Disseminated intravascular coagulation complicating mild or asymptomatic maternal COVID-19.

BACKGROUND: Hypercoagulability frequently complicates moderate or severe COVID-19 and can result in venous thromboembolism, arterial thrombosis, or microvascular thrombosis. Disseminated intravascular coagulation, however, is uncommon. OBJECTIVE: We sought to describe the clinical presentation and outcome in a series of pregnant patients with mild or asymptomatic COVID-19 who had disseminated intravascular coagulation. STUDY DESIGN: This was a retrospective case series. Cases were solicited via e-mails targeted to obstetrical providers in the Mednax National Medical Group and a restricted maternal-fetal medicine Facebook page. Inclusion criteria were: hospital admission during pregnancy, positive test for SARS-CoV-2 within 2 weeks of admission, and maternal disseminated intravascular coagulation defined as ≥2 of the following: platelet count ≤100,000 per mm3, fibrinogen ≤200 mg/dL, and prothrombin time ≥3 seconds above the upper normal limit. Exclusion criteria were severe COVID-19 requiring ventilation within an hour of diagnosis of coagulopathy or use of anticoagulants at the time of diagnosis. Maternal and newborn records were abstracted and summarized with descriptive statistics. RESULTS: Inclusion criteria were met in 19 cases from October 2020 through December 2021. Of these, 18 had not received any COVID-19 vaccine, and 1 had unknown vaccination status. Median gestational age on hospital admission was 30 weeks (interquartile range, 29-34 weeks). The main presenting symptom or sign was decreased fetal movement (56%) or nonreassuring fetal heart rate pattern (16%). COVID-19 was asymptomatic in 79% of cases. Two of the 3 defining coagulation abnormalities were found in 89% of cases and all 3 in the remaining 11%. Aspartate aminotransferase was elevated in all cases and ≥2 times the upper normal limit in 69%. Only 2 cases (11%) had signs of preeclampsia other than thrombocytopenia or transaminase elevation. Delivery was performed on the day of admission in 74% and on the next day in the remaining 26%, most often by cesarean delivery (68%) under general anesthesia (62%) because of nonreassuring fetal heart rate pattern (63%). Postpartum hemorrhage occurred in 47% of cases. Blood product transfusions were given in 95% of cases, including cryoprecipitate (89% of cases), fresh/frozen plasma (79%), platelets (68%), and red cells (63%). Placental histopathology was abnormal in 82%, with common findings being histiocytic intervillositis, perivillous fibrin deposition, and infarcts or necrosis. Among the 18 singleton pregnancies and 1 twin pregnancy, there were 13 live newborns (65%) and 7 stillbirths (35%). Among liveborn neonates, 5-minute Apgar score was ≤5 in 54%, and among cases with umbilical cord blood gases, pH ≤7.1 was found in 78% and base deficit ≥10 mEq/L in 75%. Positive COVID-19 tests were found in 62% of liveborn infants. CONCLUSION: Clinicians should be alert to the possibility of disseminated intravascular coagulation when a COVID-19 patient complains of decreased fetal movement in the early third trimester. If time allows, we recommend evaluation of coagulation studies and ordering of blood products for massive transfusion protocols before cesarean delivery if fetal tracing is nonreassuring.

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.

SARS-CoV-2 placentitis - report of two cases and review of the literature.

Covid-19 disease caused by severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) continues to be a global public health problem. Since the pandemic outbreak in early 2020, a number of cases have been reported in pregnant women whose infection has led to severe complications including preterm birth, miscarriage, intrauterine growth restriction or intrauterine fetal demise. The results of the current studies suggest that the transplacental transmission of infection from mother to fetus is a rare event and that the complications listed above are more likely due to damage of placental tissue. In this article, we describe two cases of SARS-CoV-2 placentitis with special consideration to the morphology and differential dia-gnosis of this newly defined entity.

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.

The Potential Benefit of Hydroxychloroquine in Chronic Placental Inflammation of Unknown Etiology Associated with Adverse Pregnancy Outcomes.

