Trophoblast Necrosis Research Articles

Clinical, Morphological and Multiplex Analysis of a Case of COVID-19-Associated Placental and Fetal Organ Damage at 16 Weeks Gestation

Abstract. COVID-19-associated damage to the placenta and fetal organs is possible among infected pregnant women. This phenomenon is associated with the presence of the virus in the placental tissue itself and transplacental transmission of SARS-CoV-2 from mother to fetus and occurs in case of severe course of the disease in the mother. However, reliable and clinically significant morphological changes in COVID-19-associated placental damage are still a subject of controversy and speculation. The aim of this article is to present a clinical case analysis and evaluation of the morphological features and results of multiplex analysis of COVID-19- associated fetal and placental tissue damage. Materials and methods. Placental and fetal tissue samples were examined using routine histological methods and immunohistochemical studies of the expression of antibodies to CD15 (MMA), CD3 (MRQ-39), CD68 (KP-1), CD138 (DB-A38). The spectroscopic study was performed using the InSpectr M spectrometer with an excitation wavelength of 532 nm. Results The study revealed an inflammatory infiltrate in the fetal membranes, in the umbilical vein wall, in the stroma of the villi, basal plate and intervillous space, forming thrombi of the vessels of the villi, chorionic plate, intervillous space, trophoblast necrosis, abundant deposition of perivillous fibrin. Spectroscopically, signs of changes in the quantitative and qualitative composition of the amino acids proline, phenylalanine, tyrosine and tryptophan, as well as the appearance of non-standard amino acids (hydroxyproline) and protein isoforms, signs of instability of the acid-base balance were revealed. Conclusion. Among the identified changes, both those characteristic of COVID-19-associated placental damage and non-specific ones associated with the body's inflammatory/cytokine response to COVID-19 and persistent placental infection are determined. The results of the multiplex analysis identified a promising direction in understanding the biological basis and essence of this pathology.

SARS-CoV-2 Infection during Delivery Causes Histopathological Changes in the Placenta.

SARS-CoV-2 can damage human placentas, leading to pregnancy complications, such as preeclampsia and premature birth. This study investigates the histopathological changes found in COVID-19-affected placentas. This study included 23 placentas from patients with active COVID-19 during delivery and 22 samples from patients without COVID-19 infection in their medical history. The samples underwent histopathological examination for pathology, such as trophoblast necrosis, signs of vessel damage, or fetal vascular malperfusion. Newborns from the research group have lower weights and Apgar scores than healthy newborns. In the COVID-19 group, calcifications and collapsed intervillous space were more frequent, and inflammation was more severe than in the healthy group. At the same time, the placenta of SARS-CoV-2-positive patients showed signs of accelerated vascular maturation. Trophoblast necrosis was found only in the placentas of the research group. The expression of CD68+ was elevated in the COVID-19 cohort, suggesting that macrophages constituted a significant part of the inflammatory infiltrate. The increase in lymphocyte B markers was associated with placental infarctions, while high levels of CD3+, specific for cytotoxic T lymphocytes, correlated with vascular injury. SARS-CoV-2 is associated with pathological changes in the placenta, including trophoblast necrosis, calcification, and accelerated villous maturation. Those changes appear to be driven by T cells and macrophages, whose increased expression reflects ongoing histiocytic intervillositis in the placenta.

Sonographic Signs of SARS-CoV-2 Placentitis. Association with Pregnancy Outcome.

Being associated with a systemic infection, SARS-CoV-2 affects multiple organs, including the placenta. SARS-CoV-2 placentitis is a new condition that shows the destructive effects of fibrin deposition in the perivillous area, chronic histiocytic intervillositis and trophoblast necrosis after the placenta is infected with SARS-CoV-2. Until now, there have been no published reports regarding the ultrasound signs of massive perivillous fibrin deposition and the recommended monitoring for these cases. Our aim was to analyze the sonographic appearance of the placenta in a series of SARS-CoV-2 infected pregnant women during their third trimester. In all cases included in the present study, we performed serial obstetrical ultrasounds every seven days until delivery, followed by histopathological examination of the placenta postpartum. In women with intrauterine growth restriction (IUGR), sonographic images of the placentas revealed that they matured faster within three weeks of receiving a COVID-19 diagnosis and reached a more rapid senescence. In all cases, there was a gradual increase in placental calcification from week to week, but only in pregnant women with a grade 3 placenta at the moment of inclusion in the study the deterioration was severe, leading to placental insufficiency and subsequently to IUGR. The cases who had an increased placental degree at the time of infection were associated with abnormally rapid placental aging. These aspects can be evaluated sonographically.

