Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury

Abstract

Context.— Perinatal death is an increasingly important problem as the COVID-19 pandemic continues, but the mechanism of death has been unclear. Objective.— To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for SARS-CoV-2. Design.— Case-based retrospective clinico-pathological analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. Results.— All 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis, the three findings constituting SARS-CoV-2 placentitis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25/68) and chronic villitis (32%; 22/68). The majority (19, 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. Conclusions.— The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

COVID-19 in pregnancy: implications for fetal brain development

“…P681R mutation may also affect virulence and tissue tropism by enhanced S protein cleavability by furin [148,149], a transmembrane serine protease that is widely expressed by both the placental syncytiotrophoblast [150,151] and fetal brain tissue [134]. Although a characteristic histopathological signature associated with maternal SARS-CoV-2 infection was not clearly identified with the ancestral strain [83,84,152,153], SARS-CoV-2 placentitisthe triad of histiocytic intervillositis, perivillous fibrin, and villous trophoblastic necrosis in the setting of SARS-CoV-2 infectionhas emerged as a histopathologic entity observed in association with both Alpha-and Delta-variant maternal SARS-CoV-2 infections, and has been linked to poor pregnancy outcomes including stillbirth in case reports [154,168]. Although definitive evidence linking Delta-variant SARS-CoV-2 placentitis to increased risk for fetal infection is lacking to date, these observations suggest the biological possibility that prenatal Delta-variant SARS-CoV-2 could lead to global placental dysfunction, and breach of the placental immune barrier.…”

SARS-CoV-2 Can Infect Human Embryos

“…The finding that preimplantation embryos are susceptible to SARS-CoV-2 infection raises the possibility of viral transmission from either the mother or father to the developing embryo. Vertical transmission of SARS-CoV-2 between pregnant mothers and fetuses has been reported [33][34][35][36][37][38], albeit considerably later in pregnancy. Of note, these studies implicate the placenta, which develops from the trophectoderm, as the principal site of viral infection and subsequent transmission [35,[38][39][40].…”

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

“…In the largest investigation of the cause of stillbirth and early neonatal death occurring with pregnant mothers having COVID-19, Schwartz and colleagues examined placentas infected with SARS-CoV-2 from 64 stillborn fetuses and four early neonatal deaths [ 93 ]. Because SARS-CoV-2 infection of the placenta is so uncommon, a multi-institutional study involving contributions from 12 countries was necessary to amass sufficient cases for analysis.…”

“…The effects of SARS-CoV-2 placentitis, placental dysfunction and malperfusion produces fetal hypoxia, which is likely exacerbated by additional pathology findings such as placental hemorrhages, thrombohematomas, villitis, maternal vascular malperfusion, and in some cases, small placental size. The placental destruction from SARS-CoV-2 placentitis averages over three-quarters of the placental volume and effectively renders the placenta incapable of performing its function in oxygenating the fetus [ 93 ]. The ensuing placental insufficiency eventually results in hypoxic ischemic injury to the vital organs of the fetus, causing intrauterine demise.…”

“…Maternal viremia with SARS-CoV-2 has been described to occur in cases of SARS-CoV-2 placentitis and intrauterine fetal demise [ 97 ], and it is highly probable that reported cases of SARS-CoV-2 placentitis and stillbirth were the result of an episode of the virus circulating in the mothers’ bloodstream at some time during the pregnancy. In the 68 cases of stillbirth and early neonatal death from placental insufficiency arising from SARS-CoV-2 placentitis described by Schwartz et al [ 93 ], as well as the six perinatal deaths from Ireland described by Fitzgerald et al [ 78 ], the five stillborns from France reported by Debucs et al [ 92 ], five stillborns from Sweden reported by Zaigham et al [ 91 ], and others [ 98 ], the mothers were all unvaccinated for coronavirus.…”