Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Perinatal aspects of sars-cov-2 infection during pregnancy: A potential cause for concern

Ever since the beginning of COVID-19 pandemic, uncertainty regarding clinical presentation and differences among various subpopulations exist. With more than 209,870,000 confirmed cases and more than 4,400,000 deaths worldwide, we are facing the new era of health crisis which will undoubtedly impair global health, economic and social circumstances. In the past year, numerous genetic mutations which code SARS-CoV-2 proteins led to the occurrence of new viral strains, with higher transmission rates. Apart from the implementation of vaccination, the effect of SARS-CoV-2 on pregnancy outcome and maternal fetal transmission remains an important concern. Although neonates diagnosed with COVID-19 were mostly asymptomatic or presented with mild disease, the effect on early pregnancy is yet to be evident. While positive finding of SARS-CoV-2 RNA in some samples such as amniotic fluid, placental tissue, cord blood and breast milk exists, additional research should confirm its association with transplacental transmission.Copyright © 2022, Dr. Mladen Stojanovic University Hospital. All rights reserved.

Impact of SARS-CoV-2 infection in pregnancy on fetal immune state

SARS-CoV-2 infection during pregnancy is associated with increased risk of adverse maternal and pregnancy outcomes. Maternal COVID- 19 is associated with immune activation and inflammatory response in the pregnant individual and an altered immune repertoire in the placenta. Mother-to-child transmission of infection is reported but uncommon. Still, the potential impact of maternal SARS-CoV-2 infection on the immunologic and inflammatory state of the infant is of interest, both for the acute health of the newborn and longer-term outcomes. In this talk, we will discuss the mixed data from cord blood and infant studies of cytokine profiles, transcriptomics, immunophenotyping, and functional studies. We will address the timing and severity of maternal infection as we explore the potential immunological consequences of in utero exposure to maternal SARS-CoV-2 infection.

Mesenchymal Stem/Stromal Cells: DEVELOPMENT OF A GMP BANKING PROCESS FOR UMBILICAL CORD MESENCHYMAL STROMAL CELLS (UC-MSCS) AND USE OF UC-MSC IN CHARACTERISATION ASSAYS, FUNCTIONAL ASSAYS AND GENE EDITING STUDIES

Background & Aim: The pro-angiogenic, immunoregulatory and anti- inflammatory properties of MSCs are being exploited for the development of cellular therapies, including the treatment of graft versus host disease (GvHD), inflammatory bowel disease and COVID-19. SNBTS have developed a GMP process to bank umbilical cord MSCs (UC-MSCs) whereby we can reliably bank 100 vials of 10 million P2 UC-MSCs per cord. Each of these vials can be extensively expanded and stored for specific applications. The ultimate aim of the bank is for off-the-shelf clinical use, e.g., in GvHD or as an adjuvant therapy in Islet transplantations. Methods, Results & Conclusion(s): During process development, different basal media and supplements were screened for proliferation and MSC marker expression. Cells grown in promising media combinations were then tested for tri-lineage differentiation (identity), their chemokine/cytokine expression and T-cell inhibition (function) assessed. Medium selected for further GMP development and scale up was ultimately determined by all round performance and regulatory compliance. GMP-like UC-MSCs were shown to have immune-modulatory activity in T-cell proliferation assays at 4:1 or 16:1 ratios. Co-culture of UC-MSCs and freshly isolated leukocytes, +/- the immune activating agent LPS, show a dose dependent survival effect on leukocytes. In particular, neutrophils, which are normally very short lived in vitro demonstrated increased viability when co-cultured with UCMSCs. The survival effect was partially reproduced when UC-MSC were replaced with conditioned medium or cell lysate indicating the involvement of soluble factors. This improved neutrophil survival also correlates with results from leukocyte migration studies that demonstrate neutrophils to be the main cell type attracted to MSCs in in vitro and in vivo. Genetic modification of UC-MSC may improve their therapeutic potential. We have tested gene editing by CRISPR/Cas9 technology in primary UC-MSCS. The CXCL8 gene, highly expressed in UC-MSC, was targeted in isolates from several different donors with editing efficiencies of 78-96% observed. This translated to significant knockdown of CXCL8 protein levels in resting cells, however after stimulation levels of CXCL8 were found to be very similar in edited and non-edited UC-MSCs. This observation requires further study, but overall the results show the potential to generate future banks of primary UC-MSCS with genetically enhanced pro-angiogenic, immunoregulatory and/or anti-inflammatory activities.Copyright © 2023 International Society for Cell & Gene Therapy