Impact of SARS-CoV-2 infection during pregnancy on the placenta and fetus

Pregnant people and their fetuses are vulnerable to adverse health outcomes from coronavirus 2019 disease (COVID-19) due to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been associated with higher rates of maternal mortality, preterm birth, and stillbirth. While SARS-CoV-2 infection of the placenta and vertical transmission is rare, this may be due to the typically longer time interval between maternal infection and testing of the placenta and neonate. Placental injury is evident in cases of SARS-CoV-2-associated stillbirth with massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. Maternal COVID-19 can also polarize fetal immunity, which may have long-term effects on neurodevelopment. Although the COVID-19 pandemic continues to evolve, the impact of emerging SARS-CoV-2 variants on placental and perinatal injury/mortality remains concerning for maternal and perinatal health. Here, we highlight the impact of COVID-19 on the placenta and fetus and remaining knowledge gaps.

Placental pathology in a large (Swedish) cohort of SARS-CoV-2 infected mothers

IntroductionSARS-CoV-2 placentitis is associated with placental destruction and insufficiency and can affect perinatal outcome. The aim of the current study was to contribute with increased knowledge regarding placental histology in maternal SARS-CoV-2 infection during the pregnancy, as well as the correlation to the severity of maternal SARS-CoV-2 infection. Material and methodsThis retrospective observational study included 116 women who had a verified SARS-CoV-2 infection during pregnancy and gave birth between April 2020 and February 2022 in theStockholm region, Sweden. Placental tissue was evaluated regarding several histopathological parameters, amongst them detection of the triad of characteristics of placental SARS-CoV-2 infection: chronic histiocytic intervillositis, fibrin deposition and villous trophoblast necrosis, and immunohistochemistry for ORF-3 protein expression was used for confirmation. Medical records were reviewed for maternal characteristics and neonatal outcome. ResultsSARS-CoV-2 placentitis was present in one-fifth of the examined placentas admitted to the institute due to maternal SARS-CoV-2 infection, out of which 86,4 % were delivered by acute caesarian section (ACS), all on fetal indication, and one pregnancy ended in stillbirth. Half of the cases without placentitis were delivered by ACS, out of which 50 % were on fetal indication. There was a clear tendency of a shorter time gap between confirmed maternal SARS-CoV-2 infection and delivery in the placentitis group. DiscussionThe presence of SARS-CoV-2 placentitis does not seem to correlate with maternal factors or the severity of infection. It does correlate with development of placental dysfunction of acute/subacute onset and is often manifested as reduced fetal movements.

SARS-CoV-2 Infection in Late Pregnancy and Childbirth from the Perspective of Perinatal Pathology.

This review focuses on SARS-CoV-2 infection in placental and fetal tissues. Viremia is rare in infected pregnant women, and the virus is seldom amplified from placental tissues. Definite and probable placental infection requires the demonstration of viral RNA or proteins using in situ hybridization (ISH) and immunohistochemistry (IHC). Small subsets (1.0-7.9%, median 2.8%) of placentas of SARS-CoV-2-positive women showed definite infection accompanied by a characteristic histopathology named SARS-CoV-2 placentitis (SP). The conventionally accepted histopathological criteria for SP include the triad of intervillositis, perivillous fibrin deposition, and trophoblast necrosis. SP was shown to be independent of the clinical severity of the infection, but associated with stillbirth in cases where destructive lesions affecting more than 75% of the placental tissue resulted in placental insufficiency and severe fetal hypoxic-ischemic injury. An association between maternal thrombophilia and SP was shown in a subset of cases, suggesting a synergy of the infection and deficient coagulation cascade as one of the mechanisms of the pathologic accumulation of fibrin in affected placentas. The virus was amplified from fetal tissues in approximately 40% of SP cases, but definite fetal involvement demonstrated using ISH or IHC is exceptionally rare. The placental pathology in SARS-CoV-2-positive women also includes chronic lesions associated with placental malperfusion in the absence of definite or probable placental infection. The direct viral causation of the vascular malperfusion of the placenta in COVID-19 is debatable, and common predispositions (hypertension, diabetes, and obesity) may play a role.

