SARS-CoV-2 placentitis, stillbirth, and maternal COVID-19 vaccination: clinical-pathologic correlations

Abstract

Stillbirth is a recognized complication of COVID-19 in pregnant women that has recently been demonstrated to be caused by SARS-CoV-2 infection of the placenta. Multiple global studies have found that the placental pathology present in cases of stillbirth consists of a combination of concurrent destructive findings that include increased fibrin deposition that typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. These 3 pathologic lesions, collectively termed SARS-CoV-2 placentitis, can cause severe and diffuse placental parenchymal destruction that can affect >75% of the placenta, effectively rendering it incapable of performing its function of oxygenating the fetus and leading to stillbirth and neonatal death via malperfusion and placental insufficiency. Placental infection and destruction can occur in the absence of demonstrable fetal infection. Development of SARS-CoV-2 placentitis is a complex process that may have both an infectious and immunologic basis. An important observation is that in all reported cases of SARS-CoV-2 placentitis causing stillbirth and neonatal death, the mothers were unvaccinated. SARS-CoV-2 placentitis is likely the result of an episode of SARS-CoV-2 viremia at some time during the pregnancy. This article discusses clinical and pathologic aspects of the relationship between maternal COVID-19 vaccination, SARS-CoV-2 placentitis, and perinatal death.

Keywords: COVID-19 in pregnancy; COVID-19 vaccine; SARS-CoV-2 placentitis; massive perivillous fibrin deposition; maternal vaccination; maternal viremia; maternal-fetal tolerance; perinatal death; placental insufficiency; placental malperfusion; placental pathology; stillbirth; stillbirth prevention.

Figure 1

Gross appearance of a sectioned placenta with SARS-CoV-2 placentitis Massive perivillous fibrin deposition involves most of the placental parenchyma. Schwartz. Placentitis, stillbirth, and maternal COVID-19 vaccination. Am J Obstet Gynecol 2023.

Figure 2

Placenta with SARS-CoV-2 placentitis and MPFD from a stillborn fetus Microscopic image. Fibrin has completely obstructed the intervillous space, and there is severe ischemic necrosis of the chorionic villi. Hematoxylin and eosin staining, ×10. MPFD, massive perivillous fibrin deposition. Schwartz. Placentitis, stillbirth, and maternal COVID-19 vaccination. Am J Obstet Gynecol 2023.

Figure 3

A placenta exhibiting SARS-CoV-2 placentitis Massive perivillous fibrin deposition is present, in which the intervillous space is completely obstructed with fibrin, remnants of histiocytes, and cellular and karyorrhectic debris, preventing maternal blood flow and oxygen delivery to the villi. The syncytiotrophoblast is necrotic, and there is chronic histiocytic intervillositis. Hematoxylin and eosin staining, ×10. Photograph courtesy of Fabio Facchetti, MD, PhD, Pathology Unit, Department of Molecular and Translational Medicine, Università degli Studi di Brescia, Brescia, Italy. Schwartz. Placentitis, stillbirth, and maternal COVID-19 vaccination. Am J Obstet Gynecol 2023.

Figure 4

Placenta from a stillborn preterm fetus with SARS-CoV-2 placentitis Immunohistochemistry demonstrates intense positivity for SARS-CoV-2 spike antigen in the syncytiotrophoblast and villous stromal cells. Antibody to SARS-CoV-2 spike protein, ×20. Schwartz. Placentitis, stillbirth, and maternal COVID-19 vaccination. Am J Obstet Gynecol 2023.

Figure 5

Proposed mechanisms of development of placental infection and SARS-CoV-2 placentitis Proposed mechanisms of placental infection with SARS-CoV-2 following maternal viremia and development of SARS-CoV-2 placentitis. The high magnification photograph of placenta in the upper right demonstrates a maternal white blood cell, probably a macrophage, staining for SARS-CoV-2 using immunohistochemistry and circulating in the intervillous space, adjacent to the infected syncytiotrophoblast. CV, chorionic villus; IVS, intervillous space; SYN, syncytiotrophoblast. Schwartz. Placentitis, stillbirth, and maternal COVID-19 vaccination. Am J Obstet Gynecol 2023.