Routine placental histopathology findings from women testing positive for SARS-CoV-2 during pregnancy: Retrospective cohort comparative study.

OBJECTIVE: To assess the impact of maternal Coronavirus disease 2019 (COVID-19) infection on placental histopathological findings in an unselected population and evaluate the potential effect on the fetus, including the possibility of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN: Retrospective cohort comparative study of placental histopathological findings in patients with COVID-19, compared with controls. SETTING: During the COVID-19 pandemic, placentas were studied from women at University College Hospital London who reported and/or tested positive for COVID-19. POPULATION: Of 10 508 deliveries, 369 (3.5%) women had COVID-19 during pregnancy, with placental histopathology available for 244 women. METHODS: Retrospective review of maternal and neonatal characteristics, where placental analysis had been performed. This was compared with available, previously published, histopathological findings from placentas of unselected women. MAIN OUTCOME MEASURES: Frequency of placental histopathological findings and relevant clinical outcomes. RESULTS: Histological abnormalities were reported in 117 of 244 (47.95%) cases, with the most common diagnosis being ascending maternal genital tract infection. There was no statistically significant difference in the frequency of most abnormalities compared with controls. There were four cases of COVID-19 placentitis (1.52%, 95% CI 0.04%-3.00%) and one possible congenital infection, with placental findings of acute maternal genital tract infection. The rate of fetal vascular malperfusion (FVM), at 4.5%, was higher compared with controls (p = 0.00044). CONCLUSIONS: In most cases, placentas from pregnant women infected with SARS-CoV-2 virus do not show a significantly increased frequency of pathology. Evidence for transplacental transmission of SARS-CoV-2 is lacking from this cohort. There is a need for further study into the association between FVM, infection and diabetes.

Development of placental lesions after recovery from COVID-19 during pregnancy: case-control study.

OBJECTIVE: To study whether the occurrence and type of placental lesions vary according to the time of onset of COVID-19 in pregnant women. DESIGN: Case-control study. SETTING: Departments of Gynaecology-Obstetrics and Pathology, Strasbourg University Hospital, France. POPULATION: Cases were 49 placentas of women with COVID-19. Controls were 50 placentas from women who had a past history of molar pregnancy. COVID-19 placentas were categorised based on whether birth occurred at more or less than 14 days post-infection. METHODS: Comparison between case and controls. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes were recorded. Macroscopic and microscopic examination of the placentas was performed. RESULTS: The rate of vascular complications was higher in the COVID groups than in the controls (8 [16.3%] versus 1 [2%], p = 0.02). Signs of fetal (22[44.9%] versus 13 [26%], p = 0.05) and maternal (44 [89.8%] versus 36 [72.0%], p = 0.02) vascular malperfusion and signs of inflammation (11 [22.4%] versus 3 [6.0%], p = 0.019) were significantly more common in the COVID-19 groups than in the control group. Fetal malperfusion lesions (9 [39.1%] versus 13 [50.0%], p = 0.45) and placental inflammation (4 [17.4%] versus 7 [26.9%], p = 0.42) rates were not significantly different between the two COVID-19 groups. Chronic villitis was significantly more common when the delivery occurred >14 days after infection than in the group that delivered <14 days after infection (7 [26.9%] versus 1 [4.4%], p = 0.05). CONCLUSIONS: Our study suggests that SARS-COV-2 induces placental lesions that evolve after disease recovery, especially with the development of inflammatory lesions, such as chronic villitis.

Impact of asymptomatic and mild COVID-19 infection on fetal growth during pregnancy.

