Infants born to those who tested positive for COVID-19 during pregnancy may have neurodevelopmental issues after birth, according to new preliminary findings from two separate studies out of the U.S. and Spain.

The peer-reviewed U.S. study, published in the journal JAMA Network Open on June 9, looked at 7,772 infants delivered during the pandemic between March and September 2020 at six hospitals in Massachusetts, 222 of whom had prenatal exposure to SARS-CoV-2. Results showed that the latter group of infants were more likely to receive a neurodevelopmental diagnosis in the first year after birth.

Separately, a small Spanish study compared 21 cases where the parent tested positive during pregnancy and 21 babies who had no exposure during pregnancy at the Marqués de Valdecilla University Hospital in Santander, Spain. Analysis showed that infants who were exposed in utero demonstrated more motor skill difficulties six weeks after birth, findings that were presented at the 30th European Congress of Psychiatry in early June.

The two studies are the latest to look at infant neurodevelopment and prenatal exposure to maternal SARS-CoV-2 infection. Some previous research found an association between the two, while some studies have suggested that maternal stress during the pandemic could be a major contributing factor to these adverse neurodevelopmental changes.

Both new studies highlighted the preliminary nature of their findings and said that a larger study over a longer period of observation was needed to better understand the results.

U.S. STUDY

When comparing infants who were exposed during pregnancy with those who were not, researchers in the U.S. study found that a diagnosis involving motor function or speech and language, was “significantly more common” among babies who had been exposed, particularly if the exposure occurred during the third trimester.

“Our findings identifying an association between prenatal SARS-CoV-2 exposure and neurodevelopmental diagnoses at 12 months are consistent with a large body of literature including human and animal studies linking maternal viral infection and maternal immune activation with offspring neurodevelopmental disorders later in life, some of which can be foreshadowed as early as the first year of life,” the authors wrote in the study.

Researchers found that 14 of the 222 exposed babies, or 6.3 per cent, and 227 or the 7550 unexposed infants, or 3 per cent, received a diagnosis of some form of neurodevelopmental disorder, including those involving motor function, expressive language, and speech. The median time to diagnosis was also earlier among those who were exposed in utero – at 214 days – compared with 275 days among those who were not.

The results were notable even when accounting for preterm delivery, but because these children are still only two years old or younger, larger studies with a longer-follow-up period were necessary to confirm whether there is a definitive connection, researchers said.

The scientists also found that 14.4 per cent of those who tested positive during their pregnancy gave birth prematurely, or before 37 weeks, compared with 8.7 per cent of those who did not get infected. Previous studies elsewhere have also noted a higher risk of preterm birth among those who caught COVID-19 while pregnant.

“Notably, although we identified greater risk of preterm delivery among SARS-CoV-2 positive mothers as in prior studies, adjustment for preterm birth did not account for all of the observed increased risk of incurring a neurodevelopmental diagnosis,” according to the paper.

“Moreover, the magnitude of this association was only modestly diminished among infants delivered at 37 weeks or later.”

The study noted some limitations to its research, a key element being the short-time frame of the analysis.

“We cannot exclude the possibility that additional neurodevelopmental effects will become apparent later in life; indeed, the offspring analyzed here are younger than the age at which neurodevelopmental disorders such as autism are typically diagnosed,” the authors said.

“Conversely, there may be a form of ascertainment bias arising from greater concern for offspring of mothers who were ill during pregnancy—that is, parents may be more inclined to seek evaluation, or clinicians more inclined to diagnose or refer for evaluation.”

SPANISH STUDY

Newborns who had been exposed to the virus before birth had more difficulty relaxing and adapting their bodies when they were being held and cuddled, and also had greater difficulty controlling their head and shoulder movements compared to those who had no exposure, according to researchers behind the Spanish study. Like the U.S. paper, the differences were more notable if the infection occurred late in the pregnancy.

Hormonal and other biochemical analyses, movement responses, and other tests were conducted during and after pregnancy on the parent, while infant tests included measuring movements and behaviours according to the Neonatal Behavioral Assessment Scale (NBAS).

“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data shows that their risk is increased in comparison to those not exposed to COVID in the womb,” said Dr. Rosa Ayesa Arriola, a neuropsychologist and senior researcher at the Valdecilla Research Institute (IDIVAL) and the project lead for the study, in a statement.

Spanish researchers only presented data from the pregnancy and six-week postnatal assessment and said it was part of an ongoing project that will continue to monitor language and motor development.

“In babies who are so young there are several things we just can’t measure, such as language skills or cognition. We also need to be aware that this is a comparatively small sample, so we are repeating the work, and we will follow this up over a longer period,” said co-researcher Nerea San Martin Gonzalez in a statement.

PANDEMIC STRESS?

Dr. Torri Metz, with the University of Utah Health’s Department of Obstetrics and Gynecology, said that the preliminary data from the U.S. study were critically important, but noted that the results are from children who were exposed to the early and Alpha variants of COVID-19, as they are the only ones old enough to undergo some of the more rigorous neurodevelopmental assessments.

“Given that we are only 2 years into the pandemic, much of the effect of in utero exposure to maternal SARS-CoV-2 infection remains poorly understood,” said Metz, who was not involved with the study, in an editorial commentary in JAMA Network Open.

Previous studies have already suggested a link between severe infection and higher stillbirths and preterm birth risks. An earlier longitudinal cohort study from China involving 57 babies who had prenatal exposure to COVID-19 found deficits in the social-emotional area of neurodevelopment at three months of age. One study found that the Delta variant substantially damaged the placenta. Authors from another recent paper involving individuals exposed and unexposed to COVID-19 during pregnancy suggested that the developmental setbacks could be the result of being pregnant during the pandemic itself, rather than the exposure to the virus itself.

Meanwhile, a Canadian preprint study out of Alberta Children’s Hospital based on a large cross-Canada sample of pregnant individuals showed elevated prenatal maternal distress was associated with changes in the brain development of their babies.

“We wonder whether it is the virus itself or the societal changes and stresses of the pandemic that are adversely affecting childhood outcomes,” Metz said, adding that knowledge about the effects of other variants is still lacking.

“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. As a retrospective cohort study, [the U.S. study] …can only demonstrate associations, and causality cannot be determined.”