Confirming Vertical Fetal Infection With Coronavirus Disease 2019: Neonatal and Pathology Criteria for Early Onset and Transplacental Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 From Infected Pregnant Mothers

Abstract

Increasing numbers of pregnant women with COVID-19 are being reported around from the world. The majority of neonates delivered to pregnant women infected with the new coronavirus SARS-CoV-2 have been negative for the virus, but a small number have tested positive for infection. It is important to determine whether vertical transmission of COVID-19 occurs and the mechanisms for its development. Based on a number of clinical and laboratory findings it has been suggested that transplacental transmission may be occurring, but a method to confirm this is necessary. This communication analyzes and evaluates the covariables that have been discussed as potential indicators of vertical and, specifically, intrauterine transmission including the timing of onset of neonatal illness, neonatal viral test positivity, neonatal antibody testing for IgG and IgM, and viral analysis of swabs of whole specimens of placental tissue. None of these methods can provide confirmatory evidence that infection developed prior to labor and delivery, or that transplacental transmission occurred. This commentary proposes that diagnosis of early-onset neonatal COVID-19 infection should be limited to neonates with positive RT-PCR testing for SARS-CoV-2 within the initial 72 hours of life. It also proposes that the occurrence of intrauterine transplacental SARS-CoV-2 among infected mother-infant dyads be based upon identification of SARS-CoV-2 in chorionic villous cells using immunohistochemistry or such nucleic acid methods such as in situ hybridization. Evaluating placentas from neonates with COVID-19 using these methods will be instrumental in determining the potential role and prevalence of transplacental transmission of the coronavirus.

Placental Pathology of COVID-19 with and without Fetal and Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk Factors for Transplacental Transmission of SARS-CoV-2

“…This represented the first report of pregnant women and their neonates testing positive for COVID-19 in which the fetal tissues of the placenta were found to be infected using molecular methods. These findings by Patanè et al [23] were consistent with the published criteria of Schwartz et al [22] for the identification of intrauterine transplacental maternal-fetal infection.…”

“…It is important to distinguish between intrauterine transplacental transmission of SARS-CoV-2 from an infected mother to her fetus from other mechanisms of vertical and neonatal infection. Schwartz et al have proposed placental pathology criteria for the diagnosis of transplacental SARS-CoV-2 transmission between infected maternal-neonatal dyads [22]. These criteria are based upon the molecular identification of the virus on the fetal side of the placenta, such as in cells of the trophoblast or chorionic villous stroma, by demonstrating either viral antigens by immunohistochemistry or through detection of viral nucleic acid using RNA in situ hybridization or RNAscope methods.…”

The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors

“…These cerebrovascular manifestations may be due to impairment of the distinct features of the brain vasculature, namely the blood-brain-barrier and the neurovascular unit, a functional entity composed of endothelial cells and perivascular cells 38–41 . Moreover, neurological/encephalitic manifestations similar to those described in adults such as white matter injury (bilateral gliosis of the deep white periventricular- and subcortical matter), lethargy, hypertonia, hyperexcitability, and high-pitched crying were also reported in human neonates born to SARS-CoV-2 infected mothers 42, 43 . The fetuses/neonates were infected via transplacental transmission of SARS-CoV-2 leading to placental inflammation and neonatal viremia, and these neurological symptoms can be associated to cerebral vasculitis 42, 43 .…”

“…Moreover, neurological/encephalitic manifestations similar to those described in adults such as white matter injury (bilateral gliosis of the deep white periventricular- and subcortical matter), lethargy, hypertonia, hyperexcitability, and high-pitched crying were also reported in human neonates born to SARS-CoV-2 infected mothers 42, 43 . The fetuses/neonates were infected via transplacental transmission of SARS-CoV-2 leading to placental inflammation and neonatal viremia, and these neurological symptoms can be associated to cerebral vasculitis 42, 43 . These observations together with the reported “vascular symptoms” like Kawasaki syndrome are especially interesting given that the brain- and peripheral vasculature are established during fetal and postnatal developmental periods 42–48 .…”

“…The fetuses/neonates were infected via transplacental transmission of SARS-CoV-2 leading to placental inflammation and neonatal viremia, and these neurological symptoms can be associated to cerebral vasculitis 42, 43 . These observations together with the reported “vascular symptoms” like Kawasaki syndrome are especially interesting given that the brain- and peripheral vasculature are established during fetal and postnatal developmental periods 42–48 .…”