Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma.

BACKGROUND: Pregnant women are at greater risk of adverse outcomes, including mortality, as well as obstetrical complications resulting from COVID-19. However, pregnancy-specific changes that underlie such worsened outcomes remain unclear. METHODS: Plasma samples were collected from pregnant women and non-pregnant individuals (male and female) with (n = 72 pregnant, 52 non-pregnant) and without (n = 29 pregnant, 41 non-pregnant) COVID-19. COVID-19 patients were grouped as asymptomatic, mild, moderate, severe, or critically ill according to NIH classifications. Proteomic profiling of 7,288 analytes corresponding to 6,596 unique protein targets was performed using the SOMAmer platform. RESULTS: Herein, we profile the plasma proteome of pregnant and non-pregnant COVID-19 patients and controls and show alterations that display a dose-response relationship with disease severity; yet, such proteomic perturbations are dampened during pregnancy. In both pregnant and non-pregnant state, the proteome response induced by COVID-19 shows enrichment of mediators implicated in cytokine storm, endothelial dysfunction, and angiogenesis. Shared and pregnancy-specific proteomic changes are identified: pregnant women display a tailored response that may protect the conceptus from heightened inflammation, while non-pregnant individuals display a stronger response to repel infection. Furthermore, the plasma proteome can accurately identify COVID-19 patients, even when asymptomatic or with mild symptoms. CONCLUSION: This study represents the most comprehensive characterization of the plasma proteome of pregnant and non-pregnant COVID-19 patients. Our findings emphasize the distinct immune modulation between the non-pregnant and pregnant states, providing insight into the pathogenesis of COVID-19 as well as a potential explanation for the more severe outcomes observed in pregnant women.

Pregnant COVID-19 patients are at increased risk of experiencing complications and severe outcomes compared to the general population. However, the reasons for this heightened risk are still unclear. We measured the proteins present in the blood of pregnant and non-pregnant patients with COVID-19 and compared these to healthy individuals. We found that some COVID-19-associated proteins were present at lower levels in pregnant women, which could help to protect the fetus from harmful inflammation, the body's natural response to infection. While some proteins affected by COVID-19 are shared between pregnant and non-pregnant patients, others were distinctly affected only in pregnant women, providing a potential explanation for the more severe outcomes in this group.

Single-Cell Immunobiology of the Maternal-Fetal Interface.

Pregnancy success requires constant dialogue between the mother and developing conceptus. Such crosstalk is facilitated through complex interactions between maternal and fetal cells at distinct tissue sites, collectively termed the "maternal-fetal interface." The emergence of single-cell technologies has enabled a deeper understanding of the unique processes taking place at the maternal-fetal interface as well as the discovery of novel pathways and immune and nonimmune cell types. Single-cell approaches have also been applied to decipher the cellular dynamics throughout pregnancy, in parturition, and in obstetrical syndromes such as recurrent spontaneous abortion, preeclampsia, and preterm labor. Furthermore, single-cell technologies have been used during the recent COVID-19 pandemic to evaluate placental viral cell entry and the impact of SARS-CoV-2 infection on maternal and fetal immunity. In this brief review, we summarize the current knowledge of cellular immunobiology in pregnancy and its complications that has been generated through single-cell investigations of the maternal-fetal interface.

Population-Level Study on Fetal Deaths and Preterm Births during SARS-CoV-2 Pandemic in the State of Michigan.

OBJECTIVE: The aim of the study is to explore the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on preterm birth at different gestational ages and fetal death in the state of Michigan. STUDY DESIGN: Data on live births and fetal deaths in the state of Michigan from March to November in the years 2017 through 2020 were obtained from Michigan Department of Health and Human Services (MDHHS). Preterm birth rate, fetal death rate (per 1,000 live births) overall and stratified by race and maternal comorbidities during the period of pandemic (March-November 2020) were compared with the same period (March-November) in the prepandemic years (2017-2019). RESULTS: Of 328,879 live births and 1,470 fetal deaths during the study period, 77,983 live births and 242 fetal deaths were reported in 2020. Compared with prepandemic years, fetal death rate per 1,000 live births was significantly lower in 2020 (3.1 vs. 4.7 [2017], 5.2 [2018], 4.4 [2019], p-value <0.001). The adjusted risk for fetal death in 2020 was decreased (odds ratio [OR] = 0.64 [95% confidence interval (CI): 0.56-0.74], p <0.0001), compared with prepandemic years. Fetal death was significantly associated with African-American race, pregnancy hypertension and prepregnancy diabetes. No significant difference in the proportion of preterm births (<37 weeks' gestation) was noted between pandemic and prepandemic years (9.9 vs. 10.0%, p = 0.50). There was no significant difference in the risk of preterm birth across gestational age strata (<28, 28-316/7, 32-366/7, 37-416/7, and >42 weeks) between pandemic and prepandemic years on multinomial analysis. Significant associations with preterm birth across all years included African American race, lower level of maternal education, pregnancy-induced hypertension, chronic hypertension, prepregnancy diabetes, congenital anomalies, previous preterm birth, and prolonged rupture of membranes >12 hours. CONCLUSION: Fetal death rate was significantly lower whereas preterm births remained unchanged during pandemic in comparison with prepandemic years in the state of Michigan. KEY POINTS: · A decrease in fetal death rate was noted during SARS CoV-2 pandemic in the State of Michigan.. · Overall state-wide rates of preterm birth did not change in 2020, compared to previous years.. · Significant risk factors associated with preterm birth and fetal deaths did not differ between prepandemic and pandemic years..

