Researchers at UHealth—the University of Miami Health System and the University of Miami Miller School of Medicine have shown that, in two cases, COVID-19 infection breached the placenta and caused brain damage in the newborn.

While admitted to the Neonatal Intensive Care Unit (NICU) at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center, a teaching hospital affiliated with UHealth and the Miller School, both infants had tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies detectable in blood, indicating that either antibodies crossed the placenta, or passage of the virus occurred and the immune response was the baby’s.

Both infants experienced seizures, small head sizes and developmental delays, and one infant died at 13 months of age. The study titled, “Maternal SARS-CoV-2, Placental Changes and Brain Injury in Two Neonates” was published April 6, in the journal Pediatrics. This is the first study to confirm cross-placental SARS-Cov-2 transmission leading to brain injury in the newborn.

“Many women are affected by COVID-19 during pregnancy, but to see these kinds of problems in their infants at birth was clearly unusual”, said Shahnaz Duara, M.D., professor of pediatrics at the University of Miami Miller School of Medicine, the medical director of the NICU at Holtz Children’s Hospital, and senior author on the study. “We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Early during the COVID-19 pandemic, this group of neonatologists had observed transient lung disease and sometimes blood pressure issues among newborns who had similarly tested negative at birth but were born to COVID-19 positive mothers. This was hinted at infection but left unclear whether the problems were caused by inflammatory placental cytokines or whether the SARS-CV-2 virus crossed the placenta and injured the baby.

“If we saw a baby who presented this way, we would call it hypoxic ischemic encephalopathy (brain damage caused by decreased blood flow),” said Michael Paidas, M.D., professor and chair of the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of Miami Miller School of Medicine and Jackson’s chief of service for obstetrics and gynecology. “But it wasn’t lack of blood flow to the placenta that caused this. As best we can tell, it was the viral infection.” Hypoxic ischemic encephalopathy in newborns, by definition, requires a sentinel event in the mother during labor prior to detecting neurological injury in the newborn at birth.

Ali G. Saad, M.D., a Miller School professor, neuropathologist, and director of the pediatric and perinatal pathology service at Holtz Children’s, examined both placentas and found signature placental pathological changes caused by SARS-CoV-2 in both placentas, and also examined major changes in the brain that came to autopsy: “I was struck by the unexplained severity of the loss of the white matter and the presence of features of hypoxia/ischemia in the cerebral cortex. We became suspicious that the virus, somehow, managed to breach the placental barrier to damage the central nervous system, but this had not been documented before”.

Jayakumar Aramugam, Ph.D., a neuroscientist and molecular biologist in the Department of Obstetrics, Gynecology and Reproductive Sciences, who along with Dr. Paidas showed the presence of virus in both patients’ placentas and also in the brain of the infant who died. Analysis of both placentas clearly demonstrated severe inflammatory changes in each placenta. Also striking, was the absence of a critical placental hormone, human chorionic gonadotrophin, which while essential for all fetal development is particularly important for brain development.

The authors stress that these were rare occurrences. UM clinicians have seen hundreds of pregnant women and delivering mothers with COVID-19 positivity; however, these were the only two women whose babies experienced the devastating brain injuries described in the paper. In both cases, the mothers contracted the infection in their second trimesters, and subsequently cleared it, but one had a repeat infection in their third trimesters, suggesting an unusual maternal and/or fetal immune response to the virus may have played a role.

“We need to continue our research to figure out why these two babies experienced such devastating results,” said Merline Benny, M.D., assistant professor of pediatrics, a neonatologist and first author on the paper. “Once we fully understand the causes, we can develop the most appropriate interventions.”