Just over four years since Covid emerged, it has become increasingly clear that infections in pregnant mothers can lead to serious health risks in infants.

The latest finding: Babies born to mothers who had Covid during pregnancy had “unusually high rates” of respiratory distress at birth or shortly thereafter, according to a study published Wednesday in the journal Nature Communications.

The authors defined respiratory distress as having at least two out of four symptoms: a slow breathing rate, pale or bluish skin, flaring nostrils or a retraction of the chest with each breath.

The study enrolled 221 pregnant women with Covid — mostly Black or Hispanic women in Los Angeles. None of the nearly 200 babies studied, who were born between April 2020 and August 2022, tested positive for Covid at birth. Around 17% were diagnosed with respiratory distress — higher than the average among newborns, which estimates put around 5% to 7%.

“The average duration of a hospital stay for these infants was about 24 days. They were quite sick,” said Dr. Olivia Man, the lead author of the study.

Other effects of Covid during pregnancy, according to prior research, include an increased risk of severe illness and death for the mother, preterm birth, stillbirth and neurodevelopmental issues in the first year of a child’s life.

A 2022 study on those developmental issues found that Covid during pregnancy was associated with delayed speech or motor skills, though the link isn’t fully understood. A follow-up study found that the association was only statistically significant in male babies, while another study found no association at all.

“We don’t know if these early speech and motor delays will go on to be matched by later neurodevelopmental diagnoses like autism or ADHD,” said Dr. Andrea Edlow, a maternal-fetal medicine specialist at Massachusetts General Hospital who conducted some of that research.

These risks aren’t exclusive to Covid. Having the flu during pregnancy increases the odds of preterm birth and birth defects, and some studies have also linked bacterial and viral infections during pregnancy to a risk of autism and depression in children.

“There are various infections that affect fetuses in different ways, but we’ve not had something like this that has affected a generation all at the same time,” said Dr. Shahnaz Duara, a professor of pediatrics at the University of Miami Miller School of Medicine.

“Twenty years from now, the kids who were born during the pandemic, we will be looking at them in a different way,” she said. “Because it’s not the odd kid here and there — it’s waves upon waves upon waves of women who have had Covid during pregnancy.”

Does Covid trigger inflammation in a fetus?

In the new study, the timing of a mother’s infection didn’t seem to have an effect on whether a baby experienced respiratory issues, but her vaccination status did. Infants born to unvaccinated mothers had three times the odds of respiratory distress than those whose moms had received at least one mRNA vaccine dose.

As for why babies exposed to Covid in the womb may develop health issues, inflammation is the leading hypothesis.

When a pregnant person gets Covid, their body may ramp up the production of cytokines — proteins involved in the immune response — that trigger inflammation. This could increase inflammation in their baby as well.

It’s possible that these inflammatory proteins cross the placenta. But the experts interviewed said the likelier explanation is that a mother’s inflammation activates immune cells in the placenta, which then activate immune cells in the infant.

Dr. Mary Prahl, an associate professor of pediatrics at the University of California, San Francisco said there appears to be “some sort of signaling on the infant side that’s saying, ‘Hey, something’s wrong. Let’s release all of our cytokines and our inflammatory markers to fight what’s happening.'”

Indeed, the new study found elevated levels of inflammatory proteins in blood samples taken from the newborns.

“What we think is happening is that Covid creates this sort of inflammatory cascade in the mother, and that these infants are responding to their mother’s own inflammation,” said Man, who conducted the research as a medical student at the University of California, Los Angeles.

“The risk of transmitting the actual virus in utero from mother to child is very low,” she added.

Man’s study found, in particular, that the inflammatory response in infants disrupted the normal function of cilia — hairlike structures that remove pathogens or particulate matter from the lungs.

“The implications would be that these children may be less likely to clear future infections or they may have significant difficulty breathing later in life,” she said.

In theory, Man added, long-term consequences could include asthma. Her study also found elevated levels of an antibody called immunoglobulin E, which have been linked to allergies. But more research is needed.

Of course, not all babies whose mothers get Covid in pregnancy experience negative outcomes.

“We certainly don’t want to scare pregnant people,” Edlow said.

Premature birth can raise the risk of developmental delays and breathing issues on its own — though 38% of the babies with respiratory distress in Man’s study were born full term.

Edlow noted, as well, that infants born between 37 and 39 weeks still have an increased risk of mild respiratory distress, so “it would be very hard to tease apart how much of that is actually due to some inflammation in the neonates that’s from Covid.”

Is there an optimal time to get vaccinated during pregnancy?

Covid vaccines are safe at any point in pregnancy, and the Centers for Disease Control and Prevention doesn’t specify an ideal trimester.

Duara said protection from vaccines tends to wane after four to six months, so she suggested that “somewhere between 12 and 18 weeks is probably a good time to get it because you will still have immunity by the time your baby’s born.”

Getting vaccinated during pregnancy, she added, tends to give newborns higher antibody levels than a Covid infection in pregnancy does, so even pregnant mothers who get Covid should get the shot if eligible.

“If it’s time for you to get another booster, take it,” Duara said.

Edlow, meanwhile, said research suggests that vaccinating mothers in the early third trimester maximizes the antibody levels transferred to babies, though she cautioned against waiting for that reason.

“If you’ve never been vaccinated, you shouldn’t be trying to time your Covid vaccine to optimize antibody protection for your neonate,” she said. “You should be thinking about yourself.”