Maternal Inflammation during Pregnancy and Neurodevelopmental Disorders

Abstract: The SARS-CoV-2 novel coronavirus (COVID-19) pandemic has led to over 6.25 million confirmed cases and~375,000 deaths worldwide, yet very little is currently known about the prevalence of COVID-19 infectionduring pregnancy nor the impact of the pandemic on pregnant women and their unborn children. The goal ofthis competing revision application is to establish a new pregnancy cohort to investigate the impact ofthe COVID-19 pandemic on child neurodevelopment. Maternal inflammation during pregnancy can resultfrom immune dysregulation due to infections or stress. The COVID-19 pandemic may therefore result inincreased maternal inflammation during pregnancy. Several lines of evidence suggest that inflammation canhave deleterious effects on fetal neurodevelopment. Our overarching hypothesis is that maternal COVID-19 infection and/or pandemic-related stress during pregnancy will increase risk of neurodevelopmentaldisorders (NDD) in children via in utero exposure to heightened maternal inflammation duringpregnancy. Neonatal blood reflects the maternal gestational immune profile, and IgG antibodies and pro-inflammatory cytokines measured in newborn bloodspots reflect past/present maternal infection. Thus, wefurther hypothesize that neonatal levels of immune markers (antibodies, cytokines, chemokines) willreflect maternal COVID-19 exposures during pregnancy and correlate with NDD risk. We propose alongitudinal pregnancy cohort study of women who were members of KPNC and pregnant during the COVID-19 pandemic in 2020. Utilizing prospectively collected information recorded in the electronic health records ofthe large and diverse cohort of ~40,000 pregnant women and their children receiving care at KaiserPermanente Northern California (KPNC), patient reported data from ~20,000 women who complete the KPNCCOVID-19 pregnancy survey, and newborn bloodspots from babies born to COVID-19 positive women(N~550), we will investigate the impact of the COVID-19 pandemic on child neurodevelopment. We willcompare NDD diagnosed in the first 24 months of life between children born to women 1) with and withoutCOVID-19 infection during pregnancy, and 2) by varying levels of maternal stress during pregnancy. We willalso examine levels of neonatal immune markers (antibodies, cytokines, chemokines) in relation to maternalCOVID-19 infection status and NDD in the child. This large scale and comprehensive study provides a uniqueopportunity to examine, in real-time, the impact of the coronavirus pandemic on child neurodevelopment in thefirst years of life, and establishes a novel framework to continue exploring the relationships between maternaland neonatal immune dysregulation and a range of neurodevelopmental disorders as they emerge over time.Findings will contribute to the development of prenatal and newborn screening for adverse neurodevelopment,ultimately enabling earlier intervention and primary prevention.