Association of maternal adverse childhood experiences with inflammatory and growth factor pathway activity during pregnancy: a cross-sectional proteomics-based KEGG pathway analysis in the ECHO cohort.
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While maternal histories of adverse childhood experiences (ACEs) have been linked to altered immune signaling during pregnancy, the specific inflammatory pathways underlying these associations remain poorly characterized. We leveraged high-dimensional proteomics to examine associations between maternal ACEs and pregnancy-associated inflammatory signaling pathways defined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and tested whether these associations were moderated by neighborhood-level social vulnerability during pregnancy. Participants included pregnant individuals enrolled in the Environmental influences on Child Health Outcomes (ECHO) Cohort (N = 770). Circulating inflammatory proteins were assayed from maternal plasma using the Olink Target 96 Inflammation panel. Protein markers were mapped to Human Genome Organisation (HUGO) Gene Nomenclature Committee gene symbols and aggregated into KEGG pathway scores using curated definitions. Linear regression models evaluated associations between continuous maternal ACE scores and each pathway score. Following correction for multiple comparisons, higher maternal ACE exposure was associated with higher activity across 12 KEGG-annotated protein pathways, including AGE-RAGE, non-alcoholic fatty liver disease, chemokine, Th17 differentiation, HIF-1, cellular senescence, Rap1, NOD-like receptor signaling, transcriptional misregulation in cancer, and infection-related pathway signaling. Domain-specific analyses identified the most consistent associations for childhood household dysfunction. Neighborhood-level social vulnerability during pregnancy did not moderate ACE-inflammation associations but was independently associated with higher KSHV infection and NOD-like receptor signaling pathway scores. Together, these findings indicate that maternal ACEs and prenatal social vulnerability are independently associated with small, but directionally consistent, differences in overlapping inflammatory and growth-related protein signals during pregnancy.