SARS‐CoV‐2 placentitis and severe pregnancy outcome after maternal infection: A Danish case series

SARS-CoV-2 infection during pregnancy may cause viral inflammation of the placenta, resulting in fetal demise even without fetal or newborn infection. The impact of timing of the infection and the mechanisms that cause fetal morbidity and mortality are not well understood. To describe placental pathology from women with confirmed SARS-CoV-2 infection during pregnancy, a SARS-CoV-2 immunohistochemistry-positive placenta and late miscarriage, stillbirth, neonatal death, or medically indicated birth due to fetal distress. The triad of trophoblastic necrosis, inflammatory intervillous infiltrates, and increased perivillous fibrinoid deposition was present in all 17 placentas; the pregnancies resulted in eight stillbirths, two late miscarriages (19 and 21 weeks' gestation), and seven liveborn children, two of which died shortly after delivery. The severity of maternal COVID-19 was not reflected by the extent of the placental lesions. In only one case, SARS-CoV-2 was detected in lung tissue samples from the fetus. The majority events (miscarriage, stillbirth, fetal distress resulting in indicated birth, or livebirth, but neonatal death) happened shortly after maternal SARS-CoV-2 infection was diagnosed. Seven of eight sequenced cases were infected with the Delta (B.1.617.2) virus strain. We consolidate findings from previous case series describing extensive SARS-CoV-2 placentitis and placental insufficiency leading to fetal hypoxia. We found sparse evidence to support the notion that SARS-CoV-2 virus had infected the fetus or newborn.

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

IntroductionSARS-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. MethodsWe 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. ResultsTwelve 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. DiscussionIn 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 Histopathological "Placentitis Triad" Is Specific for SARS-CoV-2 Infection, and Its Acute Presentation Can Be Associated with Poor Fetal Outcome.

(1) Background: Placental histological lesions reported in relation with SARS-CoV-2 infection are various, with potential consequences such as fetal growth retardation, prematurity or stillbirth/neonatal death. We report here on a placental pathological association which could be specific for SARS-CoV-2 infection and associated with poor fetal outcome; (2) Methods: We collected all the placental pathological examinations performed in Brest University Hospital (France) since the beginning of COVID-19 pandemic with a known maternal SARS-CoV-2 infection and a poor pregnancy outcome. In these cases, we described the pathological lesions and we searched for these lesions in a large series of placentas collected and examined in the same institution before the SARS-CoV-2 pandemic; (3) Results: Three cases with severe fetal outcome (tardive abortion, prematurity, neonatal death), from the first to the third trimesters of pregnancy, were included. The three cases showed features of massive and acute "placentitis triad" consisting in massive perivillous fibrin deposition, sub-acute intervillositis and trophoblastic necrosis. This association was not encountered in any of 8857 placentas analyzed during the period between 2002 and 2012 in our institution; (4) Conclusions: The "placentitis triad" appears to be specific for SARS-CoV-2 infection and, in case of massive and acute presentation, could result in poor fetal outcome.

SARS-CoV-2 placentitis, stillbirth, and maternal COVID-19 vaccination: clinical–pathologic correlations

Stillbirth is a recognized complication of COVID-19 in pregnant women that has recently been demonstrated to be caused by SARS-CoV-2 infection of the placenta. Multiple global studies have found that the placental pathology findings present in cases of stillbirth consists of a combination of concurrent destructive findings that include increased fibrin deposition which typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis and trophoblast necrosis. These three pathological lesions, collectively termed SARS-CoV-2 placentitis, can cause severe and diffuse placental parenchymal destruction that can affect greater than 75% of the placenta, effectively rendering the placenta incapable of performing its function of oxygenating the fetus and leading to stillbirth and neonatal death via malperfusion and placental insufficiency. Placental infection and destruction can occur in the absence of demonstrable fetal infection. Development of SARS-CoV-2 placentitis is a complex process that may have both an infectious and immunological basis. An important observation is that in all reported cases of SARS-CoV-2 placentitis causing stillbirth and neonatal death the mothers were unvaccinated. SARS-CoV-2 placentitis is likely the result of an episode of SARS-CoV-2 viremia at some time during the pregnancy. This article discusses clinical and pathological aspects of the relationship between maternal COVID-19 vaccination, SARS-CoV-2 placentitis and perinatal death.

