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1.
Croat Med J ; 62(2): 130-136, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33938652

RESUMO

AIM: To examine the characteristics of pregnancies at a very advanced maternal age and the effect of parity on adverse obstetric outcomes. METHODS: We retrospectively reviewed the records of women who gave birth at the Obstetrics and Gynecology Department of Okmeydani Training and Research Hospital between January 2012 and December 2019. Overall, 22 448 of women were younger than 40 and 593 were aged 40 and older. Women aged 40 and older were divided into the primiparous (52 or 8.77%) and multiparous group (541 or 91.23%). RESULTS: Significantly more women aged 40 and older had a cesarean section. The most common indications for a secondary cesarean delivery in both age groups were a previous cesarean procedure or uterine operation. The most frequent indication for primary cesarean section in both groups was fetal distress. Cesarean section rates due to non-progressive labor, fetal distress, and preeclampsia were significantly more frequent in primiparous women compared with multiparous women aged 40 and older. In primiparous women, fetal birth weight was lower and preeclampsia/gestational hypertension frequency were higher. CONCLUSION: Since primiparity was a risk factor for lower fetal birth weight and preeclampsia/gestational hypertension in the age group of 40 years and above, more attention should be paid to the follow-up and treatment of these patients.


Assuntos
Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Adulto , Cesárea/efeitos adversos , Feminino , Humanos , Idade Materna , Pessoa de Meia-Idade , Paridade , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Gravidez , Estudos Retrospectivos , Fatores de Risco
2.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808559

RESUMO

Preeclampsia affects about 3-8% of all pregnancies. It represents a complex and multifaceted syndrome with at least several potential pathways leading to the development of disease. The main dogma in preeclampsia is the two-stage model of disease. Stage 1 (placental stage) takes place in early pregnancy and is thought to be impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries that leads to reduced placental perfusion and release of numerous biological factors causing endothelial damage and development of acute maternal syndrome with systemic multiorgan failure (stage 2-the onset of maternal clinical symptoms, maternal stage). Recently, in the light of the vast body of evidence, two-stage model of preeclampsia has been updated with a few novel pathways leading to clinical manifestation in the second part of pregnancy. This paper reviews current state of knowledge about pathophysiology of preeclampsia and places particular focus on the recent advances in understanding of uterine artery remodeling alterations, as well as the role of microRNAs in preeclampsia.


Assuntos
Suscetibilidade a Doenças , MicroRNAs/genética , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/etiologia , Artéria Uterina/patologia , Remodelação Vascular , Biomarcadores , Decídua/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Modelos Biológicos , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Trofoblastos/metabolismo , Artéria Uterina/metabolismo , Remodelação Vascular/genética
3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670947

RESUMO

Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin-proteasome and autophagy-lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction.


Assuntos
Macroautofagia , Placenta/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Animais , Feminino , Humanos , Lisossomos/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Agregação Patológica de Proteínas
4.
Hypertens Res ; 44(4): 386-398, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33469197

RESUMO

This review assesses markers of endothelial dysfunction (ED) associated with the maternal syndrome of preeclampsia (PE). We evaluate the role of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected preeclamptic women. Furthermore, we briefly discuss the potential of lopinavir/ritonavir (LPV/r), dolutegravir (DTG) and remdesivir (RDV) in drug repurposing and their safety in pregnancy complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In HIV infection, the trans-activator of transcription protein, which has homology with vascular endothelial growth factor, impairs angiogenesis, leading to endothelial injury and possible PE development despite neutralization of their opposing immune states. Markers of ED show strong evidence supporting the adverse role of ART in PE development and mortality compared to treatment-naïve pregnancies. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, exploits angiotensin-converting enzyme 2 (ACE 2) to induce ED and hypertension, thereby mimicking angiotensin II-mediated PE in severe cases of infection. Upregulated ACE 2 in pregnancy is a possible risk factor for SARS-CoV-2 infection and subsequent PE development. The potential effectiveness of LPV/r against COVID-19 is inconclusive; however, defective decidualization, along with elevated markers of ED, was observed. Therefore, the safety of these drugs in HIV-positive pregnancies complicated by COVID-19 requires attention. Despite the observed endothelial protective properties of DTG, there is a lack of evidence of its effects on pregnancy and COVID-19 therapeutics. Understanding RDV-ART interactions and the inclusion of pregnant women in antiviral drug repurposing trials is essential. This review provides a platform for further research on PE in the HIV-COVID-19 syndemic.


