In Utero Exposure to Maternal COVID-19 Has No Association With Abnormal Neurodevelopment

Exposure to maternal COVID-19 in utero is not associated with impaired neurodevelopment of offspring up to age 24 months, according to results of a recent trial published in the Journal of the American Medical Association.¹

The results of this trial should provide reassurance to expecting mothers who get infected with SARS-CoV-2, the virus that causes COVID-19, during their pregnancy that their child will not experience abnormal neurodevelopment. However, the evidence does suggest sensitivity of the developing brain of a fetus to maternal immune activation; further research in this regard will be necessary.¹

Maternal infection with COVID-19 is associated with a significant inflammatory response. Oftentimes, this immune response is persistent, regardless of severity of disease. Furthermore, maternal COVID-19 infection can raise the risk of having poor birth outcomes, including low birth rate, smaller babies, and stillbirth. The association between maternal infection and neurodevelopment outcomes in their offspring is undetermined, with studies garnering mixed results, though most have found no association.^2,3

In this trial, the investigators aimed to investigate whether in utero exposure to maternal COVID-19 was indeed associated with abnormal neurodevelopmental screening results. The investigators utilized the Ages & Stages Questionnaires Third Edition (ASQ-3) to screen children up to 24 months old in a large prospective cohort on their neurodevelopment. An abnormal score in the screening was defined as scoring below the predefined threshold on any of 5 domains: communication, problem-solving, gross motor, fine motor, and social skills.¹

A total of 2003 pregnant individuals who enrolled prior to 10 weeks’ gestation and completed study activities were included in the trial. Of these, 217 (10.8%) participants experienced a SARS-CoV-2 infection during pregnancy; over half of these infections occurred during the first trimester of pregnancy. Importantly, most infections (189 [87.1%]) were primary infections in unvaccinated individuals.¹

Among children at age 12 months (1757), 64 of 198 (32.3%) of those exposed had abnormal ASQ-3 scores, compared with 458 of 1559 (29.4%) of those unexposed. For children at age 18 months (1522), 36 of 161 (22.4%) among those exposed had abnormal scores, while 279 of 1361 (20.5%) among unexposed children had abnormal scores. Lastly, among children at age 24 months (1523), 29 of 151 (19.2%) of exposed children had abnormal scores, compared with 230 of 1372 (16.8%) for those unexposed.¹

Overall, after adjusting for confounders, the estimated percentage of children with abnormal neurodevelopment remained similar by exposure status, with no association between infection and abnormal ASQ-3 scores at age 12 months, 18 months, or 24 months. These conclusions were not impacted by the addition of preterm delivery and infant sex in the association analysis.¹

The investigators also determined whether the risk to offspring differed based on whether the infection occurred without prior vaccination vs as a breakthrough infection following vaccination. Based on positive evidence indicating the benefits for newborns of COVID-19 vaccinated mothers, it could be assumed that vaccination would reduce the risk of abnormal neurodevelopment in exposed individuals. Interestingly, these findings were null, with no increased risk with or without prior vaccination.^1,4

Some strengths and limitations of the trial were discussed. Strengths included the prospective nature of the trial, the surveillance screening for asymptomatic infection that patients underwent, and the long duration of childhood follow-up. Limitations included the volunteer recruitment of participants in the trial, the imperfect completion of study activities, and the cohort size, which had relatively limited infections.¹

“Ongoing, long-term studies across diverse cohorts are necessary to clarify the full spectrum of sequelae that may have resulted from the COVID-19 pandemic,” the investigators concluded.¹

REFERENCES

1. Jaswa EG, Huddleston HG, Lindquist KJ, et al. In utero exposure to maternal COVID-19 and offspring neurodevelopment through age 24 months. JAMA Netw Open. 2024;7(10):e2439792

2. Shook LL, Fourman LT, Edlow AG, et al. Immune responses to SARS-CoV-2 in pregnancy: implications for the health of the next generation. J Immunol. 2022;209(8):1465-1473. doi:10.4049/jimmunol.2200414

3. Gallagher A. Maternal COVID-19 infection raises risks of low birth weight, preterm birth, and stillbirth. Pharmacy Times. Published January 18, 2022. Accessed October 29, 2024. https://www.pharmacytimes.com/view/maternal-covid-19-infection-raises-risks-of-low-birth-weight-preterm-birth-and-stillbirth

4. Ferruggia K. Researchers find benefits for newborns of COVID-19-vaccinated mothers. Pharmacy Times. Published February 9, 2024. Accessed October 29, 2024. https://www.pharmacytimes.com/view/researchers-find-benefits-for-newborns-of-covid-19-vaccinated-mothers