Covid-19: Is the placenta a safe space

Problem: Several large studies have demonstrated that COVID-19 pregnant individuals are at a significant risk for severe disease and adverse pregnancy outcomes. The mechanisms underlying these phenomena remain to be elucidated and are the focus of our project. Although fetal and placental infection is rare, placental abnormalities and adverse pregnancy outcomes associated with placental dysfunction in COVID-19 cases have been widely reported. In particular, placental thrombosis and lesions consistent with maternal vascular malperfusion (MVM) of the placenta are common in individuals with COVID-19. Since thrombotic complications have been associated with COVID-19, it is not surprising that pregnant individuals with COVID- 19 are at risk for placental thrombosis. Method of Study: Placentas were evaluated histologically. Extracellular vesicles were isolated by serial centrifugation. Result(s): Adverse pregnancy outcomes associated with these placental lesions, including hypertensive disorders of pregnancy (gestational hypertension and preeclampsia), small for gestational age (SGA, birthweight < 10th percentile for gestational age), and preterm birth (PTB, < 37 weeks) are significantly increased among pregnant individuals with COVID-19. Placental infection with SARSCoV- 2 is uncommon, but multiple inflammatory and metabolic factors are likely to affect the placenta, including circulating extracellular vesicles (EVs) derived from various organs that have been associated with COVID-19 pathology and disease severity.We have analyzed over 500 placentas from COVID-19 pregnancies and found marked changes in placental morphology, characterized by abnormal maternal and fetal vessels, intervillous thrombi, and fibrin deposition, even in the face of mild or asymptomatic disease. We detected increased levels of small EVs in maternal serum from COVID-19 cases compared to controls and increased levels of mitochondrial DNA in EVs from COVID-19 cases. In in vitro experiments, we found increased oxidative stress in uterine endothelial cells and primary trophoblasts. Syncytialization of trophoblast cells following exposure to EVs from pregnant COVID-19 patients was markedly reduced. RNAseq of trophoblast cells exposed to EVs from pregnant COVID-19 patients revealed disruption of multiple pathways related to mitochondria function, oxidative stress, coagulation defects, and inflammation. Timing of infection during pregnancy (first, second, and third trimester) altered EV size distribution, cargo content, and functional consequences of trophoblast EV exposure. Conclusion(s): Our studies show that COVID-19 infection during pregnancy has profound effects on placenta morphology and function. It remains to be determined what the long-term consequences are on the offspring.

CASE REPORT: FETAL DEATH in UTERO COMPLICATED by DISSEMINATED INTRAVASCULAR COAGULATION in MATERNAL COVID-19 INFECTION

Background: COVID-19 infection during pregnancy is associated with an increased risk of stillbirth, likely due to placental insufficiency through the associated inflammatory response and hypoperfusion. A spectrum of associated placental changes has been reported. Whilst pregnancy alone is a hypercoagulable state, concurrent COVID-19 further increases the risk of coagulopathy. Disseminated intravascular coagulation (DIC) is uncommon in pregnancy but is increased in both COVID-19 infection and fetal death in utero (FDIU). Method(s): Case report. Informed written consent was obtained from the patient. Result(s): A 31-year-old G5P2 presented with a FDIU at 23 + 3 weeks gestation, in the setting of maternal COVID-19 infection without respiratory symptoms or oxygen requirements. The pregnancy had been uncomplicated, and her presenting issue was two days of reduced fetal movements, when FDIU was confirmed on ultrasound. On admission, the case was further complicated by disseminated intravascular coagulopathy (DIC). This DIC could have resulted from COVID-19 infection, FDIU or a combination of both. Placental histopathology showed evidence of inflammation, with chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The inflammatory response, evidenced by histopathological findings of CHI and MPFD, likely contributed to placental insufficiency and FDIU. Conclusion(s): COVID-19 infection is associated with increased risk of hematological abnormalities, placental inflammation and pregnancy loss. This case is the first to report both DIC and CHI in the context of FDIU in COVID-19 infection. We present this case to highlight the impact of COVID-19 infection on placental function, coagulation disturbances and subsequently adverse pregnancy outcomes.

PERICARDIAL INVOLVEMENT ASSOCIATED WITH SARS-COV-2 INFECTION. PROSPECTIVE OBSERVATION IN THE COVID- WARD.

