SARS-CoV-2 Can Infect the Placenta and Is Not Associated with Specific Placental Histopathology: A Series of 19 Placentas from COVID-19+ Mothers

Background:  Congenital infection of SARS-CoV-2 appears to be exceptionally rare despite many cases of COVID-19 during pregnancy. Robust proof of placental infection requires demonstration of viral localization within placental tissue. Only 2 of the few cases of possible vertical transmission have demonstrated placental infection. None have shown placental expression of the ACE2 or TMPRSS2 protein, both required for viral infection.  Methods:  We examined 19 COVID-19 exposed placentas for histopathologic findings, and for expression of ACE2, and TMPRSS2 by immunohistochemistry. Direct placental SARS-CoV-2 expression was studied by two methods - nucleocapsid protein expression by immunohistochemistry, and RNA expression by in-situ hybridization. Findings:  ACE2 membranous expression in the syncytiotrophoblast of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the trophoblast. In addition, cytotrophoblast and extravillous trophoblast express ACE2. No ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST.  In 2 of 19 cases SARS-CoV-2 RNA was present in the placenta focally in the syncytiotrophoblast and cytotrophoblast.  There was no characteristic histopathology present in our cases including the 2 placental infections. Interpretation:  We found that the placenta is capable of being infected but that this event is rare. We propose one explanation could be the polarized expression of ACE2 away from the maternal blood and pronounced paucity of TMPRSS2 expression in trophoblast. Funding Statement: Vickery-Colvin Award from the Department of Pathology, Massachusetts General Hospital and Advanced Cell Diagnostics. Research reported in this publication was partially supported by the Career Development Program in Substance Use and Addiction Medicine of the National Institutes of Health under award number K12DA043490. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. Declaration of Interests: Disclosures: D.T.T. has received consulting fees from Merrimack Pharmaceuticals, Ventana Roche, Foundation Medicine, Inc., and EMD Millipore Sigma, which are not related to this work. D.T.T. is a founder and has equity in PanTher Therapeutics and TellBio, Inc., which is not related to this work. D.T.T. is co-founder and own equity in ROME Therapeutics, which is not related to this work. Parts of this work were supported by ACD-Biotechne (N.D., V.D., D.T.T.). Dr. Ting’s interests were reviewed and are managed by Mass General Brigham in accordance with their conflict of interest policies. M.M.-K. has received consulting fees rom H3 Biomedicine and AstraZeneca and institutional grant support from Novartis, all of which are not related to this work. D.J.R. received royalties from UpToDate and Cambridge University Press as an author, not related to this work. All other authors declare no competing interests. Ethics Approval Statement: Institutional review board approval (IRB2020P001116 and IRB2020P001001) and Research support agreement (RSA2020A005296).