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Maternal SARS-CoV-2, Placental Changes and Brain Injury in 2 Neonates
Merline Benny1, Emmalee S Bandstra1, Ali G Saad2
1Division of Neonatology, Department of Pediatrics.
Insights
Maternal SARS-CoV-2 infection during pregnancy can cause severe neurodevelopmental problems in newborns, including seizures and developmental delays. Placental inflammation and oxidative stress may lead to fetal brain injury, with potential direct viral impact.
Area of Science:
- Neurology
- Infectious Diseases
- Neonatology
Background:
- In utero exposure to severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) raises concerns for long-term neurodevelopmental sequelae in neonates.
- Maternal SARS-CoV-2 infection has been linked to adverse pregnancy outcomes, but its specific impact on fetal neurodevelopment requires further investigation.
Purpose of the Study:
- To investigate the clinical, pathological, and immunohistochemical findings in neonates born to mothers with SARS-CoV-2 infection.
- To explore the potential mechanisms of fetal brain injury following maternal SARS-CoV-2 infection.
Main Methods:
- Case report of two neonates born to SARS-CoV-2 positive mothers.
- Clinical assessment including neurological examination, neuroimaging (MRI), and laboratory tests (SARS-CoV-2 antibodies, inflammatory markers).
- Placental pathology examination and immunohistochemical analysis for SARS-CoV-2 proteins and inflammatory markers. Postmortem brain examination in one case.
Main Results:
- Both neonates presented with early-onset seizures, acquired microcephaly, and developmental delay.
- MRI revealed severe parenchymal atrophy and cystic encephalomalacia.
- Placentas showed SARS-CoV-2 presence, fetal vascular malperfusion, and elevated inflammatory/oxidative stress markers.
- Postmortem brain analysis detected SARS-CoV-2 in the deceased infant, with viral proteins localized in brain tissue.
Conclusions:
- Maternal SARS-CoV-2 infection during the second trimester, leading to placentitis, can trigger inflammatory responses and oxidative stress, causing fetal brain injury.
- The findings suggest that SARS-CoV-2 infection of the fetoplacental unit can lead to significant long-term neurodevelopmental sequelae.
- The neurological presentation in these infants mimicked hypoxic-ischemic encephalopathy, highlighting the critical need for considering maternal SARS-CoV-2 infection in the differential diagnosis.
Abstract:
Long-term neurodevelopmental sequelae are a potential concern in neonates following in utero exposure to severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2). We report 2 neonates born to SARS-CoV-2 positive mothers, who displayed early-onset (day 1) seizures, acquired microcephaly, and significant developmental delay over time. Sequential MRI showed severe parenchymal atrophy and cystic encephalomalacia. At birth, neither infant was SARS-CoV-2 positive (nasopharyngeal swab, reverse transcription polymerase chain reaction), but both had detectable SARS-CoV-2 antibodies and increased blood inflammatory markers. Placentas from both mothers showed SARS-CoV-2-nucleocapsid protein and spike glycoprotein 1 in the syncytiotrophoblast, fetal vascular malperfusion, and significantly increased inflammatory and oxidative stress markers pyrin domain containing 1 protein, macrophage inflammatory protein 1 βη, stromal cell-derived factor 1, interleukin 13, and interleukin 10, whereas human chorionic gonadotropin was markedly decreased. One infant (case 1) experienced sudden unexpected infant death at 13 months of age. The deceased infant's brain showed evidence of SARS-CoV-2 by immunofluorescence, with colocalization of the nucleocapsid protein and spike glycoprotein around the nucleus as well as within the cytoplasm. The constellation of clinical findings, placental pathology, and immunohistochemical changes strongly suggests that second-trimester maternal SARS-CoV-2 infection with placentitis triggered an inflammatory response and oxidative stress injury to the fetoplacental unit that affected the fetal brain. The demonstration of SARS-CoV-2 in the deceased infant's brain also raises the possibility that SARS-CoV-2 infection of the fetal brain directly contributed to ongoing brain injury. In both infants, the neurologic findings at birth mimicked the presentation of hypoxic-ischemic encephalopathy of newborn and neurologic sequelae progressed well beyond the neonatal period.
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