SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers

Abstract

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 two 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. 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. ACE2 membranous expression in the syncytiotrophoblast (ST) of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the ST. 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 ST and cytotrophoblast. There was no characteristic histopathology present in our cases including the two placental infections. 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.

Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women

“…Importantly, there was also cytotrophoblast and extravillous trophoblast expression of ACE2. In contrast, no ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells [14]. ACE2 protein is enriched per unit volume in the placenta and ovary, compared to other tissues, despite a low mRNA level detected in the two tissues [15].…”

“…Smithgall and colleagues found no evidence of direct viral infection of the placenta, using in-situ hybridization (ISH) for the S-gene encoding the spike protein and immunohistochemistry with the monoclonal-SARS-CoV-2 spike-antibody 1A9 [12]. Conversely, in two of 19 cases reported by Hecht et al [14], SARS-CoV-2 RNA was present in placental villi focally, in both the ST and cytotrophoblast [14]. Moreover, three of 11 placentas having swabs taken from villi and fetal membranes tested positive for SARS-CoV-2 [16].…”

“…In a case series, Baergen and Heller found that ten of 20 (10/20, 50%) cases of COVID positive patients showed some evidence of FVM or fetal vascular thrombosis (FTV) [13]. Moreover, Hecht and colleagues examined placentas of nineteen COVID-19 exposed women and found that there was no characteristic histopathology present among the 19 cases (compared to control groups), despite localization of SARS-CoV-2 in two placentas by immunohistochemistry (IHC) or RNA expression by in situ hybridization (ISH) [14].…”

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

“…Individual and combinations of abnormalities of maternal vascular malperfusion, fetal vascular malperfusion, inflammatory lesions including chorioamnionitis and villitis, and even absence of pathology findings have been reported in placentas from neonates testing negative for COVID-19. The significant variance in pathology findings among non-transmitting placentas has led to one article entitled "SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology" [40].…”

“…In 2 hospitals in Boston, Hecht et al examined placentas from 19 pregnant women having COVID-19 in the peripartum period and compared the findings with 3 sets of control placentas from women who were uninfected with the coronavirus [40]. The authors found that there were no specific gross or microscopic findings in placentas from women with COVID-19.…”