该关联的影响。
该队列包括1,131,899对母婴，其中18,374名儿童被诊断为自闭症。母亲的女性不孕症史（所有定义）与儿童自闭症显著相关，在调整协变量后该关联仍然显著（特定不孕症的风险比（HR）=1.14（95%置信区间，1.03 - 1.26））。即使在调整了母亲不孕症后，儿童母亲姨妈的不孕症诊断也与儿童自闭症风险显著相关（HR = 1.10（95%置信区间，1.00 - 1.20））。
在这项基于人群的出生队列研究中，我们发现有不孕症史的母亲所生儿童患自闭症的风险略高，该关联在女性不孕症的各种定义中保持一致，并且在对人口统计学、儿童和母体因素进行调整后仍然显著。该研究首次表明，共同的家族因素，可能包括遗传和非遗传因素，可能同时影响女性不孕症和儿童自闭症风险，这表明需要进一步研究这些家族效应。
