Increased risk for autism spectrum disorder (ASD) associated with gestational fever, infections, stress and other inflammatory events and innate immune responses and dysregulation suggest the need to study the potential role of prenatal COVID-19 exposures and ASD and to understand underlying biological mechanisms in order to work towards early identification and prevention of risk.

Schmidt and colleagues propose to continue enrollment, data and sample collection, and specimen processing for MARBLES (Markers of Autism Risk in Babies: Learning Early Signs), the first and only actively recruiting epidemiologic cohort of younger siblings of children with ASD that enrolls during pregnancy. Her lab has a unique opportunity in MARBLES to prospectively study the critical prenatal period when ASD is likely to originate and when COVID-19 is likely to interact with inherited ASD risk to have developmental impacts. Early enrollment and regular prenatal specimen collection provides opportunities to examine timing of prenatal exposures, biologic responses and their associations with later neurodevelopmental outcomes. Not only are these younger siblings at 12-fold higher risk for ASD than children in the general population, but mothers and children with ASD show increased immune dysregulation and inflammation which could increase their susceptibility to the effects of the COVID-19 pandemic and SARS-CoV-2 in pregnancy. Prenatal stress also increases risk for ASD in the child, potentially through inflammatory processes, which could further compound susceptibility in these families whose parents already experience higher reported stress levels.

MARBLES recruits mothers who have a child with clinically confirmed ASD and are pregnant with another child in order to understand what influences the outcomes of the younger siblings, through what pathways, and to identify early markers of ASD. Participants are drawn from Northern California, where the overall SARS-CoV-2 infection rate for pregnant women in January 2021 was 7.4 percent and over 10 percent for Latinx and certain racial groups. Since 2006, MARBLES has enrolled 526 mother-child pairs, including 466 (89 percent) live-born children, of which 409 (88 percent) are still actively involved, demonstrating excellent retention in the study. Comprehensive data is prospectively collected on exposures and health. Over 25,000 prenatal, delivery and postnatal biospecimens have been collected and processed to date, including maternal blood, urine, vaginal swabs, hair, saliva, breast milk, placenta, cord blood, baby saliva, feces and meconium. Our specimen collection rates are above 95 percent for most, including blood and fecal samples.

MARBLES is currently funded by a cohort maintenance grant that supports half-pace recruitment until June 2021 and follow-up until the grant ends in October 2024; scientific aims (but not collection) are supported by a National Institutes of Health R01 grant investigating how gastrointestinal tract problems may relate to the fecal microbiome, exposures and ASD risk.

Schmidt and colleagues plan to leverage the existing infrastructure of the MARBLES cohort study and continue to prospectively collect data and biospecimens in this study and for a general population comparison group. The SFARI Director Award will help to avoid a recruitment and collection gap in valuable prospectively collected data and biologic specimens during the pandemic that will inform biologic responses to COVID-19 pandemic — the stress, virus and vaccines — on maternal immune dysregulation, neurodevelopment and ASD recurrence risk in this uniquely susceptible population.