Placental histopathology after SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis

Abstract

Objectives : To report the spectrum of placental pathology findings in pregnancies complicated by SARS-CoV-2 infection. Methods : MEDLINE, EMBASE, Google Scholar and the Web of Science databases were searched up to August 11 th , 2021. Histopathological anomalies included maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), acute inflammatory pathology (AIP), chronic inflammatory pathology (CIP), increased perivillous fibrin and intervillous thrombosis. Sub-analyses including only symptomatic women and high-risk pregnancies were also performed. Histopathological analysis of the placenta included gross examination, histopathology on hematoxylin and eosin (H&E), immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), qRT-PCR on placental tissue, and transmission electron microscope (TEM). Random-effect meta-analyses were used to analyze the data. Results : Fifty-seven studies (1009 pregnancies) were included. MVM was reported in 31.4% (95% CI 21.0-42.8) of placentas, while FVM was observed in 26.9% of cases (95% CI 19.2-35.4). AIP and CIP were reported in 22.6% (95% CI 16.8-28.9) and 26.2% (95% CI 18.9-34.2) of cases, respectively. Increased perivillous fibrin was observed in 32.7% (95% CI 24.1-42.0) of placentas undergoing histopathological analysis, while intervillous thrombosis were observed in 14.6% (95% CI 10.6-21.8) of cases. Other placental findings, including either basal plate with attached myometrial fibers, microscopic accretism, villous edema, increased circulating nucleated Red Blood Cells or membranes with hemorrhage were reported in 38% (95% CI 28.5-48.0) of cases, while only 17.4% (95% CI 10.9-25.0) did not present any abnormal histological findings. Sub-analyses according to maternal symptoms due to SARS-CoV-2 infection or the presence of a high-risk pregnancy showed similar distribution of the different histopathological anomalies to that reported in the main analysis. The risk of placental histopathological anomalies was also higher when considering only case-control studies comparing women with SARS-CoV-2 infection with healthy controls. Conclusions : A significant proportion of placentas where SARS-CoV-2 occurred during pregnancy shows histopathological findings suggesting placental hypoperfusion and inflammation. Future multicenter prospective blinded studies are needed to correlate these placental lesions with pregnancy outcomes.

Placental Macrophages Following Maternal SARS-CoV-2 Infection in Relation to Placental Pathology

“…Whilst we identified an increase in both maternal and fetal vascular malperfusion in our systematic review of studies reported between December 2019 and July 2020 (3), Girolamo et al, reported similar findings (22), and placental hypoperfusion and inflammation were identified in a more recent systematic review and meta-analysis. Other research has identified no associated placental pathology following third trimester infection, at either the macro-or microscopic level (23), or statistically significant increases in features, such as fibrin deposition (7).…”

Fetal growth and hemodynamics during SARS-CoV-2 infection: a short literature review

“…The findings from our systematic review showed that a large proportion of pregnancies complicated by SARS-CoV-2 infection have placental histopathological abnormalities consistent with placental inflammation and hypoperfusion, while only about 17.4% of these pregnancies showed no placental anomalies. Sub-group analyses according to the presence of maternal symptoms or high-risk pregnancy showed similar results with the large majority of placenta from women with SARS-CoV-2 infection in pregnancy [11].…”

“…It has been shown that the COVID-19 virus enters into human cells by interacting with the angiotensinconverting-enzyme receptor and there is evidence that the concentrations of these receptors are increased in the pregnant uterus and placenta [11]. These findings have been subsequently confirmed by the increased prevalence of signs of decidual arteriopathy in the placenta of infected pregnant women, demonstrating a link between infection and impaired placental function.…”

Risk for Stillbirth Among Women With and Without COVID-19 at Delivery Hospitalization — United States, March 2020–September 2021

“…Although stillbirth was a rare outcome overall, a COVID-19 diagnosis documented during the delivery hospitalization was associated with an increased risk for stillbirth in the United States, with a stronger association during the period of Delta variant predominance. A previous study of pregnancies complicated by SARS-CoV-2 infection identified placental histopathologic abnormalities, suggesting that placental hypoperfusion and inflammation might occur with maternal COVID-19 infection ( 5 ); these findings might, in part, explain the association between COVID-19 and stillbirth. Among deliveries with COVID-19 documented during the delivery hospitalization, certain underlying medical conditions and markers of maternal morbidity, including the need for intensive care, were associated with stillbirth.…”