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Neurodevelopmental sequelae and microcephaly in two newborns after in utero exposure to SARS-CoV-2, with nucleocapsid and spike proteins in the brain of the deceased infant and in both placentas

The long-term neurodevelopmental sequelae are a potential concern in neonates after in utero exposure to severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2). This report by American scientists summarizes the severe neurodevelopmental sequelae that were found in two neonates after in utero exposure to SARS-CoV-2, with nucleocapsid (N) and spike (S) proteins detected in the brain of the deceased infant and both placentas.

The study presents cases of two infants born in the third trimester to mothers who had COVID-19 infection during pregnancy. Reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swabs was used for diagnosis of the SARS-CoV-2 infection. Both mothers tested positive several weeks before a delivery. At birth, neither infant was positive for SARS-CoV-2, but both infants had SARS-CoV-2 IgG, combined (total) IgG, IgM, and IgA reactivity to a recombinant derivative of SARS-CoV-2 spike protein, and markedly elevated serum levels of inflammatory markers and cytokines.

Case 1: A premature infant

A male infant of 32 weeks gestational age, appropriately grown, was born with Apgar scores of 4 and 7. The mother was healthy until 27 weeks of gestation, when she was admitted to the intensive care unit for pneumonia and multisystem disease, diagnosed as the SARS-CoV-2 infection by RT-PCR.

After the birth, the newborn immediately had a seizure-like activity and poor respiratory efforts, which required intubation and assisted ventilation. The initial chest radiograph showed bilateral confluent densities, that were not completely resolved after full respiratory recovery. The conventional electroencephalography (EEG) revealed a frequent occurrence of multifocal epileptiform discharges, consistent with a diagnosis of status epilepticus.

At 24 hours of age, the newborn’s RT-PCR test for SARS-CoV-2 was negative. However, laboratory tests showed SARS-CoV-2 IgG, combined (total) IgG, IgM, and IgA reactivity to a recombinant derivative of SARS-CoV-2 spike protein, and markedly elevated serum levels of inflammatory markers and cytokines. After three months, the infant was discharged with microcephaly and seizures. His neurologic examination at 12 months of age was abnormal, with head lag, truncal hypotonia, hyperreflexia, and delayed developmental milestones.

At 13 months of age, the infant suddenly died. The brain autopsy findings revealed a significant reduction in brain weight and cerebral white matter volume, enlarged ventricles, extensive gliosis and evidence of a virus throughout the brain. Immunofluorescence identified the SARS-CoV-2 S1 protein, colocalized with the N protein, throughout the infant’s brain.

Case 2: Full-term infant

A female infant, 39 weeks of gestational age, appropriately grown, was born with Apgar scores of 4 and 6. The mother reported an asymptomatic SARS-CoV-2 positivity in the late second trimester, followed by a negative test. Although asymptomatic, she tested positive again at the time of vaginal delivery, which was complicated by chorioamnionitis. Because the infant had apnea, she required nasal continuous positive airway pressure. Additionally, antibiotics were administered for suspected sepsis. Her neurological examination revealed mild hypotonia, but was otherwise normal. At 16 hours of age, she developed clinical seizures confirmed by conventional EEG.

At 24 hours of age, her RT-PCR test for SARS-CoV-2 was negative, but laboratory tests showed SARS-CoV-2 IgG, combined (total) IgG, IgM, and IgA reactivity to a recombinant derivative of SARS-CoV-2 spike protein, and elevated serum levels of inflammatory markers and cytokines. There was a cerebrospinal fluid pleocytosis, but no viruses or bacteria were detected. At three months of age, the results of brain magnetic resonance imaging revealed severe parenchymal atrophy and cystic encephalomalacia. At one year of age, the follow-up exam showed microcephaly, with low axial tone, head lag, increased appendicular tone, hyperreflexia, clonus, and significant neurodevelopmental delay with inability to roll over or sit unsupported.