Transplacental transfer of SARS-CoV-2 variant antibodies following COVID-19 vaccination during pregnancy

Problem: Despite being over 3 years into the pandemic, infants remain highly undervaccinated and at a high risk for hospitalization due to COVID-19. Further investigation as to how maternal health decisions for immunization can reduce morbidity from infant COVID-19 by providing passive immunity is necessary. The objective of this study was to describe the rates of SARS-CoV-2 variant antibody transfer from mother to infant cord blood by trimester ofmaternal vaccination. Methods of study: This is an observational cohort study including mother-infant dyads receiving primary or subsequent booster COVID- 19 vaccines during pregnancy.Unvaccinated, but SARS-CoV-2 infected dyads with were included as a comparison group. We quantified median titer and interquartile range (IQR) for SARS-CoV-2 receptor binding domain (RBD) IgG in infant cord blood samples at delivery using the mesoscale discovery platform (electrochemiluminescence). Primary outcome was infant cord IgG titer by trimester of vaccination for the WA1/2022 RBD IgG and current circulating, immune evasive XBB RBD IgG. Secondary outcome is the percent detectable IgG for each variant. Sensitivity analysis was performed based on known SARS-CoV-2 infection. Result(s): Eighty-three mother-infant dyads were included in this analysis. Seven were vaccinated in the first trimester, 37 in the second trimester, 33 in the third trimester, and 6 were unvaccinated and infected. Twenty-three (30%) of the vaccinated group had known SARS-CoV-2 infection. Most received monovalent mRNA COVID-19 vaccines during pregnancy, aside from two who received the viralvectored Ad26.COV2.S, and two received the bivalent mRNA vaccine during pregnancy. The median cord blood WA1/2020 RBD IgG titer was 5370 (412-7296) for first, 1225 (589-3289) for second, 2623 (664-5809) for third trimester in individuals who received aCOVID-19 vaccine dose during pregnancy, and 45 (10-187) in those unvaccinated and infected. After excluding thosewith infection, the cord blood IgG was 514 (106-4182), 1070 (518-2317), and 2477 (664-4470) for first, second, and third trimester, respectively. The rate of detectable WA1/2020 RBD IgG was 100% for all three trimesters, even when excluding infected individuals. For theXBBvariant, cord bloodRBDIgG titer was 284 (43-1296) for first, 66 (32-227) for second, 173 (45-389) for third trimester, and 10 (10-11) in the unvaccinated/infected group. Excluding infections, the cord blood XBB RBD IgG was 54 (10-128), 44 (25-181), and 152 (45-360) for first, second, and third trimester vaccination, respectively. The rate of detectable XBB IgG in those who received a vaccine during pregnancy were 83%, 91%, and 90% for first, second, and third trimester respectively, compared to 17% in the unvaccinated/infected group. Excluding infections, the rate of XBB RBD IgG detection was 66%, 89%, and 95% for first, second, and third trimester vaccination, respectively. Conclusion(s): Vaccination during pregnancy leads to high rates of detectable cord blood IgG specific to SARS-CoV-2 WA1/2020 variant and current circulating variants (XBB), regardless of trimester of vaccination. Infection history leads to higher cord blood IgG in vaccinated;however, infection alone without vaccination leads to lower titer and greater rates of undetectable cord IgG at delivery.

