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1.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166285, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1460712

ABSTRACT

During pregnancy, a series of physiological changes are determined at the molecular, cellular and macroscopic level that make the mother and fetus more susceptible to certain viral and bacterial infections, especially the infections in this and the companion review. Particular situations increase susceptibility to infection in neonates. The enhanced susceptibility to certain infections increases the risk of developing particular diseases that can progress to become morbidly severe. For example, during the current pandemic caused by the SARS-CoV-2 virus, epidemiological studies have established that pregnant women with COVID-19 disease are more likely to be hospitalized. However, the risk for intensive care unit admission and mechanical ventilation is not increased compared with nonpregnant women. Although much remains unknown with this particular infection, the elevated risk of progression during pregnancy towards more severe manifestations of COVID-19 disease is not associated with an increased risk of death. In addition, the epidemiological data available in neonates suggest that their risk of acquiring COVID-19 is low compared with infants (<12 months of age). However, they might be at higher risk for progression to severe COVID-19 disease compared with older children. The data on clinical presentation and disease severity among neonates are limited and based on case reports and small case series. It is well documented the importance of the Zika virus infection as the main cause of several congenital anomalies and birth defects such as microcephaly, and also adverse pregnancy outcomes. Mycoplasma infections also increase adverse pregnancy outcomes. This review will focus on the molecular, pathophysiological and biophysical characteristics of the mother/placental-fetal/neonatal interactions and the possible mechanisms of these pathogens (SARS-CoV-2, ZIKV, and Mycoplasmas) for promoting disease at this level.


Subject(s)
COVID-19/etiology , COVID-19/transmission , Mycoplasma Infections/etiology , Mycoplasma Infections/transmission , Pregnancy Complications, Infectious , Zika Virus Infection/etiology , Zika Virus Infection/transmission , Biomarkers , Breast Feeding/adverse effects , Disease Susceptibility , Female , Host-Pathogen Interactions/immunology , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange , Mycoplasma , Placenta/immunology , Placenta/metabolism , Placenta/microbiology , Placenta/virology , Pregnancy , SARS-CoV-2 , Zika Virus
3.
Placenta ; 115: 70-77, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433733

ABSTRACT

Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.


Subject(s)
Maternal-Fetal Exchange/physiology , Placenta/metabolism , Animals , Antiviral Agents/pharmacokinetics , Biological Transport/physiology , COVID-19/drug therapy , COVID-19/transmission , COVID-19/virology , Female , Humans , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange/drug effects , Placenta/drug effects , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/virology , SARS-CoV-2/metabolism , Species Specificity , Yolk Sac/metabolism , Yolk Sac/physiology , Zika Virus/metabolism , Zika Virus Infection/drug therapy , Zika Virus Infection/transmission
4.
Cells ; 10(9)2021 09 12.
Article in English | MEDLINE | ID: covidwho-1408629

ABSTRACT

Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell-cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3'-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.


Subject(s)
COVID-19/therapy , Extracellular Vesicles/metabolism , Mesenchymal Stem Cells/metabolism , MicroRNAs/therapeutic use , SARS-CoV-2/physiology , 3' Untranslated Regions/genetics , Animals , Antiviral Agents/pharmacology , Base Sequence , Cell Line , Conserved Sequence/genetics , Female , Genome, Viral , Humans , Models, Biological , Mutation/genetics , Placenta/metabolism , Pregnancy , RNA, Viral/genetics , SARS-CoV-2/genetics
5.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166248, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1372892

ABSTRACT

The COVID-19 pandemic has infected nearly 178 million people and claimed the lives of over 3.8 million in less than 15 months. This has prompted a flurry of research studies into the mechanisms and effects of SARS-CoV-2 viral infection in humans. However, studies examining the effects of COVID-19 in pregnant women, their placentae and their babies remain limited. Furthermore, reports of safety and efficacy of vaccines for SARS-CoV-2 in pregnancy are limited. This review concisely summarises the case studies and research on COVID-19 in pregnancy, to date. It also reviews the mechanism of infection with SARS-CoV-2, and its reliance and effects upon the renin-angiotensin-aldosterone system. Overall, the data suggest that infection during pregnancy can be dangerous at any time, but this risk to both the mother and fetus, as well as placental damage, increases during the third trimester. The possibility of vertical transmission, which is explored in this review, remains contentious. However, maternal infection with SARS-CoV-2 can increase risk of miscarriage, preterm birth and stillbirth, which is likely due to damage to the placenta.