Purpose. To identify the occurrence and structure of changes in the pericardium ultrasonography among patients who have undergone COVID-19 and have cardiological symptoms, as well as to compare these changes with the pericarditis aspects and the infection time duration in a prospective cohort observational study. Methods. Inclusion/exclusion criteria: current or transferred COVID-19, new symptoms that occurred during or after infection and forced to consult a cardiologist, the absence of other prerequisites for pericarditis and vaccination against SARS-CoV-2. Echocardiography was performed with an emphasis on the pericardium and an assessment of the echogenicity amplification, the area of the hyperechoic zone, thickness and artifacts, as well as a questionnaire. Results. From 05.2020 to On 10.2020, 335 patients from the covid ward and 284 patients from the out-patient clinic were included. 86% of patients had transient chest discomfort. The peaks of treatment accrued to 4-5 and 10-11 weeks (Me 10[2-36] (1 to 64) weeks) from SARS-CoV-2 infection occurred. Typical ECG changes were registered in 3%, pericardial friction noise - in 7% of patients. In 20% of patients discomfort in the heart area was the first, in 27% - the dominant, in 14% - the only symptom of COVID-19. According to EchoCG data, 96% of the examined patients had ultrasound signs of different changes in the pericardium: slight effusion in 65%, signs of tamponade in 2%, thickening in 12%, local hyperechogenicity in 83%, local adhesion in 8% of patients. The group without pericardial changes was distinguished by the presence of epicardial fat >7 mm. A combination of the echo-cardiography criteria with the second symptom recorded at the visit or earlier was present in 76% of the applicants. Comparison of the recorded ultrasound patterns with the time elapsed since infection allowed us to distinguish ultrasound phases: 1) the phase of damage (pattern of initial edema) occurred at 1 week, 2) the phase of edema /exudation (pattern of visible effusion) - at 3 weeks, 3) fibrosis (pattern of pericardial compaction) - at 11 weeks, 4) regression of inflammatory changes (pattern of local fibrin deposition) - on week 22, 5) residual signs of transferred inflammation may be visualized in patients with symptoms 44 weeks after COVID-19. Conclusions. Consideration of the infectious process triggered by SARS-CoV-2, as a systemic inflammation, allows us to interpret the phenomenon of pericardial involvement as a reactive serositis having ultrasound phases. It was possible to trace some patterns of echocardiography at different stages of the infectious and post-infectious period. Clinical data of 76% of patients can be interpreted as pericarditis, changes in 20% - as an increase in echogenicity of the pericardium.Copyright © 2022 Russian Electronic Journal of Radiology. All rights reserved.

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.

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 present in cases of stillbirth consists of a combination of concurrent destructive findings that include increased fibrin deposition that typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. These 3 pathologic lesions, collectively termed SARS-CoV-2 placentitis, can cause severe and diffuse placental parenchymal destruction that can affect >75% of the placenta, effectively rendering it 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 immunologic 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 pathologic aspects of the relationship between maternal COVID-19 vaccination, SARS-CoV-2 placentitis, and perinatal death.

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.

Maternal thrombocytopenia due to inflammatory changes in the placenta precedes fetal death associated with COVID-19

Introduction: Acute coagulopathy, specific placental change, and fetal death are reported in pregnant women with COVID-19;however, the pathogenesis of them remains unknown. We report two cases of stillbirth in pregnant women with COVID-19 who showed acute coagulopathy and their placentas showed characteristic pathological findings due to COVID-19. Case: Case 1: A 28-year-old pregnant woman (gravida 3, para 2) who had undergone two cesarean sections had a fever of 39 degree and was positive for SARS-CoV-2 at 26 weeks of gestation. She showed thrombocytopenia and subsequent coagulopathy on day 7, and her fetus was dead on day 9. She underwent a cesarean section after blood transfusion and her coagulability thereafter improved. Case 2: A 35-year-old pregnant woman (gravida 3, para 2) who had no symptoms was positive for SARS-CoV-2 at 20 weeks of gestation. She also presented with thrombocytopenia on day 5. Her fetus was dead, and she went into labor spontaneously and virginally delivered a stillborn baby on day 9. Her coagulability thereafter returned to normal. Placental histology of both cases showed intervillous infiltration of histiocytes, necrosis of trophoblast, and fibrin deposition, and the expression of SARS-CoV-2 spike protein was observed in the syncytiotrophoblasts of the villi. Discussion(s): Specific placental changes related to COVID-19 are thought to be the result of an immune response rather than direct infection with SARS-CoV-2. The placental changes induced by COVID-19 might have caused fetal death. When managing pregnant women with COVID-19, thrombopenia may be a predictive marker of fetal death following placental inflammatory changes. Copyright © 2022