BACKGROUND: During pregnancy, certain viral infections are known to significantly affect fetal development. Data regarding the impact of COVID-19 viral infection in pregnancy, specifically in asymptomatic or mild cases, remains limited. This presents a challenge in providing prenatal counseling and antepartum surveillance in pregnancies complicated by COVID-19 infection. Placenta studies have demonstrated that vascular malperfusion patterns attributed to COVID-19 appear to depend on the timing of infection. Given these placental changes, we aim to evaluate the impact of COVID-19 on fetal growth in pregnant patients with asymptomatic or mild disease, stratified by trimester of infection. We hypothesize that COVID-19 infection, especially early in pregnancy, increases the risk of fetal growth restriction (FGR). STUDY DESIGN: This is a single institution, retrospective cohort study of patients ages 16-55 years old with a singleton delivery between December 10, 2020, and April 19, 2021 who had not received a COVID-19 vaccination prior to delivery. COVID-19 infection during pregnancy was defined as a positive SARS-CoV-2 RT-PCR test. FGR was defined as an estimated fetal weight less than the 10th percentile for gestational age or abdominal circumference less than the 10th percentile for gestational age. Maternal and fetal characteristics, including FGR, were compared between women with versus without COVID-19 infection during pregnancy. RESULTS: Among 1971 women with a singleton delivery, 208 (10.6 %) had a prior asymptomatic or mild COVID-19 infection during pregnancy. With the exception in the median prenatal BMI being significantly higher in the COVID-19 group (median, 27.5 vs 26.3, p = 0.04), there were no significant differences in demographics, baseline maternal comorbidities or gestational age between those with versus without COVID-19 infection during pregnancy, or in the proportion of their offspring with FGR (3.4 % (7/208) vs 4.8 % (84/1763), p = 0.36). When the 208 women were stratified by the timing of their COVID-19 infection, the proportion with an offspring with FGR was 8.7 % (2/23), 1.2 % (1/84), and 4.0 % (4/101), for those first diagnosed with COVID-19 during the 1st, 2nd, and 3rd trimesters, respectively (p = 0.72 Cochran-Armitage test for trend). CONCLUSION: Asymptomatic or mild COVID-19 infection in pregnancy, regardless of timing of infection, does not appear to be associated with FGR. Routine serial fetal growth assessment may not be warranted solely for history of COVID-19 infection.

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

OBJECTIVE: To correlate clinical outcomes to pathology in SARS-CoV-2 infected placentas in stillborn and live-born infants presenting with fetal distress. DESIGN: Retrospective, observational. SETTING: Nationwide. POPULATION: Five stillborn and nine live-born infants from 13 pregnant women infected with SARS-CoV-2 seeking care at seven different maternity units in Sweden. METHODS: Clinical 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 MEASURES: Maternal and fetal clinical outcomes and placental pathology in stillborn and live-born infants. RESULTS: Reduced 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. CONCLUSIONS: SARS-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.

A SARS-CoV-2 Delta Variant Case Manifesting as Extensive Placental Infection and Fetal Transmission.

INTRODUCTION: Studies indicate a very low rate of SARS-CoV-2 detection in the placenta or occasionally a low rate of vertical transmission in COVID-19 pregnancy. SARS-CoV-2 Delta variant has become a dominant strain over the world and possesses higher infectivity due to mutations in its spike receptor-binding motif. CASE PRESENTATION: To determine whether SARS-CoV-2 Delta variant has increased potential for placenta infection and vertical transmission, we analyzed SARS-CoV-2 infection in the placenta, umbilical cord, and fetal membrane from a case where an unvaccinated mother and her neonate were COVID-19 positive. A 35-year-old primigravida with COVID-19 underwent an emergent cesarean delivery due to placental abruption in the setting of premature rupture of membranes. The neonate tested positive for SARS-CoV-2 within the first 24 h, and then again on days of life 2, 6, 13, and 21. The placenta exhibited intervillositis, increased fibrin deposition, and syncytiotrophoblast necrosis. Sequencing of viral RNA from fixed placental tissue revealed SAR-CoV-2 B.1.167.2 (Delta) variant. Both spike protein and viral RNA were abundantly present in syncytiotrophoblasts, cytotrophoblasts, umbilical cord vascular endothelium, and fetal membranes. CONCLUSION: We report with strong probability the first SARS-CoV-2 Delta variant transplacental transmission. Placental cells exhibited extensive apoptosis, senescence, and ferroptosis after SARS-CoV-2 Delta infection.

Management of Placental Transfusion to Neonates After Delivery.

This review summarizes high-quality evidence supporting delayed umbilical cord clamping to promote placental transfusion to preterm and term neonates. In preterm neonates, delayed cord clamping may decrease mortality and the need for blood transfusions. Although robust data are lacking to guide cord management strategies in many clinical scenarios, emerging literature is reviewed on numerous topics including delivery mode, twin gestations, maternal comorbidities (eg, gestational diabetes, red blood cell alloimmunization, human immunodeficiency virus [HIV] infection, and severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) and neonatal complications (eg, fetal growth restriction, congenital heart disease, and the depressed neonate). Umbilical cord milking is an alternate method of rapid placental transfusion, but has been associated with severe intraventricular hemorrhage in extremely preterm neonates. Data on long-term outcomes are discussed, as well as potential contraindications to delayed cord clamping. Overall, delayed cord clamping offers potential benefits to the estimated 140 million neonates born globally every year, emphasizing the importance of this simple and no-cost strategy.

