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Clinical Context

During key developmental windows, maternal and placental inflammation and altered cytokine expression, as could be triggered by maternal COVID-19, may affect the developing fetal brain. Epidemiologic studies have shown that maternal infection in pregnancy is associated with adverse neurodevelopmental outcomes.

Some adults and children have neuropsychiatric symptoms and region-specific changes in brain morphology after COVID-19 persisting up to a year after acute illness. COVID-19 may be associated with preterm delivery and other birth complications, with greater infection severity linked to greater preterm risk.

Study Synopsis and Perspective

Infants exposed to SARS-CoV-2 in utero are at increased risk for neurodevelopmental disorders in the first year of life, new research suggests, but whether it is exposure to the pandemic or maternal exposure to the virus itself that may harm early childhood neurodevelopment is unclear, cautioned investigators, led by Roy Perlis, MD, MSc, with Massachusetts General Hospital, Boston, Massachusetts.

"In this analysis of 222 offspring of mothers infected with SARS-CoV-2, compared with the offspring of 7550 mothers in the control group (not infected) delivered during the same period, we observed neurodevelopmental diagnoses to be significantly more common among exposed offspring, particularly those exposed to third-trimester maternal infection," they wrote.

The study was published June 1 in JAMA Network Open.

The study included 7772 mostly singleton live births across 6 hospitals in Massachusetts between March and September 2020, including 222 (2.9%) births to mothers with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) testing during pregnancy.

In all, 14 of 222 children born to SARS-CoV-2--infected mothers (6.3%) were diagnosed with a neurodevelopmental disorder in the first year of life vs 227 of 7550 unexposed offspring (3%) (unadjusted odds ratio [OR] 2.17 [95% CI: 1.24, 3.79]; P = .006).

In models adjusted for preterm delivery, as well as race, ethnicity, insurance status, child sex, and maternal age, COVID-exposed offspring were significantly more likely to receive a neurodevelopmental diagnosis in the first year of life (adjusted odds ratio [aOR 1.86 [95% CI: 1.03, 3.36]; P = .04).

The magnitude of the association with neurodevelopmental disorders was greater with third-trimester SARS-CoV-2 infection (aOR 2.34 [95% CI: 1.23, 4.44]; P = .01).

The majority of these diagnoses reflected developmental disorders of motor function or speech and language.

The researchers noted the finding of an association between prenatal SARS-CoV-2 exposure and neurodevelopmental diagnoses at 12 months are in line with a "large body of literature" linking maternal viral infection and maternal immune activation with offspring neurodevelopmental disorders later in life.

They cautioned, however, that whether a definitive connection exists between prenatal SARS-CoV-2 exposure and adverse neurodevelopment in offspring is not yet known, in part because children born to women infected in the first wave of the pandemic have not reached their second birthday: a time when neurodevelopment disorders such as autism are typically diagnosed.

There is also the risk for ascertainment bias arising from greater concern for offspring of infected mothers who were ill during pregnancy. These parents may be more inclined to seek evaluation, and clinicians may be more inclined to diagnose or refer for evaluation, the researchers noted.

Nonetheless, as reported by Medscape Medical News, the study results support those of research released at the European Psychiatric Association (EPA) 2022 Congress^[2]; those results also showed an association between maternal SARS-CoV-2 infection and impaired neurodevelopment in 6-week-old infants.

In an accompanying commentary,^[3] Torri D. Metz, MD, MS, with University of Utah Health, Salt Lake City, Utah, said the preliminary findings of Perlis and colleagues are "critically important, yet many questions remain.

"Essentially all of what we know now about the effects of in utero exposure to maternal SARS-CoV-2 infection is from children who were exposed to the early and Alpha variants of SARS-CoV-2, as those are the only children now old enough to undergo rigorous neurodevelopmental assessments," Metz pointed out.

Ultimately, Metz said it is not surprising that the pandemic and in utero exposure to maternal SARS-CoV-2 infection may adversely affect neurodevelopmental outcomes in young children.

Yet, as a retrospective cohort study, the study can only demonstrate associations, not causality.

"This type of work is intended to be hypothesis-generating, and that goal has been accomplished as these preliminary findings generate numerous additional research questions to explore," Metz wrote.

Among them: Are there genetic predispositions to adverse outcomes? Will we observe differential effects by SARS-CoV-2 variant, by severity of infection, and by trimester of infection? Is it the virus itself or all of the societal changes that occurred during this period, including differences in how those changes were experienced among those with and without SARS-CoV-2?

"Perhaps the most important question is how do we intervene to help mitigate the adverse effects of the pandemic on young children," Metz noted.

"Prospective studies to validate these findings, tease out some of the nuance, and identify those at highest risk will help health care practitioners appropriately dedicate resources to improve outcomes as we follow the life course of this generation of children born during the COVID-19 pandemic," she added.

The study was supported by the National Institute of Mental Health and the National Institute of Child Health and Human Development. Metz reported receiving personal fees and grants from Pfizer Inc. and grants from GestVision.

Clinical Implications

• Maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring, even after accounting for preterm delivery.
• The preliminary findings need confirmation in larger, prospective, adequately powered studies with longer follow-up.
• Implications for the Healthcare Team: While further studies are needed, members of the healthcare team should continue to provide education on evidence-based mitigation strategies as COVID-19 may be associated with preterm delivery and other birth complications.

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