O-054 COVID-19 during pregnancy, maternal immune response and neonatal cell-specific immunity

Pathogens are a major threat to maternal health and the progression of pregnancy. The immune response during normally progressing pregnancies, primarily the suppression of inflammation, likely accounts for this high susceptibility of pregnant women to infections. An increased morbidity and mortality related to influenza, COVID-19 and malaria has been reported for pregnant women, compared to non-pregnant women. Especially influenza infections during pregnancy have been well studied, as humans are severely and recurrently affected by seasonal epidemics and random pandemics. Besides severe maternal symptoms such as acute cardiopulmonary events, pneumonia, and acute respiratory distress syndrome, maternal influenza infection also causes foetal complications, such as intrauterine growth restriction, preterm birth or even foetal death. However, vertical transmission of the influenza virus across the placenta and infection of the foetus has not been observed, suggesting that the pregnancy pathologies are maternally derived.In addition to influenza-mediated adverse conditions, the recent COVID-19 pandemic has underscored that infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can also lead to severe illnesses in pregnant women, accompanied by a higher risk for foetal loss or preterm birth. Fortunately, with the ongoing pandemic, large cohort studies and meta-analyses revealed that vertical transmission and related fetal infection is a rare complication affecting only 1-3% of SARS-CoV-2 infections in pregnancy. These low risk for placental infection is likely due to the inefficient SARS-CoV-2 virus replication in placental tissues. Since understanding SARS-CoV-2-related pathogenicity during pregnancy is highly relevant, we initiated a study early in 2020, to which we have recruited more than 160 pregnant women with COVID-19. Our comprehensive placental analyses unearthed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection and in convalescent pregnant women. Furthermore, we could show inefficient SARS-CoV-2 replication in placental tissues in vitro, which provides a rationale for the low ex vivo viral expression. We detected specific SARS-CoV-2 T cell responses in mothers within a few days upon infection, which is undetectable in cord blood. Reports by others have shown that maternal SARS-CoV-2 during pregnancy may cause placental insufficiency, defined by increased perivillous fibrin deposition, histiocytic intervillositis and trophoblast necrosis. These changes can cause extensive placental damage leading to placental malperfusion and insufficiency that is incompatible with intrauterine survival. Considering that multiple SARS-CoV-2 variants of concern which emerged until today may affect pregnant women differently and bear a differential risk for pregnancy complication. This, continuous vigilance is needed in order to provide best protection of the highly vulnerable group of pregnant women and their unborn children.Trial registration number

Single-cell RNA sequencing reveals immunological rewiring at the maternal-fetal interface following asymptomatic/mild SARS-CoV-2 infection.

While severe coronavirus 2019 (COVID-19) is associated with immune activation at the maternal-fetal interface, responses to asymptomatic/mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy remain unknown. Here, we assess immunological adaptations in blood and term decidua in response to asymptomatic/mild disease in pregnant women. We report attenuated antigen presentation and type I interferon (IFN) signaling pathways, loss of tissue-resident decidual macrophages, and upregulated cytokine/chemokine signaling in monocyte-derived decidual macrophages. Furthermore, we describe increased frequencies of activated tissue-resident T cells and decreased abundance of regulatory T cells with infection while frequencies of cytotoxic CD4/CD8 T cells are increased in the blood. In contrast to decidual macrophages, type I IFN signaling is higher in decidual T cells. Finally, infection leads to a narrowing of T cell receptor diversity in both blood and decidua. Collectively, these observations indicate that asymptomatic/mild COVID-19 during pregnancy results in remodeling of the immunological landscape of the maternal-fetal interface, with a potential for long-term adverse outcomes for the offspring.

Clinical-pathological features in placentas of pregnancies with SARS-CoV-2 infection and adverse outcome: case series with and without congenital transmission.

ObjectiveTo correlate clinical outcomes to pathology in SARS‐CoV‐2 infected placentas in stillborn and live‐born infants presenting with fetal distress.DesignRetrospective, observational.SettingNationwide.PopulationFive stillborn and nine live‐born infants from 13 pregnant women infected with SARS‐CoV‐2 seeking care at seven different maternity units in Sweden.MethodsClinical outcomes and placental pathology were studied in 14 cases (one twin pregnancy) of maternal SARS‐CoV‐2 infection with impaired fetal outcome. Outcomes were correlated to placental pathology in order to investigate the impact of virus‐related pathology on the villous capillary endothelium, trophoblast and other cells.Main outcome measuresMaternal and fetal clinical outcomes and placental pathology in stillborn and live‐born infants.ResultsReduced fetal movements were reported (77%) and time from onset of maternal COVID‐19 symptoms to signs of fetal distress among live‐born infants was 6 (3–12) days and to diagnosis of stillbirth 11 (2–25) days. Two of the live‐born infants died during the postnatal period. Signs of fetal distress led to emergency caesarean section in all live‐born infants with umbilical cord blood gases and low Apgar scores confirming intrauterine hypoxia. Five stillborn and one live‐born neonate had confirmed congenital transmission. Massive perivillous fibrinoid deposition, intervillositis and trophoblast necrosis were associated with SARS‐CoV‐2 placental infection and congenital transmission.ConclusionsSARS‐CoV‐2 can cause rapid placental dysfunction with subsequent acute fetal hypoxia leading to intrauterine fetal compromise. Associated placental pathology included massive perivillous fibrinoid deposition, intervillositis and trophoblast degeneration.

