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.

Predictive factors for severe placental damage in pregnant women with SARS-CoV-2 infection.

INTRODUCTION: SARS-Cov-2 infection during pregnancy can lead to severe placental lesions characterized by massive perivillous fibrin deposition, histiocytic intervillositis and trophoblast necrosis. Diffuse placental damage of this kind is rare, but can sometimes lead to obstetric complications, such as intrauterine fetal death (IUFD). The objectives of this study were to identify possible predictors of severe placental lesions. METHODS: We retrospectively studied 96 placentas from SARS-Cov-2 positive pregnant women who gave birth between March 2020 and March 2022. Cases with and without severe placental lesions were compared in terms of clinical and laboratory findings. RESULTS: Twelve of the 96 patients had severe placental lesions. There was no significant association with diabetes, obesity or severe clinical maternal disease. In contrast, presence of severe placental lesions was significantly associated with neonatal intensive care, cesarean section, prematurity, IUFD, intrauterine growth restriction (IUGR), gestational age, maternal hypofibrinogenemia and thrombocytopenia. No cases of severe placental lesions were observed in vaccinated patients or in those with the Omicron variant. DISCUSSION: In these patients, severe placental lesions due to SARS-Cov-2 were significantly associated with the presence of coagulation abnormalities (hypofibrinogenemia and thrombocytopenia), IUGR and gestational age. These results support laboratory and ultrasound monitoring of these parameters in pregnant women with SARS-Cov-2 infection, especially during the second trimester, to predict potential negative fetal outcomes.

The effects of preconception and early gestation SARS-CoV-2 infection on pregnancy outcomes and placental pathology.

OBJECTIVE: To evaluate if peri-pregnancy timing of a PCR+ test for SARS-CoV-2 RNA affects pregnancy outcomes and placental pathology. METHODS: This is a retrospective cohort study conducted in a tertiary center. Pregnancy outcomes and placental pathology were compiled for women who tested positive for SARS-CoV-2 RNA from a nasopharyngeal swab assessed by RT-PCR. The population comprised four groups that were PCR+ preconception (T0) or in the 1st (T1), 2nd (T2), or 3rd (T3) trimester of pregnancy. A fifth, control group (TC) tested PCR- for SARS-CoV-2 before delivery. RESULTS: Seventy-one pregnancies were studied. The T0 group exhibited lower gestational ages at delivery, had infants with the lowest birth weights, the highest rate of pregnancy loss before 20 weeks. Features of maternal vascular malperfusion and accelerated villous maturation were prominent findings in the histopathology of placentas from women PCR+ for SARS-CoV-2 RNA, especially in the T0 and the T1 groups. CONCLUSION: Women at highest risk for pregnancy complications are those who test PCR+ for viral RNA preconception or during first trimester of pregnancy.

Glycation-Driven Inflammation: COVID-19 Severity in Pregnant Women and Perinatal Outcomes.

The link between being pregnant and overweight or obese and the infectivity and virulence of the SARS CoV-2 virus is likely to be caused by SARS-CoV-2 spike protein glycosylation, which may work as a glycan shield. Methylglyoxal (MGO), an important advanced glycation end-product (AGE), and glycated albumin (GA) are the results of poor subclinical glucose metabolism and are indices of oxidative stress. Forty-one consecutive cases of SARS-CoV-2-positive pregnant patients comprising 25% pre-pregnancy overweight women and 25% obese women were recruited. The aim of our study was to compare the blood levels of MGO and GA in pregnant women with asymptomatic and symptomatic SARS-CoV-2 infection with pregnant women without SARS-CoV-2 infection with low risk and uneventful pregnancies and to evaluate the relative perinatal outcomes. The MGO and GA values of the SARS-CoV-2 cases were statistically significantly higher than those of the negative control subjects. In addition, the SARS-CoV-2-positive pregnant patients who suffered of moderate to severe COVID-19 syndrome had higher values of GA than those infected and presenting with mild symptoms or those with asymptomatic infection. Premature delivery and infants of a small size for their gestational age were overrepresented in this cohort, even in mild-asymptomatic patients for whom delivery was not indicated by the COVID-19 syndrome. Moreover, ethnic minorities were overrepresented among the severe cases. The AGE-RAGE oxidative stress axis on the placenta and multiple organs caused by MGO and GA levels, associated with the biological mechanisms of the glycation of the SARS-CoV-2 spike protein, could help to explain the infectivity and virulence of this virus in pregnant patients affected by being overweight or obese or having gestational diabetes, and the increased risk of premature delivery and/or low newborn weight.

SARS-CoV-2, Placental Histopathology, Gravity of Infection and Immunopathology: Is There an Association?

