Maternal-infant immune signatures in infants at risk for SARS-CoV-2-associated neurodevelopmental disorders

Maternal immune activation during pregnancy has been associated with abnormal infant neurodevelopment. During the COVID-19 pandemic, we enrolled pregnant individuals with laboratory-confirmed SARS-CoV-2 infection into a cohort study conducted in Los Angeles, United States, and Rio de Janeiro, Brazil, and monitored their infants for neurodevelopmental outcomes. We reported a ten-fold higher rate of developmental delay in 172 SARS-CoV-2-exposed children (11.6%) compared to 128 pre-pandemic controls (1.6%) and a nearly 2-fold higher frequency of positive screens for autism spectrum disorder (ASD) in 218 SARS-CoV-2-exposed (10.1%) children as compared to 527 unexposed control children (5.7%) evaluated through standardized developmental tools. To identify potential biomarkers of SARS-CoV-2-associated risk of abnormal infant neurodevelopment, we evaluated the serum immunoprofiles of a subset of mother-infant dyads from this cohort. Serum proteomics profiling of 34 newborns (27 SARS-CoV-2-exposed and 7 controls) revealed 62 biomarkers dysregulated in SARS-CoV-2-exposed children at risk for neurodevelopmental disorders, including activation of nicotinamide biosynthesis, microglial cells, and neutrophil extravasation. Maternal serum profiling of 51 women (33 SARS-CoV-2-positive and 18 controls) identified 34 biomarkers associated with upregulated apoptosis signaling in COVID-19 affected pregnancies. Our findings suggest prenatal SARS-CoV-2 infection is potentially associated with dysregulation of maternal-infant peripheral immunity profiles reportedly associated with neurodevelopmental disorders. Serum proteomics revealed dysregulated biomarkers associated with neuronal inflammatory pathways in children with antenatal maternal SARS-CoV-2 exposure, providing potential mechanistic insight into the higher frequency of neurodevelopmental disorders.