Pregnant people respond to COVID-19 differently depending on the sex of their unborn child, according to a study released yesterday (October 19) in Science Translational Medicine. Male placentas produced more proinflammatory genes and proteins than female placentas after the parent contracted COVID-19, and people gestating sons produced fewer antibodies following infection. They also passed fewer protective antibodies on to the fetus. 

“What’s interesting about that is it means that the sex of the baby can dictate how the mother responds to a viral infection,” Akiko Iwasaki, a virologist and immunologist at Yale University who was not involved in the study, tells STAT. “We knew that maternal infection can significantly impact the fetus, but this means that there is cross-talk between the fetus and the mother. That’s exciting because it adds an extra layer to what we are used to thinking about.”

Since the early days of the COVID-19 pandemic, researchers have noted differences in how the immune systems of men and women respond to SARS-CoV-2. Men are more likely to contract and die from the coronavirus, for example, and a study led by Iwasaki hinted at reasons why: men tend to mount a slower immune response than women, she and her colleagues found, but they also produce more proinflammatory molecules, making them more susceptible to complications such as cytokine storms.

See “Sex Differences in Immune Responses to Viral Infection

Yet little has been known about how pregnancy and COVID-19 affect one another. To find out, researchers at Massachusetts General Hospital and Harvard Medical School began biobanking blood and placenta samples in April 2020, according to STAT. In the new study, the research team analyzed placentas, maternal blood, and cord blood from 68 pregnant people, 38 of whom contracted COVID-19 during the third trimester of their pregnancies (all were unvaccinated, as this was before the vaccines were fully developed).

The team found that compared to placentas from pregnancies unaffected by COVID-19, in response to COVID-19 infection, male placentas that had been exposed to SARS-CoV-2 had higher expression of proinflammatory immune activation genes called interferon-stimulated genes (ISGs), and produced more cytokines, than female placentas. This shift may help protect male fetuses from infection, but inflammation in the uterus has also been linked to an increased risk of developing neurodevelopmental or metabolic disease later in life, according to a Massachusetts General Hospital press release

See “Maternal Obesity and Diabetes Linked to Autism in Children

“What the downstream effects are going to be for the child we still don’t know,” Andrea Edlow, a maternal fetal medicine doctor at Mass General and assistant professor at Harvard Medical School, tells STAT. Edlow co-led the current study as well as another, also published in Science Translational Medicine, that looked at how pregnant people respond to vaccines. “But it’s definitely going to be important to follow up the development of these children on the basis of sex because we see these really profound changes in the placenta that suggest that the intrauterine environment is suddenly altered even in the setting of mild maternal disease.”

The sex of the fetus seemed to affect the immune response of the pregnant parent as well. SARS-CoV-2-infected patients produced fewer antibodies when carrying a male fetus than when carrying a female, meaning they also transferred fewer protective antibodies to male babies. In the press release, Edlow notes that this may leave males more susceptible to COVID-19 infection after birth, and that it could explain why pregnant people are more vulnerable to developing severe COVID-19.

Ruth Karron, a virologist and pediatric infectious diseases professor at the Johns Hopkins Bloomberg School of Public Health who was not involved in the study, tells STAT that even as scientists continue to tease apart the details of how pregnancy shapes responses to both infection and vaccination, the prevailing message must be that vaccination is important. “The data is of interest, but I think it doesn’t at this time have practical implications in terms of vaccine rollout other than what we already know—which is that 97% of pregnant people who have been hospitalized with Covid in this country are unvaccinated.”