(1) Background: As the pandemic months progress, more and more evidence shows that the placenta acts as a "barrier" to SARS-CoV-2, although rare cases of vertical transmission have been described. (2) Methods: In an attempt to investigate whether the symptoms' severity was related to different placental histological characteristics and the immune microenvironment, we subdivided 29 placentas from 29 mothers positive for SARS-CoV-2 into two groups, depending on the symptomatology (moderate/severe vs. asymptomatic/mild), performing immunohistochemical investigations for CD4 + and CD8 + T lymphocytes, as well as for CD68 + macrophage. We also evaluated the immuno-expression of the ACE2 receptor at the placental level. These two groups were compared to a control group of 28 placentas from 28 SARS-CoV-2-negative healthy mothers. (3) Results: The symptoms (likely to be related to viremia) were statistically significantly correlated (p < 0.05) with histopathological changes, such as maternal malperfusion, decidual arteriopathy, blood vessel thrombus of fetal relevance. Furthermore, the immuno-expression of ACE2 was significantly lower in SARS-CoV-2-positive groups vs. control group (p = 0.001). (4) Conclusions: There is still much to study and discover regarding the relationship between SARS-CoV-2 and histological changes in placentas and how the latter might contribute to various neonatal clinical outcomes, such as prematurity.

Gestational SARS-CoV-2 infection is associated with placental expression of immune and trophoblast genes.

INTRODUCTION: Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy. METHODS: We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fisher's exact tests, Spearman correlations and linear regression models. RESULTS: The median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term (≥37 weeks), and gestational age at delivery did not differ between the SARS-CoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants. DISCUSSION: SARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring.

COVID-19 & differential effects in twins: Insights from Placenta Pathology.

INTRODUCTION: COVID-19 has been associated with several adverse pregnancy outcomes, including perinatal loss. Differential effects of COVID-19 in a twin pregnancy may provide unique insights into virus-placental interactions. We present a case of perinatal loss of a female fetus with survival of the male co-twin in a pregnancy complicated by COVID-19 and premature delivery. METHODS: Viral detection methods recommended by the NICHD task force were used to identify SARS-CoV-2 and its viral receptors in the placentas and fetal tissue (Antoun et al., 2020) [1] RESULTS: Compared with the surviving twin, we found a more severe intervillous necrosis and a relatively low detection of ACE2 membranous expression in the syncytiotrophoblasts of the female twin that succumbed. DISCUSSION: The interactions of SARS-CoV-2 and ACE2 at the maternal fetal interface within the placenta may play a significant role in perinatal loss, and the effects of fetal sex and gestational age at time of infection need to be explored further.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

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.

Diffuse and Localized SARS-CoV-2 Placentitis: Prevalence and Pathogenesis of an Uncommon Complication of COVID-19 Infection During Pregnancy.

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).

Low-level SARS-CoV-2 viremia coincident with COVID placentitis and stillbirth.

SARS-CoV-2 infection in pregnancy and COVID placentitis are associated with an increased risk of stillbirth. We sought to investigate the presence of maternal viremia in people with SARS-CoV-2 infection during pregnancy who had histologic placentitis versus those without placentitis. SARS-CoV-2 qRT-PCR was performed on plasma from 6 patients with COVID placentitis and 12 matched controls without placentitis. SARS-CoV-2 infection occurred between 4/2020-1/2021; the latency between SARS-CoV-2 diagnosis and delivery was 0-76 days. Two placentitis cases demonstrated viremia (1 stillbirth and 1 well infant), while 12/12 controls were negative. Future research may consider viremia as a possible marker of COVID placentitis.

Special Issue "Emerging Virus Infections in Adverse Pregnancy Outcomes".

Dear contributors and readers, [...].

Low placental weight and altered metabolic scaling after severe acute respiratory syndrome coronavirus type 2 infection during pregnancy: a prospective multicentric study.

OBJECTIVES: A higher risk of adverse pregnancy outcomes is associated with SARS-CoV-2 infection; this could be partially explained by an altered placental function. Because histopathology is often unspecific, we aimed to assess placental weight, birthweight/placental weight (b/p) ratio, and the metabolic scaling exponent ß, an indicator of normal fetal-placental growth, to analyze placental function. METHODS: We included 153 singleton pregnancies with SARS-CoV-2-positive PCR result who delivered at three referring hospitals in Switzerland. Placental weight and b/p ratio were compared to published reference charts. Logistic regression analysis investigated the role of time of infection and other confounding factors on placental weight. The scaling exponent ß was compared to the reference value of 0.75. RESULTS: Placental weight was inferior or equal to the tenth centile in 42.5% (65 of 153) and to the third centile in 19% (29 of 153) of the cases. The risk of low placental weight was not influenced by the trimester in which infection occurred. The b/p ratio was >50th centile in 80.4% (123 of 153) of the cases. The incidence of foetal growth restriction, preeclampsia, and gestational diabetes was 11.8% (18 of 153), 3.3% (5 of 153), and 19.6% (30 of 153). Linear regression modelling revealed a pathologic metabolic scaling exponent ß of 0.871 ± 0.064 (R2 = 0.56). DISCUSSION: SARS-CoV-2 infection during pregnancy was associated with a higher incidence of low placental weight, an increased b/p ratio, and an abnormal scaling exponent ß in our cohort. This could be particularly relevant for the still controversial issue of an increased stillbirth rate in SARS-CoV-2 infection during pregnancy. In this regard, intensified foetal surveillance should be mandatory in these pregnancies.

