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 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 neurodevelopmental 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 neurodevelopmental 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 neurodevelopment. We will compare 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, 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.
