By Liz Szabo
Stress levels among expectant mothers have soared. Pregnant women with covid are five times as likely as uninfected pregnant people to require intensive care and 22 times as likely to die. Infected moms are four times as likely to have a stillborn child.
Yet some of the pandemic’s greatest threats to infants’ health may not be apparent for years or even decades.
That’s because babies of covid-infected moms are 60% more likely to be born very prematurely, which increases the danger of infant mortality and long-term disabilities such as cerebral palsy, asthma and hearing loss, as well as a child’s risk of adult disease, including depression, anxiety, heart disease and kidney disease.
“Some of these conditions do not show up until middle childhood or early adult life, but they have their origins in fetal life,” said Dr. Evdokia Anagnostou, a child neurologist at Holland Bloorview Kids Rehabilitation Hospital and a pediatrics professor at the University of Toronto.
For fetuses exposed to covid, the greatest danger is usually not the coronavirus itself, but the mother’s immune system.
Both severe covid infections and the strain of the pandemic can expose fetuses to harmful inflammation, which can occur when a mother’s immune system is fighting a virus or when stress hormones send nonstop alarm signals.
Prenatal inflammation “changes the way the brain develops and, depending on the timing of the infection, it can change the way the heart or kidneys develop,” Anagnostou said.
At least 150,000 pregnant people have been diagnosed with covid; more than 25,000 of them have been hospitalized, and 249 have died, according to the Centers for Disease Control and Prevention.
Although most babies will be fine, even a small increase in the percentage of children with special medical or educational needs could have a large effect on the population, given the huge number of covid infections, Anagnostou said.
“If someone has a baby who is doing well, that is what they should focus on,” Anagnostou said. “But from a public health point of view, we need to follow women who experienced severe covid and their babies to understand the impact.”
Learning From History
Previous crises have shown that the challenges fetuses face in the womb — such as maternal infections, hunger, stress and hormone-disrupting chemicals — can leave a lasting imprint on their health, as well as that of their children and grandchildren, said Dr. Frederick Kaskel, director of pediatric nephrology at the Children’s Hospital at Montefiore.
People whose mothers were pregnant during surges in the 1918 influenza pandemic, for example, had poorer health throughout their lives, compared with Americans born at other times, said John McCarthy, who is a medical student at Albert Einstein College of Medicine and co-wrote a recent review in JAMA Pediatrics with Kaskel.
Researchers don’t know exactly which moms were infected with pandemic flu, McCarthy said. But women who were pregnant during major surges — when infection was widespread — had children with higher rates of heart disease or diabetes. These children were also less successful in school, less economically productive and more likely to live with a disability.
Because organ systems develop during different periods of pregnancy, fetuses exposed during the first trimester may face different risks than those exposed toward the end of pregnancy, McCarthy said. For example, people born in the fall of 1918 were 50% more likely than others to develop kidney disease; that may reflect an exposure to the pandemic in the third trimester, while the kidneys were still developing.
Nearly two years into the covid pandemic, researchers have begun to publish preliminary observations of infants exposed to covid infections and stress before birth.
Although Anagnostou noted that it’s too early to reach definitive conclusions, “there is evidence that babies born to moms with severe covid infections have changes to their immune system,” she said. “It’s enough to make us worry a little bit.”
Damaging a Fetal Security System
The good news about the coronavirus is that it seldom crosses the placenta, the organ tasked with protecting a developing fetus from infections and providing it with oxygen. So moms with covid rarely give the virus to their children before birth.
That’s important, because some viruses that directly infect the fetus — such as Zika — can cause devastating birth defects, said Dr. Karin Nielsen-Saines, a specialist in pediatric infectious diseases at UCLA’s David Geffen School of Medicine.
But studies also suggest that inflammation from a mother’s covid infection can injure the placenta, said Dr. Jeffery Goldstein, an assistant professor of pathology at Northwestern University’s Feinberg School of Medicine. In a study published last year, Goldstein and his co-authors found that placentas from covid-infected moms had more abnormal blood vessels than placentas from patients without covid, making it harder for them to deliver sufficient oxygen to the fetus.
Preeclampsia occurs when blood vessels in the placenta don’t develop or function properly, forcing the mother’s heart to work harder to get blood to the fetus, which may not receive enough oxygen and nutrients. Preeclampsia also predisposes women to heart attacks and strokes later in life.
Rewiring the Immune System
In some cases, covid also appears to rewire a baby’s immune response, Nielsen-Saines said.