MANAGEMENT OF PNEUMOTHORAX AND PNEUMOMEDIASTINUM IN COVID-19 PATIENTS WITH ARDS

SESSION TITLE: What Lessons Will We Take From the Pandemic? SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Since the emergence of COVID-19, many serious complications have arisen especially in the setting of Acute Respiratory Distress Syndrome (ARDS) in the intensive care unit. Historically, ARDS and mechanical ventilation is associated with higher rates of pneumothorax. It has been well described that ARDS is the result of inflammatory lung injury, with increased activation of circulating neutrophils, complement and proinflammatory mediators leading to loss of surfactant, alveolar atelectasis, and fibrin deposition. This leads to a less compliant lung parenchyma, and higher airway pressures, which has been attributed as a risk factor for pneumothorax. The management of pneumothorax varies depending on the etiology of the pneumothorax. In the case of iatrogenic pneumothorax (i.e. mechanical ventilation), tube thoracostomy is generally recommended, however the size of the chest tube inserted remains less clear. METHODS: This is a multi-center retrospective cohort study of 88 hospitalized patients with a diagnosis of COVID-19 and pneumothorax or pneumomediastinum between the dates of 3/11/2020 to 01/26/2021. Patient demographics, comorbidities, laboratory and hemodynamic data were collected as well as ventilator settings, lung mechanics, and clinical patient outcome data including type of intervention and rate of resolution of pneumothorax. Final statistical analysis is pending. RESULTS: Our preliminary results reveal that there was a higher rate of resolution of pneumothorax with a large bore chest tube (LBCT) compared to a small bore chest tube (SBCT). There was no significant difference in lung compliance or tidal volume in cc/kg between the patients with a resolving pneumothorax compared to the patients with a nonresolving pneumothorax. Overall mortality rate among all patients was 70.4%. CONCLUSIONS: Patients with a large bore chest tube placed are more likely to have resolution of pneumothorax compared to small bore chest tube or serial X-ray. Lung compliance and tidal volume were not significantly different between patients that had a resolving pneumothorax compared to nonresolving pneumothorax. It is important to manage a pneumothorax early on to reduce associated morbidity. CLINICAL IMPLICATIONS: The development of pneumothorax in COVID patients with ARDS has significant associated morbidity and mortality. Utilization of a large bore chest tube may result in improved rates of resolution of pneumothorax. DISCLOSURES: No relevant relationships by Nathalie Antonios No relevant relationships by Colby Baker No relevant relationships by Jessica Johnson No relevant relationships by Karen Sayad

Placental pathologies and fetal outcome in pregnant women with COVID-19: A retrospective study

Objective: To describe histopathologic findings in the placentas in women with coronavirus disease 2019 (COVID-19) during pregnancy. Methods: In a cross-sectional study, 38 pregnant women with COVID-19 and undergoing delivery between March 2020 and January 2022, were included. The patients had positive polymerase chain reaction (PCR) test for SARS-CoV-2 infection and the placentas after delivery were sent for histopathologic evaluation based on the Amsterdam Placental Workshop Group Consensus Statement and assessed by two pathologists. Results: Our results showed that maternal vascular malperfusion was the most common and was present in 17 cases (44.7%). These features included accelerated villous maturation (36.8%) distal villous hypoplasia (5.3%), placental infarction (5.3%) and intervillous fibrin deposition (10.5%). Other pathologic findings included focal calcification (10.5%), intravillous congestion and hemorrhage (10.5%), sub-chorionic hemorrhage (5.3%), acute villitis, chronic histiocytic intervillositis and delayed villous maturation each in one case (2.6%). Twelve out of 38 cases showed no significant pathologic changes. Fetal outcomes included neonatal intensive care unit admission rate of 13.2%, dyspnea 31.6%, newborn's anosmia 7.9%, intrauterine fetal demise 2.6%, asphyxia 2.6% and neonate COVID infection 5.3%. Conclusions: Microvasculopathy, as a sign of maternal vascular malperfusion, is a common finding in placentas from SARS-CoV-2 positive pregnant women in the present study. Further studies with larger sample sizes and comparative studies between COVID-19 positive and negative, as well as information from patient follow-up are suggested.

