Placental Pathology After SARS-CoV-2 Infection in the Pre-Variant of Concern, Alpha / Gamma, Delta, or Omicron Eras

Abstract

Objectives. The goal of this study is to describe placental pathology after infection with SARS-CoV-2 before the predominance of variants of concern (pre-VOC) and during eras of predominant transmission of the Alpha & Gamma (co-circulating), Delta, and Omicron variants. Methods. We used county-level variant data to establish population-level variant proportions, SARS-CoV-2 PCR to identify cases, and IgG serology to exclude latent infections from controls and histopathologic examination to identify placental pathology. Results. We report findings in 870 placentas from pregnancies complicated by SARS-CoV-2 including 90 with infection in the Alpha/Gamma era, 60 from the Delta era and 56 from the Omicron era. Features of maternal vascular malperfusion (MVM), including decidual arteriopathy, were significantly more frequent after SARS-CoV-2 infection. The risk of these findings varied over time, with the highest rates in the Delta era. Increased COVID-19 severity and the presence of comorbidities strengthened these associations. Conclusion. MVM is a feature of SARS-CoV-2 infection in pregnancy. Lesion frequency changed with the predominant circulating virus and should be considered with new variants.

Keywords: COVID-19; SARS-CoV-2; decidual arteriopathy; maternal vascular malperfusion; placenta; variants of concern.

Figure 1.

SARS-CoV-2 variant frequency over time. Alpha and Gamma variants emerge together and become dominant March 2021 – June 2021. Delta appears in April but represents almost all infections by the week of June 27, 2021. Omicron becomes dominant December 19, 2021. Numbers above the graph indicate the number of patients sampled that week.

Figure 2.

Histology. Representative H&E images of placental diagnoses. Mural hypertrophy of membrane arterioles (A). Persistent muscularization of basal plate arterioles (B). Accelerated villous maturation at 37 weeks gestation, characterized by lower villous diameter, increased stromal density and syncytial knots (C). versus Delayed villous maturation at 39 weeks gestation characterized by larger villous diameter, looser stroma, increased vascularity, and fewer syncytial knots (D). Objective magnification 10x, scale bar 300 µm.

Figure 3.

SARS-CoV-2 infection is associated with increased risk of MVM findings, particularly decidual arteriopathy. SARS-CoV-2 infection, or variant of concern other than Omicron, was associated with the presence of at least 1 MVM feature (A). Accelerated villous maturation was increased in SARS-CoV-2 and delta. (B). Decidual arteriopathy was associated with SARS-CoV-2 infection in the pre-VOC era, but the association weakened in the Alpha / Gamma era. It was stronger in the Delta and Omicron (C). Delayed villous maturation was decreased (D). after SARS-CoV-2 infection, significantly so in the Delta and Omicron eras. ***: uncorrected p < 0.001, **: p < 0.01, *:p < 0.05. MVM: maternal vascular malperfusion; pre-VOC: era prior to any predominant variant of concern.

Figure 4.

Increasing severity of COVID-19 is associated with increased risk of MVM findings. Asymptomatic SARS-CoV-2 infection was associated with the presence of at least 1 MVM feature, with increasing risk in mild or moderate to severe COVID-19 (A). Accelerated villous maturation was markedly increased after moderate to severe COVID-19 (B). Decidual arteriopathy was associated with SARS-CoV-2 infection at all severities, but particularly moderate to severe disease (C). Delayed villous maturation was non-significantly decreased in all severities of COVID 1-9 (D). ***: uncorrected p < 0.001, **: p < 0.01, *:p < 0.05. MVM: maternal vascular malperfusion.

Figure 5.

Impact of comorbidities on MVM in the context of SARS-CoV-2 infection. In a stepwise fashion comorbidities, SARS-CoV-2, and SARS-CoV-2 with comorbidities are associated with increased risk of any feature of MVM (A). particularly, accelerated villous maturation (B) and decidual arteriopathy (C). The risk of abnormally delayed villous maturation is decreased (D). Groups are compared using chi-squared and post-hoc Fisher exact tests. a: significantly different from non-comorbid controls; c: significantly different from non-comorbid SARS-CoV-2. MVM: maternal vascular malperfusion.

Figure 6.

Frequency of selected diagnoses throughout the pandemic. Features of MVM (black line) were identified in 60% of patients with symptomatic SARS-CoV-2 diagnosed in April 2020, but only 29% of patients diagnosed with SARS-CoV-2 in October 2020. Decidual arteriopathy (blue line) rates mirrored those of MVM overall. Note there are only 2 patients in February 2022.