Maternal infections during pregnancy can increase the risk to offspring of developing a neurodevelopmental disorder. Given the global prevalence and severity of infection with Severe Acute Respiratory Syndrome related Coronavirus 2 (SARS-CoV-2), the objective of this study was to determine if in utero exposure to severe maternal SARS-CoV-2 infection alters infant neurodevelopmental outcomes at 12 months and to identify potential biological markers of adverse infant outcomes. Mother-infant dyads exposed to severe SARS-CoV-2 infection (requiring hospitalization) during pregnancy and age and sociodemographic matched control dyads were recruited from Monash Medical Centre, Australia in 2021/22 and prospectively assessed over 12 months. Maternal serum cytokine levels and Edinburgh Postnatal Depression Scale (EPDS) scores were assessed at birth. DNA methylation was assessed from infant buccal swabs at birth (Illumina EPIC BeadChip). Infant neurodevelopmental outcomes at 12 months were assessed using the Ages and Stages Questionnaire (ASQ-3). Mothers exposed to severe SARS-CoV-2 exhibited elevated serum IL-6 and IL-17A and higher EPDS scores than controls at birth. Infants exposed to severe SARS-CoV-2 in utero demonstrated over 3000 significant differentially methylated sites within their genomes compared to non-exposed (adjusted p-value < 0.05), including genes highly relevant to ASD and synaptic pathways. At 12 months, severe SARS-CoV-2 exposed infants scored lower on the ASQ-3 than non-exposed infants, and communication and problem-solving scores negatively correlated with maternal IL-6 levels at birth. DNA methylation changes therefore unveil potential mechanisms linking infection exposure to delayed neurodevelopment and maternal serum IL-6 levels may be a potential biomarker of child developmental delay.

怀孕期间的母体感染会增加后代患神经发育障碍的风险。鉴于严重急性呼吸系统综合症相关冠状病毒 2 （SARS-CoV-2） 感染的全球患病率和严重程度，本研究的目的是确定子宫内暴露于严重的母体 SARS-CoV-2 感染是否会改变 12 个月时的婴儿神经发育结局，并确定不良婴儿结局的潜在生物标志物。2021/22 年从澳大利亚莫纳什医疗中心招募了在怀孕和年龄期间暴露于严重 SARS-CoV-2 感染（需要住院）的母婴二人组和社会人口学匹配的对照二人组，并在 12 个月内进行了前瞻性评估。出生时评估母体血清细胞因子水平和爱丁堡产后抑郁量表 （EPDS） 评分。从婴儿出生时的口腔拭子 （Illumina EPIC BeadChip） 中评估 DNA 甲基化。使用年龄和阶段问卷 （ASQ-3） 评估 12 个月时的婴儿神经发育结局。与对照组相比，暴露于严重 SARS-CoV-2 的母亲在出生时表现出血清 IL-6 和 IL-17A 升高以及 EPDS 评分更高。与未暴露的婴儿相比，在子宫内暴露于严重 SARS-CoV-2 的婴儿在其基因组中表现出超过 3000 个显著的差异甲基化位点（调整后的 p 值 < 0.05），包括与 ASD 和突触通路高度相关的基因。在 12 个月时，严重暴露于 SARS-CoV-2 的婴儿在 ASQ-3 上的得分低于未暴露的婴儿，沟通和解决问题的分数与出生时母体 IL-6 水平呈负相关。 因此，DNA 甲基化变化揭示了将感染暴露与神经发育延迟联系起来的潜在机制，母体血清 IL-6 水平可能是儿童发育迟缓的潜在生物标志物。