The impact of COVID-19 vaccinations on stillbirth rates among pregnant women in the Metro-Detroit area.

Infection by COVID-19 increases maternal morbidity and mortality prompting both the American College of Obstetrics and Gynecology and the Society of Maternal Fetal Medicine to strongly recommend vaccination during pregnancy. Limited data exist assessing the risk of intrauterine fetal death (IUFD) associated with COVID vaccination during pregnancy. This was a retrospective chart review at a large multisite hospital system in Metro Detroit which reviewed data from 13,368 pregnancies. We compared IUFD rates between vaccinated and unvaccinated patients. The rate of stillbirths among unvaccinated women (0.75%) was not statistically different from those who were vaccinated (0.60%). Individuals with government insurance were less likely to be vaccinated and more likely to have IUFD in comparison to patients with private insurance. The rate of stillbirths among Black women was significantly higher than among White women at a rate of 1.1% compared to 0.53% (p=0.008) with no difference in stillbirth rates among vaccinated vs unvaccinated racial distribution. Lastly, it is worth noting that the overall vaccination rate at our healthcare system in pregnancy was very poor (0.26%). In conclusion, this is a large population of highly diverse patients which indicates that COVID-19 vaccination does not lead to IUFD. We plan to use this data to help drive an educational vaccination campaign to try to increase our COVID-19 vaccination rate in our pregnant patients. Systemic racism and social determinants of health have played a large factor in COVID-19 outcomes, and our data highlights that this is the case for IUFD in Black women. Improvements must be made to identify barriers for these women to allow for better pregnancy outcomes. We acknowledge that individuals with government insurance may also have other barriers to healthcare or face healthcare inequity which leaves room for improvement on getting these individuals vaccinated and getting the resources they need to have better pregnancy outcomes.

Case report: Umbilical vessel aneurysm thrombosis and factor V Leiden mutation leading to fetal demise.

Complicated pregnancies are nowadays a major public health concern, with possible lethality or sequelae both for the mother and the fetus. Blood coagulation disorders (including antiphospholipid syndrome, factor V Leiden mutation and antithrombin deficiency) and hypertensive gestational disorders are very well-known contributors of complicated pregnancies with poor fetal outcome, such as intrauterine growth retardation (IUGR) and fetal demise. Less commonly, vascular malformations of the placenta can also potentially lead to serious complications such as IUGR and fetal death. These malformations include hypercoiled umbilical cord, umbilical cord knot, umbilical cord varix, umbilical cord arterial or venous aneurysm, and velamentous insertion of the umbilical cord potentially leading to Benckiser's hemorrhage. Here, we report the case of a 29-year-old Gravida 2 Para 0 mother with previous history of stillbirth and smoking, admitted to the obstetrics department for the absence of fetal movement at 38 weeks of amenorrhea (WA). First-trimester and second-trimester routine ultrasounds were otherwise normal. Ultrasound performed at 38 WA revealed a 83 × 66 × 54 mm cystic heterogenous mass at the umbilical cord insertion. After delivery, fetal and placental pathology as well as maternal blood testing were performed. Fetal pathology was otherwise normal, except for diffuse congestion and meconial overload suggesting acute fetal distress. Fetal karyotype was normal (46 XX). Placental pathology revealed an umbilical artery aneurysm (UAA) at the base of the insertion of the umbilical cord, lined with a CD34+ CD31+ endothelium. After dissection, the aneurysm was filled with hemorrhagic debris, indicating aneurysm thrombosis. Histopathology revealed associated maternal vascular malperfusion (MVM) and increased peri-villous fibrin (IPF). Maternal blood tests revealed heterozygous factor V Leiden mutation, without other associated auto-immune conditions (such as antiphospholipid syndrome). Umbilical artery aneurysms remain extremely rare findings in the placenta, with <20 reported cases. Umbilical artery aneurysms have tendency to be located at the base of the insertion of the placenta, and lead to fetal demise in more than 60% of cases, mainly due to aneurysmal thrombosis, hematoma, possible vascular compression and/or rupture. Umbilical vessel aneurysms can be associated with trisomy 18 or 13. In our case, the association of factor V Leiden mutation, a hypercoagulable state, with UAA could explain massive thrombosis of the aneurysmal lumen and sudden fetal demise. Further consideration of current guidelines for surveillance and management of UAA would allow appropriate planned delivery in maternal care settings.

Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections.