Macerated stillbirth

Stillbirth is defined as the birth of a viable baby without signs of life. They account for more than 2.5 million intrauterine deaths per year worldwide and are associated with a number of risk factors, the most important of which are maternal and placental factors. Autopsy provides information that may be of use in determining time since death, gestational age of the fetus, mode of death, cause of fetal demise, and the likelihood of recurrence. The format of the autopsy is guided by parental consent, but even when consent is limited, valuable information may be obtained by careful consideration of antemortem test results, imaging, and genetic testing. Where there is a delay between death and delivery, fetuses are affected by maceration, which may increase the technical complexity of the autopsy and impart a number of artefactual changes, which should not be misinterpreted as genuine pathology. The most common pathologies encountered at autopsy are placental abnormalities, changes related to maternal disorders, malformations, and central nervous system pathology. © Springer Nature Switzerland AG 2022. All rights reserved.

Analysis of Prolonged Caesarean Section Response Time in True Emergency Obstetric Care during Covid-19 Pandemic Era: Study at Kariadi Tertiary Hospital Indonesia

Intro: COVID-19 pandemic era makes quality of obstetric triage care including caesarean section in obstetric true emergency cases delayed. Maternal fetal triage index (MFTI) score is an instrument used to define true emergency in obstetric cases. Decision to delivery interval (DDI) is time interval from caesarean section decision to delivery within <30 minutes standard in emergency cases.This study was designed to evaluate the decision to delivery time interval and its effect on perinatal outcomes and the associated factors during category-1 emergency caesarean section deliveries. Method(s): A prospective observational descriptive study was conducted from 2020-2022 at Kariadi tertiary Hospital. A total of 40 clients who were undergone category-1 emergency caesarean section were included in this study. This is a indepht analysis pregnant women confirmed with COVID-19 infection and had true emergency cases based on MFTI score (stat-priority 1). Finding(s): Among 346 pregnant women with COVID-19, total 160 C-section cases with 40 eligible data were included in this study. Gestational age mostly in their second and third trimester. Maternal comorbidities were diabetes in pregnancy, HIV, pre eclampsia, SLE and thyroid disease. This study showed that DDI <30 minutes were found in 34 cases (85%), DDI 30-60 minutes as many as 6 (15%), and no (0%) DDI >60 minutes. Emergency cases with the shortest DDI were umbilical cord prolapse 3 (100%), fetal distress 14 (93%), placental abruption 5 (83%), impending uterine rupture 5 (83%), and antepartum hemorrhage 7 (70%). Perinatal outcome were Apgar score lower than 7 at 1 minutes (25%) and stillbirth (5%). Conclusion(s): Most of DDI in this study met the recommendation of <30 minutes, but some cases did not meet the standard. This can be caused by multifactorial factors such as advice from the doctor in charge, patient transfer distance, operating room preparation, and anesthetic preparation due to COVID-19.Copyright © 2023

POLYFUNCTIONAL SARS-CoV-2-SPECIFIC T CELLS PERSIST IN TISSUE OF COVID-19 CONVALESCENTS

Background: T cells play an essential role in SARS-CoV-2 immunity, including in defense against severe COVID-19. However, most studies analyzing SARSCoV- 2-specific T cells have been limited to analysis of blood. Furthermore, the role of T cells in SARS-CoV-2 immunity in pregnant women, which are at disproportionately higher risk of severe COVID-19, is poorly understood. Method(s): Here, we quantitated and deeply phenotyped SARS-CoV-2-specific T cells from convalescent women (n=12) that had mild (non-hospitalized) COVID-19 during pregnancy. Endometrial, maternal blood, and fetal cord blood specimens were procured at term, which ranged from 3 days to 5 months post-infection. SARS-CoV-2-specific T cells were deeply analyzed by CyTOF using a tailored phenotyping panel designed to assess the effector functions, differentiation states, and homing properties of the cells. Result(s): SARS-CoV-2-specific T cells were more abundant in the endometrium than in maternal or fetal cord blood. In a particularly striking example, in one donor sampled 5 months after infection, SARS-CoV-2-specific CD8+ T cells comprised 4.8% of total endometrial CD8+ T cells, while it only reached 1.4% in blood. Endometrial SARS-CoV-2-specific T cells were more frequently of the memory phenotype relative to their counterparts in maternal and fetal cord blood, which harbored higher frequencies of naive T cells. Relative to their counterparts in blood, endometrial SARS-CoV-2-specific T cells exhibited unique phenotypic features, including preferential expression of the T resident memory marker CD69, inflammatory tissue-homing receptor CXCR4, and the activation marker 4-1BB. Endometrial T cells were highly polyfunctional, and could secrete IFNg, TNFa, MIP1b, IL2, and/or IL4 in response to spike peptide stimulation. By contrast, their counterparts in blood preferentially produced the cytolytic effectors perforin and granzyme B. Conclusion(s): Polyfunctional SARS-CoV-2-specific T cells primed by prior exposure to the virus are abundant and persist in endometrial tissue for months after infection. These cells exhibit unique phenotypic features including preferential expression of select chemokine receptors and activation molecules. Compared to their blood counterparts, the effector functions of these cells are more cytokine-driven and less cytolytic. The long-term persistence of these cells in the endometrium may help protect future pregnancies from SARS-CoV-2 re-infection.