Assuntos
/complicações , Endotélio/fisiopatologia , Infecções por HIV/complicações , Pré-Eclâmpsia/etiologia , Adulto , /terapia , Feminino , Infecções por HIV/fisiopatologia , Infecções por HIV/terapia , Humanos , Recém-Nascido , Pandemias , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/terapia , Gravidez
5.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33215219

RESUMO

Preeclampsia (PE) is a common obstetric disease occurring after 20 weeks of gestation. Hypoxia­inducible factor (HIF)­3α potentially functions as a regulatory factor in PE development, however its specific molecular mechanism remains to be elucidated. The present study aimed to investigate the function of HIF­3α in trophoblast cell line HTR­8/SVneo, to provide a better understanding of the pathology and treatment of PE. Normal and PE placentas were obtained from pregnant women. HTR8/SVneo cells were cultured under the condition of normoxia or hypoxia, pretreated with or without AG490, then transfected with HIF­3α. The gene expression levels of HIF­3α and Fms like tyrosine kinase receptor (Flt) 1 extracted from the placentas and cells were detected by reverse transcription­quantitative PCR, and the expression levels of proteins and Janus kinase signal transducer and activator of transcription (JAK/STAT) phosphorylation were detected by western blot analysis. Viability and apoptosis of the treated cells were assessed by MTT and flow cytometry. The results demonstrated that HIF­3α and Flt­1 gene expression levels of PE placentas were reduced compared with normal placentas. Under a hypoxic environment, the expression levels of HIF­3α and Flt­1, the phosphorylation of JAK/STAT and the cell viability of HTR8/SVneo cells were increased at first and then reduced, whereas cell apoptosis was promoted over time. Under chronic hypoxia, the expression levels of HIF­3α and Flt­1, JAK/STAT pathway phosphorylation and cell viability of AG490­treated HTR8/SVneo cells were reduced, but cell apoptosis was promoted. However, the upregulation of HIF­3α in HTR8/SVneo cells markedly reversed the effects of AG490 on the cells under hypoxia. Thus, the present study preliminarily demonstrated that HIF­3α was involved in PE development by regulating extravillous cytotrophoblast growth via Flt­1 and the JAK/STAT signaling pathway.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Hipóxia/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Proteínas Repressoras/metabolismo , Trofoblastos/metabolismo , Adulto , Apoptose , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Regulação para Baixo , Feminino , Humanos , Janus Quinase 2/metabolismo , Placenta/metabolismo , Gravidez , Proteínas Repressoras/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Regulação para Cima , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
PLoS One ; 15(9): e0239030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915914

RESUMO

Hemopexin and α1-microglobulin act as scavengers to eliminate free heme-groups responsible for hemoglobin-induced oxidative stress. The present study evaluated maternal and fetal plasma concentrations of these scavengers in the different phenotypes of placenta-mediated disorders. Singleton pregnancies with normotensive fetal growth restriction [FGR] (n = 47), preeclampsia without FGR (n = 45) and preeclampsia with FGR (n = 51) were included prospectively as well as uncomplicated pregnancies (n = 49). Samples were collected at delivery and ELISA analysis was applied to measure the hemopexin and α1-microglobulin concentrations. In maternal blood in preeclampsia with and without FGR, hemopexin was significantly lower (p = 0.003 and p<0.001, respectively) and α1-microglobulin was significantly higher (p<0.001 in both) whereas no difference existed in normotensive FGR mothers compared to controls. In contrast, in fetal blood in growth restricted fetuses with and without preeclampsia, both hemopexin and α1-microglobulin were significantly lower (p<0.001 and p = 0.001 for hemopexin, p = 0.016 and p = 0.013 for α1-microglobulin, respectively) with no difference in fetuses from preeclampsia without FGR in comparison to controls. Thus, hemopexin and α1-microglobulin present significantly altered concentrations in maternal blood in the maternal disease -preeclampsia- and in cord blood in the fetal disease -FGR-, which supports their differential role in placenta-mediated disorders in accordance with the clinical presentation of these disorders.