Subject(s)
COVID-19/metabolism , Fetus/immunology , Infectious Disease Transmission, Vertical/prevention & control , Pregnancy Complications, Infectious/virology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , Fetus/virology , Humans , Infant, Newborn , Pandemics , Placenta/metabolism , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , SARS-CoV-2/isolation & purification
6.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166244, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1356140

ABSTRACT

The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.


Subject(s)
Placenta/virology , Pregnancy Complications, Infectious/virology , Virus Diseases/physiopathology , COVID-19/metabolism , Female , Fetus/virology , HIV Infections/metabolism , HIV-1/pathogenicity , Humans , Infectious Disease Transmission, Vertical/statistics & numerical data , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/epidemiology , SARS-CoV-2/pathogenicity , Zika Virus/pathogenicity , Zika Virus Infection/metabolism
7.
Clin Sci (Lond) ; 135(15): 1805-1824, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1337133

ABSTRACT

In times of coronavirus disease 2019 (COVID-19), the impact of severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection on pregnancy is still unclear. The presence of angiotensin-converting enzyme (ACE) 2 (ACE2), the main receptor for SARS-CoV-2, in human placentas indicates that this organ can be vulnerable for viral infection during pregnancy. However, for this to happen, additional molecular processes are critical to allow viral entry in cells, its replication and disease manifestation, particularly in the placenta and/or feto-maternal circulation. Beyond the risk of vertical transmission, COVID-19 is also proposed to deplete ACE2 protein and its biological actions in the placenta. It is postulated that such effects may impair essential processes during placentation and maternal hemodynamic adaptations in COVID-19 pregnancy, features also observed in several disorders of pregnancy. This review gathers information indicating risks and protective features related to ACE2 changes in COVID-19 pregnancies. First, we describe the mechanisms of SARS-CoV-2 infection having ACE2 as a main entry door and current evidence of viral infection in the placenta. Further, we discuss the central role of ACE2 in physiological systems such as the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS), both active during placentation and hemodynamic adaptations of pregnancy. Significant knowledge gaps are also identified and should be urgently filled to better understand the fate of ACE2 in COVID-19 pregnancies and the potential associated risks. Emerging knowledge will be able to improve the early stratification of high-risk pregnancies with COVID-19 exposure as well as to guide better management and follow-up of these mothers and their children.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Placenta/virology , Pregnancy Complications, Infectious/metabolism , Receptors, Coronavirus/metabolism , SARS-CoV-2/pathogenicity , Biomarkers/metabolism , COVID-19/transmission , COVID-19/virology , Female , Humans , Infectious Disease Transmission, Vertical , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/virology , Risk Factors , Virus Internalization
8.
Reprod Toxicol ; 104: 134-142, 2021 09.
Article in English | MEDLINE | ID: covidwho-1331182

ABSTRACT

AZD1222 (ChAdOx1 nCoV-19) is a COVID-19 vaccine that is not yet licensed for use during pregnancy. To support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies, a non-clinical developmental and reproductive toxicity study was performed to evaluate its effects on fertility and reproductive processes of female CD-1 mice during the embryofetal development phase, and postnatal outcomes during the littering phase. Immunogenicity assessments were also made in dams, fetuses, and pups. There were no vaccine-related unscheduled deaths throughout the study. Furthermore, there were no vaccine-related effects on female reproduction, fetal or pup survival, fetal external, visceral, or skeletal findings, pup physical development, and no abnormal gross pathology findings in pups or dams. Antibody responses raised in dams were maintained throughout gestation and postnatal periods, and seroconversion in fetuses and pups indicate placental and lactational transfer of immunoglobulins. Together with clinical data from non-pregnant people, these results support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Immunogenicity, Vaccine , Vaccination , Animals , Biomarkers/blood , COVID-19 Vaccines/toxicity , Female , Fetus/drug effects , Fetus/immunology , Fetus/metabolism , Gestational Age , Lactation/immunology , Lactation/metabolism , Maternal-Fetal Exchange , Mice , Placenta/immunology , Placenta/metabolism , Pregnancy , Prenatal Exposure Delayed Effects , Risk Assessment , Seroconversion
9.
Biochim Biophys Acta Mol Basis Dis ; 1867(11): 166218, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1323748

