Lin Mei-Chen, Pan Yi-Jiun, Wu Chi-Shin, Liu Chia-Lin, Chen Pei-Chun, Thompson Wesley K, Fan Chun-Chieh, Wang Shi-Heng
National Center for Geriatrics and Welfare Research, National Health Research Institutes, Zhunan, Taiwan.
Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
Mol Psychiatry. 2025 May;30(5):1791-1800. doi: 10.1038/s41380-024-02787-z. Epub 2024 Oct 10.
In utero and early childhood infections have been associated with an increased risk of neurodevelopmental disorders; however, the observed associations may be confounded by familial predispositions. This study examined the neurodevelopmental disorders attributable to maternal infections during pregnancy and early childhood infections during the first year of life, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), tic disorders, and mental retardation (MR). We performed population and sibling comparison analyses to account for unmeasured familial confounding factors. We conducted a register-based cohort study with 2,885,662 individuals (comprising 1,864,660 full siblings) born in Taiwan between 2001 and 2018 and followed up until 2021. We employed Cox regression analysis to assess the association between in utero and early childhood infections requiring hospitalization and the subsequent risk of neurodevelopmental disorders. In the population analyses, an offspring exposed to maternal infection had an increased risk for ASD (hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.13-1.26), ADHD (HR = 1.14, 95% CI: 1.11-1.18), and MR (HR = 1.21, 95% CI: 1.13-1.30). These associations attenuated toward null in the sibling analyses. Individuals exposed to early childhood infection had an increased risk for ASD (HR = 1.13, 95% CI: 1.10-1.16), ADHD (HR = 1.16, 95% CI: 1.15-1.18), tic disorders (HR = 1.12, 95% CI: 1.09-1.15), and MR (HR = 1.64, 95% CI: 1.60-1.69) in the population analyses; these associations were also significant for ASD (HR = 1.14, 95% CI: 1.07-1.21) and MR (HR = 1.52, 95% CI: 1.44-1.62) in the sibling analyses. The association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors. Conversely, infection in early childhood may be attributable to it being a sensitive period and may play a role in the subsequent risk of ASD and MR.
子宫内和幼儿期感染与神经发育障碍风险增加有关；然而，观察到的关联可能会受到家族易感性的混淆。本研究调查了孕期母亲感染和生命第一年幼儿期感染所致的神经发育障碍，包括自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）、抽动障碍和智力障碍（MR）。我们进行了人群和同胞比较分析，以解释未测量的家族混杂因素。我们开展了一项基于登记的队列研究，研究对象为2001年至2018年在台湾出生的2885662人（包括1864660对全同胞），随访至2021年。我们采用Cox回归分析来评估子宫内和幼儿期需要住院治疗的感染与随后神经发育障碍风险之间的关联。在人群分析中，暴露于母亲感染的后代患ASD（风险比（HR）=1.19，95%置信区间（CI）：1.13 - 1.26）、ADHD（HR = 1.14，95% CI：1.11 - 1.18）和MR（HR = 1.21，95% CI：1.13 - 1.30）的风险增加。这些关联在同胞分析中减弱至无关联。在人群分析中，暴露于幼儿期感染的个体患ASD（HR = 1.13，95% CI：1.10 - 1.16）、ADHD（HR = 1.16，95% CI：1.15 - 1.18）、抽动障碍（HR = 1.12，95% CI：1.09 - 1.15）和MR（HR = 1.64，95% CI：1.60 - 1.69）的风险增加；这些关联在同胞分析中对于ASD（HR = 1.14，95% CI：1.07 - 1.21）和MR（HR = 1.52，95% CI：1.44 - 1.62）也具有显著性。孕期母亲感染与后代神经发育风险之间的关联在很大程度上归因于家族混杂因素。相反，幼儿期感染可能归因于其为敏感时期，并且可能在随后的ASD和MR风险中起作用。