OBJECTIVE: This study aimed to describe the characteristics of fetal demise after SARS-CoV-2 infections and clarify whether it is associated with clinical severity, placental lesions, or malformations or due to actual fetal infections. DATA SOURCES: PubMed and Web of Science databases were searched between December 1, 2019, and April 30, 2022. STUDY ELIGIBILITY CRITERIA: Cohort, cross-sectional, and case-control studies and case series or case reports describing stillbirths or late miscarriages (ie, pregnancy loss occurring between 14 and 22 weeks of gestation, before and after the onset of labor) from mothers with SARS-CoV-2 infection during pregnancy (demonstrated by at least 1 positive real-time reverse transcription-polymerase chain reaction from nasopharyngeal swabs and/or SARS-CoV-2 placental infection). No language restriction was applied; cases with other causes possibly explaining the fetal demise were excluded. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines were followed. The quality of the case series and case reports was evaluated using the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data and placental and fetal virology and histology findings were collected. Data were summarized with descriptive statistics using the World Health Organization criteria to classify disease severity and fetal-neonatal infections. RESULTS: Data from 184 mothers and 190 fetuses were analyzed. No clear link to maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demise cases occurred during the second and third trimesters of pregnancy, approximately 6 to 13 days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms. Most placentas (88%) were positive for SARS-CoV-2 or presented the histologic features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (85%-91%). Of note, 11 fetuses (5.8%) had a confirmed in utero transmitted SARS-CoV-2 infection, and 114 fetuses (60%) had a possible in utero transmitted SARS-CoV-2 infection. CONCLUSION: The synthesis of available data showed that fetal demise generally occurs a few days after the infection with histologic placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

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.

Maternal-Fetal Characteristics of Pregnant Women With Severe COVID Disease and Maternal-Neonatal Characteristics of Neonates With Early-Onset SARS-CoV-2 Infection: A Prospective Data Analysis.

Introduction COVID-19 and its mutants have significantly impacted the health care system, claiming numerous lives and adding to the morbidity. The data are scarce to describe the effect of disease severity on pregnancy outcomes, the possibility of mother-to-child transmission, and neonatal outcomes of COVID-positive babies. This study aimed to report the maternal and fetal characteristics of pregnant women with severe COVID disease as well as maternal and neonatal characteristics of neonates with early-onset SARS-CoV-2 infection. Materials and methods This is a prospective data analysis of pregnant women with severe COVID disease and neonates with early-onset SARS-CoV-2 infection. The disease parameters including demographic data, clinical presentation, investigations, management, and maternal and neonatal outcomes were recorded and analyzed. Results India has faced three waves till now. At the study center, a total of 165 (60, 68, and 37 in the first, second, and third waves, respectively) COVID-positive pregnant women were admitted during all three waves. No severe COVID disease with pregnancy was noted in the first and third waves. During the second wave (March to June 2021), 15 pregnant women were found to have severe COVID disease. All of them had COVID-related symptoms, with the majority requiring supplementary oxygen at presentation. Nine of these women had intrauterine fetal demise at admission. Nearly 73% were in their second trimester, and the rest were in the third trimester. There was raised total leukocyte count and alanine transaminase in 73% and raised aspartate transaminase in all cases. All of them were admitted to the intensive care unit. Two women in their third trimester had a termination of pregnancy by cesarean section, and one of the neonates had early neonatal death due to perinatal asphyxia. Both the neonates were COVID-19 positive. Eleven women with critical illness succumbed to the disease. No neonate was found to have early-onset SAR-CoV-2 infection during the first and third waves. Only 11 neonates tested positive for SARS-CoV-2 at the time of birth during the second wave. None of them had any COVID-related symptoms. Preterm birth was reported in four cases. The average Apgar scores at 1 and 5 minutes were 6.9 and 8.09, respectively. The average birth weight was 2,551.81 grams. All neonates were initially kept in the neonatal intensive care unit. Out of 11, four neonates required treatment in the form of positive-pressure ventilation, chest compressions, high-flow nasal oxygen, and non-invasive and invasive ventilation. Neonatal mortality was documented in two cases. Six mothers had one or more positive results in either amniotic fluid, placental membrane, or vaginal or cervical swab, highlighting the possibility of antepartum or intrapartum transmission. Conclusion Severe COVID disease during pregnancy was associated with high rates of intrauterine fetal demise and maternal mortality. Raised liver enzymes might be taken as a predicting factor for severe disease. On the other hand, early-onset neonatal SARS-CoV-2 infection is mostly asymptomatic and has a good prognosis. Additionally, mother-to-child transmission of SARS-CoV-2 is possible in the antepartum and intrapartum periods.

