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1.
Medicine (Baltimore) ; 99(40): e22152, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019392

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) produces numerous problems for maternal and fetal outcomes. However, the precise molecular mechanisms of GDM are not clear. METHODS: In our study, we randomly assigned 22 pregnant women with fasting glucose concentrations, 1 hour oral glucose tolerance test (1H-OGTT) and 2 hour oral glucose tolerance test (2H-OGTT), different than 28 normal pregnant women from a sample of 107 pregnant women at the First Affiliated Hospital of Jinan University in China. Lipopolysaccharide (LPS), interleukin 1 alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) were measured from blood plasma of pregnant women and umbilical arteries using ultraviolet spectrophotometry. Hematoxylin & Eosin (H&E), Periodic acid-Schiff (PAS) or Masson staining were performed to examine whether diabetes mellitus altered the morphology of placenta. Quantitative PCR (Q-PCR), western blotting and immunofluorescent staining were performed to examine whether diabetes mellitus and autophagy altered the gene expressions of the placental tissue. RESULTS: We found that women with GDM exhibited increased placental weight and risk of neonatal infection. The concentrations of IL-6 protein and IL-8 protein in GDM were increased in both maternal and umbilical arterial blood. H&E, Masson and PAS staining results showed an increased number of placental villi and glycogen deposition in patients with GDM, but no placental sclerosis was found. Q-PCR results suggested that the expression levels of HIF-1α and the toll like receptor 4 (TLR4)/ myeloid differential protein-88 (MyD88)/ nuclear factor kappa-B (NF-κB) pathway were increased in the GDM placenta. Through Western Blotting, we found that the expression of NF-kappa-B inhibitor alpha (IKBα) and Nuclear factor-κB p65 (NF-κB p65) in GDM placenta was significantly enhanced. We also showed that the key autophagy-related genes, autophagy-related 7 (ATG7) and microtubule-associated protein 1A/1B-light chain 3 (LC3), were increased in GDM compared with normal pregnant women. CONCLUSIONS: Our results suggest that women with GDM exhibit an increased risk of neonatal infection via inflammation and autophagy in the placenta.


Assuntos
Diabetes Gestacional/sangue , Placenta/patologia , Adulto , Diabetes Gestacional/genética , Feminino , Sangue Fetal , Teste de Tolerância a Glucose , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Recém-Nascido , Inflamação/sangue , Inflamação/genética , Placenta/microbiologia , Gravidez , Resultado da Gravidez , Receptor 4 Toll-Like/sangue
2.
Placenta ; 101: 13-29, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911234

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified after a cluster of cases in Wuhan, China in December 2019. Whether vertical transmission or placental pathology might occur following maternal infection during pregnancy remains unknown. This review aimed to summarise all studies that examined the placenta or neonates following infection with SARS-CoV-2, or closely related highly pathogenic coronavirus (SARS-CoV-1, or the Middle East respiratory syndrome coronavirus (MERS-CoV)). Structured literature searches found 50 studies that met the inclusion criteria. Twenty studies reported placental histopathology findings in third trimester placentas following maternal SARS-CoV-2 infection. Using the Amsterdam Consensus criteria to categorise the histopathology results, evidence of both fetal vascular malperfusion (35.3% of cases; 95% Confidence Interval (CI) 27.7-43.0%) and maternal vascular malperfusion (46% of cases; 95% CI 38.0-54.0%) were reported, along with evidence of inflammation in the placentas (villitis 8.7% cases, intervillositis 5.3% of cases, chorioamnionitis 6% of cases). The placental pathologies observed in SARS-CoV-2 were consistent with findings following maternal SARS-CoV-1 infection. Of those tested, a minority of neonates (2%) and placental samples tested positive for SARS-CoV-2 infection (21%). Limited conclusions can be drawn about the effect of maternal SARS-CoV-2 infection on placental pathology as most lack control groups and the majority of reports followed third trimester infection. Collaboration to maximise the number of samples examined will increase the reliability and generalisability of findings. A better understanding of the association between maternal SARS-CoV-2 infection and placental pathology will inform maternity care during the coronavirus pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Transmissão Vertical de Doença Infecciosa , Placenta/patologia , Pneumonia Viral/patologia , Complicações Infecciosas na Gravidez/patologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/transmissão , Feminino , Humanos , Recém-Nascido , Pandemias , Placenta/irrigação sanguínea , Placenta/virologia , Circulação Placentária/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/transmissão , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Vírus da SARS/patogenicidade , Vírus da SARS/fisiologia
3.
Ultrasound Obstet Gynecol ; 56(5): 773-776, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32853442

