Hill Rachel A, Gibbons Andrew, Suwakulsiri Wittaya, Taseska Angela, Darke Hayley, Malhotra Atul, Yee Hnin, Fahey Michael, Hunt Rod W, Lim Izaak, Palmer Kirsten, Sundram Suresh
Department of Psychiatry, Monash University, Clayton, Vic, Australia.
Department of Paediatrics, Monash University, Clayton, Vic, Australia.
Mol Psychiatry. 2025 May;30(5):1976-1984. doi: 10.1038/s41380-024-02808-x. Epub 2024 Oct 30.
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. Mothers exposed to severe SARS-CoV-2 infections show elevated pro-inflammatory cytokines. Infants exposed in utero to severe SARS-CoV-2 infection show altered DNA methylation at birth and delayed development at 12 months of age. Created in Biorender.com.
孕期母亲感染会增加后代患神经发育障碍的风险。鉴于严重急性呼吸综合征相关冠状病毒2（SARS-CoV-2）感染的全球流行率和严重性，本研究的目的是确定子宫内暴露于母亲严重SARS-CoV-2感染是否会改变婴儿12个月时的神经发育结局，并确定不良婴儿结局的潜在生物学标志物。2021年/22年从澳大利亚莫纳什医疗中心招募了孕期暴露于严重SARS-CoV-2感染（需要住院治疗）的母婴二元组以及年龄和社会人口学匹配的对照二元组，并对其进行了为期12个月的前瞻性评估。出生时评估母亲血清细胞因子水平和爱丁堡产后抑郁量表（EPDS）评分。从出生时的婴儿口腔拭子中评估DNA甲基化（Illumina EPIC BeadChip）。使用年龄与发育进程问卷（ASQ-3）评估婴儿12个月时的神经发育结局。暴露于严重SARS-CoV-2的母亲在出生时血清IL-6和IL-17A水平升高，且EPDS评分高于对照组。与未暴露的婴儿相比，子宫内暴露于严重SARS-CoV-2的婴儿在其基因组内显示出超过3000个显著的差异甲基化位点（校正p值<0.05），包括与自闭症谱系障碍（ASD）和突触通路高度相关的基因。在12个月时，暴露于严重SARS-CoV-2的婴儿在ASQ-3上的得分低于未暴露的婴儿，并且沟通和解决问题的得分与出生时母亲的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，母亲血清IL-6水平可能是儿童发育延迟的潜在生物标志物。暴露于严重SARS-CoV-2感染的母亲显示促炎细胞因子升高。子宫内暴露于严重SARS-CoV-2感染的婴儿在出生时显示DNA甲基化改变，在12个月大时发育延迟。由Biorender.com创建。
