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 11th, 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.