RESUMO

We report a case of a pregnant woman with COVID-19 who developed coagulopathy in the absence of severe clinical symptoms. A polymerase chain reaction test of a vaginal swab was positive for SARS-CoV-2 RNA, suggesting a possibility of perinatal transmission. Cesarean delivery was performed because of a non-reassuring fetal heart rate; the placenta showed increased perivillous fibrin deposition and intervillositis. Moreover, placental infection with SARS-CoV-2 was demonstrated by placental immunostaining. The findings suggest a possible relationship between placental fibrin deposition and chronic and acute intervillositis, non-reassuring fetal heart rate and coagulopathy in pregnant women with COVID-19. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Coagulação Intravascular Disseminada/virologia , Pneumonia Viral/diagnóstico , Complicações Hematológicas na Gravidez/virologia , Complicações Infecciosas na Gravidez/diagnóstico , Adulto , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/transmissão , Coagulação Intravascular Disseminada/diagnóstico , Feminino , Frequência Cardíaca Fetal , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Pandemias , Placenta/patologia , Placenta/virologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/transmissão , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/patologia
4.
EBioMedicine ; 59: 102951, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32818801

RESUMO

BACKGROUND: . The occurrence of trans-placental transmission of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection remains highly debated. Placental positivity for SARS-CoV-2 has been reported in selected cases, but infection or virus-associated disease of fetal tissues or newborns remains to be demonstrated. METHODS: We screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women who delivered between February 7 and May 15, 2020, including 15 tested positive for SARS-CoV-2 RNA, 34 tested negative, and 52 not evaluated as they did not meet testing criteria (32), or delivered before COVID-19 pandemic declaration (20). Immunostain for SARS-CoV-2 nucleocapsid (N) was performed in the placentas of all COVID-19 positive women. One placenta resulted positive for the SARS-CoV-2 S and N proteins, which was further studied by RNA-in situ hybridization and RT-PCR for S transcripts, and by electron microscopy. A comprehensive immunohistochemical and immunofluorescence analysis of the placental inflammatory infiltrate completed the investigations. FINDINGS: SARS-CoV-2 S and N proteins were strongly expressed in the placenta of a COVID-19 pregnant woman whose newborn tested positive for viral RNA and developed COVID-19 pneumonia soon after birth. SARS-CoV-2 antigens, RNA and/or particles morphologically consistent with coronavirus were identified in villous syncytiotrophoblast, endothelial cells, fibroblasts, in maternal macrophages, and in Hofbauer cells and fetal intravascular mononuclear cells. The placenta intervillous inflammatory infiltrate consisted of neutrophils and monocyte-macrophages expressing activation markers. Absence of villitis was associated with an increase in the number of Hofbauer cells, which expressed PD-L1. Scattered neutrophil extracellular traps (NETs) were identified by immunofluorescence. INTERPRETATION: We provide first-time evidence for maternal-fetal transmission of SARS-CoV-2, likely propagated by circulating virus-infected fetal mononuclear cells. Placenta infection was associated with recruitment of maternal inflammatory cells in the intervillous space, without villitis. PD-L1 expression in syncytiotrophoblast and Hofbaeur cells, together with limited production of NETs, may have prevented immune cell-driven placental damage, ensuring sufficient maternal-fetus nutrient exchanges.


Assuntos
Infecções por Coronavirus/transmissão , Placenta/virologia , Pneumonia Viral/transmissão , Adulto , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Macrófagos/virologia , Microscopia Eletrônica , Nasofaringe/virologia , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Placenta/citologia , Placenta/patologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Gravidez , RNA Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
5.
Life Sci ; 261: 118351, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32858039