SARS-CoV-2 and Placental Pathology: Malperfusion Patterns Are Dependent on Timing of Infection During Pregnancy.

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at different points in the pregnancy timeline may affect maternal and fetal outcomes remains unknown. We sought to characterize the impact of SARS-CoV-2 infection proximate and remote from delivery on placental pathology. We performed a secondary analysis of placental pathology from a prospective cohort of universally tested SARS-CoV-2 positive women >20 weeks gestation at 1 institution. Subjects were categorized as having acute or nonacute SARS-CoV-2 based on infection <14 or ≥14 days from delivery admission, respectively, determined by nasopharyngeal swab, symptom history, and serologies, when available. A subset of SARS-CoV-2 negative women represented negative controls. Placental pathology was available for 90/97 (92.8%) of SARS-CoV-2 positive women, of which 26 were from women with acute SARS-CoV-2 infection and 64 were from women with nonacute SARS-CoV-2. Fetal vascular malperfusion lesions were significantly more frequent among the acute SARS-CoV-2 group compared with the nonacute SARS-CoV-2 group (53.8% vs. 18.8%; P=0.002), while frequency of maternal vascular malperfusion lesions did not differ by timing of infection (30.8% vs. 29.7%; P>0.99). When including 188 SARS-CoV-2 negative placentas, significant differences in frequency of fetal vascular malperfusion lesions remained between acute, nonacute and control cases (53.8% vs. 18.8% vs. 13.2%, respectively; P<0.001). No differences were noted in obstetric or neonatal outcomes between acutely and nonacutely infected women. Our findings indicate timing of infection in relation to delivery may alter placental pathology, with potential clinical implications for risk of thromboembolic events and impact on fetal health.

SARS-CoV-2 Infection and Placental Pathology.

Placental pathophysiology in SARS-CoV-2 infection can help researchers understand more about the infection and its impact on the maternal/neonatal outcomes. This brief review provides an overview about some aspects of the placental pathology in SARS-CoV-2 infection. In total, 11 papers were included. The current literature suggests that there are no specific histopathological characteristics in the placenta related to SARS-CoV-2 infection, but placentas from infected women are more likely to show findings of maternal and/or fetal malperfusion. The most common findings in placentas from infected women were fibrin deposition and intense recruitment of inflammatory infiltrates. The transplacental transmission of this virus is unlikely to occur, probably due to low expression of the receptor for SARS-CoV-2 in placental cell types. Further studies are needed to improve our knowledge about the interaction between the virus and the mother-fetus dyad and the impact on maternal and neonatal/fetal outcomes.

A fisiopatologia da placenta na infecção por SARS-CoV-2 pode ajudar os pesquisadores a entender mais sobre a infecção e seu impacto nos resultados maternos/neonatais. Esta revisão breve fornece uma visão geral sobre alguns aspectos da patologia placentária na infecção por SARS-CoV-2. Ao todo, 11 artigos foram incluídos. A literatura atual sugere que não há características histopatológicas específicas nas placentas relacionadas à infecção por SARS-CoV-2, mas as placentas de mulheres infectadas têm maior probabilidade de apresentar achados de má perfusão materna e/ou fetal. Os achados mais comuns em placentas de mulheres infectadas foram deposição de fibrina e intenso recrutamento de infiltrado inflamatório. A transmissão transplacentária deste vírus é improvável, devido à baixa expressão do receptor para SARS-CoV-2 em tipos de células da placenta. Mais estudos são necessários para melhorar nosso conhecimento sobre a interação entre o vírus e a díade mãe-feto e o impacto nos resultados maternos e neonatais/fetais.

Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

COVID-19 as an independent risk factor for subclinical placental dysfunction.

