In Reply Open Access

In Reply.—I was very pleased to read the Letter to the Editor by Toto et al in response to our recent article.¹  Their description of an 11-week interval between the initial confirmed maternal coronavirus disease 2019 (COVID-19) infection and delivery in which the placenta was found to have immunohistochemical evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein staining is interesting. It is noteworthy that although active inflammatory abnormalities were present—chronic histiocytic intervillositis and chronic villitis—the syncytiotrophoblast did not show evidence of SARS-CoV-2 immunohistochemical staining at this stage, with positivity limited to villous stromal macrophages (Hofbauer cells) and capillary endothelium. This staining pattern is especially interesting as the susceptibility and kinetics of SARS-CoV-2 viral infection in the constituent cells of the maternal-fetal interface are currently unknown. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) for cell entry. Syncytiotrophoblast and vascular endothelial cells express ACE2,^2,3  while syncytiotrophoblastic expression of TMPRSS2 has been reported in some studies⁴  but not others. Hofbauer cells, which stained positively for SARS-CoV-2 nucleocapsid protein in this Letter to the Editor, do not appear to have the ACE2 surface receptor for SARS-CoV-2 binding,^2,5  and also appear to lack TMPRSS2.⁵  Perhaps this case represents the opportunity to view the natural history of prolonged placental infection due to SARS-CoV-2, as previously published cases of maternal and placental infection have occurred more proximate to delivery. It is also notable that despite the pathology findings and prior symptomatic maternal infection, the newborn tested negative for SARS-CoV-2.

This report also suggests at least 2 potential possibilities to explain the clinical and pathologic findings. The placenta has multiple innate immune mechanisms to protect the fetus from infection: these include production of antiviral molecules that can inhibit viral infections; pattern recognition receptors including Toll-like receptors and RIG-I–like receptors that induce antimicrobial signaling pathways; production of type III interferons (IFN-λs) and C19MC microRNAs that restrict viral infections; active transport of antibodies to the fetus through expression of IgG (immunoglobulin G) receptors neonatal FcRn and FcγRIII that are present on the syncytiotrophoblast surface; and physical structure of the syncytiotrophoblastic barrier. Placental macrophages at the maternal-fetal interface, such as Hofbauer cells, may also potentially have antimicrobial functions in SARS-CoV-2 infection, although this remains unknown.⁶  Perhaps these and other factors were sufficient in this case to prevent fetal infection despite placental involvement. Alternatively, given the 11-week interval between maternal infection and delivery, is it possible that the fetus became infected with SARS-CoV-2 following transplacental transmission, but subsequently cleared the coronavirus before delivery? It has been noted that neonatal test positivity for SARS-CoV-2 is frequently transient, becoming negative in many newborn infants a short time following a positive result.^7,8 

As is occurring with so many communications in obstetric, placental, and perinatal COVID-19, this thought-provoking report introduces more questions than it answers in our attempts to understand the pathophysiology of this emergent coronavirus infection during pregnancy.