Study Finds Sex-Specific Neurodevelopmental Differences in Children Born to Mothers with Covid-19 During Pregnancy

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As per numerous epidemiological studies using large-scale administrative or health registry data sets, maternal infection or immune activation during pregnancy has been linked to various neurodevelopmental disorders in offspring. Early studies on birth dates relative to influenza pandemics identified an association between pregnancy During influenza exposure and schizophrenia hospitalization in offspring.

More recent investigations directly examined the association between offspring neurodevelopmental risk and maternal infection outside pandemic periods. They found an increased risk for autism spectrum disorder and major depression following maternal infection.   

According to a JAMA Network, with the COVID-19 pandemic, there is a crucial need to understand the extent to which maternal exposure to SARS-CoV-2 may have similar effects on offspring as seen in prior studies of infection during pregnancy.

Recent studies have suggested sex-specific responses to SARS-CoV-2 infection, with upregulation of placental interferon signaling and reduced maternal anti–SARS-CoV-2 antibodies among male compared with female offspring. Direct investigations of neurodevelopmental diagnoses among SARS-CoV-2–exposed offspring have begun to emerge, but limited sample sizes and short follow-up periods have made it challenging to interpret the results.  

Electronic health record (EHR)–based studies can provide a way to rapidly assemble larger cohorts to address the urgent need for information about potential neurodevelopmental consequences of maternal SARS-CoV-2 infection. In a previous study, the authors reported preliminary evidence of an association between in-utero exposure to SARS-CoV-2 and a delay in motor and speech milestones in children at one year of age based on EHR data.

In this study, the authors sought to examine this risk in a cohort four times larger to address two questions that could not be explored in the prior study: are there sex-specific differences in risk, and was pregnancy during the pandemic, compared with before, associated with neurodevelopmental risk independent of SARS-CoV-2 exposure? As in prior work, the authors also extended follow-up for a subset of this cohort to estimate whether neurodevelopmental effects were evident by 18 months rather than 12 months.  

A study involving a cohort of 18,355 infants born during the COVID-19 pandemic identified a statistically significant increase in the risk of neurodevelopmental disorders among male offspring. The study used two complementary approaches to minimize the potential confounding variables, and the effects were not attributable to preterm delivery, which was significantly more common among SARS-CoV-2-exposed offspring.

The cohort was restricted to offspring with 12-month follow-up visits within their hospital system, which yielded results of similar magnitude, indicating that the results were less likely to be a consequence of differential follow-up among exposed offspring. The study observed a similar pattern in a smaller subset of offspring for whom 18 months had elapsed since birth, but the 95% CI for this association included 1.00. The results suggest the importance of assembling larger cohorts to determine whether the increased risk noted at 12 months persists.  

The findings are consistent with abundant evidence that the developing male brain is more vulnerable to in-utero environmental effects. The study also detected a modest increase in the risk for neurodevelopmental diagnosis, similar among male and female offspring, associated with pandemic-era deliveries compared to 2018 and 2019.

The increased odds of any neurodevelopmental diagnosis at 12 months in pandemic-born children was statistically significant in a pooled analysis of both sexes compared to the pre-pandemic 2019 cohort. The results suggest that any secular trends reflecting birth during the pandemic are likely to have a more modest impact on observed neurodevelopmental risk in offspring than maternal SARS-CoV-2 infection itself. 




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