Extracorporeal membrane oxygenation use in a 26-week pregnant female with a severe COVID-19 infection: Case report

Background: The SARS-COV-19 (COVID-19) pandemic has been an unprecedented global health crisis that has had far reaching implications and has exposed various susceptible patient populations including pregnant women. The effect of COVID-19 on pregnant women is an area of current research, with many studies focusing on maternal and fetal outcomes and maternal-fetal transmission of the virus. Current research suggests that COVID-19 presents similarly in both non-pregnant and pregnant women. Although COVID-19 is rarely vertically transmitted, it is currently unclear whether or not COVID-19 has an effect on the incidence of IUFD in pregnant patients. Case Description: Here, we report the case of a 23-year-old female approximately 26 weeks pregnant, recently diagnosed with COVID-19. The patient required intubation during evaluation in the emergency department (ED) and ultimately was placed on extracorporeal membrane oxygenation (ECMO) while in the intensive care unit (ICU). During the ICU stay intrauterine fetal demise (IUFD) was diagnosed and a spontaneous en caul vaginal delivery occurred. Conclusions: Currently, there is limited data available regarding the effect, or complications, of COVID-19 on the three trimesters of pregnancy. There is also limited data on the use of ECMO in pregnant patients with a COVID-19 infection. The case reported here is further evidence of the necessity of further research into the effects of COVID-19 on pregnant patients and the utilization of ECMO in these cases. © 2022 Laparoscopic Surgery.All right reserved.

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.

SARS-CoV-2 Placental Infection in an Unvaccinated Mother Resulting in Fetal Demise.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy may have devastating complications including fetal demise. Here, we describe a case of SARS-CoV-2 infection in a second-trimester pregnancy. The placenta demonstrated the presence of SARS-CoV-2 viral RNA along with intervillositis and perivillous fibrin deposition. SARS-CoV-2 directly infects the trophoblastic cells of the placenta through the angiotensin-converting enzyme 2 receptor. This case report details the clinical history of a SARS-CoV-2-infected pregnancy with fetal demise. In addition, we show the images of the placental pathology and SARS-CoV-2 RNA in situ studies.

Intrauterine Fetal Demise in the Third Trimester of Pregnancy Associated With Mild Infection With the SARS-CoV-2 Delta Variant Without Protection From Vaccination.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a higher infection rate in pregnant women than age-matched adults. With increased infectivity and transmissibility, the Delta variant is predominant worldwide. METHODS: In this study, we describe intrauterine fetal demise in unvaccinated women with mild symptoms of SARS-CoV-2 Delta variant infection. RESULTS: Histology and elevated proinflammatory responses of the placenta suggest that fetal demise was associated with placental malperfusion due to Delta variant infection. CONCLUSIONS: This study suggests that the Delta variant can cause severe morbidity and mortality to fetuses. Vaccination should continue to be advocated and will likely continue to reduce SARS-CoV-2 infection risks for pregnant women and their fetuses.

Intrauterine Fetal Demise After Uncomplicated COVID-19: What Can We Learn from the Case?

BACKGROUND: SARS-CoV-2 infection in pregnant women can lead to placental damage and transplacental infection transfer, and intrauterine fetal demise is an unpredictable event. CASE STUDY: A 32-year-old patient in her 38th week of pregnancy reported loss of fetal movements. She overcame mild COVID-19 with positive PCR test 22 days before. A histology of the placenta showed deposition of intervillous fibrinoid, lympho-histiocytic infiltration, scant neutrophils, clumping of villi, and extant infarctions. Immunohistochemistry identified focal SARS-CoV-2 nucleocapsid and spike protein in the syncytiotrophoblast and isolated in situ hybridization of the virus' RNA. Low ACE2 and TMPRSS2 contrasted with strong basigin/CD147 and PDL-1 positivity in the trophoblast. An autopsy of the fetus showed no morphological abnormalities except for lung interstitial infiltrate, with prevalent CD8-positive T-lymphocytes and B-lymphocytes. Immunohistochemistry and in situ hybridization proved the presence of countless dispersed SARS-CoV-2-infected epithelial and endothelial cells in the lung tissue. The potential virus-receptor protein ACE2, TMPRSS2, and CD147 expression was too low to be detected. CONCLUSION: Over three weeks' persistence of trophoblast viral infection lead to extensive intervillous fibrinoid depositions and placental infarctions. High CD147 expression might serve as the dominant receptor for the virus, and PDL-1 could limit maternal immunity in placental tissue virus clearance. The presented case indicates that the SARS-CoV-2 infection-induced changes in the placenta lead to ischemia and consecutive demise of the fetus. The infection of the fetus was without significant impact on its death. This rare complication of pregnancy can appear independently to the severity of COVID-19's clinical course in the pregnant mother.

Infrequent Placental and Fetal Involvement in SARS-CoV-2 Infection: Pathology Data from a Large Medical Center.

