Stillbirth after COVID-19 in Unvaccinated Mothers Can Result from SARS-CoV-2 Placentitis, Placental Insufficiency, and Hypoxic Ischemic Fetal Demise, Not Direct Fetal Infection: Potential Role of Maternal Vaccination in Pregnancy

Abstract

Stillbirth is a recently recognized complication of COVID-19 in pregnant women. Other congenitally transmitted infections from viruses, bacteria and parasites can cause stillbirth by infecting fetal organs following transplacental transmission of the agent from the maternal bloodstream. However, recent research on pregnant women with COVID-19 having stillbirths indicates that there is another mechanism of stillbirth that can occur in placentas infected with SARS-CoV-2. In these cases, viral infection of the placenta results in SARS-CoV-2 placentitis, a combination of concurrent destructive findings that include increased fibrin deposition which typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis and trophoblast necrosis. These three pathological lesions, in some cases together with placental hemorrhage, thrombohematomas and villitis, result in severe and diffuse placental parenchymal destruction. This pathology can involve greater than one-half of the placental volume, averaging 77% in the largest study of 68 cases, effectively rendering the placenta incapable of performing its function of oxygenating the fetus. This destructive placental process can lead to stillbirth and neonatal death via malperfusion and placental insufficiency which is independent of fetal infection. Fetal autopsies show no evidence that direct infection of fetal organs is contributory. Because all mothers examined have been unvaccinated, maternal vaccination may prevent viremia and consequent placental infection.

Keywords: COVID-19; SARS-CoV-2; SARS-CoV-2 placentitis; chronic histiocytic intervillositis; intrauterine fetal demise; massive perivillous fibrin deposition; placenta; placental insufficiency; pregnancy; stillbirth; trophoblast necrosis; vaccination.

Figure 1

Low power image of placenta with SARS-CoV-2 placentitis from a stillborn fetus showing the pattern of positive staining of the villous syncytiotrophoblast for SARS-CoV-2 antigen. Antibody to SARS-CoV-2 spike protein, ×4.

Figure 2

Massive perivillous fibrin deposition in a placenta from a stillborn fetus delivered to a mother with COVID-19. This placenta was positive for SARS-CoV-2 and had greater than 90% tissue destruction. Hematoxylin & eosin staining, ×4.

Figure 3

Higher magnification of a placenta with SARS-CoV-2 infection and SARS-CoV-2 placentitis. There is massive perivillous fibrin deposition with ischemic necrosis of the chorionic villi and villous trophoblast. There is complete obstruction of the intervillous space with fibrin which prevents maternal blood flow though this region of the placenta. Hematoxylin & eosin staining, ×10.

Figure 4

Chronic histiocytic intervillositis is present demonstrating histiocytes within the remnants of the intervillous spaces in a placenta with massive perivillous fibrin deposition and trophoblast necrosis. This stillborn fetus was delivered to a mother with COVID-19. The syncytiotrophoblast of this placenta was strongly positive for SARS-CoV-2 antigens using immunohistochemistry. Hematoxylin & eosin staining, ×20.

Figure 5

This placenta was infected with SARS-CoV-2 and demonstrates necrosis of the villous trophoblast. The intervillous space is complete obstructed with fibrin, remnants of histiocytes, and cellular and karyorrhectic debris, preventing maternal blood flow and oxygen delivery to the villi. Hematoxylin & eosin staining, ×20. Photograph courtesy of Fabio Facchetti, MD, PhD, Pathology Unit, Department of Molecular and Translational Medicine, Università degli Studi di Brescia (Brescia, Italy).

Figure 6

The syncytiotrophoblast is strongly positive for SARS-CoV-2 antigen in the placenta from a stillborn fetus delivered at 35 weeks 4 days to a mother with COVID-19 infection. Cells in the villous stroma can also be seen as staining positive for the virus. Antibody to SARS-CoV-2 spike protein, ×20.