Study linking COVID in utero to increased risk of developmental delays spurs debate

A new study, which raised concerns that COVID during pregnancy might significantly increase the risk of developmental delays in a child's first year of life, is receiving both praise and criticism.

The research, conducted by a team at Massachusetts General Hospital, examined the electronic medical records of more than 7,500 patients at six hospitals. The resulting study found that, for children exposed to COVID in utero, the likelihood of a developmental delay — such as a speech or motor delay — within 12 months of birth was 80%-90% higher than for a child without a known exposure in utero.

The researchers cautioned that delays identified at such an early age can resolve as a child matures, or may be addressed with early interventions. Still, they said, the higher rate in the COVID group concerned them.

“This is something we have to pay attention to,” said Roy Perlis, co-author of the study published last week in JAMA Network Open and director of the Center for Quantitative Health at MGH.

There is a consensus in the medical community that COVID poses a particular risk to pregnant people. It has been shown to increase the chances of severe illness and the likelihood of preterm birth. However, any link between COVID during pregnancy and the health of the fetus is unknown — and much debated.

Critics questioned the study's findings and cautioned it could cause unnecessary stress during pregnancy, which is known to be bad for the fetus. 

The overall chance of developmental delay is low regardless of COVID. In the MGH study, 3% of children without a known in utero exposure exhibited a developmental issue compared to 6% of children exposed to COVID in utero.

The Findings

When the MGH team noticed a possible link appearing in the data between exposure to COVID in pregnancy and later developmental delays in infants, they buckled down to make sure they hadn't made a mistake.

“My thought was, we need to really work hard to see if there's a way we can make it go away," Perlis said. "Slicing and dicing the data, going through our code, making sure there's not some reason we would have a false positive effect.”

Yet, the association remained even after researchers accounted for a host of other factors including maternal age, race and ethnicity, and type of insurance (which is seen as a proxy for income). The team also found the risk was above and beyond anything associated with preterm birth, which can also increase the likelihood of developmental delays. All of the medical records reviewed for the study came from Massachusetts hospitals.

"The good news is, in all other respects, the offspring looked extremely normal," Perlis said. "We're not seeing lung signals. We're not seeing cardiac signals. We're not seeing anything else in the offspring that we might worry about."

Many of the delays that were seen in the study were nonspecific, as is common at such a young age. For example, Perlis said, a pediatrician might notice a kid is "not reaching at the age we would expect them to reach, or not babbling at the age where we would expect them to babble."

And, he emphasized, delays may not have long-term consequences.

"In many cases, these are diagnoses that resolve with age. So it may well be that, when we go back and look at these children after 18 months or two years, they've caught up," he said. "But we wanted to establish a method for studying this group so that if there are problems later on, we will be able to detect them as early as possible."

Researchers Have Mixed Views of the Results

This new research should be taken “with a very large grain of salt and a lot of caution,” said Dani Dumitriu, a professor of pediatrics and psychiatry at Columbia University Irving Medical Center who was not involved in the study.

The delays found in the study, she said, could be due at least in part to the likelihood that children exposed to COVID in utero received extra close monitoring from parents and pediatricians after birth. According to Perlis, however, those children were no more likely than other children in the study to be diagnosed with other health issues.

“I'm very worried about having a paper like this unnecessarily stressing out moms.”

Dani Dumitriu, Columbia University Irving Medical Center

Dumitriu questioned the study's methodology, including what she said was a surprisingly low rate of patients testing positive for COVID.

Earlier this year, Dumitriu published a smaller study in JAMA Pediatrics finding no link between COVID exposure in utero and developmental delays at six months. The study was based on a parent questionnaire. Instead, the study found stress — broadly defined as giving birth during a global pandemic — was a significant concern during pregnancy and linked to a higher risk of developmental delays in all children compared to what was seen pre-pandemic.

“I'm very worried about having a paper like this unnecessarily stressing out moms,” Dumitriu said of the new research from the MGH team. “Then that will increase adverse neurodevelopmental risk because now they're worried.”

Another limitation of the study, it's authors acknowledge, is that it lacks data on several important questions including whether vaccination status has an impact, whether the trimester of infection matters, or whether the severity of the parent’s infection is linked to a higher risk in their offspring.

Perlis explained that the data was drawn from a sample of people who caught COVID very early in the pandemic — and often in their third trimester — because the researchers wanted to make sure the children were at least a year old before they started their analysis.

He said his team plans to expand the study and follow these children on a long-term basis. He hopes to have more answers about the impact of vaccination status and severity of illness in the next six months.

Some in the field have welcomed the research and defended the new findings.

“It’s a really well-done study,” said Benjamin al-Haddad, a neonatology fellow at the University of Washington, who did not work on the study.

A few years ago, he published a very large study in JAMA Psychiatry linking serious infections while pregnant — including urinary tract infections, pneumonia and influenza — to a higher risk of long-term psychiatric conditions in children. In particular, that study found an increased risk of autism and depression. These conditions take years and sometimes decades to diagnose, but al-Haddad said the new findings about COVID align with his and others' research.

“I don't think the results were surprising,” he said.

Why Infection May Affect Fetal Development

Scientists are still working to explain what is happening inside the fetal brain during an infection, but al-Haddad theorizes that later neurological issues may result from the inflammation an infection can trigger.

He said one theory is that inflammation adversely affects cells that support neurons in the brain. Another area of research looks at whether inflammation changes the location and number of neurotransmitters, such as serotonin receptors.

Al-Haddad said the chances of a long-term diagnosis after an infection in utero are small for any individual.

“Even though we see this at a population level — and that's scary — for an individual person who is pregnant, their risk is actually pretty small,” he said. "That's the reassuring part."