Role of biomarkers (sFlt-1/PlGF) in cases of COVID-19 for distinguishing preeclampsia and guiding clinical management.

OBJECTIVES: To analyze soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factors (PlGF) concentrations and their ratio in pregnant and postpartum women with suspected COVID-19, and further investigate conditions associated with an increased ratio (sFlt-1/PlGF > 38), including preeclampsia (PE) and severe acute respiratory syndrome (SARS). STUDY DESIGN: The present study is a secondary analysis of a prospective cohort. Blood samples were collected at time of COVID-19 investigation and the serum measurements of sFlt-1 and PlGF were performed. Clinical background, SARS-CoV-2 infection characteristics, maternal and perinatal outcomes were further analyzed. MAIN OUTCOME MEASURES: Serum measurements of sFlt-1 and PlGF; obstetrics and clinical outcomes. RESULTS: A total of 97 SARS-CoV-2 unvaccinated women with suspected infection were considered, 76 were COVID-19 positive cases and 21 COVID-19 negative. Among COVID-19 positive cases, 09 presented with SARS and 11 were diagnosed with PE, of which 6 had SARS-CoV-2 infection in first and second trimester (04 with sFlt-1/PlGF ≥ 38) and 05 with PE and COVID-19 diagnosed at the same time, during third trimester (03 with sFlt-1/PlGF ≥ 38). Five presented with PE with severe features. sFlt-1/PlGF ratio was significantly higher in the COVID-19 positive/PE positive group compared to COVID-19 positive/PE negative group (p-value = 0.005), with no increase in cases complicated by SARS. CONCLUSIONS: sFlt-1/PlGF ratio could be a useful tool for differential diagnosis and adequate counseling among cases of COVID-19 and PE, especially if severe disease. COVID-19 early in pregnancy could potentially be a risk factor for PE later during gestation.

COVID-19 and pregnancy: clinical outcomes; mechanisms, and vaccine efficacy.

As the COVID-19 pandemic continues into its third year, emerging data indicates increased risks associated with SARS-CoV-2 infection during pregnancy, including pre-eclampsia, intrauterine growth restriction, preterm birth, stillbirth, and risk of developmental defects in neonates. Here, we review clinical reports to date that address different COVID-19 pregnancy complications. We also document placental pathologies induced by SARS-CoV-2 infection, entry mechanisms in placental cells, and immune responses at the maternal-fetal interface. Since new variants of SARS-CoV-2 are emerging with characteristics of higher transmissibility and more effective immune escape strategies, we also briefly highlight the genomic and proteomic features of SARS-CoV-2 investigated to date. Vector and mRNA-based COVID-19 vaccines continue to be rolled out globally. However, because pregnant individuals were not included in the vaccine clinical trials, some pregnant individuals have safety concerns and are hesitant to take these vaccines. We describe the recent studies that have addressed the effectiveness and safety of the current vaccines during pregnancy. This review also sheds light on important areas that need to be carefully or more fully considered with respect to understanding SARS-CoV-2 disease mechanisms of concern during pregnancy.

Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens.

Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.

Golden Syrian Hamsters as a Model for Revisiting the Role of Biological Sex Differences in SARS-CoV-2 Infection.

There is growing evidence that coronavirus disease 2019 (COVID-19) affects males more severely than females, including compelling evidence indicating that biological sex is an important clinical factor influencing disease pathology and outcomes. In their recent article in mBio, S. Dhakal, C. A. Ruiz-Bedoya, R. Zhou, P. S. Creisher, et al. (mBio 12:e00974-21, 2021, https://doi.org/10.1128/mBio.00974-21) find further evidence to support this hypothesis as they interrogate biological sex differences in the pathogenesis and clinical features of COVID-19 in the golden Syrian hamster model. Their study probes SARS-CoV-2 infection in terms of loss of body mass, recovery, lung compromise, viral replication, inflammatory response, immune response, and, most importantly, the role of estrogen. They also demonstrate the value of a novel unbiased, quantitative chest computed tomography (CT) imaging approach. The golden Syrian hamster model holds a promising opportunity to further investigate how biological sex acts as a primary determinant in SARS-CoV-2 pathogenesis, as also demonstrated in this study.

SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. METHODS: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S). FINDINGS: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia. CONCLUSIONS: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women. FUNDING: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women.

Background: This study aims to investigate whether maternal SARS-CoV-2 status affects placental pathology. Methods: A retrospective case-control study was conducted by reviewing charts and slides of placentas delivered between April 1 to July 24, 2020. Clinical history of "COVID-19" was searched in Pathology Database (CoPath). Controls were matched with SARS-CoV-2-negative women with singleton deliveries in the 3rd-trimester. Pathological features were extracted from placental pathology reports. Results: Twenty-one 3rd trimester placentas from SARS-CoV-2-positive women were identified and compared to 20 placentas from SARS-CoV-2-negative women. There were no significant differences in individual or group gross or microscopic pathological features. Within the SARS-CoV-2+ group, there are no differences between symptomatic and asymptomatic women. Conclusion: Placentas from SARS-CoV-2-positive women do not demonstrate a specific pathological pattern. Pregnancy complicated with COVID-19 during the 3rd trimester does not have a demonstrable effect on placental structure and pathology.

SARS-CoV2 and pregnancy: An invisible enemy?

Coronavirus disease 2019 or COVID-19 is an emerging viral disease caused by a member of the betacoronavirus family, SARS-CoV-2. Since its' emergence in December 2019, it has rapidly caused close to half a million fatalities globally. Data regarding the impact of COVID-19 on pregnancy are limited. Here, we review pathological findings in placentas from women who tested positive for SARS-CoV-2 as well as information on pregnancy outcomes associated with related and highly pathogenic coronaviruses (ie, severe acute respiratory syndrome (SARS-COV) and the Middle East respiratory syndrome, MERS). We present immune-inflammatory correlates of COVID-19 in pregnancy and review the role of the Renin Angiotensin System in the pathogenesis of COVID-19 in pregnancy. Greater understanding of the pathogenesis of SARS-CoV-2 in the placenta will yield important insight into potential therapeutic interventions for pregnant women with COVID-19.