Stillbirth after COVID-19 in Unvaccinated Mothers Can Result from SARS-CoV-2 Placentitis, Placental Insufficiency, and Hypoxic Ischemic Fetal Demise, Not Direct Fetal Infection: Potential Role of Maternal Vaccination in Pregnancy.

Stillbirth is a recently recognized complication of COVID-19 in pregnant women. Other congenitally transmitted infections from viruses, bacteria and parasites can cause stillbirth by infecting fetal organs following transplacental transmission of the agent from the maternal bloodstream. However, recent research on pregnant women with COVID-19 having stillbirths indicates that there is another mechanism of stillbirth that can occur in placentas infected with SARS-CoV-2. In these cases, viral infection of the placenta results in SARS-CoV-2 placentitis, a combination of concurrent destructive findings that include increased fibrin deposition which typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis and trophoblast necrosis. These three pathological lesions, in some cases together with placental hemorrhage, thrombohematomas and villitis, result in severe and diffuse placental parenchymal destruction. This pathology can involve greater than one-half of the placental volume, averaging 77% in the largest study of 68 cases, effectively rendering the placenta incapable of performing its function of oxygenating the fetus. This destructive placental process can lead to stillbirth and neonatal death via malperfusion and placental insufficiency which is independent of fetal infection. Fetal autopsies show no evidence that direct infection of fetal organs is contributory. Because all mothers examined have been unvaccinated, maternal vaccination may prevent viremia and consequent placental infection.

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

Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. 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). 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. 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. 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.

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.

Chronic Histiocytic Intervillositis: A Placental Histopathologic Feature in Vertical Transmission of Maternal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Introduction/ObjectiveVertical transmission of severe acute respiratory syndrome associated with coronavirus-2 (SARS-CoV-2) infection has been reported as a rare occurrence. The purpose of this study is to identify any specific placental histopathologic abnormalities associated with SARS-CoV-2 infection, compare differences between mothers with symptomatic and asymptomatic coronavirus disease 2019 (COVID-19), and determine the frequency of vertical transmission.Methods/Case ReportPlacentas from mothers diagnosed with COVID-19 during pregnancy and delivered at Stony Brook University Hospital were identified. A control group of mothers with a negative COVID-19 test was selected from the same period. The frequency of histopathologic characteristics defined by the Amsterdam Placental Workshop Group Consensus was compared using chi-square tests between the following cohorts: COVID-19 positive mothers against COVID-19 negative mothers and symptomatic COVID-19 mothers against asymptomatic COVID-19 positive mothers.Results (if a Case Study enter NA)A retrospective study reviewed 23 placentas from mothers with COVID-19 for features of maternal vascular malperfusion, fetal vascular malperfusion, and inflammatory changes. 11 mothers displayed symptomatic COVID-19, and 12 mothers were asymptomatic. One neonate tested positive for SARS-CoV-2. No significant differences were identified in the frequency of the examined placental histopathologic characteristics between COVID-19 positive and negative mothers. The degree of COVID-19 severity did not significantly impact the frequency of examined histopathologic features. Interestingly, in the case with vertical transmission, the placenta demonstrated the only finding of chronic histiocytic intervillositis (CHI) with associated trophoblast necrosis.ConclusionComparing across groups based on COVID-19 status, this study found no specific placental histopathologic features associated with maternal SARS-CoV-2 infection, regardless of symptom severity. However, in one case of vertical transmission, CHI was a unique histopathologic feature. These findings are consistent with the current literature. Further large-scale investigations are needed to establish additional patterns of specific placental histopathology, incidence and contributing factors of vertical transmission of COVID-19, and the impact of CHI in future pregnancies of affected women.

