Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic

Background: During gestation, stressors to the fetus, including viral exposure or maternal psychological distress, can fundamentally alter the neonatal epigenome, and may be associated with long-term impaired developmental outcomes. The impact of in utero exposure to the COVID-19 pandemic on the newborn epigenome has yet to be described. Methods: This study aimed to determine whether there are unique epigenetic signatures in newborns who experienced otherwise healthy pregnancies that occurred during the COVID-19 pandemic (Project RESCUE). The pre-pandemic control and pandemic cohorts (Project RESCUE) included in this study are part of a prospective observational and longitudinal cohort study that evaluates the impact of elevated prenatal maternal stress during the COVID-19 pandemic on early childhood neurodevelopment. Using buccal swabs collected at birth, differential DNA methylation analysis was performed using the Infinium MethylationEPIC arrays and linear regression analysis. Pathway analysis and gene ontology enrichment were performed on resultant gene lists. Results: Widespread differential methylation was found between neonates exposed in utero to the pandemic and pre-pandemic neonates. In contrast, there were no apparent epigenetic differences associated with maternal COVID-19 infection during pregnancy. Differential methylation was observed among genomic sites that underpin important neurological pathways that have been previously reported in the literature to be differentially methylated because of prenatal stress, such as NR3C1. Conclusions: The present study reveals that the onset and continuation of the COVID-19 pandemic has fundamentally altered the epigenomes of newborns born during this time, even in otherwise healthy pregnancies, which should be considered in current and future epigenetic studies and may act as a critical biomarker of stress. DNA was extracted from buccal swab samples from pre-pandemic (CTL) and pandemic-exposed newborns (RES). Illumina Infinium EPIC BeadChip protocol was completed following manufacturer's specifications and DNA quality was determiend using Qubit Fluorometer. 300ng of DNA was bisulfite converted using Zymo DNA Methylation Lightning kit.