ABSTRACT

Throughout history, pandemics of infectious diseases caused by emerging viruses have spread worldwide. Evidence from previous outbreaks demonstrated that pregnant women are at high risk of contracting the diseases and suffering from adverse outcomes. However, while some viruses can cause major health complications for the mother and her fetus, others do not appear to affect pregnancy. Viral surface proteins bind to specific receptors on the cellular membrane of host cells and begin therewith the infection process. During pregnancy, the molecular features of these proteins may determine specific target cells in the placenta, which may explain the different outcomes. In this review, we display information on Variola, Influenza, Zika and Corona viruses focused on their surface proteins, effects on pregnancy, and possible target placental cells. This will contribute to understanding viral entry during pregnancy, as well as to develop strategies to decrease the incidence of obstetrical problems in current and future infections.


Subject(s)
Placenta/virology , Pregnancy Complications, Infectious/virology , Viral Envelope Proteins/metabolism , Virus Diseases/virology , Female , Humans , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Variola virus/metabolism , Variola virus/pathogenicity , Virus Diseases/metabolism , Zika Virus/metabolism , Zika Virus/pathogenicity
10.
Bull Exp Biol Med ; 171(3): 399-403, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1320105

ABSTRACT

A comparative morphological study was carried out to analyze the number of syncytial knots and VEGF expression in placental villi in parturient women with COVID-19 categorized by the disease severity. The number of syncytial knots was assessed on specimens stained with hematoxylin and eosin. VEGF expression was determined by immunohistochemical analysis in syncytiotrophoblast and villous endothelial cells. Morphological study of the placenta tissue of parturient women with COVID-19 showed increased numbers of syncytial knots in the villi, indicating the development of preplacental hypoxia. High VEGF expression in syncytiotrophoblast and vascular endotheliocytes reflects a stereotyped response to hypoxia and can underlie the development of a preeclampsia-like syndrome. The number of syncytial knots and VEGF expression in placental villi in parturient women with COVID-19 depended on the disease severity.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , Chorionic Villi/metabolism , Placenta/metabolism , Vascular Endothelial Growth Factor A/metabolism , Female , Humans , Immunohistochemistry , Pregnancy , SARS-CoV-2/pathogenicity
11.
Cells ; 10(7)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1314589

ABSTRACT

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2.


Subject(s)
COVID-19/genetics , MicroRNAs/genetics , Pregnancy Complications, Infectious/genetics , Adult , COVID-19/blood , COVID-19/diagnosis , Female , Humans , MicroRNAs/analysis , MicroRNAs/blood , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/diagnosis , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
12.
Sci Rep ; 11(1): 14390, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1309469

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic affected people at all ages. Whereas pregnant women seemed to have a worse course of disease than age-matched non-pregnant women, the risk of feto-placental infection is low. Using a cohort of 66 COVID-19-positive women in late pregnancy, we correlated clinical parameters with disease severity, placental histopathology, and the expression of viral entry and Interferon-induced transmembrane (IFITM) antiviral transcripts. All newborns were negative for SARS-CoV-2. None of the demographic parameters or placental histopathological characteristics were associated with disease severity. The fetal-maternal transfer ratio for IgG against the N or S viral proteins was commonly less than one, as recently reported. We found that the expression level of placental ACE2, but not TMPRSS2 or Furin, was higher in women with severe COVID-19. Placental expression of IFITM1 and IFITM3, which have been implicated in antiviral response, was higher in participants with severe disease. We also showed that IFITM3 protein expression, which localized to early and late endosomes, was enhanced in severe COVID-19. Our data suggest an association between disease severity and placental SARS-CoV-2 processing and antiviral pathways, implying a role for these proteins in placental response to SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Placenta/metabolism , SARS-CoV-2/pathogenicity , Adult , Angiotensin-Converting Enzyme 2/metabolism , Female , Furin/metabolism , Humans , Immunoglobulin G/metabolism , Infectious Disease Transmission, Vertical , Male , Nucleocapsid Proteins/metabolism , Pregnancy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/virology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
13.
Cells ; 10(7)2021 07 08.
Article in English | MEDLINE | ID: covidwho-1302161

ABSTRACT

COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies (n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women (n = 6). Second trimester placental explants (16-20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression (p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta (p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Gene Expression , Placenta/metabolism , Pregnancy Complications, Infectious/genetics , Premature Birth/etiology , Adult , COVID-19/genetics , COVID-19/transmission , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Lymphocytes/metabolism , Monocytes/metabolism , Placenta/cytology , Pregnancy , Premature Birth/genetics , SARS-CoV-2/isolation & purification
14.
Clin Nutr ESPEN ; 43: 1-8, 2021 06.
Article in English | MEDLINE | ID: covidwho-1240256

ABSTRACT

BACKGROUND & AIMS: Maternal gestational infection is a well-characterized risk factor for offsprings' development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses. METHOD: Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed. RESULTS: Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect. CONCLUSIONS: Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2.