Placental findings

The histopathological examination of placental tissue revealed in both placentas thrombosis and recanalization of stem villous vessels, stromal fibrosis, and increased stromal karyorrhexis of the terminal villi. The presence of thrombosis and apoptosis in placental tissue was associated with maternal-fetal vascular malperfusion and placental ischemia, resulting in deterioration of placental function. Immunofluorescence analysis detected the presence of the SARS-CoV-2 N and S proteins in the syncytiotrophoblast of both placentas.

Both placentas were also analyzed for inflammatory and modulating factors that directly or indirectly adversely affect the development of the fetal central nervous system. These findings were compared with those of placentas from two age- and gender-matched SARS-CoV-2 negative mothers.

The results showed that there was a significant increase in inflammatory and oxidative stress markers, such as macrophage inflammatory protein 1β (MIP1-β), stromal cell-derived factor 1, interleukin 13, and interleukin 10, compared to controls. The authors noted that inflammation of the fetal-placental unit leads to the development of the fetal inflammatory response syndrome, resulting in fetal hypoxia, compromise of the blood-brain barrier and fetal brain injury. It has been previously demonstrated that elevated concentrations of placental proinflammatory MIP1-β and IL-13 impair neurodevelopment of the fetus.

In addition, placental human chorionic gonadotropin (hCG) was markedly decreased in the SARS-CoV-2 positive placentas. This hormone induces uterine angiogenesis and vasculogenesis to ensure adequate blood supply to the placenta. The placental hCG also has a neuroprotective role, protecting developing fetal brain from hypoxic neurodegeneration. Thus, researchers suggested that decreased concentrations of placental hCG suggest a placental compromise.

A previous study of the placental arteries in women who gave birth to live full-term newborns while developing COVID-19 during pregnancy revealed severe thickening of the vascular wall and occlusion of the vascular lumen. The findings showed a two-fold increase in wall thickness and a five-fold reduction in the lumen area. An immunohistochemistry analysis demonstrated the association of placental vascular remodeling with smooth muscle proliferation and fibrosis.  https://discovermednews.com/severe-vascular-remodeling-of-placental-arteries-in-women-with-sars-cov-2-during-pregnancy/

In conclusion, clinical findings, placental pathology, and immunohistochemical findings strongly suggest that second-trimester maternal SARS-CoV-2 infection with placentitis triggered an inflammatory response and oxidative stress injury to the feto-placental unit, which in turn affected the fetal brain. Although SARS-CoV-2 was not detectable in the nasopharyngeal swabs of two newborns, the presence of anti-SARS-CoV-2 antibodies and the elevated levels of proinflammatory mediators, together with the neuropathological findings in the brain of the deceased infant, indicate that brain damage was caused either by the placental infection or/and by an undetected infection of the fetal brain in utero. Immunofluorescence detected the SARS-CoV-2 S1 and N proteins in both placentas and throughout the brain of the deceased infant, raising the possibility that SARS-CoV-2 infection of the fetal brain has directly contributed to brain damage.

It is worth noting that recent animal study showed significant level of maternal-fetal transmission of SARS-CoV-2 in later stages of mice pregnancy. The results also showed a viral tropism for various cells of the fetal brain, such as endothelial cells of blood vessels, barrier cells of the choroid plexus, neurons and glial cells. A concerning degree of gliosis was observed in the brains of infected fetuses, but there was no increase in cell death. https://discovermednews.com/experimental-evidence-of-maternal-fetal-transmission-of-sars-cov-2-and-viral-tropism-for-fetal-brain-cells/

According to the authors, this case report of neurodevelopmental sequelae after in utero exposure to SARS-CoV-2 demonstrates that midtrimester maternal SARS-CoV-2 infection can infect the placenta and fetal brain. This subsequently triggers a cascade of inflammatory events in both the placenta and fetus, which can lead to severe brain lesions and progressive neurological sequelae.

This study was published in Pediatrics.

Journal Reference

Merline Benny, et al. Maternal SARS-CoV-2, Placental Changes and Brain Injury in 2 Neonates. Pediatrics 2023; e2022058271. (Open Access)  https://doi.org/10.1542/peds.2022-058271

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