Assuntos
alfa-Globulinas/metabolismo , Retardo do Crescimento Fetal/sangue , Heme/metabolismo , Hemopexina/metabolismo , Pré-Eclâmpsia/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/etiologia , Depuradores de Radicais Livres/sangue , Humanos , Recém-Nascido , Estresse Oxidativo , Pré-Eclâmpsia/etiologia , Gravidez , Estudos Prospectivos
8.
Am J Physiol Heart Circ Physiol ; 319(3): H661-H681, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762557

RESUMO

Preeclampsia is a major complication of pregnancy manifested as hypertension and often intrauterine growth restriction, but the underlying pathophysiological mechanisms are unclear. Predisposing genetic and environmental factors cause placental maladaptations leading to defective placentation, apoptosis of invasive cytotrophoblasts, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia. Placental ischemia promotes the release of bioactive factors into the maternal circulation, causing an imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and proangiogenic vascular endothelial growth factor, placental growth factor, and transforming growth factor-ß. Placental ischemia also stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin type 1 receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, causing generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels, leading to decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increases in vasoconstrictors such as endothelin-1 and thromboxane A2. The bioactive factors also target vascular smooth muscle and enhance the mechanisms of vascular contraction, including cytosolic Ca2+, protein kinase C, and Rho-kinase. The bioactive factors could also target matrix metalloproteinases and the extracellular matrix, causing inadequate vascular remodeling, increased arterial stiffening, and further increases in vascular resistance and hypertension. As therapeutic options are limited, understanding the underlying vascular mechanisms and molecular targets should help design new tools for the detection and management of hypertension in pregnancy and preeclampsia.


Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/metabolismo , Placenta/irrigação sanguínea , Pré-Eclâmpsia/metabolismo , Artéria Uterina/metabolismo , Animais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isquemia/metabolismo , Isquemia/fisiopatologia , Placentação , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Transdução de Sinais , Artéria Uterina/fisiopatologia , Remodelação Vascular , Rigidez Vascular
9.
Medicine (Baltimore) ; 99(28): e21198, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664166

RESUMO

INTRODUCTION: Kasabach-Merritt Syndrome (KMS) is an extremely rare disease in adults, which lead to consumptive coagulopathy characterized by severe hypofibrinogenemia and thrombocytopenia. PATIENT CONCERNS:: a 25-year-old Chinese pregnant women complicated by preeclampsia and KMS presented with refractory postpartum hemorrhage and incision bleeding after cesarean section. DIAGNOSIS: The diagnosis of KMS was made based on clinical manifestation of Kaposiform Hemangioendothelioma, severe hypofibrinogenemia and thrombocytopenia. INTERVENTIONS: After a poor response to massive blood products transfusion for 1 week, corticosteroid treatment was initiated for 3 days. OUTCOMES: The patient reached a normal platelet count and a mild anemia within 4 weeks. Two months later, all laboratory values had returned to normal, and the incision was healing well. CONCLUSION: Pregnancy complicated by preeclampsia and surgery may have contributions for the development of Kasabach-Merritt syndrome. Corticosteroid is indicated in the episode of acute Kasabach-Merritt syndrome after the failure of massive blood transfusion.