Subject(s)
Brain , COVID-19/complications , Choline/therapeutic use , Fetal Development , Mothers , Nutritional Status , Pregnancy Complications, Infectious/virology , Animals , Brain/drug effects , COVID-19/metabolism , COVID-19/virology , Child Development/drug effects , Choline/pharmacology , Developmental Disabilities/etiology , Developmental Disabilities/prevention & control , Dietary Supplements , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Omega-3/therapeutic use , Female , Fetal Development/drug effects , Fetus/drug effects , Folic Acid/pharmacology , Folic Acid/therapeutic use , Humans , Infant , Inflammation/complications , Inflammation/metabolism , Nutritional Requirements , Pandemics , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/metabolism , SARS-CoV-2 , Vitamin D/pharmacology , Vitamin D/therapeutic use
15.
Virchows Arch ; 479(4): 715-728, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1209750

ABSTRACT

Infection by SARS-CoV-2 has been shown to involve a wide range of organs and tissues, leading to a kaleidoscope of clinical conditions. Within this spectrum, an involvement of the fetal-maternal unit could be expected, but, so far, the histopathological evaluation of placentas delivered by women with SARS-CoV-2 infection did not show distinct hallmarks. A consecutive series of 11 placentas, delivered by 10 women with COVID-19 admitted to our Obstetrics and Gynecology clinic have been investigated and compared to a control cohort of 58 pre-COVID-19 placentas and 28 placentas delivered by women who had a previous cesarean section. Four out of eleven placentas showed changes consistent with chronic villitis/villitis of unknown etiology (VUE), while in one case, chronic histiocytic intervillositis was diagnosed. Thrombo-hemorrhagic alterations were observed in a subset of cases. Compared to the control cohort, chronic villitis/VUE (p < 0.001), chronic deciduitis (p = 0.023), microvascular thrombosis (p = 0.003), presence of infarction areas (p = 0.047) and of accelerated villous maturation (p = 0.005) showed higher frequencies in placentas delivered by women with COVID-19. Chronic villitis/VUE (p = 0.003) and accelerated villous maturation (p = 0.019) remained statistically significant by restricting the analysis to placentas delivered after a previous cesarean section. The observed differences in terms of pathological findings could be consistent with SARS-CoV-2 pathogenesis, but just a subset of alterations remained statistically significant after adjusting for a previous cesarean section. A careful consideration of potential confounders is warranted in future studies exploring the relationship between COVID-19 and pregnancy.


Subject(s)
COVID-19/pathology , Placenta/pathology , Adult , COVID-19/metabolism , Chorionic Villi/pathology , Chorionic Villi/virology , Cohort Studies , Female , Humans , Inflammation/pathology , Inflammation/virology , Placenta/metabolism , Placenta/virology , Pregnancy , SARS-CoV-2/isolation & purification , Thrombosis/pathology , Thrombosis/virology
16.
J Mol Histol ; 52(3): 427-435, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1192191

ABSTRACT

SARS-CoV-2, the leading cause of COVID-19 pandemic, was detected for the first time in Wuhan. In this study, we investigated the potential undesirable maternal and feto-neonatal consequences of COVID-19, and the related pathophysiological alterations in mother, neonate, and especially in the placenta as a vital organ, were reviewed. Also, the possibility of vertical transmission of virus and placental abnormalities were evaluated. The pregnant women were a vulnerable population for COVID-19, and several obstetric consequences were reported following SARS-CoV-2 infection. The higher risk of abruption, preterm labor, maternal death, stillbirth, intrauterine growth restriction, and newborns with fetal distress were adverse pregnancy and perinatal outcomes of COVID-19. Despite the ACE2 expression on placental components was confirmed, there is no agreement on the mother-child vertical transmission of this virus. Therefore, feto-neonatal consequences might be associated with placental abnormalities. The placental abnormalities are characterized by feto-maternal vascular malperfusion. Additionally, these adverse consequences lead to early termination of pregnancy in some cases, mostly via cesarean section. The pregnant women screening, coordination between healthcare personnel and neonatal unit, and infected women quarantine may decrease the risk of maternal and neonatal death after delivery.


