Scientists led by the Lieber Institute for Brain Development are studying how a mother’s SARS-CoV-2 infection during pregnancy affects the biology of the placenta and the corresponding pathway of the baby’s brain development, including risk for neurodevelopmental disorders such as schizophrenia and autism. This work was made possible by a $3 million, five-year grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health.
The project announced today stems from a collaboration between the Lieber Institute for Brain Development at Johns Hopkins Medicine’s campus in Baltimore, Children’s National Hospital in Washington, D.C., and the Integrated Research Center for Women’s Health at Innova Health System in Virginia.
The group aims to get a clearer picture of how a mother’s infection with SARS-CoV-2 during pregnancy affects neurodevelopment in the womb, the effects of which may be seen early in a child’s life. Researchers hope to understand how infection interacts with other factors related to brain development, including genetic risk for neurodevelopmental disorders, maternal stress and social determinants of health. The team will study whether the relationship between maternal SARS-CoV-2 infection and the offspring’s brain development is mediated by changes in placental biology and activation of the maternal immune system. They will also measure any differences in the effects of SARS-CoV-2 between female and male infants and in the offspring of vaccinated and unvaccinated mothers.
We know that what happens in the womb is critical to the early stages of development, especially in the brain, and we also know that viral infections in pregnant women can put offspring at risk for brain development disorders. We suspect that exposure to SARS-CoV-2 in utero may also affect brain development, with possible consequences later in life in some of those born during the pandemic.”
Gianluca Orsini, MD, PhD, principal investigator on the project and investigator at the Lieber Institute for Brain Development
Dr. Orsini said the researchers hope to translate their findings into clinical interventions as quickly as possible.
“We expect that this study, made possible by generous and insightful funding from the National Institutes of Health, will benefit this vulnerable population in a timely manner, by offering preventive and treatment interventions and guidelines for women exposed to SARS-CoV-2 and their children,” explained Dr. Orsini. “The results of this study help us understand the mechanism through which other infectious and non-infectious exposures during pregnancy pose a threat to the developing brain.”
Preliminary data shows that pregnant women with symptoms of SARS-CoV-2 infection are at increased risk of preterm birth, placental abnormalities, prenatal and perinatal complications such as pre-eclampsia and fetal growth restriction. All of these complications have been found to increase a child’s risk of developing neurodevelopmental disorders later in life.
The study will include 500 pairs of mothers and children from Northern Virginia, half with symptomatic SARS-CoV-2 infection and half without symptoms, along with 400 healthy subjects. Dr. Larry Maxwell, Head of the Inova Women’s Service Line, and Thomas Konrads, Director of Women’s Health Research for the Inova Women’s Service Line, will coordinate the collection and analysis of biological samples from patients prior to the pandemic as well as at various periods during the pandemic.
In addition, the team at Inova will use laser microdissection technology to collect specific cells from the placenta for protein analysis, as well as for use by investigators at the Lieber Institute for Brain Development for genetic testing and RNA sequencing. Genetic and proteomic data will be combined to assess the effects of SARS-CoV-2 infection on the placenta of infected mothers compared to uninfected pregnant women serving as controls.
Sarah Mulkey, MD, a neurologist and neonatologist at Children’s National Hospital, will lead the neurodevelopmental assessments of babies born to mothers with SARS-CoV-2 infection during pregnancy to understand any long-term neurological effects in sons of mothers cared for at Innova. The researchers will assess the children’s neurodevelopment at 24 and 36 months of age. This work is based on Dr. Mulkey’s longitudinal neurodevelopmental assessments in infants exposed to Zika virus in utero.
“What we’ve learned is that even when children don’t have birth defects associated with Zika virus, we still find differences in children’s early development compared to children who haven’t been exposed to Zika virus,” Dr. Mulkey said. “With SARS-CoV-2, there is still a lot we don’t know. But by better understanding the long-term impact of exposure to COVID during pregnancy, we can finally find ways to prevent negative outcomes.”
The scientists aimed to evaluate factors that might mediate or mitigate the relationship between a mother’s injury and her child’s neurodevelopmental outcome. These factors include components of the maternal immune system, changes in the placenta, genetic and protein changes, and the sex of the fetus. They will also consider the impact of social determinants of health, including conditions in the places where people live, learn, work and play that contribute to health risks and outcomes.
Notably, the study cohort from the Inova Health System is racially and ethnically diverse and reflects vulnerable populations severely affected by the pandemic and health disparities. By identifying the mechanisms at work in the neurodevelopmental complications resulting from maternal SARS-CoV-2 infection, scientists hope to discover how to reduce or mitigate any ill effects.
Dr. Orsini, principal investigator of the project at the Lieber Institute for Brain Development, has focused his research on investigating the role of the early life environment in influencing the pathophysiology of a neurodevelopmental disorder. His research examined the biology of the placenta, its relationship to genetic risk for schizophrenia, and how early life complications might interact with the genome to increase that risk.
“The placenta is an important organ for research on early child development, even though it is often discarded after birth without investigation,” said Dr. Daniel Weinberger, MD, executive director of the Lieber Institute for Brain Development and researcher on the grant. .
“The placenta is an organ of the fetus, not the mother,” Dr. Weinberger noted. “It is a rich source of information about the genome and embryonic environment of a person at the time of their birth, with direct implications for the development and health of the newborn. During development, interactions with the environment bring about changes in the machinery that regulates the function of a person’s genome. These interactions are thought to underlie many developmental disorders such as schizophrenia.
NIH Program Director Dr. Sai Magee supports this award that will address specific factors or mechanisms responsible for brain development following SARS-CoV-2 infection during pregnancy, leading to the identification of biomarkers that may allow prediction of the health of the mother and the well-being of the offspring.