In order to determine the frequency of SARS-CoV-2 placental and fetal involvements, we analyzed placentas of 197 women positive for infection at delivery and fetal tissues in cases of pregnancy loss in women positive by SARS-CoV-2 PCR (N = 2) and COVID-19 serology (N = 4), using in situ hybridization (ISH), immunohistochemistry (IHC) and, in selected cases, RT-PCR of tissue homogenates. The virus was identified in situ, accompanied by intervillositis, in 2 of 197 placentas (1.02%). In three more cases, SARS-CoV-2 was detected by tissue PCR without in situ localization and placental inflammation. There were no maternal mortality or association of placental infection with the clinical severity of COVID-19. All tested neonates born to SARS-CoV-2-positive women (N = 172) were negative for the virus. There were three pregnancy losses among 197 infected women and in two cases available fetal tissues were negative for SARS-CoV-2. In one of four fetal autopsies performed in women with positive COVID-19 serology, the mother-to-child transmission (MTCT) could be inferred based on positive SARS-CoV-2 nucleocapsid IHC in fetal pulmonary endothelium. Placental involvement by SARS-CoV-2 is rare, but may be underestimated due to its transient nature. MTCT is even rarer, supporting the protective role of placenta in SARS-CoV-2 infection.

Placental lesions and SARS-Cov-2 infection: Diffuse placenta damage associated to poor fetal outcome.

INTRODUCTION: Pregnant women with covid-19 are more likely to experience preterm birth. The virus seems to be associated with a wide range of placental lesions, none of them specific. METHOD: We collected cases of Covid-19 maternal infection during pregnancy associated with poor pregnancy outcomes, for which we received the placenta. We studied clinical data and described pathological findings of placenta and post-mortem examination of fetuses. We performed an immunohistochemical study and RT-PCR of SARS-Cov-2 on placenta samples. RESULTS: We report 5 cases of poor fetal outcome, 3 fetal deaths and 2 extreme premature neonates, one with growth restriction, without clinical and biological sign of SARS-Cov-2 infection. All placenta presented massive perivillous fibrin deposition and large intervillous thrombi associated with strong SARS-Cov-2 expression in trophoblast and SARS-CoV-2 PCR positivity in amniotic fluid or on placenta samples. Chronic histiocytic intervillositis was present in 4/5 cases. Placental ultrasound was abnormal and the sFLT1-PIGF ratio was increased in one case. Timing between mothers' infection and the poor fetal outcome was ≤10 days in 4 cases. The massive placental damage are directly induced by the virus whose receptors are expressed on trophoblast, leading to trophoblast necrosis and massive inflammation in villous chamber, in a similar way it occurs in diffuse alveolar damage in adults infected by SARS-Cov-2. DISCUSSION: SARS-Cov-2 can be associated to a rare set of placental lesions which can lead to fetal demise, preterm birth, or growth restriction. Stronger surveillance of mothers infected by SARS-Cov-2 is required.

Clinical characteristics, prognostic factors, and maternal and neonatal outcomes of SARS-CoV-2 infection among hospitalized pregnant women: A systematic review.

BACKGROUND: Pregnant women represent a potentially high-risk population in the COVID-19 pandemic. OBJECTIVE: To summarize clinical characteristics and outcomes among pregnant women hospitalized with COVID-19. SEARCH STRATEGY: Relevant databases were searched up until May 29, 2020. SELECTION CRITERIA: Case series/reports of hospitalized pregnant women with laboratory-confirmed COVID-19. DATA COLLECTION AND ANALYSIS: PRISMA guidelines were followed. Methodologic quality was assessed via NIH assessment tools. MAIN RESULTS: Overall, 63 observational studies of 637 women (84.6% in third trimester) with laboratory-confirmed SARS-CoV-2 infection were included. Most (76.5%) women experienced mild disease. Maternal fatality, stillbirth, and neonatal fatality rates were 1.6%, 1.4%, and 1.0%, respectively. Older age, obesity, diabetes mellitus, and raised serum D-dimer and interleukin-6 were predictive of poor outcomes. Overall, 33.7% of live births were preterm, of which half were iatrogenic among women with mild COVID-19 and no complications. Most women underwent cesarean despite lacking a clear indication. Eight (2.0%) neonates had positive nasopharyngeal swabs after delivery and developed chest infection within 48 hours. CONCLUSIONS: Advanced gestation, maternal age, obesity, diabetes mellitus, and a combination of elevated D-dimer and interleukin-6 levels are predictive of poor pregnancy outcomes in COVID-19. The rate of iatrogenic preterm birth and cesarean delivery is high; vertical transmission may be possible but has not been proved.