Placental Thrombosis Resulting in Hypoxic Ischemic Encephalopathy in an Infant of a Mother with Covid-19

Case Report: Since the beginning of the Coronavirus Disease 2019 (COVID-19) pandemic, there has been much work to understand the negative effects of SARS-CoV-2 on tissues expressing the Angiotensin Converting Enzyme-2 (ACE2) receptor, including the placenta. However, there is limited information regarding placental pathology findings in mothers with COVID-19 and the effects of SARS-CoV-2 on the placenta. The available research reports effects on the fetus ranging from minimal to intrauterine fetal demise. Case Description: A 4680g baby boy was born at 38+1 weeks of gestation to 36y old G4P1021 female via repeat cesarian section. The pregnancy was complicated by advanced maternal age, chronic hypertension with superimposed pre-eclampsia with severe features, BMI of 80, and SARS-CoV-2 infection. The mother had mild COVID-19 symptoms and did not require hospitalization or oxygen support. Prenatal ultrasounds were limited due to body habitus. At the time of delivery, there was clear amniotic fluid. Upon delivery the infant was cyanotic and limp and was brought to the warmer immediately. Non-invasive positive pressure ventilation was initiated at 5 minutes of life with improvement in infant color and oxygen saturation. He was then admitted to the Neonatal Intensive Care Unit (NICU). APGARs were 2, 3, 5, and 7 at 1, 5, 10, and 15 minutes respectively. Cord gases showed severe metabolic acidosis. The patient was diagnosed with hypoxic-ischemic encephalopathy (HIE) and therapeutic hypothermia was initiated. Both the NICU and obstetric teams were unable to identify a clear perinatal cause of HIE in this patient. Later, the placenta pathology report revealed a large placenta for estimated gestational age corresponding to the 75th percentile, villous parenchyma with focal chorangiosis and thrombi, with unremarkable fetal membrane and three vessel umbilical cord. The cause of HIE was then thought to be due to the placental thrombi likely caused by SARS-CoV-2 infection. Discussion(s): Fetal vascular malperfusion and fetal vascular thrombus have been noted as a common finding in the placentas of pregnant women who test positive for SARS-CoV-2. There are various causes of HIE, from maternal, placental and fetal factors. This patient had no clinically evident hypoxic event, but information was limited due to the lack of monitoring of the fetus in utero. Given the mother's SARS-CoV-2 infection and the placental pathology findings, it is likely that the cause of this patient's HIE was related to the effects on the placenta from SARS-CoV-2. Conclusion(s): As more information comes to light about the effects of SARS-CoV-2 on the placenta, it is important to consider a maternal SARS-CoV-2 infection during pregnancy as a cause of HIE in a newborn.