Subject(s)
COVID-19/metabolism , Infectious Disease Transmission, Vertical , Placenta/metabolism , Pregnancy Complications, Infectious/metabolism , SARS-CoV-2/metabolism , Adult , COVID-19/pathology , Female , Humans , Infant, Newborn , Placenta/pathology , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/pathology , Pregnancy Complications, Infectious/virology
17.
J Med Virol ; 93(5): 2769-2773, 2021 May.
Article in English | MEDLINE | ID: covidwho-1070767

ABSTRACT

The coronavirus disease 2019 (COVID-19), which had spread to the world from Wuhan (China) in late December, was announced as a pandemic by the World Health Organization in March 2020. In addition to acute respiratory syndrome symptoms, this virus also affects nonrespiratory organs, according to existing data. ACE2 and TMPRSS2, which play a critical role in the entrance of SARS-COV-2 into the cell, are coexpressed in placental development stages, so the placenta also carries a risk for this virus. Many studies have shown that this virus causes some histopathological changes in the placenta. The vertical transmission of the virus is not yet clear, but available data have shown that the indirect effects of the virus can be seen on the fetus. This article focuses on revealing the effects of the virus on the placenta in all aspects.


Subject(s)
COVID-19/epidemiology , Placenta/virology , Pregnancy Complications, Infectious/epidemiology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/therapy , COVID-19/transmission , Cytokine Release Syndrome/immunology , Female , Humans , Infectious Disease Transmission, Vertical , Placenta/cytology , Placenta/immunology , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/immunology , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Stem Cell Transplantation
18.
Clin Ther ; 43(2): 308-318, 2021 02.
Article in English | MEDLINE | ID: covidwho-1064961

ABSTRACT

PURPOSE: The majority of pregnancies affected by maternal coronavirus disease 2019 (COVID-19) do not result in fetal transmission. However, several studies have identified parenchymal changes in their placental tissues, suggesting a placental response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the maternal-fetal interface. Although many COVID-19 placental studies have focused on the expression of the canonical SARS-CoV-2 entry proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2, further characterization of subcellular molecules involved in viral trafficking have not yet been investigated in these tissues. Of interest are Rab proteins, a family of small GTPase proteins that direct intracellular transport between different endocytic organelles. Rab5 and Rab7 in particular have previously been implicated in HIV and cytomegalovirus invasion of placental trophoblast cells in vitro; the localization of these molecules has not been fully characterized within the human maternal-fetal interface, however, or within placental tissues from SARS-CoV-2-infected pregnancies. METHODS: Using fluorescent immunohistochemistry, Rab5 and Rab7 placental localization and comparative fluorescence intensity were explored in a cohort of placental tissues from pregnancies affected by maternal COVID-19 disease (COVID, n = 15) compared with contemporary control subjects (Control, n = 10). Fluorescence intensity was quantified by using corrected total cell fluorescence values. FINDINGS: Within placental villi, Rab5 was consistently localized in syncytiotrophoblast and cytotrophoblast cells. Rab5 had significantly higher mean (SEM) fluorescence intensity in the COVID cohort (Control, 1.96 [0.16]; COVID, 2.62 [0.09]; P = 0.0014). In contrast, although Rab7 was also localized within placental villous syncytiotrophoblast and cytotrophoblast cells, mean (SEM) Rab7 fluorescence intensity was significantly downregulated in COVID vs Control placentas (Control, 35.9 [4.1]; COVID, 20.1 [0.52]; P = 0.0001). IMPLICATIONS: This differential expression of Rab5 and Rab7 suggests that placental endocytic pathways may be altered at the maternal-fetal interface in pregnancies affected by maternal SARS-CoV-2 infection. As key molecules governing intracellular vesicle transport, including viral trafficking, Rab GTPase proteins may be of interest for ongoing studies examining placental responses to COVID-19 in pregnancy.