SARS-CoV-2 SPIKE BINDS FIBRINOGEN-INDUCING ABNORMAL INFLAMMATORY BLOOD CLOTS

Background: Life threatening thrombotic events involving both the arterial and venous systems are prominently present in SARS-CoV-2 infected individuals presenting with severe COVID-19. Abnormal clotting also occurs in asymptomatically or mildly infected individuals and in people experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). Clinical management of this clotting disorder has proven difficult in part because these fibrin clots are highly resistant to plasmin-mediated fibrinolysis. Methods: An array of different binding, biochemical, microscopic, and in vivo assays were performed in these studies. All experiments were performed at least three times in triplicate and reported differences were shown to be statistically significant. Results: We find that SARS-CoV-2 Spike directly binds to the terminal clotting factors, fibrinogen and fibrin (Kd of 5.3 μ M and 0.4 μ M respectively). Mixing Spike and plasma accelerates fibrin polymerization. Scanning electron microscopy reveals an abnormal clot structure with finer, denser, and roughened fibrin fibers. Scanning peptide competition assays indicate Spike binds fibrin at three sites: 1) the plasmin cleavage site needed for fibrinolysis;2) a site involved in innate immune signaling via fibrin binding to Complement Receptor 3 (CR3);and 3) a site with no known function. Examination of mice injected 24h earlier with Spike pseudotyped HIV-ΔEnv virions reveals extensive intra-and extravascular fibrin deposition in the lung accompanied by endothelial activation, loss of tight junctions, increased influx of macrophages, and the generation of high levels of reactive oxygen species. This thromboinflammatory response is not observed when Bald virions are injected or when Spike pseudotyped virions are injected into mice lacking fibrinogen. Intriguingly, these Spike-induced proinflammatory effects are blocked by an anti-fibrin monoclonal antibody, 5B8, which interferes with fibrin binding to CR3. Conclusion: Our findings reveal that the SARS-CoV-2 Spike protein binding to fibrinogen/fibrin results in the formation of structurally abnormal, fibrinolysis-resistant blood clots whose inflammatory effects are effectively neutralized by a specific fibrin-targeting monoclonal antibody. While COVID-19 clotting was thought to occur as a result of systemic inflammation, our findings suggest clotting during SARS-CoV-2 infection in fact is a driver of inflammation. Targeting fibrin could lead to novel therapeutic approaches for patients with acute COVID-19 and PASC.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placental Infection Is Associated With Massive Perivillous Fibrin Deposition at the Maternal-Fetal Interface: A Preliminary Study.

We observed an increased frequency of massive perivillous fibrin deposition (MPFD) during the second coronavirus disease 2019 (COVID-19) pandemic wave dominated by the Alpha variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MPFD associated with 100% reverse transcription polymerase chain reaction (RT-PCR) positivity for SARS-CoV-2 and detection by immunohistochemistry. The Alpha variant was identified in all placentas with MPFD that could be sequenced.

Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.

SARS-COV2 placentitis and pregnancy outcome: A multicentre experience during the Alpha and early Delta waves of coronavirus pandemic in England.

Background: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis. Methods: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected. Findings: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described. Interpretation: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation. Funding: There was not funding associated with this study.

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.

Exploring the pathways of inflammation and coagulopathy in COVID-19: A narrative tour into a viral rabbit hole.

Worldwide COVID-19 pandemic has taken a huge toll of morbidity and mortality. In selected patients, classified as severe, the overwhelming inflammatory state imposed by this infection is accompanied by a hypercoagulable state, hallmarked by a unique pattern; a marked increase in D-dimer, out of proportion to other markers of coagulopathy. In this review, we turn a spotlight to this phenomenon, offering a unified conceptual model depicting the leading hypotheses of coagulopathy in COVID-19. The key players of the coagulation cascades accompanying the COVID-19 inflammation malfunction on virtually every level; tissue factor expression is amplified, physiological anti-coagulant pathways (anti-thrombin, protein C and S, and the inhibitor of the tissue factor pathway) are impaired and fibrinolysis is inhibited. Components of autoimmunity, the complement system amongst others, further contribute to the pathology. As data continue to gather, our model offers a pathophysiological overview of COVID-19 coagulopathy, defined by the resultant histopathology: either intra-vascular or extra-vascular. We hope this review will facilitate understanding and serve as a lead point to future therapeutic directives.