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Early life exposure to SARS-CoV-2 and offspring neurodevelopment: detecting a non-linear relationship requires a complex approach

Pediatric Research (2024)Cite this article

The spectrum of neurodevelopmental outcomes for children born during the COVID-19 pandemic with either antenatal exposure to maternal SARS-CoV-2 infection or early postnatal SARS-CoV-2 infection continues to be an area of uncertainty and of important ingoing investigations. Rebecca Jackson and colleagues conducted a systematic review to assess the impact of antenatal or neonatal exposure to SARS-CoV-2 on neurodevelopmental outcomes in infancy in both infants born preterm and those born at term.1 Studies conducted to date have varied in their findings on the effects to neurodevelopmental outcomes, but many of these studies are limited by not having a control group of non-exposed infants, only including infants born to mothers asymptomatic or with low symptom severity, or by not analyzing preterm and term infant outcomes separately.1 Preterm newborns may have greater vulnerability to adverse neurodevelopmental outcomes, and preterm birth can be the outcome of complicated pregnancies with viral infection; thus, it is commendable the effort of Jackson and colleagues to assess the effect of SARS-CoV-2 early life exposure taking into account the role of preterm birth. Despite multiple cohort studies being conducted over the last several years assessing infant outcomes following SARS-CoV-2 exposure, only five studies met the inclusion criteria for the systematic review since many did not include a contemporaneous non-exposed control group.1 Unfortunately, the authors did not include in their analysis well-powered samples where the effect of in utero exposure on risk for neurodevelopmental disorders was assessed using electronic health records, which can provide helpful information to understand outcomes.2

The systematic review by Jackson and colleagues found studies to be inconsistent in their findings and overall, in term-born infants a difference in neurodevelopment during infancy was not seen, and in preterm-born infants, too few were reported to have a meaningful conclusion.1 However, some of the reported effect sizes are not negligible, and the confidence intervals are consistent with the possibility of an important effect of antenatal exposure to SARS-CoV-2 on neurodevelopmental outcomes in a subset of infants. For example, among term-born infants the odds ratio (OR) associated with viral exposure is 2.90 for fine motor development, with 14.43 as the upper confidence interval.1 It is therefore desirable that similar studies should not base their conclusions only on a significance threshold and should include an analysis of the effect of the exposure on the variance of the outcome, to identify a subset of infants with a possible deleterious effect of the exposure. This systematic review indicates a need for additional studies of preterm and term infants and for longer term outcomes following antenatal or neonatal SARS-CoV-2 exposure. However, the findings by Jackson and colleagues, as any findings of impacts or lack of impact on infant neurodevelopment following early-in-life exposure to SARS-CoV-2 infection must be interpreted with caution.

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Funding

The authors have grant support by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (grant numbers R01HD107140 [PI: Ursini] and R01HD102445 [PI: Mulkey]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Prenatal Pediatrics Institute, Children’s National Hospital, Washington, DC, USA

    Sarah B. Mulkey

  2. Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Sarah B. Mulkey

  3. Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Sarah B. Mulkey

  4. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA

    Gianluca Ursini

  5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Gianluca Ursini

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  1. Sarah B. Mulkey
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Correspondence to Sarah B. Mulkey.

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Mulkey, S.B., Ursini, G. Early life exposure to SARS-CoV-2 and offspring neurodevelopment: detecting a non-linear relationship requires a complex approach. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03104-8

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