Subject(s)
COVID-19/metabolism , Placenta/metabolism , Pregnancy Complications, Infectious/metabolism , Trophoblasts/metabolism , rab GTP-Binding Proteins/metabolism , rab5 GTP-Binding Proteins/metabolism , Female , Humans , Pregnancy , Pregnancy Complications, Infectious/virology , SARS-CoV-2
19.
Ultrasound Obstet Gynecol ; 57(2): 248-256, 2021 02.
Article in English | MEDLINE | ID: covidwho-1060145

ABSTRACT

OBJECTIVES: To examine the characteristics and distribution of possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target cells in the human trophectoderm (TE) and placenta. METHODS: Bioinformatics analysis was performed based on published single-cell transcriptomic datasets of early TE and first- and second-trimester human placentae. We conducted the transcriptomic analysis of 4198 early TE cells, 1260 first-trimester placental cells and 189 extravillous trophoblast cells (EVTs) from 24-week placentae (EVT_24W) using the SMART-Seq2 method. In addition, to confirm the bioinformatic results, we performed immunohistochemical staining of three first-trimester, three second-trimester and three third-trimester placentae from nine women recruited prospectively to this study. We evaluated the expression of the SARS-CoV-2-related molecules angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). RESULTS: Via bioinformatic analysis, we identified the existence of ACE2 and TMPRSS2 expression in human TE as well as in first- and second-trimester placentae. In the human TE, 54.4% of TE1 cells, 9.0% of cytotrophoblasts (CTBs), 3.2% of EVTs and 29.5% of syncytiotrophoblasts (STBs) were ACE2-positive. In addition, 90.7% of TE1 cells, 31.5% of CTBs, 22.1% of EVTs and 70.8% of STBs were TMPRSS2-positive. In placental cells, 20.4% of CTBs, 44.1% of STBs, 3.4% of EVTs from 8-week placentae (EVT_8W) and 63% of EVT_24W were ACE2-positive, while 1.6% of CTBs, 26.5% of STBs, 1.9% of EVT_8W and 20.1% of EVT_24W were TMPRSS2-positive. Pathway analysis revealed that EVT_24W cells that were positive for both ACE2 and TMPRSS2 (ACE2 + TMPRSS2-positive) were associated with morphogenesis of branching structure, extracellular matrix interaction, oxygen binding and antioxidant activity. The ACE2 + TMPRSS2-positive TE1 cells were correlated with an increased capacity for viral invasion, epithelial-cell proliferation and cell adhesion. Expression of ACE2 and TMPRSS2 was observed on immunohistochemical staining in first-, second- and third-trimester placentae. CONCLUSIONS: ACE2- and TMPRSS2-positive cells are present in the human TE and placenta in all three trimesters of pregnancy, which indicates the possibility that SARS-CoV-2 could spread via the placenta and cause intrauterine fetal infection. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , Placenta/enzymology , RNA/biosynthesis , Serine Endopeptidases/biosynthesis , Trophoblasts/enzymology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/enzymology , COVID-19/virology , Female , Fetus/metabolism , Fetus/virology , Gene Expression Profiling/methods , Humans , Infectious Disease Transmission, Vertical , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/enzymology , Pregnancy Complications, Infectious/virology , Prospective Studies , RNA/genetics , RNA/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/genetics , Single-Cell Analysis , Trophoblasts/metabolism
20.
Early Hum Dev ; 155: 105322, 2021 04.
Article in English | MEDLINE | ID: covidwho-1053333

ABSTRACT

From the moment of the identification of SARS-CoV-2 as an etiological agent of the severe clinical pictures of pneumonia that were being slowly observed all over the world, numerous studies have been conducted to increase the knowledge about what was an unknown virus until then. The efforts were mainly aimed to acquire epidemiological, microbiological, pathogenetic, clinical, diagnostic, therapeutic and preventive information in order to increase the available weapons to fight an infection which was rapidly taking on the characteristics of the pandemic. Given the topicality of the problem, not everything has yet been fully understood and clarified, especially in the maternal-fetal­neonatal field, where we are beginning to question what could be the outcomes of newborn babies born to mothers who contracted SARS-CoV-2 infection during pregnancy. Thus, the aim of this review is to analyze the long-term outcomes of this infection that could affect the offspring, regardless of a possible maternal-fetal transmission, focusing on, above all, the role of maternal immune activation and the expression of the Angiotensin-converting enzyme 2 (ACE2) in particular at the placental level.


Subject(s)
COVID-19/complications , Infant, Newborn, Diseases/virology , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , Adaptive Immunity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/therapy , COVID-19/transmission , Female , Fetal Development , Humans , Infant, Newborn , Infant, Newborn, Diseases/embryology , Infant, Newborn, Diseases/metabolism , Infectious Disease Transmission, Vertical , Placenta/immunology , Placenta/metabolism , Pregnancy , Time Factors
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