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

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.

Analysis of placental pathology after COVID-19 by timing and severity of infection.

BACKGROUND: COVID-19 during pregnancy can have serious effects on pregnancy outcomes. The placenta acts as an infection barrier to the fetus and may mediate adverse outcomes. Increased frequency of maternal vascular malperfusion has been detected in the placentas of patients with COVID-19 compared with controls, but little is known about how the timing and severity of infection affect placental pathology. OBJECTIVE: This study aimed to examine the effects of SARS-CoV-2 infection on placental pathology, specifically whether the timing and severity of COVID-19 affect pathologic findings and associations with perinatal outcomes. STUDY DESIGN: This was a descriptive retrospective cohort study of pregnant people diagnosed with COVID-19 who delivered between April 2020 and September 2021 at 3 university hospitals. Demographic, placental, delivery, and neonatal outcomes were collected through medical record review. The timing of SARS-CoV-2 infection was noted, and the severity of COVID-19 was categorized on the basis of the National Institutes of Health guidelines. The placentas of all patients with positive nasopharyngeal reverse transcription-polymerase chain reaction COVID-19 testing were sent for gross and microscopic histopathologic examinations at the time of delivery. Nonblinded pathologists categorized histopathologic lesions according to the Amsterdam criteria. Univariate linear regression and chi-square analyses were used to assess how the timing and severity of SARS-CoV-2 infection affected placental pathologic findings. RESULTS: This study included 131 pregnant patients and 138 placentas, with most patients delivered at the University of California, Los Angeles (n=65), followed by the University of California, San Francisco (n=38) and Zuckerberg San Francisco General Hospital (n=28). Most patients were diagnosed with COVID-19 in the third trimester of pregnancy (69%), and most infections were mild (60%). There was no specific placental pathologic feature based on the timing or severity of COVID-19. There was a higher frequency of placental features associated with response to infection in the placentas from infections before 20 weeks of gestation than that from infections after 20 weeks of gestation (P=.001). There was no difference in maternal vascular malperfusion by the timing of infection; however, features of severe maternal vascular malperfusion were only found in the placentas of patients with SARS-CoV-2 infection in the second and third trimesters of pregnancy, not in the placentas of patients with COVID-19 in the first trimester of pregnancy. CONCLUSION: Placentas from patients with COVID-19 showed no specific pathologic feature, regardless of the timing or severity of the disease. There was a higher proportion of placentas from patients with COVID-19-positive tests in earlier gestations with evidence of placental infection-associated features. Future studies should focus on understanding how these placental features in SARS-CoV-2 infections go on to affect pregnancy outcomes.

Histopathological Changes in Placenta of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) Infection and Maternal and Perinatal Outcome in COVID-19.

Background: Whether vertical transmission or placental pathology occurs after maternal infection during pregnancy remains unknown. There is a clear need for studies on the impact of COVID-19 on pregnancy outcome. A systemic inflammatory or hypercoagulable state may be the contributing factor for placental pathology. Methods: The pregnant women with COVID-19 who delivered between May 2020 and May 2021 were followed and data were collected about pregnancy course and placentas were examined for macro- and microscopical changes and were compared to controls with non-infected women. Results: Placenta of COVID-19-infected females had increased prevalence of decidual arteriopathy and placental injury reflecting hypoxia and uteroplacental insufficiency within the intervillous space. Features of maternal vascular malperfusion such as increased syncytial knots were present in 100% cases. Fibrinoid necrosis was seen in 100% cases and increased focal perivillous fibrin depositions were presented in 37.7% cases. About one fourth infected placentas had evidence of villitis. Even after matching for comorbidities like preeclampsia, these changes were present. Conclusion: The most common pathological findings of the placenta of COVID-19 infections are signs of maternal and fetal malperfusion. Future studies should target infections in different stage of gestation, including first and second trimesters.

Histomorphological evaluation of placenta in SARS-CoV-2 patients: A cross-sectional study.

