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 trajectory of the child's brain development, including the risk for neurodevelopmental disorders such as schizophrenia and autism. The work is made possible by a $3 million, five-year grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, part of the National Institutes of Health.
The project announced today stems from a collaboration between the Lieber Institute for Brain Development on the Johns Hopkins medical campus in Baltimore, Children's National Hospital in Washington, D.C., and the Women's Health Integrated Research Center at Inova Health System in Virginia.
The group aims for a clearer picture of how a mother's SARS-CoV-2 infection during pregnancy affects neurodevelopment in utero, the effects of which may manifest early in a child's life. The researchers hope to understand how the infection interacts with other factors relevant to brain development, including genomic 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 offspring brain development is mediated by changes in the biology of the placenta and the activation of the mother's immune system. They will also gauge any differences in the effects of SARS-CoV-2 between female and male children and in the offspring of vaccinated and unvaccinated mothers.
We know that what happens in the womb is crucial to the early stages of development, particularly of the brain, and we also know that viral infections contracted by pregnant women can place offspring at higher risk for disorders of brain development. We suspect that exposure to SARS-CoV-2 in utero may affect the developing brain too, with potential outcomes manifesting later in life in a portion of those born over the course of the pandemic."
Gianluca Ursini, M.D., Ph.D., principal investigator of the project and investigator at the Lieber Institute for Brain Development
The researchers hope to turn their findings into clinical interventions as quickly as possible, Dr. Ursini said.
"We expect that this study, made possible by the generous and visionary funding of the NIH, will benefit this vulnerable population in a timely manner, by informing preventive and therapeutic interventions and guidelines for SARS-CoV-2-exposed women and their infants," Dr. Ursini explained. "The results of this study could help us understand the mechanism through which other infectious and non-infectious exposures during pregnancy pose a threat to the developing brain."
Preliminary data show that pregnant people with symptomatic SARS-CoV-2 infections are more likely to have a preterm delivery, abnormalities in the placenta, and prenatal and perinatal complications such as preeclampsia and fetal growth restriction. All these complications have been found to increase a child's risk of neurodevelopmental disorders later in life.
The study will involve 500 pairs of mothers and babies from northern Virginia, half of whom had symptomatic SARS-CoV-2 infections and half of whom were asymptomatic, along with 400 healthy controls. Dr. Larry Maxwell, President of the Inova Women's Service Line, and Thomas Conrads, Director of Women's Health Research for the Inova Women's Service Line, will coordinate assembly and analysis of biological samples from patients prior to the pandemic as well as at different intervals during the pandemic.
Additionally, 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 genomic testing and RNA sequencing. The genetic and proteomic data will be combined to assess the effects of SARS-CoV-2 infection on the placenta in infected mothers compared to uninfected pregnant women serving as controls.
Sarah Mulkey, M.D., a prenatal-neonatal neurologist at Children's National Hospital, will lead the neurodevelopmental evaluations of the infants born to mothers with SARS-CoV-2 infection during pregnancy to understand any long-term neurological effects in offspring from mothers cared for at Inova. The researchers will evaluate the children's neurodevelopment at both 24 and 36 months of age. This work builds upon Dr. Mulkey's longitudinal neurodevelopmental evaluations in children exposed to Zika virus in utero.
"What we've learned is that even when babies don't have Zika-virus-related birth defects, we still find differences in early child development compared to children who weren't exposed to Zika virus," said Dr. Mulkey. "With SARS-CoV-2, there is still so much we don't know. But by better understanding the long-term impact of COVID exposure during pregnancy, we can ultimately find ways to prevent adverse outcomes."
The scientists aim to assess the factors that might mediate or moderate the relationship between a mother's infection and her child's neurodevelopmental outcomes. These factors include the components of a mother's immune system, changes in the placenta, gene and protein changes, and fetal sex. They will also consider the impact of social determinants of health, including the conditions in the places where people live, learn, work and play that contribute to health risks and outcomes.
Notably, the study group from Inova Health System is racially and ethnically diverse and reflects the vulnerable populations highly impacted by the pandemic and health disparities. By identifying the mechanisms at work in neurodevelopmental complications from maternal SARS-CoV-2 infection, scientists hope to discover how to limit or ameliorate any ill effects.
Dr. Ursini, the principal investigator for the project at the Lieber Institute for Brain Development, has focused his research on investigating the role of the early life environment in affecting the pathophysiology of neurodevelopmental disorder. His research has examined placental biology, its relationship to genomic risk for schizophrenia, and how early-life complications might interact with the genome to increase that risk.
"The placenta is a critical organ for research about early child development, though it is most often discarded after birth without investigation," said Dr. Daniel Weinberger, M.D., Director and CEO of the Lieber Institute for Brain Development and an investigator on this 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 the fetal environment of a person at the time of their birth, with direct implications for the growth and health of the newborn. Throughout development, interactions with the environment make changes in the machinery that regulates the function of a person's genome. These interactions are thought to underly many developmental disorders such as schizophrenia."
NIH Program Director Dr. Sai Majji is supportive of this award that will address specific factors or mechanisms that are responsible for brain development following SARS-CoV-2 infection during pregnancy, leading to identifying biomarkers that may allow prognostication for maternal health and the well-being of the offspring.