SARS-CoV-2 ANTIBODY RESPONSES POST-INFECTION IN PREGNANCY BY VACCINATION STATUS

Background: We evaluated SARS-CoV-2 antibody binding and neutralization responses at delivery among pregnant persons with prior SARS-CoV-2 infection by vaccine status. Method(s): We enrolled participants with evidence of prior SARS-CoV-2 infection detected in pregnancy (anti-nucleocapsid [anti-N] IgG+ on enrollment or prior RT-PCR+ or antigen+) and followed them through delivery. Maternal delivery and cord blood samples were tested for SARS-CoV-2 binding antibodies to spike (anti-S) (from vaccination and/or infection) and anti-N (from infection only) IgG by Abbott Architect followed by neutralizing antibodies (classified as neutralizing if serum dilution inhibited infection by 50% [ND50 heat] >=20 and R2 >=0.9) if sample volume allowed. Positive IgG thresholds were Abbott index >=1.4 for anti-N and >=50 AU/mL for anti-S. Chi-squared test was used to compare differences in proportions between groups. Wilcoxon rank sum test was used to compare medians. Result(s): Among 71 participants with delivery and cord samples, median age was 33 years (interquartile range [IQR] 30-35) and median gestational age was 31.7 weeks (IQR 18.0-37.9) at enrollment in pregnancy. By delivery, 17 (24%) participants were unvaccinated, 21 (30%) were partially vaccinated or had completed a primary series, and 33 (46%) were boosted. Median time from infection (RT-PCR+ or antigen+ result) to delivery was 16.7 weeks (IQR 9.7- 24.3). At delivery, 33 (46%) of maternal (median 3.2 index) and 37 (52%) of cord samples (median 3.1 index) were anti-N IgG+. Participants with >=1 vaccine were more likely to be anti-S IgG+ than those unvaccinated (100% vs. 82%, p< 0.01), have higher median anti-S IgG+ (25,000 vs 1,019 AU/ml, p< 0.01), and have neutralizing antibodies (100% vs. 81%, p< 0.01) with higher median log10 neutralization (1:4.00 vs 1:2.41, p< 0.01) at delivery. Similarly, cord blood from participants with >=1 vaccine was more likely to be anti-S IgG+ than those unvaccinated (100% vs. 82%, p< 0.01), have higher median anti-S IgG+ (25,000 vs 1,188 AU/ml, p< 0.01), and have neutralizing antibodies (100% vs. 75%, p< 0.01) with higher median log10 neutralization (1:4.00 vs 1:2.41, p< 0.01) at delivery. Conclusion(s): Among pregnant people with prior SARS-CoV-2 infection detected during pregnancy, maternal and cord blood antibody binding and neutralization responses were higher among those receiving SARS-CoV-2 vaccination prior to delivery. (Table Presented).

Biologic Potential of Human Umbilical Cord Derived Mesenchymal Stem Cells Exposed to Maternal Smoking and Active Sars-Cov-2 Infection at Delivery

Purpose of Study: COVID-19 caused by the SARS-CoV-2 virus has led to a worldwide pandemic with cytokine storm as the leading cause of morbidity and mortality. It is known that pregnant women are at higher risk of viral infections given an alteration in immune response. Mothers who smoke cigarettes during pregnancy are even at higher risk. The infection varies from asymptomatic to severe disease in pregnant women depending upon the degree of inflammation and cytokine storm. At present, limited data are available to show the effects of simultaneous maternal smoking and SARS-CoV-2 infection on the biologic efficacy of human umbilical cord derived mesenchymal stem cells (MSCs). We hypothesized that SARS-CoV-2 infection in combination with smoking of the pregnant mother at the time of delivery will lead to an alteration in the growth and differential potential of cord-derived MSCs. Our aims included collection, isolation and growth of human umbilical cord derived MSCs followed by assessment of their differentiation potential. Methods Used: The study was approved by the Institutional IRB. The umbilical cords were collected from the following groups of pregnant mothers at the time of delivery: Normal (non-smoking and negative SARS-CoV-2 infection), Smoker (smoking with negative SARS-CoV-2), Covid Smoker (smoking with positive SARS-CoV-2 infection) and Covid non-smoker (non-smoking with positive SARS-CoV-2 infection). Plastic adherent cells were harvested from 3 pooled human umbilical cords from each group. These cells were cultured and underwent immunodepletion per International Society for cellular therapy guidelines to isolate MSCs. MSCs were cultured in MSC-culture media to assess the duplication time. Similarly, MSCs were cultured in differentiation media (adipocytes and osteocytes) to assess differentiation time. Summary of Results: Picture shows the duplication and differentiation time from each group. Smoker group showed the longest duplication and differentiation time. Covid non-smoker group showed the shortest duplication and differentiation time. Covid Smoker group showed similar duplication and differentiation time as normal controls. All these results were statistically significant (T-test). Conclusion(s): Maternal smoking and active SARS-CoV-2 infection at the time of delivery alters the growth and differentiation potential of cord-derived MSCs. Further in vitro and in vivo studies are currently in progress to determine how this change effects the biological potential of these cells.