Background: SARS-CoV-2 has emerged as a major pandemic of the century and little is known about the impact of maternal infection on placental histopathology. Histopathologic examination of placental tissue can contribute to significant information regarding the pathophysiology of the disease and how it affects the fetal outcome. Materials and Methods: This was a cross-sectional study conducted at the Department of Pathology, Government Doon Medical College and Hospital, Dehradun, on the placenta of 50 coronavirus disease 2019 (COVID-19)-positive pregnant females confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) from August 2020 to October 2020. Fifty term historical placentas were taken as control. Placenta sections were fixed in formalin, processed into paraffin blocks, stained with hematoxylin and eosin (H and E) stain, and visualized for any abnormality. Results: The most prominent histological finding in the placenta of pregnant women affected by COVID-19 was chorangiosis, which is a feature of fetal vascular malperfusion seen in 28 (56%) cases. Other features included maternal vascular malperfusions (MVM) such as villous crowding and agglutination in 12 (24%) cases. Tenney-Parker change was seen in 13 (26%) patients. Intervillous fibrinoid deposition and intervillous hemorrhage were seen in 37 (74%) patients and 7 (14%) patients showed significant calcification. Other findings observed were less common. Conclusion: Infection with SARS-CoV-2 may be associated with a significant impact on fetal and maternal circulation causing features of fetal and maternal malperfusion such as chorangiosis, villous crowding, and agglutination. Indicating that the infection could cause a potential rise in the risk of adverse perinatal outcomes such as intrauterine fetal growth retardation, preterm birth, or stillbirth.

Life After Amsterdam: Placental Pathology Consensus Recommendations and Beyond.

The Amsterdam Placental Workshop Group Consensus Statement on Sampling and Definitions of Placental Lesions has become widely accepted and is increasingly used as the universal language to describe the most common pathologic lesions found in the placenta. This review summarizes the most salient aspects of this seminal publication and the subsequent emerging literature based on Amsterdam definitions and criteria, with emphasis on publications relating to diagnosis, grading, and staging of placental pathologic conditions. We also provide an overview of the recent expert recommendations on the pathologic grading of placenta accreta spectrum, with insights on their clinical context. Finally, we discuss the emerging entity of SARS-CoV2 placentitis.

The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies.

INTRODUCTION: The effect of SARS-CoV-2 severity or the trimester of infection in pregnant mothers, placentas, and infants is not fully understood. METHODS: A retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021 via chart review to document the infants' weight, length, head circumference, survival, congenital abnormalities, hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria. RESULTS: Of the 115 mothers, 85.2% were asymptomatic (n = 37) or had mild (n = 61) symptoms, 13.0% had moderate (n = 9) or severe (n = 6) COVID-19, and 1.74% (n = 2) did not have symptoms recorded. Moderate and severe maternal infections were associated with increased C-section, premature delivery, infant NICU admission, and were more likely to occur in Type 1 (p = 0.0055) and Type 2 (p = 0.0285) diabetic mothers. Only one infant (0.870%) became infected with SARS-CoV-2, which was not via the placenta. Most placentas (n = 63, 54.8%) did not show specific histologic findings; however, a subset showed mild maternal vascular malperfusion (n = 26, 22.6%) and/or mild microscopic ascending intrauterine infection (n = 28, 24.3%). The infants had no identifiable congenital abnormalities, and all infants and mothers survived. DISCUSSION: Most mothers and their infants had a routine clinical course; however, moderate and severe COVID-19 maternal infections were associated with pregnancy complications and premature delivery. Mothers with pre-existing, non-gestational diabetes were at greatest risk of developing moderate or severe COVID-19. The placental injury patterns of maternal vascular malperfusion and/or microscopic ascending intrauterine infection were not associated with maternal COVID-19 severity.

Placental pathology from COVID-19-recovered (nonacute) patients.

