New insights into early brain development following in-utero COVID-19 exposure

Researchers studying prenatal exposure to SARS-CoV-2 found that it was linked to measurable differences in newborn brain structure and, by age two, lower cognitive scores and higher internalizing behaviors.

Led by the Developing Brain Institute at Children’s National Hospital, a new study in Brain, Behavior, and Immunity followed mother-baby pairs in the Washington, D.C., region and compared infants exposed to SARS-CoV-2 during pregnancy (2020–2022) with a normative pre-pandemic cohort (2016–2019). Researchers used newborn brain MRI scans and standardized toddler developmental assessments to better understand what in-utero exposure may mean as children grow.

The big picture

During past viral outbreaks, prenatal infections have been linked with later neurodevelopmental and mental health risks. The COVID-19 pandemic raised similar concerns, but the longer-term effects of in-utero exposure are still coming into focus.

In this study, researchers prospectively enrolled 142 mother baby pairs: 103 from a pre-pandemic cohort and 39 with confirmed maternal SARS-CoV-2 infection during pregnancy. Infants underwent quantitative brain MRI scans at about two weeks old during natural sleep and without sedation. When children were about 2 years old, they were assessed by trained pediatric developmental psychologists using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), alongside parent-reported social-emotional and behavioral measures using the Infant-Toddler Social and Emotional Assessment (ITSEA).

The newborn MRI findings showed that prenatal SARS-CoV-2 exposure was associated with differences in regional brain volumes, including cortical gray matter, subcortical gray matter, cerebral white matter and the left hippocampus, compared to infants from healthy pregnancies.

“At the newborn stage, we’re seeing differences in how specific brain regions are developing after in-utero exposure,” said Nickie Andescavage, MD, neonatologist at Children’s National and a senior author on the study. “Brain imaging allows us to detect these changes very early, before behavioral differences are visible.”

Two-year follow-up

At age two, toddlers exposed to SARS-CoV-2 in utero scored lower on cognitive measures and social-emotional measures compared with children in the pre-pandemic cohort. They also had higher scores on the internalizing domain of the ITSEA, a reflection of early anxiety symptoms.

The research team used mediation analyses to explore how early brain differences might relate to later outcomes. Their results suggest that differences in newborn cortical gray matter volumes statistically accounted for part of the association between prenatal exposure and lower toddler cognitive scores. In turn, lower cognitive scores statistically mediated part of the association between prenatal exposure and higher internalizing behaviors.

“Our goal was not just to identify differences, but to understand how early brain development after SARS-CoV-2 exposure might relate to later learning and behavioral outcomes,” said Susan Weiner, PhD, lead author of the study and a researcher at Children’s National. “These findings suggest that early changes in brain structure may help explain why we see differences in cognition and emotional development at toddler age.”

Why this matters for families and clinicians

For families, one of the hardest parts of the pandemic has been uncertainty about what it might mean for children born during that period. Most children exposed to SARS-CoV-2 in utero will not have severe developmental problems, and this study does not suggest outcomes are predetermined. But it does add to growing evidence that prenatal exposure may be associated with subtle differences that can be detected early.

The findings reinforce the importance of routine developmental screening and follow-up, especially for children born during the COVID era. Pediatric developmental surveillance is already a standard part of well-child care, and early identification of concerns can connect families with supportive services when they are most effective.

“The most important message is not alarm,” Andescavage said. “It’s awareness and follow-up. Early monitoring helps ensure children get support if and when they need it.”

What’s next

The authors note several limitations. The exposed cohort was relatively small, and the study population had high overall education levels, which may limit how broadly the findings apply across populations. The study also compared a pandemic cohort to a pre-pandemic cohort, making it difficult to fully separate the effects of viral exposure from broader pandemic-related stressors, even though maternal stress and anxiety were assessed.

Larger and more diverse longitudinal studies are now needed to determine whether these early differences persist, change or diminish as children reach school age and to identify factors that may protect or promote healthy development.

For now, the takeaway is practical and actionable: Children born during the COVID era, including those exposed to SARS-CoV-2 in utero, benefit from consistent developmental screening, and families should feel empowered to raise concerns early.

Read the full open access study, “The COVID generation: the neurodevelopmental consequences of in-utero COVID-19 exposure,” in Brain, Behavior, and Immunity. Additional authors from Children’s National include Yao Wu, PhD,  Jacob Jenhao Cheng, PhD, Melissa O’Connell Ligget, PhD, Cassianna McCants, PsyD, Esther Adegbulugbe, MS, Anna Mears, Diedtra Henderson and Catherine Limperopoulos, PhD.