Neonates exposed to SARS-CoV-2 in utero at higher risk of respiratory distress, study finds

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In a recently published study, Dr Nature communication, Researchers are investigating the risk of respiratory distress (RD) in neonates born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: SARS-CoV-2 followed up on COVID outcomes in uninfected newborn mother-infant pairs (COMP) study due to respiratory distress.  Image credit: Gorodenkoff / Study: Respiratory distress in uninfected neonates exposed to SARS-CoV-2 in the Mother-Infant Pairs (COMP) study. Image credit: Gorodenkoff/

How are infants affected by maternal SARS-CoV-2 infection?

SARS-CoV-2 infection during pregnancy can cause serious maternal and neonatal complications, including stillbirth, prematurity, and serious maternal health problems. Low rates of mother-to-child transmission have been reported; However, concerns remain about long-term effects on newborns.

Notably, RD has been observed in uninfected and SARS-CoV-2-exposed full-term neonates. Previous explanations have focused on maternal health problems leading to preterm birth, a known RD risk factor. However, new insights suggest that prenatal exposure may trigger an inflammatory response in the newborn’s airways, as indicated by specific proteins found in affected infants.

The role of maternal coronavirus disease 2019 (COVID-19) vaccination in preventing post-RD exposure of newborns is clear. Thus, additional research is needed to elucidate the mechanisms by which prenatal SARS-CoV-2 exposure leads to RD in neonates and explore potential preventive strategies.

About the study

In the current study, participants aged 16 years or older were recruited from the Department of Obstetrics at the University of California, Los Angeles (UCLA) between April 15, 2020, and August 31, 2022. This period was screened for SARS-CoV-2.

The study included 221 pregnant individuals and 227 exposed fetuses, resulting in 199 live births. These mother-infant pairs were observed until they were six months old. Informed consent was obtained from all participants or surrogate decision makers in case of disability.

Researchers measured neonatal RD using criteria such as respiratory rate and cyanosis, with infants classified as premature if born before 37 weeks. Self-reported race and ethnicity as well as maternal COVID-19 severity and vaccination status were assessed.

Statistical analyzes compared the population of children with and without RD, including maternal and child characteristics and pregnancy complications. Logistic regression analyzes identified maternal vaccination and prematurity as key predictors of RD, with a post hoc analysis assessing the effect of vaccination on perinatal outcomes.

In addition to statistical analysis, the researchers performed proteomic profiling to explore associations between RD and SARS-CoV-2 in a subset of children. It involved analyzing blood samples from 52 infants, comparing 45 SARS-CoV-2 exposed uninfected (SEU) infants with seven control infants born to unexposed healthy mothers. SEU infants were clustered for this analysis based on RD outcome and gestational age.

Study results

About 50% of study participants identified as black or Hispanic, followed by 24% as Asian, mixed-race, or other, and 25% as white. About 13% of study participants experienced severe or severe COVID-19, with a higher incidence reported among unvaccinated mothers.

The largest number of COVID-19 cases in the cohort occurred in the winter of 2020, followed by smaller peaks coinciding with the emergence of delta and omicron SARS-CoV-2 variants. Most mothers were vaccinated before the alpha variant became prevalent, leading to significant differences in maternal vaccination status across different viral variants. Notably, none of the infants tested positive for SARS-CoV-2 at birth; However, 17% were diagnosed with RD.

Among 34 infants with RD, the most common diagnoses after discharge from neonatal intensive care were respiratory distress syndrome (RDS), transient tachypnea of ​​the newborn, and other infections in 47%, 16%, and 16%, respectively. Although many babies were considered early preterm, because they were born at less than 34 weeks of gestation, most were late term or term. The mean time to RD resolution was approximately 24 days, with duration varying by gestational age.

Physical examination findings were nonspecific and included signs such as subcostal or intercostal retraction, abnormal breathing, or grunting. Chest X-ray findings usually show opacities, such as interstitial opacities and ground glass opacities; However, 8% were described as normal.

Unadjusted logistic regression models identified associations between neonatal RD with maternal disease severity, prematurity, and absence of maternal COVID-19 vaccination. In the proteomic pathway analysis, 52 children born in the first epidemic year were studied.

In SEU children with RD, elevated levels of various cytokines and proteins were observed, thus indicating an upregulated NACHT, leucine-rich repeat (LRR), and pyrene domain (PYD)-containing protein 3 (NLRP3) inflammasome-mediated pathways. These include elevated levels of certain cytokines such as interleukin 18 (IL-18), caspase 1 (CASP1), and interleukin 1 β (IL-1β).

Significant upregulation in biological processes related to inflammation, chemotactic response and IL-8 production was observed in preterm infants with RD. Functional network analysis suggested a predominantly T helper type 2 cell (Th2)-skewed response, associated with high immunoglobulin E (IgE) production leading to a potential hyperimmune response.

Journal Reference:

  • Mann, OM, Azamor, T., Cambou, MC etc (2024). Respiratory distress in uninfected neonates exposed to SARS-CoV-2 in the Mother-Infant Pairs (COMP) study. Nature communication. doi:10.1038/s41467-023-44549-5

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