Placental pathology can identify characteristic features of specific infectious pathogens. The histopathology of acute SARS-CoV-2 placental infection and exposure without infection has been well described. However, whether the characteristic placental pathology persists after the acute phase of the infection is less clear. We retrospectively identified 67 COVID-19-recovered pregnant patients who had placental pathology available. After reviewing the gross and histopathology, we categorized the findings and studied the placentas for evidence of chronic infection by immunohistochemistry for the spike protein of the virus. We found these placentas showed significantly increased prevalence of maternal and a trend towards significance of fetal vascular malperfusion when compared to a control group of placentas examined for the sole indication of maternal group B streptococcal colonization. None of the COVID-19-recovered placentas showed expression of the viral spike protein; therefore, we found no evidence of persistent infection of the placenta in women with a history of COVID-19 during their pregnancy. We conclude that recovery from a SARS-CoV-2 infection during pregnancy puts the pregnancy at risk for specific pathology.

The etiology of preeclampsia.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

Symptomatic versus asymptomatic COVID-19: does it impact placental vasculopathy?

This study sought to assess the impact of COVID-19 on placental vasculature in the context of maternal symptomatology - comparing asymptomatic to symptomatic pregnant patients - and disease severity - comparing pregnant patients with mild, moderate, severe, and critical COVID-19 infection. PCR-confirmed COVID-19 positive pregnant patients in a single health system who delivered between 3/2020-5/2021 included. All patients had positive COVID test and delivered during the study period. Primary outcome was incidence of any vascular malperfusion on placental pathology. Secondary outcomes were FVM and MVM on placental pathology. Placental pathology compared between symptomatic (sCOVID) and asymptomatic (aCOVID) patients. Secondary analysis of symptomatic patients, comparing placental pathology between mild disease(mCOVID) and worse disease(moderate, severe, or critical-defined by 2020 NIH guidelines) (dCOVID), also performed. Of 112 patients, 53 (47%) had symptoms. Twenty-seven (24.1%) patients had evidence of vascular malperfusion; 26 (23.2%) had MVM. When comparing aCOVID and sCOVID patients, no difference in rate of vascular malperfusion identified, nor any differences in rates of FVM or MVM. Among sCOVID patients (n = 53), 39 (74%) had mCOVID and 14 (26%) had dCOVID (moderate n = 4, severe n = 9, critical n = 1). Patients with dCOVID had earlier median delivery GA (37.4wks vs 39.2wks, p = .03). No difference in latency from diagnosis to delivery seen between mCOVID and dCOVID groups (4.4 vs 3.0wks, p = .96). Twelve (30.8%) patients had vascular malperfusion on pathology, all had mCOVID (p = .02). Eleven (28.2%) mCOVID patients had MVM; no dCOVID patients had evidence of vascular malperfusion (p = .03). No difference in FVM was found between cohorts. Symptomatic COVID-19 infection did not impact placental vasculature differently than asymptomatic infection, even when stratifying by trimester of infection. Among pregnant patients with symptomatic COVID-19, mild disease was associated with placental vascular changes on the maternal side while severe disease was not. Further studies are needed to understand the implications of these findings.

