Maternal SARS-CoV-2 infection, placenta biology, and neurodevelopmental outcomes in the offspring

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PROJECT SUMMARY The extent to which SARS-CoV-2 infection in pregnancy affects the biology of the maternal-placental-fetal triad and neurodevelopmental trajectory in offspring is not known. Early studies indicate that SARS-CoV-2 can induce alterations in the placenta which can increase risk for adverse perinatal outcomes and, based on knowledge from other infectious and inflammatory disorders in pregnancy and preliminary data on the current pandemic, increase risk for neurodevelopmental disorders (NDDs) in offspring. The long-term goal of this proposal is to timely identify the impact of the ongoing pandemic on the neurodevelopment (ND) of infants born following maternal SARS-CoV-2 infection. The objective is to analyze the relationships between maternal SARS-CoV-2 infection, placenta biology, and ND outcomes, in interaction with genomic risk (GRSs) for NDDs and sex. The central hypothesis is that maternal SARS-CoV-2 infection and infection-related pregnancy complications affect early paths of brain development, particularly in those with high GRSs for NDDs and in males, and that these effects are mediated by alterations in placenta morphology and molecular biology. The rationale underlying the proposal is that completion will define critical targets for identification and potentially prevention of NDDs in the offspring of infected mothers. The central hypothesis will be tested by pursuing the following specific aims: 1) Determine pregnancy, placental, and newborn outcomes following antenatal SARS-CoV-2 infection; 2) Investigate the relationship between SARS-CoV-2 maternal infection, GRSs for NDDs, and placenta molecular biology; 3) Evaluate the relationship between maternal SARS-CoV-2 infection in pregnancy, offspring genomic risk factors for NDDs, and ND outcomes. We will pursue the aims using an innovative combination of placenta tissue and maternal and fetal blood analysis, and comprehensive psychometric testing of early child ND. We will compare unvaccinated and vaccinated woman-placenta-infant triads exposed to SARS-CoV-2 infection during pregnancy to unvaccinated and vaccinated controls. We will study how, in a large sample of multiple ethnicities, maternal infection and stress, social determinants of health, GRSs for NDDs, and sex, adversely affect neurodevelopmental outcomes of the offspring though processes mediated by alteration in placenta gene/protein expression and maternal immune activation. The proposed research is significant, because it will characterize the relationship between maternal SARS-CoV-2 infection and neurodevelopmental outcome of the offspring, and also identify factors, molecules and genomic predictors that modulate, mediate or – as biomarkers – reveal such relationship. The proximate expected outcome of this work will be an understanding of the mechanisms through which maternal infection, genomic risk and sex, placenta biology, and postnatal factors may contribute to define risk for NDDs. The results will have an immediate positive impact to inform targeted interventions and guidelines for SARS-CoV-2 exposed women and their infants, impacting how clinicians evaluate and care for these cases, and to identify potential biomarkers of risk for NDDs in offspring of mothers with infection during pregnancy.