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Exploring Neurodevelopmental Effects on Infants From in-Utero Exposure to COVID-19

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At least 2% of the total global population have been infected with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) at some point during the current coronavirus disease 2019 (COVID-19) pandemic and more than 200 million infants were born since the onset of the pandemic. Millions of in-utero exposures to maternal SARS-CoV-2 infection are therefore likely.

Alterations in the intrauterine environment have been correlated to altered brain development and long-term offspring vulnerability for neurodevelopmental and psychiatric manifestations. Despite the lack of evidence of vertical transmission of SARS-CoV-2, past experience in human coronavirus outbreaks (SARS and Middle East respiratory syndrome) suggests severe infection during pregnancy may have implications in maternal health and a higher risk for several adverse infant outcomes.

Other viral illnesses during pregnancy are associated with a higher risk for neurodevelopmental deficits, for example – motor delays in the case of in-utero HIV-exposed uninfected infants. Early identification of at-risk children can be beneficial. Recently, increased interleukin (IL) 6 levels were detected in pregnant women with SARS-CoV-2 infection.

The Study

A new study published in JAMA Pediatrics aimed to determine the associations between fetal exposure to maternal SARS-CoV-2 infection, in-utero, and child neurodevelopmental status. The present study was based on the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with delays in social and motor development at six months of age, based on the established role of maternal immune activation on fetal brain development.

Here, infants born during the COVID-19 pandemic were compared to a historical cohort born at the same medical center, using the same neurodevelopmental assessment.

Analyses included infants enrolled in the COMBO initiative—a prospective cohort study that examined associations between in-utero exposure to maternal SARS-CoV-2 infection and the health and well-being of both mother and children—who were born between March and December 2020. Data of the historical cohort were extracted from records of the Well Baby Nursery at Morgan Stanley Children’s Hospital to examine the association between gestational diabetes, newborn neurophysiologic status and six-month neurodevelopment, and were born between 2017-2020.

Overall, 385 women from the COMBO Study were invited to participate in the 6-month assessment, of whom 70.6% completed the Ages & Stages Questionnaire, 3rd Edition (ASQ-3). The final sample included data from 255 infants in the pandemic cohort and 62 in the historical cohort.


The median age at delivery of the 255 women in the pandemic cohort was 32 years. The results showed that there were no significant group differences between exposed and unexposed infants on any of the 5 ASQ-3 subdomain scores (communication, gross-motor, fine-motor, problem-solving, or personal-social skills) at age six months.

It was noted that most mothers experienced asymptomatic or mild disease and were infected in their second or third trimester. While a small proportion had severe disease and 22% were infected in the first trimester. Neither symptom severity nor timing of infection elicited an association with any ASQ-3 subdomain score. Hence, an association between SARS-CoV-2 status, timing or severity, and ASQ-3 scores could not be detected in the primary analysis.

However, healthy term infants born during the pandemic exhibited significantly lower mean scores on the gross motor, fine-motor, and personal-social subdomains, when compared to the historical cohort.

Additionally, infants born to mothers who were in their first trimester of pregnancy during the peak of the pandemic showed a significant reduction in gross-motor, fine-motor, and personal-social scores than those from the historical cohort.

Of note, sensitivity analyses revealed a relatively greater association between neurodevelopment of infants and in-utero exposure to the pandemic compared to postnatal pandemic exposure. Furthermore, an early gestational phase during the pandemic peak correlated to the lowest gross-motor, fine-motor, and personal-social scores among the offspring, at age six months.

The findings may predict a significant public health crisis among the generation born during the COVID-19 pandemic. It was also stated that COVID-19-related stress – anxiety and depression, should be considered as a potential underlying mechanism precipitating the observed differences.

One major limitation of this study was that it was based on parent-reported measures. Therefore, it is possible that the results reflect the parental perception of infant neurodevelopment. Yet, parental perception of development impacts long-term child outcomes. Moreover, six months marks a relatively early stage of development, different developmental patterns are likely to emerge in these infants as they grow.

The findings of this analysis support the need for long-term monitoring of infants born during the COVID-19 pandemic, to mitigate substantial sequelae. Furthermore, an association was found between birth during the pandemic and infant neurodevelopmental status, regardless of the maternal SARS-CoV-2 status—which could precipitate from the maternal pandemic-related distress, and warrants future investigation.

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Schedule23 Sep 2023