Sex-specific neurodevelopmental outcomes in offspring of mothers with SARS-CoV-2 in pregnancy: an electronic health records cohort.

Importance: Prior studies using large registries suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific.

Objective: To determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared to unexposed offspring born during or prior to the pandemic period.

Design: Retrospective cohort.

Participants: Live offspring of all mothers who delivered between March 2018 and May 2021 at any of eight hospitals across two health systems in Massachusetts.

Exposure: PCR evidence of maternal SARS-CoV-2 infection during pregnancy.

Main Outcome And Measures: Electronic health record documentation of ICD-10 diagnostic codes corresponding to neurodevelopmental disorders.

Results: The pandemic cohort included 18,323 live births, including 877 (4.8%) to individuals with SARS-CoV-2 positivity during pregnancy. The cohort included 1806 (9.9%) Asian individuals, 1634 (8.9%) Black individuals, 1711 (9.3%) individuals of another race, and 12,694 (69%) White individuals; 2614 (14%) were of Hispanic ethnicity. Mean maternal age was 33.0 years (IQR 30.0-36.0). In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs. community), maternal age, and preterm status, SARS-CoV-2 positivity was associated with statistically significant elevation in risk for neurodevelopmental diagnoses among male offspring (adjusted OR 1.99, 95% CI 1.19-3.34; p=0.009) but not female offspring (adjusted OR 0.90, 95% CI 0.43-1.88; p=0.8). Similar effects were identified using matched analyses in lieu of regression.

Conclusion And Relevance: SARS-CoV-2 exposure in utero was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring in the 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

Trial Registration: NA.

Key Points: Are rates of neurodevelopmental disorder diagnoses greater among male or female children with COVID-19 exposure in utero compared to those with no such exposure? In a cohort of 18,323 infants delivered after February 2020, males but not females born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. These findings suggest that male offspring exposed to COVID-19 in utero may be at increased risk for neurodevelopmental disorders.