Title:
On Potential Association of COVID-19 Infection During Pregnancy and Epigenetic Regulation of Metabolic Pathways in Newborns

Authors:
Nezarat F, Ghajar S, Khademioureh S, Pyne S*, Dinu I*, Canada

Abstract:

Background: The COVID-19 pandemic has highlighted the increased susceptibility of pregnant women to SARS-CoV-2 infection and its short-term consequences for maternal and neonatal health, while the longer-term implications for children remain unclear. Evidence from fetal programming and epigenetic research suggests that inflammatory exposures in utero, including maternal infection, may lead to enduring changes in gene regulation that could influence metabolic and immune health later in life.

Methods: We analyzed publicly available bulk and single-cell RNA sequencing (RNA-seq) datasets from cord blood of full-term neonates with and without in utero exposure to maternal SARS-CoV-2 infection. Gene expression data were normalized and examined using a pathway-focused gene set analysis approach. Applying the Linear Combination Test to curated KEGG and Reactome gene set catalogs, we aim to identify cell-type–specific epigenetic effects and potential alterations in metabolic pathways.

Results: Bulk RNA-seq analysis revealed alterations in innate immune–related gene expression in neonates exposed to maternal COVID-19, with univariate LCT identifying multiple KEGG pathways associated with innate immunity, immune regulation, and antiviral responses. Then, multivariate LCT identified eleven pathways consistently linked to these phenotypes. Complementary single-cell RNA-seq data analyses showed cell-type–specific differential expression of genes involved in epigenetic regulation, with marked heterogeneity observed across cell populations. Pathway-level comparisons restricted to epigenetically altered cell types further identified both unique and broadly shared KEGG pathways across cell populations.

Conclusion: Together, these findings indicate that maternal SARS-CoV-2 infection during pregnancy is associated with epigenetically mediated alterations in neonatal immune and metabolic pathways that may have lasting consequences for offspring health. By linking cell-type–specific epigenetic regulation to pathways implicated in metabolic disease, this study underscores the importance of long-term follow-up and highlights potential molecular targets for early risk stratification.

DOI: http://dx.doi.org/10.51505/ijmshr.2026.10108