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

OBJECTIVE: This study aimed to report the spectrum of placental pathology findings in pregnancies complicated by SARS-CoV-2 infection. DATA SOURCES: MEDLINE, Embase, Google Scholar, and the Web of Science databases were searched up to August 11, 2021. STUDY ELIGIBILITY CRITERIA: Histopathologic anomalies included maternal vascular malperfusion, fetal vascular malperfusion, acute inflammatory pathology, chronic inflammatory pathology, increased perivillous fibrin, and intervillous thrombosis. Moreover, subanalyses of symptomatic women only and high-risk pregnancies were performed. METHODS: Histopathologic analysis of the placenta included gross examination, histopathology on hematoxylin and eosin, immunohistochemistry, fluorescence in situ hybridization, quantitative reverse transcription-polymerase chain reaction on placental tissue, and transmission electron microscope. Random-effect meta-analyses were used to analyze the data. RESULTS: A total of 56 studies (1008 pregnancies) were included. Maternal vascular malperfusion was reported in 30.7% of placentas (95% confidence interval, 20.3-42.1), whereas fetal vascular malperfusion was observed in 27.08 % of cases (95% confidence interval, 19.2-35.6). Acute and chronic inflammatory pathologies were reported in 22.68% (95% confidence interval, 16.9-29.0) and 25.65% (95% confidence interval, 18.4-33.6) of cases, respectively. Increased perivillous fibrin was observed in 32.7% (95% confidence interval, 24.1-42.0) of placentas undergoing histopathologic analysis, whereas intervillous thrombosis was observed in 14.6% of cases (95% confidence interval, 9.7-20.2). Other placental findings, including a basal plate with attached myometrial fibers, microscopic accretism, villous edema, increased circulating nucleated red blood cells, or membranes with hemorrhage, were reported in 37.5% of cases (95% confidence interval, 28.0-47.5), whereas only 17.5% of cases (95% confidence interval, 10.9-25.2) did not present any abnormal histologic findings. The subanalyses according to maternal symptoms owing to SARS-CoV-2 infection or the presence of a high-risk pregnancy showed a similar distribution of the different histopathologic anomalies to that reported in the main analysis. Moreover, the risk of placental histopathologic anomalies was higher when considering only case-control studies comparing women with SARS-CoV-2 infection with healthy controls. CONCLUSION: In pregnant women with SARS-CoV-2 infection, a significant proportion of placentas showed histopathologic findings, suggesting placental hypoperfusion and inflammation. Future multicenter prospective blinded studies are needed to correlate these placental lesions with pregnancy outcomes.

Histopathologic evaluation of placentas after diagnosis of maternal severe acute respiratory syndrome coronavirus 2 infection.

Background: The impact of maternal severe acute respiratory syndrome coronavirus 2 infection on placental histopathology is not well known. Objective: To determine if any significant placental histopathologic changes occur after the diagnosis of severe acute respiratory syndrome coronavirus 2 infection during pregnancy and whether these changes are correlated with the presence or absence of symptoms associated with the infection. Study Design: A retrospective cohort study of women diagnosed as having severe acute respiratory syndrome coronavirus 2 infection who delivered at a single center from April 9, 2020 to April 27, 2020, and had placental specimens reviewed by the Department of Pathology. Women with singleton gestations and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were eligible for inclusion. Historical controls selected from a cohort of women who delivered 6 months before the study period were matched in a 1:1 fashion by weeks of gestation at delivery. Histopathologic characteristics were evaluated in each placenta, and the incidence of these findings was compared between placentas of those who received a diagnosis of maternal severe acute respiratory syndrome coronavirus 2 infection and historical controls, and between placentas from patients with or without typical symptoms related to the infection. Statistical analyses included the use of Wilcoxon rank-sum test and Fisher's exact test for the comparison of categorical and continuous variables. Statistical significance was defined as a P value of <.05. Results: A total of 50 placentas after the diagnosis of maternal severe acute respiratory syndrome coronavirus 2 infection and 50 historical controls were analyzed. Among the placentas from patients diagnosed with severe acute respiratory syndrome coronavirus 2 infection, 3 (6%) were preterm (33 3/7, 34 6/7, and 36 6/7 weeks of gestation), 16 (32%) were from patients with typical symptoms related to the infection, and 34 (68%) were from patients without typical symptoms related to the infection. All patients had received a diagnosis of severe acute respiratory syndrome coronavirus 2 infection in the third trimester. Decidual vasculopathy was not visualized in any of the placentas from patients diagnosed as having severe acute respiratory syndrome coronavirus 2 infection. There was no statistically significant difference in placental histopathologic characteristics between the groups. Severe acute respiratory syndrome coronavirus 2 test results for all neonates at 24 hours of life were negative. Conclusion: Based on the results of this study, there are no significant placental histopathologic changes that occur after the diagnosis of severe acute respiratory syndrome coronavirus 2 infection in women during the third trimester of pregnancy compared with a gestational age-matched historical control group. Similar incidences of histopathologic findings were also discovered when comparing placentas from patients with severe acute respiratory syndrome coronavirus 2 infection with or without the presence of symptoms typically related to the infection.

Placental Pathology in COVID-19.

OBJECTIVES: To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy. METHODS: Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma. RESULTS: Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma. CONCLUSIONS: Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.