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The risk of neurodevelopmental sequelae in fetuses exposed to SARS-CoV-2 is gender-specific

The authors from the United States investigated gender-specific differences in the risk of neurodevelopmental disorders in offspring exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in utero

Previous studies have identified sexually dimorphic effects of SARS-CoV-2 on the placental immune response, with significant up-regulation of type I, II, and III interferon signaling pathways in the placentas with male fetuses and down-regulation in the placentas with female fetuses. The lower levels of anti-SARS-CoV-2 antibodies were detected in mothers infected with SARS-CoV-2 with male fetuses compared to infected mothers with female fetuses.

In addition, a recent animal study that investigated the possibility of maternal-fetal transmission of SARS-CoV-2 and the effects of viral transmission on the developing fetal brain showed higher rates and levels of viral infection in male fetuses than in females.

These findings suggest that fetal gender may influence the maternal immune response to the virus and that male fetuses can be more vulnerable to SARS-CoV-2 infection.


About the study

The researchers analyzed the hospital’s electronic health records. They defined the primary outcome as any diagnosis of a neurodevelopmental disorder, based on the presence of at least one ICD10 code in the ‘developmental’ category. These codes included F8x, which refers to pervasive and specific developmental disorders, including developmental disorders of speech and language (F80), specific developmental disorders of scholastic skills (F81), specific developmental disorders of motor function (F82), pervasive developmental disorders (F84), other/unspecific disorder of psychological development (F88/89), and code F7x, which refers to intellectual disabilities.

The authors compared the pandemic cohort, born during the pandemic, regardless of their  SARS-CoV-2 exposure status, with two groups. The first group included all live births in 2018, before the pandemic, while the second group included all live births in 2019, taking into account that part of the follow-up period would take place during the pandemic.


The pandemic cohort included 18,323 live births, 877 of which were exposed to SARS-CoV-2 in utero. The mean maternal age was 33.0 years (30.0–36.0). 

Of the 877 offspring exposed to SARS-CoV-2 in utero, 3.0% (26 infants) were diagnosed with neurodevelopmental disorder during the first 12 months of their life. The adjusted regression models accounting for race, ethnicity, insurance status, hospital type, maternal age, and preterm status demonstrated that SARS-CoV-2 positivity was associated with significantly increased risk for diagnosis of a neurodevelopmental disorder only in male offspring.

At the 18-month follow-up, the results were available for 551 COVID-exposed and 13435 COVID-unexposed offspring, and they were consistent with results observed at the 12-month follow-up. Significantly increased risk for diagnosis of neurodevelopmental disorder was observed only in male offspring.


This study demonstrated that the risk of neurodevelopmental sequelae in fetuses exposed to maternal SARS-CoV-2 infection was gender-specific. At the 12-month and 18-month follow-up, an increased risk for neurodevelopmental disorders was found in male offspring, but not in female offspring exposed to maternal COVID-19 in utero

These results suggest that male fetuses may be more vulnerable to maternal SARS-CoV-2 infection, but, larger studies should more accurately assess and characterize this risk.


This study has been published on a preprint server and is currently being reviewed.

Journal Reference

Edlow AG, Castro VM, Shook LL. Sex-specific neurodevelopmental outcomes in offspring of mothers with SARS-CoV-2 in pregnancy: an electronic health records cohort.  medRxiv preprint




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