RESUMO

AIMS: Numerous studies suggest that excessive maternal inflammation and defective extravillous trophoblast (EVT) invasion could contribute to the development of preeclampsia (PE), but the underlying mechanism remains unclear. Some evidence suggests that CyPA is elevated in PE. This research aims to investigate the effect of recombinant human CyPA on trophoblast migration and invasion both in vitro and in vivo. MATERIALS AND METHODS: We detected the expression and localization of CyPA in human placenta and explored the effects of CyPA on cell migration and invasion on HTR8/SVneo cell. Additionally, the expression levels of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway were detected. We established a mouse model by injecting pregnant mice with recombinant human CyPA and measured blood pressure, albumin/creatinine ratio, fetal and placenta weight of mice. Moreover, we examined the placental histology and MMP-2/9 and p38/ERK/JNK expression. KEY FINDINGS: Our results showed that CyPA inhibited the migration and invasion of HTR8/SVneo cells in a dose-dependent manner, decreasing the expression of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway. Silencing CyPA could reverse the above effects. Moreover, CyPA could induce PE-like features in pregnant mice and disrupt the structure of the mouse placenta by reducing the junctional zone area. CyPA attenuated the trophoblast invasiveness in mice placenta by downregulating MMP-2/9 expression and p38/ERK/JNK pathway activity. SIGNIFICANCE: We proposed that CyPA could inhibit trophoblast migration and invasion both in vitro and in vivo, which was involved in PE development.


Assuntos
Movimento Celular , Ciclofilina A/metabolismo , Sistema de Sinalização das MAP Quinases , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/patologia , Trofoblastos/enzimologia , Trofoblastos/patologia , Adulto , Animais , Regulação para Baixo/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Rim/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Placenta/enzimologia , Placenta/patologia , Gravidez , Resultado da Gravidez
6.
Life Sci ; 261: 118314, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835699

RESUMO

AIMS: Placental tissues from patients with preeclampsia (PE) and in the lipopolysaccharide (LPS)-induced PE-like model were used to investigate the implication of placental inflammation and apoptosis in PE. Whether the beneficial effects of nicotine are related to inhibition of placental inflammation and apoptosis in the PE-like model were investigated. MAIN METHODS: Placental apoptosis was detected in PE patients and the PE-like rat model by TUNEL staining. Changes in the number of CD68+ macrophages in placental tissues from PE patients were detected by immunofluorescent staining. The mRNA expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL-1ß), MCP-1, and proteins involved in extrinsic or intrinsic apoptosis signaling in the PE-like model was determined by qRT-PCR; immunofluorescent staining was used to detect the expression of TNF-α receptor (TNFR1), MCP-1 and apoptosis-related proteins. KEY FINDINGS: Placental apoptosis was increased in both PE patients and the PE-like model, more macrophages infiltrated into placenta in PE patients. A significant upregulation in mRNA expression of TNF-α, IL-1ß, MCP-1, and caspase 3, caspase 8, caspase 9 was found in the PE-like rats compared to the control animals, the immunoreactivity of placental MCP-1, TNFR1, and apoptosis-related proteins (caspase 3, caspase 8, caspase 9, Bax) was also enhanced; nicotine treatment significantly reversed those changes. SIGNIFICANCE: Our data suggests that the protective effects of nicotine are associated with inhibiting placenta inflammation and apoptosis, and nicotine might be a potentially therapeutic candidate for preventing preeclampsia.


Assuntos
Inflamação/tratamento farmacológico , Nicotina/farmacologia , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/prevenção & controle , Adulto , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Adulto Jovem
7.
Mod Pathol ; 33(11): 2092-2103, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32741970

RESUMO

Congenital infection of SARS-CoV-2 appears to be exceptionally rare despite many cases of COVID-19 during pregnancy. Robust proof of placental infection requires demonstration of viral localization within placental tissue. Only two of the few cases of possible vertical transmission have demonstrated placental infection. None have shown placental expression of the ACE2 or TMPRSS2 protein, both required for viral infection. We examined 19 COVID-19 exposed placentas for histopathologic findings, and for expression of ACE2, and TMPRSS2 by immunohistochemistry. Direct placental SARS-CoV-2 expression was studied by two methods-nucleocapsid protein expression by immunohistochemistry, and RNA expression by in situ hybridization. ACE2 membranous expression in the syncytiotrophoblast (ST) of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the ST. In addition, cytotrophoblast and extravillous trophoblast express ACE2. No ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST. In 2 of 19 cases, SARS-CoV-2 RNA was present in the placenta focally in the ST and cytotrophoblast. There was no characteristic histopathology present in our cases including the two placental infections. We found that the placenta is capable of being infected but that this event is rare. We propose one explanation could be the polarized expression of ACE2 away from the maternal blood and pronounced paucity of TMPRSS2 expression in trophoblast.