Evidence of vertical transmission of SARS-CoV-2 and interstitial pneumonia in second-trimester twin stillbirth in asymptomatic woman. Case report and review of the literature.

Data on the vertical transmission rate of COVID-19 in pregnancy are limited, although data reporting mother-fetal transmission in the second trimester of pregnancy are controversial. We described a case of second-trimester twin stillbirth in a woman with SARS-CoV-2 infection in which placental and fetal markers of infection were detected, despite the absence of respiratory syndrome. The patient developed clinical chorioamnionitis and spontaneously delivered 2 stillborn infants. Placental histology and immunohistochemistry demonstrated SARS-CoV-2 infection mostly within the syncytiotrophoblast, and fetal autopsy showed the development of interstitial pneumonia. Our findings demonstrated that in utero vertical transmission is possible in asymptomatic pregnant women with SARS-CoV-2 infection and that infection can lead to severe morbidity in the second trimester of pregnancy.

Fetal Deaths in Ireland Due to SARS-CoV-2 Placentitis Caused by SARS-CoV-2 Alpha.

CONTEXT.­: A severe third wave of COVID-19 disease affected Ireland in the first 3 months of 2021. In this wave, 1 second-trimester miscarriage and 6 stillbirths were observed in the Irish population because of placental insufficiency as a result of SARS-CoV-2 placentitis. This observation was at odds with the country's previous experience with COVID-19 disease in pregnant mothers. OBJECTIVE.­: To describe the clinical and pathologic features of these pregnancy losses. DESIGN.­: Retrospective review of clinical and pathologic data of cases of second-trimester miscarriage, stillbirth, or neonatal death identified by perinatal pathologists as being due to SARS-CoV-2 placentitis during the third wave of COVID-19 in Ireland. RESULTS.­: Clinical and pathologic data were available for review in 6 pregnancies. Sequencing or genotyping of the virus identified SARS-CoV-2 alpha (B.1.1.7) in all cases. Three of the 6 cases had maternal thrombocytopenia, and fetal growth restriction was not prominent, suggesting a rapidly progressive placental disease. CONCLUSIONS.­: The identification of SARS-CoV-2 alpha in all these cases suggests that the emergence of the variant was associated with an increased risk of fetal death due to SARS-CoV-2 placentitis when compared with the original virus. Maternal thrombocytopenia may have potential as a clinical marker of placentitis, but other inflammatory markers need investigation. Three of the 6 women had been assessed for reduced fetal movements in hospital some days before the fetal deaths actually occurred; this could suggest that there may be a window for intervention in some cases.

Severe placental lesions due to maternal SARS-CoV-2 infection associated to intrauterine fetal death.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause severe placental lesions leading rapidly to intrauterine fetal death (IUFD). From August 2020 to September 2021, in the pathology department of Toulouse Oncopole, we analyzed 50 placentas from COVID-19-positive unvaccinated mothers. The purpose of our study is to describe the clinicopathological characteristics of these placental damages and to understand the pathophysiology. Ten of them (20%) showed placental lesions with positive immunohistochemistry for SARS-CoV-2 in villous trophoblasts. In five cases (10%), we observed massive placental damage associating trophoblastic necrosis, fibrinous deposits, intervillositis, as well as extensive hemorrhagic changes due to SARS-CoV-2 infection probably responsible of IUFD by functional placental insufficiency. In five other cases, we found similar placental lesions but with a focal distribution that did not lead to IUFD but live birth. These lesions are independent of maternal clinical severity of COVID-19 infection because they occur despite mild maternal symptoms and are therefore difficult to predict. In our cases, they occurred 1-3 weeks after positive SARS-CoV-2 maternal real-time polymerase chain reaction testing and were observed in the 2nd and 3rd trimesters of pregnancies. When these lesions are focal, they do not lead to IUFD and can be involved in intrauterine growth restriction. Our findings, together with recent observations, suggest that future pregnancy guidance should include stricter pandemic precautions such as screening for a wider array of COVID-19 symptoms, enhanced ultrasound monitoring, as well as newborn medical surveillance.