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

Abstract

The mechanism(s) by which neonates testing positive for coronavirus disease 2019 (COVID-19) acquire their infection has been largely unknown. Transmission of the etiological agent, SARS-CoV-2, from mother to infant has been suspected but has been difficult to confirm. This communication summarizes the spectrum of pathology findings from pregnant women with COVID-19 based upon the infection status of their infants and addresses the potential interpretation of these results in terms of the effects of SARS-CoV-2 on the placenta and the pathophysiology of maternal-fetal infection. Placentas from pregnant women with COVID-19 and uninfected neonates show significant variability in the spectrum of pathology findings. In contrast, placentas from infected maternal-neonatal dyads are characterized by the finding of mononuclear cell inflammation of the intervillous space, termed chronic histiocytic intervillositis, together with syncytiotrophoblast necrosis. These placentas show prominent positivity of syncytiotrophoblast by SARS-CoV-2, fulfilling the published criteria for transplacental viral transmission as confirmed in fetal cells through identification of viral antigens by immunohistochemistry or viral nucleic acid using RNA in situ hybridization. The co-occurrence of chronic histiocytic intervillositis and trophoblast necrosis appears to be a risk factor for placental infection with SARS-CoV-2 as well as for maternal-fetal viral transmission, and suggests a potential mechanism by which the coronavirus can breach the maternal-fetal interface.

Keywords: COVID-19; SARS-CoV-2; chronic histiocytic intervillositis; fetal COVID-19 infection; maternal COVID-19 infection; maternal-fetal COVID-19; neonatal COVID-19 infection; placental COVID-19 infection; placental pathology; placental risk factors; transplacental COVID-19 infection; trophoblast necrosis; vertical transmission.

Figure 1

Placenta from a maternal-neonatal dyad with COVID-19. There is prominent chronic histiocytic intervillositis present in which the inflammatory cells in the intervillous space stained positive with the CD68 antibody. Necrosis of the syncytiotrophoblast layer on chorionic villi is visible even at this magnification. The findings, in this case, were indicative of intrauterine transplacental transmission of SARS-CoV-2. This placenta was described in [23]. Hematoxylin & eosin, ×10 magnification.

Figure 2

Placenta from the same maternal-neonatal dyad as in Figure 1 in which there was intrauterine maternal-fetal transmission of COVID-19. The confluent areas of brown staining at the periphery of the chorionic villi represents trophoblast infection identified by immunohistochemistry using an antibody to SARS-CoV-2 nucleocapsid protein. Positive staining is also present in inflammatory cells in the intervillous space. This placenta was described in [23]. ×20 magnification.

Figure 3

RNAscope for COVID-19 spike protein viral RNA (brown dots) staining positive within the syncytiotrophoblast of multiple chorionic villi. The trophoblast in these villi are intact and have not yet undergone necrosis. There is an intense viral load present. This placenta was described in [23]. ×40 magnification.

Figure 4

Higher magnification of placenta from a pregnant woman with COVID-19 in a case of transplacental SARS-CoV-2 fetal infection. Chronic histiocytic intervillositis is present in which the intervillous space is crowded with mononuclear inflammatory cells and necrotic cell debris and fibrin. Trophoblast necrosis can be seen on the surface of some chorionic villi. This placenta is described in [24]. Hematoxylin & eosin, ×20 magnification. Photograph courtesy of Fabio Facchetti, MD, Ph.D. of the University of Brescia, Italy.