Assuntos
Infecções por Coronavirus/virologia , Placenta/patologia , Placenta/virologia , Pneumonia Viral/virologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Betacoronavirus , Infecções por Coronavirus/patologia , Feminino , Humanos , Pandemias , Peptidil Dipeptidase A/biossíntese , Placenta/metabolismo , Pneumonia Viral/patologia , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/patologia , RNA Viral/análise , Serina Endopeptidases/biossíntese
8.
Histopathology ; 77(6): 994-999, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32692408

RESUMO

AIMS: The wide variety of affected organ systems associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection highlights the need for tissue-specific evaluation. We compared placentas from SARS-CoV-2-positive and SARS-CoV-2-negative women in our hospital in New York City, which became the epicenter of the coronavirus disease 2019 pandemic in March 2020. To date, some limited studies have been published on placentas from SARS-CoV-2-positive women. The aim of our study, in addition to describing histomorphology, was to utilize in-situ hybridization (ISH) for the S-gene encoding the spike protein and immunohistochemistry (IHC) with the monoclonal SARS-CoV-2 spike antibody 1A9 for placental evaluation. METHODS AND RESULTS: In this study, 51 singleton, third-trimester placentas from SARS-CoV-2-positive women and 25 singleton, third-trimester placentas from SARS-CoV-2-negative women were examined histomorphologically according to the Amsterdam Criteria and with ISH and/or IHC. The corresponding clinical findings and neonatal outcomes also were recorded. Although no specific histomorphologic changes related to SARS-CoV-2 were noted in the placentas, evidence of maternal-fetal vascular malperfusion was identified, with placentas from SARS-CoV-2-positive women being significantly more likely to show villous agglutination (P = 0.003) and subchorionic thrombi (P = 0.026) than placentas from SARS-CoV-2-negative women. No evidence of direct viral involvement was identified with ISH and IHC. CONCLUSIONS: In this study, third-trimester placentas from SARS-CoV-2-positive women were more likely to show evidence of maternal-fetal vascular malperfusion; however, ISH and IHC provided no evidence of direct viral involvement or vertical transmission.


Assuntos
Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Placenta/patologia , Placenta/virologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Betacoronavirus , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Pandemias , Gravidez , Terceiro Trimestre da Gravidez
9.
PLoS One ; 15(7): e0235840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702025

RESUMO

OBJECTIVES: Maternal protein malnutrition is associated with impaired fetal growth, and lifetime consequences for the offspring. Our group has previously developed a model of protein-restriction in the non-human primate, which was associated with fetal growth restriction, stillbirth, decreased placental perfusion, and evidence of fetal hypoxia, suggesting perturbed vascular development. Our objective was to histologically characterize the micro-anatomic alterations associated with adverse pregnancy outcomes taking an approach that permits investigation of the 3D vascular structure and surrounding histology without the requirement for 3D vascular casting or relying on 2D stereology which both have methodological limitations. METHODS: Rhesus macaques were assigned in the pre-gestational period to a control diet that contained 26% protein, or study diet containing 13% protein (50% PR diet). Placental tissue was collected at delivery and processed using a clarification, immunohistochemistry, and confocal microscopy protocol published previously by our group. Three dimensional reconstructions and quantitative assessment of the vascular micro-anatomy was performed using analysis software (Imaris®) and statistical analysis accounted for maternal and fetal confounders. RESULTS: In unadjusted analysis, when comparing those pregnancies on a 50% PR diet (n = 4) with those on a control diet (n = 4), protein-restriction diet was associated with decreased maternal pre-pregnancy weight (difference of -1.975kg, 95% CI -3.267 to -0.6826). When controlling for maternal pre-pregnancy weight, fetal sex, and latency from tissue collection to imaging, a gestational protein-restriction diet was associated with decreases in total vascular length, total vascular surface area, total vascular volume, and vascular density. CONCLUSION: In this pilot study, a gestational protein-restriction diet altered the placental micro-vasculature with decreased vascular caliber and density, which may be related to the observed adverse pregnancy outcomes and perturbed placental perfusion previously demonstrated in this model.


Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Retardo do Crescimento Fetal/patologia , Transtornos da Nutrição Fetal/patologia , Placenta/patologia , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/etiologia , Transtornos da Nutrição Fetal/etiologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Macaca mulatta/embriologia , Macaca mulatta/fisiologia , Projetos Piloto , Circulação Placentária , Gravidez , Natimorto
10.
Nat Commun ; 11(1): 3572, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665677

RESUMO

SARS-CoV-2 outbreak is the first pandemic of the century. SARS-CoV-2 infection is transmitted through droplets; other transmission routes are hypothesized but not confirmed. So far, it is unclear whether and how SARS-CoV-2 can be transmitted from the mother to the fetus. We demonstrate the transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the last trimester and presenting with neurological compromise. The transmission is confirmed by comprehensive virological and pathological investigations. In detail, SARS-CoV-2 causes: (1) maternal viremia, (2) placental infection demonstrated by immunohistochemistry and very high viral load; placental inflammation, as shown by histological examination and immunohistochemistry, and (3) neonatal viremia following placental infection. The neonate is studied clinically, through imaging, and followed up. The neonate presented with neurological manifestations, similar to those described in adult patients.


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/virologia , Vasculite do Sistema Nervoso Central/virologia , Betacoronavirus , Infecções por Coronavirus/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal/fisiologia , Mães , Pandemias , Placenta/patologia , Placenta/virologia , Pneumonia Viral/patologia , Gravidez , Carga Viral , Viremia/transmissão , Adulto Jovem
11.
Am J Pathol ; 190(10): 2111-2122, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32679230

RESUMO

After a child is born, the examination of the placenta by a pathologist for abnormalities, such as infection or maternal vascular malperfusion, can provide important information about the immediate and long-term health of the infant. Detection of the pathologic placental blood vessel lesion decidual vasculopathy (DV) has been shown to predict adverse pregnancy outcomes, such as preeclampsia, which can lead to mother and neonatal morbidity in subsequent pregnancies. However, because of the high volume of deliveries at large hospitals and limited resources, currently a large proportion of delivered placentas are discarded without inspection. Furthermore, the correct diagnosis of DV often requires the expertise of an experienced perinatal pathologist. We introduce a hierarchical machine learning approach for the automated detection and classification of DV lesions in digitized placenta slides, along with a method of coupling learned image features with patient metadata to predict the presence of DV. Ultimately, the approach will allow many more placentas to be screened in a more standardized manner, providing feedback about which cases would benefit most from more in-depth pathologic inspection. Such computer-assisted examination of human placentas will enable real-time adjustment to infant and maternal care and possible chemoprevention (eg, aspirin therapy) to prevent preeclampsia, a disease that affects 2% to 8% of pregnancies worldwide, in women identified to be at risk with future pregnancies.


Assuntos
Decídua/patologia , Placenta/patologia , Pré-Eclâmpsia/patologia , Doenças Vasculares/patologia , Adulto , Feminino , Humanos , Recém-Nascido , Redes Neurais de Computação , Gravidez , Resultado da Gravidez
12.
Pediatr Infect Dis J ; 39(9): e265-e267, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32658097

RESUMO

We present a preterm infant who developed a fever and mild respiratory disease on the second day of life. Infant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal testing was positive at 24 and 48 hours of life. Placenta histopathology revealed SARS-CoV-2 infection by electron microscopy and immunohistochemistry. Further understanding of the risk factors that lead to in utero transmission of SARS-CoV-2 infection is needed.


Assuntos
Infecções por Coronavirus/transmissão , Recém-Nascido Prematuro , Transmissão Vertical de Doença Infecciosa , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/virologia , Adulto , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Feminino , Febre/virologia , Humanos , Recém-Nascido , Pandemias , Placenta/patologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Fatores de Risco
13.
Cells ; 9(8)2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32722449

RESUMO

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage, and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.


Assuntos
Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/imunologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Recém-Nascido , MicroRNAs/genética , MicroRNAs/metabolismo , Pandemias , Placenta/metabolismo , Placenta/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia
14.
J Vis Exp ; (160)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32658199

RESUMO

Chorioamnionitis is a common precipitant of preterm birth and is associated with many of the morbidities of prematurity, including necrotizing enterocolitis (NEC). However, a mechanistic link between these two conditions remains yet to be discovered. We have adopted a murine model of chorioamnionitis involving lipopolysaccharide (LPS)-induced fetal exposure to maternal inflammation (FEMI). This model of FEMI induces a sterile maternal, placental, and fetal inflammatory cascade, which is also present in many cases of clinical chorioamnionitis. Although models exist that utilize live bacteria and more accurately mimic the pathophysiology of an ascending infection resulting in chorioamnionitis, these methods may cause indirect effects on development of the immature intestinal tract and the associated developing microbiome. Using this protocol, we have demonstrated that LPS-induced FEMI results in a dose-dependent increase in pregnancy loss and preterm birth, as well as disruption of normal intestinal development in offspring. Further, we have demonstrated that FEMI significantly increases intestinal injury and serum cytokines in offspring, while simultaneously decreasing goblet and Paneth cells, both of which provide a first line of innate immunity against intestinal inflammation. Although a similar model of LPS-induced FEMI has been used to model the association between chorioamnionitis and subsequent abnormalities of the central nervous system, to our knowledge, this protocol is the first to attempt to elucidate a mechanistic link between chorioamnionitis and later perturbations in intestinal development as a potential link between chorioamnionitis and NEC.