BACKGROUND: The pandemic of the severe acute respiratory distress syndrome-associated Coronavirus-2 (SARS-CoV-2) has affected millions around the world. In pregnancy the dangers to the mother and fetus are still being explored. SARS-CoV2 can potentially compromise maternal and neonatal outcomes and this may be dependent on the pregnancy stage during which the infection occurs. OBJECTIVE: The present study was done to find the histopathological alterations in the placenta of SARS-CoV-2 positive pregnancies with either no symptoms or mild coronavirus disease (COVID)-19 related symptoms and its association with neonatal outcomes. STUDY DESIGN: This was a prospective analytical study. Twenty seven asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women with a singleton pregnancy delivered between 1st July 2020 and 15th September 2020, were included as cases. An equal number of SARS-CoV-2 negative singleton pregnancies matched for maternal and gestational age during the same period were included as controls. After delivery the histopathological examination of the placenta of these women was done and the findings recorded on a predesigned proforma based on the Amsterdam consensus criteria for evidence of maternal and fetal vascular malperfusion changes. RESULTS: The baseline characteristics were comparable between the cases and controls. The following features of maternal vascular malperfusion (MVM) were significantly higher in the placentae of COVID-19 positive pregnancies: retroplacental hematomas (RPH), accelerated villous maturation (AVM), distal villous hyperplasia (DVH), atherosis, fibrinoid necrosis, mural hypertrophy of membrane arterioles (MHMA), vessel ectasia and persistence of intramural endovascular trophoblast (PIEVT). Fetal vascular malperfusion (FVM) significantly associated with the positive pregnancies were chorioangiosis, thrombosis of the fetal chorionic plate (TFCP), intramural fibrin deposition (IMFD) and vascular ectasia. Additionally, perivillous fibrin deposition was also significantly higher in the placentae of cases. The percentage of spontaneously delivered women was comparable in the two groups. The sex and weight of the newborn and the number of live births were comparable between the two groups. CONCLUSIONS: Asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women, with otherwise uncomplicated pregnancies, show evidence of placental injury at a microscopic level. Similar findings have been demonstrated in other studies too. This placental injury apparently does not lead to poor pregnancy outcomes. The extent of this injury in symptomatic cases of COVID-19 pregnancies and its consequences on the outcomes need to be analysed.

A structured review of placental morphology and histopathological lesions associated with SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified after a cluster of cases in Wuhan, China in December 2019. Whether vertical transmission or placental pathology might occur following maternal infection during pregnancy remains unknown. This review aimed to summarise all studies that examined the placenta or neonates following infection with SARS-CoV-2, or closely related highly pathogenic coronavirus (SARS-CoV-1, or the Middle East respiratory syndrome coronavirus (MERS-CoV)). Structured literature searches found 50 studies that met the inclusion criteria. Twenty studies reported placental histopathology findings in third trimester placentas following maternal SARS-CoV-2 infection. Using the Amsterdam Consensus criteria to categorise the histopathology results, evidence of both fetal vascular malperfusion (35.3% of cases; 95% Confidence Interval (CI) 27.7-43.0%) and maternal vascular malperfusion (46% of cases; 95% CI 38.0-54.0%) were reported, along with evidence of inflammation in the placentas (villitis 8.7% cases, intervillositis 5.3% of cases, chorioamnionitis 6% of cases). The placental pathologies observed in SARS-CoV-2 were consistent with findings following maternal SARS-CoV-1 infection. Of those tested, a minority of neonates (2%) and placental samples tested positive for SARS-CoV-2 infection (21%). Limited conclusions can be drawn about the effect of maternal SARS-CoV-2 infection on placental pathology as most lack control groups and the majority of reports followed third trimester infection. Collaboration to maximise the number of samples examined will increase the reliability and generalisability of findings. A better understanding of the association between maternal SARS-CoV-2 infection and placental pathology will inform maternity care during the coronavirus pandemic.

Placental barrier against COVID-19.

Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and possible induction of pregnancy complications, including miscarriage, fetal malformations, fetal growth restriction and/or stillbirth, are serious concerns for pregnant individuals with COVID-19. According to clinical information, the incidence of vertical transmission of SARS-CoV-2 is limited to date. However, even if a neonate tests negative for SARS-CoV-2, frequent abnormal findings, including fetal and maternal vascular malperfusion, have been reported in cases of COVID-19-positive mothers. Primary receptor of SARS-CoV-2 is estimated as angiotensin-converting enzyme 2 (ACE2). It is highly expressed in maternal-fetal interface cells, such as syncytiotrophoblasts, cytotrophoblasts, endothelial cells, and the vascular smooth muscle cells of primary and secondary villi. However other route of transplacental infection cannot be ruled out. Pathological examinations have demonstrated that syncytiotrophoblasts are often infected with SARS-CoV-2, but fetuses are not always infected. These findings suggest the presence of a placental barrier, even if it is not completely effective. As the frequency and molecular mechanisms of intrauterine vertical transmission of SARS-CoV-2 have not been determined to date, intensive clinical examinations by repeated ultrasound and fetal heart rate monitoring are strongly recommended for pregnant women infected with COVID-19. In addition, careful investigation of placental samples after delivery by both morphological and molecular methods is also strongly recommended.

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.