Covid-19 Vaccinated Maternal/Cord Blood Dont Have Neutralization for Omicron Variants

Background: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and -cross neutralization capacity of maternal/ cord antibody responses to COVID-19 vaccination during pregnancy can inform neonatal immunity. Method(s): Here we characterized binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants by enzyme-linked immunosorbent assay Results: Our results reveal that current vaccination induced significantly higher (p=0.003) RBD-specific binding IgG titers in cord blood compared to maternal blood for both Wuhan and Omicron BA1 strain. Interestingly, binding IgG antibody levels for the Omicron BA1 strain were significantly lower (P< 0.0001) when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, BA4/5 specific neutralizing antibody levels were significantly lower (P< 0.0001) compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not at all detected in both maternal and cord blood. Conclusion(s): Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for Wuhan and Delta variants but not for Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for boosters as new variants emerge.

Perinatal Care during the COVID-19 Pandemic

Background: Following the pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and considering its capacity for rapid mutation, there have been many studies and articles on this novel coronavirus over the past three years. Therefore, providing knowledge and directions for management of SARS-CoV-2, for hospital staff is crucial. Hence, we collected the research information from different perspectives and summarized the guidelines for perinatal care on the topic of SARS-CoV-2, and for possible future viral pandemics. Method(s): A systematic review aimed at assessing the publications written in English and Chinese, offering different perspectives on the topic of perinatal care concerning SARS-CoV-2, was conducted using PubMed and Google Scholar from 2020 to 2022. In addition, we summarized the guidelines from the Taiwan Association of Obstetrics and Gynecology, American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, Maternal Immunization Task Force and Partners, and Academy of Breastfeeding Medicine. Result(s): Due to physiological changes, pregnant patients may be prone to have complications, especially pre-eclampsia, affecting morbidity and mortality. Most neonates of coronavirus disease (COVID-19) infected mothers did not show any clinical abnormalities due to the infection. However, compared to the general population, infected neonates needed more invasive ventilation care, while the proportion of asymptomatic neonates was less than that in the general population. Further, long term complications are still under investigation. Evidence of vertical transmission via the placenta and umbilical cord is rare but not absent. Paxlovid (nirmatrelvir/ritonavir) can be administered to patients with comorbidities, and indications for cesarean delivery does not include COVID-19 infection. Vaccination against COVID-19 should not be delayed during pregnancy and lactation. Conclusion(s): Obstetricians and gynecologists should pay more attention to pregnant women with SARS-CoV-2 because of the physiological changes and higher risks of complications, morbidity, and mortality. Early prevention with vaccination in pregnant women is the key to controlling the COVID-19 pandemic, from which we can learn how to manage the next pandemic.Copyright © 2023 The Author(s).

Epidemiological study of COVID-19 pneumonia in pregnant woman and their neonates, report of thirteen confirmed COVID-19 pregnant women

Background: In new pandemic, the probable effects of COVID-19 pneumonia on pregnant woman and their infant is one of new critical challenge for health care. Here we presented clinical symptoms, laboratory findings and outcome of COVID-19 pneumonia in pregnant woman. Method(s): In a case series study, from 15 Feb to 15 June 2020, all women with RT-PCR COVID-19 who referred to two hospitals (Taleghani and Qods Hospital) affiliated to Arak University of Medical Sciences were selected. The epidemiological and demographic variables, laboratory test and outcomes obtained from patient's medical records. Result(s): In this case series, we presented thirteen confirmed COVID-19 pregnant women. Their mean age was 34.6 (S.D.: 5.9) years and the mean gestational age was 32.4 (S.D.: 7.3) weeks. Most of patient didn't show any maternal complication and intrauterine vertical transmission. The large number of pregnant women had normal HRCT and also in terms of laboratory most of the patients had normal laboratory tests. Amniotic fluids, cord blood, the throat swab of neonate in our pregnant woman with delivery were tested for COVID-19 and all of them were negative. Conclusion(s): The COVID-19 mothers and their infant didn't have higher risk for morbidity and mortality and this virus didn't associate with intrauterine vertical transmission.Copyright © 2020 Ubiquity Press. All rights reserved.

