COVID-19 Exposure in Utero Linked to Neurodevelopmental Disorders in (Male) Offspring

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There are myriad studies suggesting maternal infection or immune activation during pregnancy increases the risk of neurodevelopmental disorders in offspring. Even animal studies have demonstrated viral and bacterial infection during pregnancy, and noninfectious maternal immune activation, are associated with various neurodevelopmental morbidities in neonates.

The COVID-19 pandemic presents a critical public health need to understand whether COVID-19—exposed offspring have an increased risk of neurodevelopmental diagnoses. A new original investigation, published this week in JAMA Network Open, sought to determine whether maternal COVID-19 infection iNeurodevelopmental Disorderss associated with sex-specific risk for neurodevelopmental disorders in infants up to 18 months after birth.

The retrospective cohort study included the live offspring of all mothers who delivered in 1 of 8 Eastern Massachusetts hospitals between January 1-December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1-December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020-May 31, 2021 (born before and followed up during the COVID-19 pandemic.

For all 3 cohorts, the investigators linked offspring to their pregnant parent by medical record number, date and time of birth, and offspring sex. They utilized electronic health records to determine maternal age, self-reported sex, race, and ethnicity, insurance type, medical history, and COVID-19 vaccination status.

The primary study outcome was the diagnosis of a neurodevelopmental disorder within 12 months of birth, or within 18 months of birth for secondary analysis. Diagnoses included pervasive and specific developmental disorders, developmental disorders of speech and language, specific developmental disorders of scholastic skills, specific developmental disorder of motor function, pervasive developmental disorders, other and unspecific disorder of psychological development, and intellectual disabilities.

A total of 18355 infants were included in the COVID-19 pandemic cohort, including 4.8% (n = 883) exposed to COVID-19 via maternal infection during pregnancy. This cohort was 51.2% male, and 69.3% White, 9.9% Asian, 8.9% Black, and 9.3% American Indian, Alaska Native, Native Hawaiian or other Pacific Islander, or more than 1 race.

Mothers with COVID-19 positivity during pregnancy were more likely to be Hispanic, Black, and to have public insurance, and their offspring were more likely to be delivered preterm.

In regression models accounting for race, ethnicity, insurance status, hospital type, maternal age, and preterm status, maternal COVID-19 positivity was associated with a statistically significant increase in risk for neurodevelopmental diagnoses at 12 months among male, but not female, offspring.

Of the 883 COVID-19—exposed offspring, 2.9% (n = 26) received a neurodevelopmental diagnosis during their first 12 months of life. This is in comparison to a 1.8% rate of neurodevelopmental diagnoses among the offspring who were not exposed to COVID-19.

After 18 months, the risk of neurodevelopmental diagnoses in male offspring was less robust. Matched analyses found similar results.

After using 2 complementary approaches to address potential cofounding variables, the investigators concluded there was a statistically significant increase in risk of neurodevelopmental disorders among male but not female offspring. “Our finding that neurodevelopment in male offspring may be more adversely impacted than in female offspring in the setting of maternal SARS-CoV-2 infection is biologically plausible and consistent with prior studies that have demonstrated sex-specific impact of maternal types I, II, and III interferon signaling on the developing placenta and fetal brain,” the study authors wrote.