Diffuse and Localized SARS-CoV-2 Placentitis

Abstract

Coronavirus disease 2019 (COVID-19) infection in pregnancy has been associated with preterm delivery and preeclampsia. A less frequent and underrecognized complication is extensive placental infection which is associated with high rates of perinatal morbidity and mortality. The frequency, early pathogenesis, and range of lesions associated with this infection are poorly understood. We conducted a population-based study of placental pathology from all mothers with COVID-19 (n=271) over an 18-month period delivering within our health system. The overall prevalence of diffuse severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, as defined by typical histology and immunohistochemical (IHC) staining for SARS-CoV-2 spike protein, was 14.8/1000, but increased to 59/1000 in preterm births. We also identified 3 cases with isolated small foci of localized SARS-CoV-2 placentitis, characterized by focal perivillous fibrin and intervillositis, which illustrate the early pathogenesis and suggest that infection may be contained in some cases. Two other placental lesions were more common in mothers with COVID-19, high-grade maternal vascular malperfusion in preterm deliveries and high-grade chronic villitis at term (5/5 cases tested of the latter were negative by IHC for SARS-CoV-2). Additional investigation of diffuse and localized SARS-CoV-2 placentitis by IHC showed loss of BCL-2, C4d staining in surrounding villi, and an early neutrophil-predominant intervillous infiltrate that later became dominated by monocyte-macrophages. We propose a model of focal infection of syncytiotrophoblast by virally infected maternal leukocytes leading to loss of BCL-2 and apoptosis. Infection is then either contained by surrounding fibrinoid (localized) or initiates waves of aponecrosis and immune activation that spread throughout the villous parenchyma (diffuse).

SARS‐CoV‐2—Placental effects and association with stillbirth

“…Due to limitations on laboratory resourcing, the audit led to a triage system whereby placentas from pregnancies with a history of maternal COVID‐19 that were otherwise uncomplicated were, from March 2022, only examined microscopically if a gross abnormality was seen. These audit findings resonate with those from another similar‐sized cohort from the USA 65 …”

“…These audit findings resonate with those from another similar-sized cohort from the USA. 65 This current lack of predictability of who will be affected, evidenced by the cases summarised in Table 3, has led to significant uncertainties in the clinical management of women in relation to trying to avoid fetal demise when variants of concern are circulating.…”

Potential molecular and cellular mechanisms for adverse placental outcomes in pregnancies complicated by SARS-CoV-2 infection—A scoping review

“…SARS-CoV-2 infection is associated with perturbations in placental immune cell infiltration [ 38 ], including increased subchorionic infiltration of neutrophils [ 40 ], intervillous infiltration of maternal macrophages and T-cells [ 19 ], elevated cluster of differentiation 14 (CD14+) macrophages [ 41 ], third trimester decidual infiltration of macrophages and natural killer (NK) cells and second trimester increases in T-cells [ 27 ]. However, the neutrophil to macrophage ratio is much higher in early, localized placentitis as compared to diffuse infection [ 33 ]. Infection is also associated with increased levels of inflammatory cytokines including interferon stimulated genes (IFI6, OAS1, CCL3) and proteins (IFNa, IFNy, CCL4), interleukin-10 (IL-10) expression [ 21 ], CXC-motif chemokine ligand 10 (CXCL10) [ 18 , 25 ], tumor necrosis factor alpha (TNFa), CXC-motif chemokine ligand 8 (CXCL8) [ 32 ], interferon gamma-induced protein 10 (IP-10), interferon gamma/ monokine induced by interferon-gamma IFNy/MIG [ 41 ], C-C motif chemokine ligand 3 and 5 (CCL3, CCL5), interleukin-6 (IL-6), interleukin-1-beta (IL1B), interferon alpha (IFNa), and interferon beta (IFNB) [ 35 ] and a decrease in interleukin-4 (IL-4) and macrophage migration inhibitory factor (MIF) expression [ 32 ].…”

“…Hypoperfusion of the placenta may be involved in the mechanism of pre-eclampsia and may lead to fetal growth restriction because of poor blood flow [ 43 ]. Complications reported to be associated with SARS-CoV-2 infection include decreased fetal movement [ 44 ], pregnancy loss [ 45 ], caesarean section [ 46 ], preterm delivery [ 33 , 47 , 48 ], hypertension [ 48 ], and preeclampsia [ 10 , 47 ]. In contrast, some studies show that outcomes are not different in those pregnancies complicated by SARS-CoV-2, including rates of stillbirth [ 49 ], PTB or preeclampsia [ 50 , 51 ], or caesarean section for fetal indication [ 50 ].…”

Acute placental insufficiency two weeks after an asymptomatic COVID-19 maternal infection: the deleterious effects of the SARS-CoV-2 placentitis

“…SARS-CoV-2 placentitis is a rare but largely unvalued and serious complication of maternal infection, large series reported a prevalence of 1-2% in infected mothers, but higher prevalence was described during the delta variant surge [7][8][9][10][11].…”