Assuntos
Corioamnionite , Intestinos/crescimento & desenvolvimento , Mães , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Doença Aguda , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Feto/patologia , Humanos , Recém-Nascido , Camundongos , Celulas de Paneth/patologia , Placenta/patologia , Gravidez
15.
Proc Natl Acad Sci U S A ; 117(27): 15852-15861, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32576693

RESUMO

In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of preterm delivery, hemorrhage, and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The messenger RNA (mRNA) encoding the guanine nucleotide exchange factor, DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly up-regulated molecule in PAS samples. Overexpression of DOCK4 increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up-regulate a cancer-like proinvasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies.


Assuntos
Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Regulação da Expressão Gênica , Placenta Acreta/metabolismo , Trofoblastos/metabolismo , Regulação para Cima , Feminino , Humanos , Miométrio , Placenta/patologia , Placenta Acreta/genética , Placenta Acreta/patologia , Pré-Eclâmpsia , Gravidez , Transcriptoma , Útero/patologia
16.
PLoS One ; 15(6): e0233007, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492036

RESUMO

BACKGROUND: In humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as "unexplained stillbirths"; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology. METHODS: Phenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples. RESULTS: There were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls. CONCLUSION: Embryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects.


Assuntos
Cardiopatias Congênitas/genética , Mutação de Sentido Incorreto , Receptor ErbB-2/genética , Natimorto/genética , Animais , Modelos Animais de Doenças , Feminino , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/genética , Bloqueio Cardíaco/metabolismo , Bloqueio Cardíaco/patologia , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Heterozigoto , Proteína Homeobox Nkx-2.5/genética , Homozigoto , Humanos , Camundongos , Camundongos Mutantes , Miocárdio/metabolismo , Miocárdio/patologia , Placenta/anormalidades , Placenta/patologia , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
J Clin Invest ; 130(9): 4947-4953, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32573498

RESUMO

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Placenta/patologia , Placenta/virologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/etiologia , Complicações Infecciosas na Gravidez/virologia , Aborto Terapêutico , Descolamento Prematuro da Placenta/etiologia , Descolamento Prematuro da Placenta/patologia , Descolamento Prematuro da Placenta/virologia , Adulto , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Microscopia Eletrônica de Transmissão , Pandemias , Filogenia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/virologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Segundo Trimestre da Gravidez , RNA Viral/genética , RNA Viral/isolamento & purificação , Carga Viral
19.
Am J Clin Pathol ; 154(1): 23-32, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: covidwho-343224

RESUMO

OBJECTIVES: To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy. METHODS: Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma. RESULTS: Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma. CONCLUSIONS: Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.


Assuntos
Infecções por Coronavirus/patologia , Placenta/patologia , Pneumonia Viral/patologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Betacoronavirus , Estudos de Casos e Controles , Feminino , Humanos , Pandemias , Placenta/irrigação sanguínea , Placenta/virologia , Gravidez , Terceiro Trimestre da Gravidez
20.
Pediatr Dev Pathol ; 23(3): 177-180, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-244953

RESUMO

This study describes the pathology and clinical information on 20 placentas whose mother tested positive for the novel Coronovirus (2019-nCoV) cases. Ten of the 20 cases showed some evidence of fetal vascular malperfusion or fetal vascular thrombosis. The significance of these findings is unclear and needs further study.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Doenças Placentárias/etiologia , Doenças Placentárias/patologia , Placenta/patologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Complicações Infecciosas na Gravidez/patologia , Trombose/etiologia , Adolescente , Adulto , Feminino , Doenças Fetais/etiologia , Doenças Fetais/patologia , Humanos , Recém-Nascido , New York , Pandemias , Gravidez , Trombose/patologia , Adulto Jovem
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