Distinct Cellular Immune Responses to SARS-CoV-2 in Pregnant Women.

Pregnant women are at increased risk of adverse outcomes, including preeclampsia and preterm birth, that may result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Pregnancy imprints specific maternal immune responses that can modulate host susceptibility to microbial infection; therefore, recent studies have focused on the humoral response against SARS-CoV-2 in pregnant women. However, the pregnancy-specific cellular immune responses triggered by SARS-CoV-2 infection are poorly understood. In this study, we undertook an extensive in vitro investigation to determine the cellular immune responses to SARS-CoV-2 particles and proteins/peptides in pregnant women. First, we show that SARS-CoV-2 particles do not alter the pregnancy-specific oxidative burst of neutrophils and monocytes. Yet, SARS-CoV-2 particles/proteins shift monocyte activation from the classical to intermediate states in pregnant, but not in nonpregnant, women. Furthermore, SARS-CoV-2 proteins, but not particles or peptide pools, mildly enhance T cell activation during pregnancy. As expected, B cell phenotypes are heavily modulated by SARS-CoV-2 particles in all women; yet, pregnancy itself further modified such responses in these adaptive immune cells. Lastly, we report that pregnancy itself governs cytokine responses in the maternal circulation, of which IFN-ß and IL-8 were diminished upon SARS-CoV-2 challenge. Collectively, these findings highlight the differential in vitro responses to SARS-CoV-2 in pregnant and nonpregnant women and shed light on the immune mechanisms implicated in coronavirus disease 2019 during pregnancy.

Tem canto, tem históriaThere Is Song, There Is History

Texto curatorial por Paula Berbert and Roberto Romero Quando a ameaça da Covid-19 alcançou os Tikmũ’ũn, em março de 2020, a memória das histórias dos antigos e de como, no passado, eles quase foram dizimados pelas doenças trazidas pelos brancos imediatamente vieram à tona. Habitantes milenares das florestas de Mata Atlântica que cobriam todo o leito dos rios Pardo, Jequitinhonha e Mucuri, os Tikmũ’ũn, mais conhecidos como Maxakali, chegaram a ser contados em apenas 49 pessoas no início da década de 1940. Desse modo, a necessidade de se proteger de uma pandemia não chegou a eles propriamente como uma novidade. Diante dessa urgência, Isael Maxakali—artista, cineasta, professor e uma das mais jovens e proeminentes lideranças de seu povo—, reuniu os homens e mulheres de sua comunidade para iniciar a quarentena. Juntos fixaram uma placa na entrada de Aldeia Verde com os dizeres: “Yãmĩyxop yã ka'ok! (Os yãmĩyxop...

The etiology of preeclampsia.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2.

Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection.

A standardized definition of placental infection by SARS-CoV-2, a consensus statement from the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development SARS-CoV-2 Placental Infection Workshop.