Association of SARS-CoV-2 placental histopathology findings with maternal–fetal comorbidities and severity of COVID-19 hypoxia

Objective SARS-CoV-2 is known to impact multiple organ systems, with growing data to suggest the potential for placental infection and resultant pathology. Understanding how maternal COVID-19 disease can affect placental histopathology has been limited by small study cohorts with mild disease, review by multiple pathologists, and potential confounding by maternal–fetal comorbidities that can also influence placental findings. This study aims to identify pathologic placental findings associated with COVID-19 disease and severity, as well as to distinguish them from changes related to coexisting maternal–fetal comorbidities. Methods This is an observational study of 61 pregnant women with confirmed SARS-CoV-2 infection who delivered and had a placental histological evaluation at NYU Langone Health between March 19, 2020 and June 30, 2020. Primary outcomes were the prevalence of placental histopathologic features and their association with maternal–fetal comorbidities and severity of COVID-19 related hypoxia. Analysis was performed using Fisher’s exact test and t-test with p < 0.05 considered significant. Results Sixty-one placentas were included in the study cohort, 71% from pregnancies complicated by at least one maternal–fetal comorbidity. Twenty-five percent of placentas were small for gestational age and 77% exhibited at least one feature of maternal vascular malperfusion. None of the histopathologic features in the examined placentas were associated with the presence of any specific maternal–fetal comorbidity. Thirteen percent of the cohort required maternal respiratory support for COVID-19 related hypoxia. Villous trophoblast necrosis was associated with maternal supplemental oxygen requirement (67 vs. 33%, p = 0.04) and intubation (67 vs. 33%, p = 0.01). Conclusion In pregnancies complicated by COVID-19 disease, there was a high prevalence of placental histopathologic changes identified, particularly features of maternal vascular malperfusion, which could not be attributed solely to the presence of maternal–fetal comorbidities. The significantly increased prevalence of villous trophoblast necrosis in women needing respiratory support suggests a connection to the severity of COVID-19 illness.

Molecular Pathology Demonstration of SARS-CoV-2 in Cytotrophoblast from Placental Tissue with Chronic Histiocytic Intervillositis, Trophoblast Necrosis and COVID-19.

A subset of placentas from pregnant women having the SARS-CoV-2 infection have been found to be infected with the coronavirus using molecular pathology methods including immunohistochemistry and RNA in situ hybridization. These infected placentas can demonstrate several unusual findings which occur together—chronic histiocytic intervillositis, trophoblast necrosis and positive staining of the syncytiotrophoblast for SARS-CoV-2. They frequently also have increased fibrin deposition, which can be massive in some cases. Syncytiotrophoblast is the most frequent fetal-derived cell type to be positive for SARS-CoV-2. It has recently been shown that in a small number of infected placentas, villous stromal macrophages, termed Hofbauer cells, and villous capillary endothelial cells can also stain positive for SARS-CoV-2. This report describes a placenta from a pregnant woman with SARS-CoV-2 that had chronic histiocytic intervillositis, trophoblast necrosis, increased fibrin deposition and positive staining of the syncytiotrophoblast for SARS-CoV-2. In addition, molecular pathology testing including RNAscope and immunohistochemistry for SARS-CoV-2 and double-staining immunohistochemistry using antibodies to E-cadherin and GATA3 revealed that cytotrophoblast cells stained intensely for SARS-CoV-2. All of the cytotrophoblast cells that demonstrated positive staining for SARS-CoV-2 were in direct physical contact with overlying syncytiotrophoblast that also stained positive for the virus. The pattern of cytotrophoblast staining for SARS-CoV-2 was patchy, and there were chorionic villi having diffuse positive staining of the syncytiotrophoblast for SARS-CoV-2, but without staining of cytotrophoblast. This first detailed description of cytotrophoblast involvement by SARS-CoV-2 adds another fetal cell type from infected placentas that demonstrate viral staining.

Ultrastructural evidence for vertical transmission of SARS-CoV-2

Since the initial correspondence by Goldsmith et al. (2020) in The Lancet, numerous electron micrographs of putative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virions in biopsy and autopsy tissues have been published. A recent review of these images (Bullock et al., 2021) indicated that previous ultrastructural reports of virions in placental tissue were misidentifications. Placental histology of mothers and neonates, both testing positive for SARS-CoV-2, is typified by chronic histiocytic intervillositis and trophoblast necrosis, with RNA in-situ hybridization/immunohistochemical findings localizing viral RNA/viral antigens to the syncytiotrophoblast (Schwartz and Morotti, 2020).