The placenta is the site of connection between maternal and fetal circulation, and the liaison is established early in pregnancy. A large variety of pregnancy complications such as preterm birth, fetal growth restriction, or pregnancy loss have placental expression and can be accompanied in some cases of acute or chronic identifiable placental inflamatory lesions. Chronic placental inflammatory (CPI) lesions include chronic villitis of unknow etiology (CVUE), chronic intervillositis of unknown etiology, CIUE (also described as chronic histiocytic intervillositis, CHI), and chronic deciduits. Hydroxychloroquine (HCQ) has been prescribed with good results during pregnancy to prevent adverse perinatal outcomes in maternal autoimmune conditions. Its success has paved the way to its use in CPI as CIUE/CHI; however, to date, there are no prospective, informatively designed, controlled studies on its value in these setting. This review aims to explore the potential role of HCQ in CPI of unknown etiology. Ideally, properly designed, probably multicentric studies should be undertaken to fully understand HCQ's role for prevention of adverse pregnancy outcomes after a chronic placental inflammation.

SARS-CoV-2 Infection in Pregnancy: Clinical Signs, Placental Pathology, and Neonatal Outcome-Implications for Clinical Care.

Introduction: The current COVID-19 pandemic has been associated with high rates of mortality and significant morbidity. Both the risk of infection for pregnant women and the risk of vertical transmission have been evaluated, and the presence of the SARS-CoV-2 virus has been demonstrated both in the placenta and in the amniochorionic membranes. However, the actual effects of this pathogen on pregnancy and on placental morphology are still unclear. Objective: To describe histopathologic findings in the placentas of women with SARS-CoV-2 infection during pregnancy and their correlation with clinical signs and perinatal outcome. Methods: Placental tissues from pregnant women with SARS-CoV-2 infection delivering between March 2020 and February 2021 were analyzed. Results: One hundred six placentas from women with SARS-CoV-2 infection during pregnancy who delivered in Fondazione Policlinico A. Gemelli were examined. Most of them were asymptomatic. All neonates had available test results for SARS-CoV-2 and only one resulted positive. Placental tissues mainly showed signs of maternal vascular malperfusion and of placenta injury in terms of syncytial node increase (96.2%), villar agglutination (77.3%), neointimal hyperplasia (76.4%), excessive fibrin deposition (43.3%), and chorangiosis (35.8%). No significant differences in the frequency of the histopathological lesions were observed according to maternal symptoms. Conclusion: Looking to placental tissues from SARS-CoV-2 positive women at the screening performed close to delivery, placental injuries could be detected without any correlation with fetal and neonatal outcomes. We hypothesize that short latency between SARS-CoV-2 infection and delivery is the main reason for these observations.

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.

SARS-CoV-2 placentitis: An uncommon complication of maternal COVID-19.

We present a case of third trimester pregnancy complicated by SARS-CoV-2 infection and subsequent reduced fetal movements, resulting in emergency Caesarean delivery with demonstrable placental SARS-CoV-2 placentitis. We show through illustration of this case and literature review that SARS-Co-V-2 placentitis is an uncommon but readily recognisable complication of maternal SARS-CoV-2 infection that may be a marker of potential vertical transmission and that may have the capacity to cause fetal compromise through a direct injurious effect on the placenta.

Placental Pathology of COVID-19 with and without Fetal and Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk Factors for Transplacental Transmission of SARS-CoV-2.

The mechanism(s) by which neonates testing positive for coronavirus disease 2019 (COVID-19) acquire their infection has been largely unknown. Transmission of the etiological agent, SARS-CoV-2, from mother to infant has been suspected but has been difficult to confirm. This communication summarizes the spectrum of pathology findings from pregnant women with COVID-19 based upon the infection status of their infants and addresses the potential interpretation of these results in terms of the effects of SARS-CoV-2 on the placenta and the pathophysiology of maternal-fetal infection. Placentas from pregnant women with COVID-19 and uninfected neonates show significant variability in the spectrum of pathology findings. In contrast, placentas from infected maternal-neonatal dyads are characterized by the finding of mononuclear cell inflammation of the intervillous space, termed chronic histiocytic intervillositis, together with syncytiotrophoblast necrosis. These placentas show prominent positivity of syncytiotrophoblast by SARS-CoV-2, fulfilling the published criteria for transplacental viral transmission as confirmed in fetal cells through identification of viral antigens by immunohistochemistry or viral nucleic acid using RNA in situ hybridization. The co-occurrence of chronic histiocytic intervillositis and trophoblast necrosis appears to be a risk factor for placental infection with SARS-CoV-2 as well as for maternal-fetal viral transmission, and suggests a potential mechanism by which the coronavirus can breach the maternal-fetal interface.