Pregnant individuals infected with SARS-CoV-2 have higher rates of intensive care unit admission, oxygen requirement, need for mechanical ventilation, and death than nonpregnant individuals. Increased COVID-19 disease severity may be associated with an increased risk of viremia and placental infection. Maternal SARS-CoV-2 infection is also associated with pregnancy complications such as preeclampsia and preterm birth, which can be either placentally mediated or reflected in the placenta. Maternal viremia followed by placental infection may lead to maternal-fetal transmission (vertical), which affects 1% to 3% of exposed newborns. However, there is no agreed-upon or standard definition of placental infection. The National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a group of experts to propose a working definition of placental infection to inform ongoing studies of SARS-CoV-2 during pregnancy. Experts recommended that placental infection be defined using techniques that allow virus detection and localization in placental tissue by one or more of the following methods: in situ hybridization with antisense probe (detects replication) or a sense probe (detects viral messenger RNA) or immunohistochemistry to detect viral nucleocapsid or spike proteins. If the abovementioned methods are not possible, reverse transcription polymerase chain reaction detection or quantification of viral RNA in placental homogenates, or electron microscopy are alternative approaches. A graded classification for the likelihood of placental infection as definitive, probable, possible, and unlikely was proposed. Manuscripts reporting placental infection should describe the sampling method (location and number of samples collected), method of preservation of tissue, and detection technique. Recommendations were made for the handling of the placenta, examination, and sampling and the use of validated reagents and sample protocols (included as appendices).

SARS-CoV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis.

OBJECTIVE: To examine the relationship between SARS-CoV-2 infection during pregnancy and the risk for preeclampsia. DATA SOURCES: MEDLINE, Embase, POPLINE, CINAHL, LILACS, and the World Health Organization COVID-19, Chinese, and preprint databases (all from December 1, 2019, to May 31, 2021). Google Scholar, bibliographies, and conference proceedings were also searched. STUDY ELIGIBILITY CRITERIA: Observational studies that assessed the association between SARS-CoV-2 infection during pregnancy and preeclampsia and that reported unadjusted and/or adjusted risk estimates and 95% confidence intervals or data to calculate them. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcome was preeclampsia. Secondary outcomes included preeclampsia with severe features, preeclampsia without severe features, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Two reviewers independently reviewed studies for inclusion, assessed their risk of bias, and extracted data. Pooled unadjusted and adjusted odds ratios with 95% confidence intervals, and 95% prediction interval were calculated. Heterogeneity was quantified using the І2 statistic, for which І2≥30% indicated substantial heterogeneity. Subgroup and sensitivity analyses were performed to test the robustness of the overall findings. RESULTS: A total of 28 studies comprising 790,954 pregnant women, among which 15,524 were diagnosed with SARS-CoV-2 infection, met the inclusion criteria. The meta-analysis of unadjusted odds ratios showed that the odds of developing preeclampsia were significantly higher among pregnant women with SARS-CoV-2 infection than among those without SARS-CoV-2 infection (7.0% vs 4.8%; pooled odds ratio, 1.62; 95% confidence interval, 1.45-1.82; P<.00001; І2=17%; 26 studies; 95% prediction interval of the odds ratio, 1.28-2.05). The meta-analysis of adjusted odds ratios also showed that SARS-CoV-2 infection during pregnancy was associated with a significant increase in the odds of preeclampsia (pooled odds ratio, 1.58; 95% confidence interval, 1.39-1.80; P<.0001; І2=0%; 11 studies). There was a statistically significant increase in the odds of preeclampsia with severe features (odds ratio, 1.76; 95% confidence interval, 1.18-2.63; І2=58%; 7 studies), eclampsia (odds ratio, 1.97; 95% confidence interval, 1.01-3.84; І2=0%, 3 studies), and HELLP syndrome (odds ratio, 2.10; 95% confidence interval, 1.48-2.97; 1 study) among pregnant women with SARS-CoV-2 infection when compared to those without the infection. Overall, the direction and magnitude of the effect of SARS-CoV-2 infection during pregnancy on preeclampsia was consistent across most prespecified subgroup and sensitivity analyses. Both asymptomatic and symptomatic SARS-CoV-2 infections significantly increased the odds of developing preeclampsial; however, it was higher among patients with symptomatic illness (odds ratio, 2.11; 95% confidence interval, 1.59-2.81) than among those with asymptomatic illness (odds ratio, 1.59; 95% confidence interval, 1.21-2.10). CONCLUSION: SARS-CoV-2 during pregnancy is associated with higher odds of preeclampsia.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 exists. The novel coronavirus canonically utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 for cell entry. Herein, building upon our previous single-cell study (Pique-Regi et al., 2019), another study, and new single-cell/nuclei RNA-sequencing data, we investigated the expression of ACE2 and TMPRSS2 throughout pregnancy in the placenta as well as in third-trimester chorioamniotic membranes. We report that co-transcription of ACE2 and TMPRSS2 is negligible in the placenta, thus not a likely path of vertical transmission for SARS-CoV-2. By contrast, receptors for Zika virus and cytomegalovirus, which cause congenital infections, are highly expressed by placental cell types. These data show that the placenta minimally expresses the canonical cell-entry mediators for SARS-CoV-2.