In an October study in the journal Cell Reports Medicine, Nielsen-Saines and her co-authors found that infants born to people with severe covid infections had a different mix of immune cells and proteins than other babies. None of the newborns tested positive for the coronavirus.
The immune changes are concerning, Nielsen-Saines said, because this pattern of immune cells and proteins has previously been found in infants with respiratory problems and in some cases poor neurodevelopment.
Notably, all the babies in her study appear healthy, said Nielsen-Saines, who plans to follow them for three years to see whether these early signals translate into developmental delays, such as problems talking, walking or interacting with others.
“How big of a difference does any of this make in the baby?” asked Anagnostou. “We won’t know for a few years. All we can do is try to be as prepared as possible.”
Increasing the Risk for Boys
Boys could face higher risks from covid, even before birth.
Males are generally more vulnerable than females as fetuses and newborns; they’re more likely to be born prematurely and to die as infants. Preterm boys also have a higher risk of disability and death.
But coronavirus infection poses special dangers, said Sabra Klein, a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.
That’s because boys are disproportionately affected by conditions linked to maternal infections. Boys are four times as likely as girls to be diagnosed with autism or attention deficit hyperactivity disorder, for example, while men are 75% more likely than women to develop schizophrenia.
Scientists don’t fully understand why boys appear more fragile in the womb, although testosterone — which can dampen immune response — may play a role, said Dr. Kristina Adams Waldorf, a professor of obstetrics and gynecology at the University of Washington.
Men generally mount weaker immune responses than women and more often develop severe covid infections. Recent research suggests boys with covid are more likely than girls to become seriously ill or develop a rare inflammatory condition called multisystem inflammatory syndrome.
New research on covid could help illuminate this vulnerability.
In a study published in October, researchers found that the sex of a fetus influences the way its placenta responds to covid, as well as how its mother’s immune system responds.
Pregnant people infected with covid made fewer antibodies against the coronavirus if they were carrying male fetuses than if they were carrying females. Mothers also transferred fewer antibodies to boys than to girls, said Dr. Andrea Edlow, senior author of the study and a maternal-fetal medicine specialist at Massachusetts General Hospital.
When examining the placentas of male fetuses after delivery, researchers found changes that could leave boys less protected against damaging inflammation.
The sex of a fetus can influence its mother’s response to other illnesses, as well.
Edlow said her findings raise questions about the “cross talk” between mother and baby. “The mom’s immune system is sensing there is a male fetus,” Edlow said. “And the fetus is actively communicating with the mom’s immune system.”
Boosting Toxic Stress
Studies consistently show that infants born to mothers who experience significant stress during pregnancy have higher rates of short- and long-term health damage — including heart defects and obesity — than babies born to women with less stress.
“We know that inflammation directly influences the way a baby’s brain develops,” said Elinor Sullivan, an associate professor in psychiatry at Oregon Health & Science University.
Lockdowns, travel restrictions and physical distancing left many pregnant women without the support of family and friends. The stress of losing a loved one, a job or a home further heightens the risks to moms and babies, said Sullivan, who is following children born during the pandemic for five years.
In research that has not yet been published, Sullivan found that babies of women who were pregnant during the pandemic showed more sadness and negative emotions in the first year of life compared with infants of women who were pregnant before the pandemic.
The findings show the importance of helping and protecting pregnant people before and after delivery, said Sullivan, who conducted a separate study that found women who received more social support were less depressed.
Italian researchers are also studying the effect of maternal stress on infants’ behavior, as well as the way their genes are regulated.
Although stress-related inflammation doesn’t alter the structure of a baby’s genes, it can influence whether they’re turned on and off, said Livio Provenzi, a psychologist at the C. Mondino National Institute of Neurology Foundation in Pavia, Italy.
In Provenzi’s study of 163 mother-baby pairs, he found differences in how genes that regulate the stress response were activated. Genes that help people respond to stress were more likely to be turned off in babies whose moms reported the most stress during pregnancy. The same moms also reported that their babies cried more and were fussier when they were 3 months old.
Researchers usually prefer to make in-person observations of babies as they interact with their mothers, Provenzi said. But because of the pandemic, Provenzi asked mothers to fill out questionnaires about infant behavior. He plans to observe mothers and babies in person when the children are 12 months old.
While vaccinating pregnant people is the best way to protect them and their fetuses from the virus, Anagnostou said, society needs to do more to preserve expectant mothers’ mental health.
“We can’t escape the fact that we’ve lived through two years of a pandemic,” Anagnostou said. “But we can think about opportunities for reducing the risk.”