Analysis of placental pathology after COVID-19 by timing and severity of infection.

BACKGROUND: COVID-19 during pregnancy can have serious effects on pregnancy outcomes. The placenta acts as an infection barrier to the fetus and may mediate adverse outcomes. Increased frequency of maternal vascular malperfusion has been detected in the placentas of patients with COVID-19 compared with controls, but little is known about how the timing and severity of infection affect placental pathology. OBJECTIVE: This study aimed to examine the effects of SARS-CoV-2 infection on placental pathology, specifically whether the timing and severity of COVID-19 affect pathologic findings and associations with perinatal outcomes. STUDY DESIGN: This was a descriptive retrospective cohort study of pregnant people diagnosed with COVID-19 who delivered between April 2020 and September 2021 at 3 university hospitals. Demographic, placental, delivery, and neonatal outcomes were collected through medical record review. The timing of SARS-CoV-2 infection was noted, and the severity of COVID-19 was categorized on the basis of the National Institutes of Health guidelines. The placentas of all patients with positive nasopharyngeal reverse transcription-polymerase chain reaction COVID-19 testing were sent for gross and microscopic histopathologic examinations at the time of delivery. Nonblinded pathologists categorized histopathologic lesions according to the Amsterdam criteria. Univariate linear regression and chi-square analyses were used to assess how the timing and severity of SARS-CoV-2 infection affected placental pathologic findings. RESULTS: This study included 131 pregnant patients and 138 placentas, with most patients delivered at the University of California, Los Angeles (n=65), followed by the University of California, San Francisco (n=38) and Zuckerberg San Francisco General Hospital (n=28). Most patients were diagnosed with COVID-19 in the third trimester of pregnancy (69%), and most infections were mild (60%). There was no specific placental pathologic feature based on the timing or severity of COVID-19. There was a higher frequency of placental features associated with response to infection in the placentas from infections before 20 weeks of gestation than that from infections after 20 weeks of gestation (P=.001). There was no difference in maternal vascular malperfusion by the timing of infection; however, features of severe maternal vascular malperfusion were only found in the placentas of patients with SARS-CoV-2 infection in the second and third trimesters of pregnancy, not in the placentas of patients with COVID-19 in the first trimester of pregnancy. CONCLUSION: Placentas from patients with COVID-19 showed no specific pathologic feature, regardless of the timing or severity of the disease. There was a higher proportion of placentas from patients with COVID-19-positive tests in earlier gestations with evidence of placental infection-associated features. Future studies should focus on understanding how these placental features in SARS-CoV-2 infections go on to affect pregnancy outcomes.

Mesenchymal Stem Cells: A Potent Cell Source for COVID-19

Coronaviruses are enveloped positive-stranded RNA viruses that cause mild to acute respiratory illness. Coronaviruses can merge envelope proteins with the host cell membranes and de-liver their genetic material. Coronavirus disease 2019 (COVID-19) is the seventh coronavirus clos-est to the severe acute respiratory syndrome (SARS) in bats that infects humans. COVID-19 at-tacks the respiratory system and stimulates the host inflammatory responses, promotes the recruit-ment of immune cells, and enhances angiotensin-converting enzyme 2 (ACE2) activities. Patients with confirmed COVID-19 have experienced fever, dry cough, headache, dyspnea, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. Inflammation is a common and important factor in the pathogenesis of COVID-19. In recent years, stem cell-based therapies represent a promising therapeutic option against various diseases. Mesenchymal stem cells (MSCs) are multipotent stem cells that can self-renew and differentiate into various tissues of mesodermal ori-gin. MSCs can be derived from bone marrow, adipose tissue, and umbilical cord blood. MSCs, with their unique immunomodulatory properties, represent a promising therapeutic alternative against diseases associated with inflammation. Several previous studies have shown that MSCs with a strong safety profile can improve the treatment of patients with COVID-19. The information in this review provides a summary of the prevention and diagnosis of COVID-19. Also, we focus on the current clinical application of MSCs for treatments of patients with COVID-19.Copyright © 2021 Bentham Science Publishers.

