Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise

Abstract

Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.

Fig. 1

Pathology of diffuse trophoblastic damage. A Grossly the placenta is pale and stiffed. B Histologically, there is diffuse collapse of intervillous space resulting in close contact among chorionic villi with necrosis of trophoblast that stains homogeneously with eosin (H&E, original magnification 20x). C At higher power nuclear signs of cell necrosis can be readily seen in the involved trophoblast whereas villous stroma is spared (H&E, original magnification 60x). D Occasional groups of preserved chorionic villi are totally surrounded of villi involved by diffuse trophoblastic damage (H&E, original magnification 10x). E immunohistochemistry for SARS-CoV-2 shows patchy trophoblast staining (original magnification 30x). F in situ hybridization shows a granular pattern of staining in trophoblast lining of chorionic villi (original magnification 30x).

Fig. 2

Focal trophoblastic damage. A In this grossly normal-looking placenta few small foci of intervillous space collapse were found as the two here depicted. Inset is shown at a higher magnification in (B) (H&E, original magnification 10x). B Intervillous space collapse and trophoblastic necrosis looks quite similar to more extensive lesions depicted in Fig. 1 (original magnification, 20X). C Immunohistochemical staining for SARS-CoV-2 nucleoprotein shows staining in the injured villi but also in the surrounding normal-looking villi (original magnification 10X). D In situ hybridization with the RNAscope probe replicates the image of immunohistochemistry (original magnification 10x).