Maternal and Fetal Effects of COVID-19 Virus on a Complicated Triplet Pregnancy: a Case Report

Background: Coronavirus disease 2019 (COVLD-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case. Case presentation: The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition. Conclusion(s): This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.Copyright © 2022 Goldstein and Associates. All rights reserved.

Placental histological findings in COVID-19 term, preterm and metabolic disorders pregnancy

Objective. In the last two years COVID-19 infection has represented a true unknown in the management of pregnancies with maternal COVID-19 positivity. However, it has not represented a serious complication, indeed it has rarely caused premature rupture of the membrane, fetal thrombosis or postnatal complications. Materials and Methods. Our retrospective cohort study included placental samples from 350 patients from San Pietro Fatebenefratelli Hospital collected in a period of 4 months. Inclusion criteria were COVID-19 positivity during childbirth or in the previous two months but also a pregnancy without previous COVID-19 infection. Anamnestic data were carried out for the histological study on each placenta. 59% of patients were COVID-19 positive (15% of these had other associated disorders like gestational diabetes, hypertension, fetal death, preterm birth) 26.5% were preterm and the 14,5% were high-risk pregnancy with COVID-19 negativity. Results. The most frequently represented lesion in a COVID-19 placenta was a mild chronic deciduitis, usually absent in placentas with normal outcome. The same deciduitis was observed in gestational diabetes placentas, although less frequently. Other rare findings were patchy fibrinoid necrosis of capsular decidua, chronic villitis, umbilical cord thrombosis. Severe lesions were rare. Conclusions. COVID-19 does not seem to have a severe impact on the health of the placenta except in rare cases in which predisposing factors coexist and determine a more serious involvement of the fetus and its appendages. COVID-19 determines a constant but mild chronic placental inflammation, that is balanced by the maternal capacity to maintain homeostasis stemming the external injuries.

FEATURES OF IMMUNOHISTOCHEMICAL MARKERS OF STEM CELLS CD-117, CD-44 IN FEMALE PLACENTAS ON THE BACKGROUND OF CHRONIC STRESS.

Background. Placenta is a subject of interest to a wide range of scientists because it is rich in stem cells and their precursors. A stem cell is a cell that has the ability to self-repair and can differentiate into offspring (daughter cells) of one or more germ layers. In recent years, scientists have obtained new data of stem cells regenerative potential. However, only isolated publications about placental stem cells are available. Therefore, our studies about placental stem cells are important for discovery of structural and molecular mechanisms, their changes under the influence of chronic stress. Objective(s): to study the features of immunohistochemical markers of pluripotent stem cells and their morphological features. Materials and methods. We examined 80 women placentas with chronic stress in comparison with control using general histological and immunohistochemical methods in the following groups: group 1 - women placentas with physiological course of pregnancy in term 38-40 weeks, group 2 - women placentas with miscarriage, group 3 - women placentas with chronic stress due to internal irradiation (4.5 Bq/kg and more), group 4 - women placentas which had COVID-19 during pregnancy. Results. There was a significant increase of stem cell markers expression in the three study groups with a significant predominance in groups 3 and 4. It was also determined the different direction of their active factors. Conclusions. The general changes of all structures of the placental barrier are detected as a result of chronic stress due to various factors: micro detachment of the decidual membrane (significant increase in cases in the studied groups);malperfusion in the structures of the maternal placental barrier;in the placenta stem cells of the three study groups in comparison with the control were found stress markers. Thus, chronic stress due to various factors causes the same type of changes in placental structures, but they have different degrees of expression - with internal irradiation doses >= 4.8 Bq/kg, these changes are most expressive.Copyright © 2022 Authors. All rights reserved.