Assuntos
Corticosteroides/uso terapêutico , Síndrome de Kasabach-Merritt/terapia , Hemorragia Pós-Parto/tratamento farmacológico , Pré-Eclâmpsia/terapia , Complicações Hematológicas na Gravidez/terapia , Adulto , Cesárea , Feminino , Humanos , Síndrome de Kasabach-Merritt/complicações , Hemorragia Pós-Parto/etiologia , Pré-Eclâmpsia/etiologia , Gravidez , Complicações Hematológicas na Gravidez/etiologia
10.
BJOG ; 127(11): 1374-1380, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32479682

RESUMO

OBJECTIVES: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre-eclampsia (PE) in pregnancies with COVID-19, and to assess their accuracy to differentiate between PE and the PE-like features associated with COVID-19. DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. PARTICIPANTS: Singleton pregnancies with COVID-19 at >20+0  weeks. METHODS: Forty-two consecutive pregnancies were recruited and classified into two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms-like tyrosine kinase-1/placental growth factor [sFlt-1/PlGF]) were assessed in women with suspected PE. MAIN OUTCOME MEASURES: Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt-1/PlGF. RESULTS: Thirty-four cases were classified as non-severe and 8 as severe COVID-19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID-19 cases (62.5%). However, abnormal sFlt-1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE-like syndrome. CONCLUSIONS: Pregnant women with severe COVID-19 can develop a PE-like syndrome that might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre-eclampsia with caution. TWEETABLE ABSTRACT: This study shows that a pre-eclampsia-like syndrome could be present in some pregnancies with severe COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Síndrome HELLP/fisiopatologia , Fator de Crescimento Placentário/metabolismo , Pneumonia Viral/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Complicações Infecciosas na Gravidez/fisiopatologia , Artéria Uterina/diagnóstico por imagem , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Betacoronavirus , Pressão Sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Feminino , Síndrome HELLP/etiologia , Síndrome HELLP/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Proteinúria/etiologia , Proteinúria/fisiopatologia , Fluxo Pulsátil , Índice de Gravidade de Doença , Centros de Atenção Terciária , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia
11.
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
12.
JAMA Netw Open ; 3(6): e205323, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585017

RESUMO

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.


Assuntos
Peso ao Nascer , Término Precoce de Ensaios Clínicos , Retardo do Crescimento Fetal/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Doenças Placentárias/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Hipertensão Pulmonar/induzido quimicamente , Recém-Nascido , Doenças do Recém-Nascido/induzido quimicamente , Doenças do Recém-Nascido/prevenção & controle , Análise de Intenção de Tratamento , Masculino , Artéria Cerebral Média/fisiologia , Mortalidade Perinatal , Inibidores da Fosfodiesterase 5/efeitos adversos , Doenças Placentárias/fisiopatologia , Pré-Eclâmpsia/etiologia , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Fluxo Pulsátil , Citrato de Sildenafila/efeitos adversos , Artérias Umbilicais/fisiologia
13.
J Biomed Sci ; 27(1): 63, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389123

RESUMO

Oxygen is essentially required by most eukaryotic organisms as a scavenger to remove harmful electron and hydrogen ions or as a critical substrate to ensure the proper execution of enzymatic reactions. All nucleated cells can sense oxygen concentration and respond to reduced oxygen availability (hypoxia). When oxygen delivery is disrupted or reduced, the organisms will develop numerous adaptive mechanisms to facilitate cells survived in the hypoxic condition. Normally, such hypoxic response will cease when oxygen level is restored. However, the situation becomes complicated if hypoxic stress persists (chronic hypoxia) or cyclic normoxia-hypoxia phenomenon occurs (intermittent hypoxia). A series of chain reaction-like gene expression cascade, termed hypoxia-mediated gene regulatory network, will be initiated under such prolonged or intermittent hypoxic conditions and subsequently leads to alteration of cellular function and/or behaviors. As a result, irreversible processes occur that may cause physiological disorder or even pathological consequences. A growing body of evidence implicates that hypoxia plays critical roles in the pathogenesis of major causes of mortality including cancer, myocardial ischemia, metabolic diseases, and chronic heart and kidney diseases, and in reproductive diseases such as preeclampsia and endometriosis. This review article will summarize current understandings regarding the molecular mechanism of hypoxia in these common and important diseases.


Assuntos
Endometriose/fisiopatologia , Cardiopatias/fisiopatologia , Hipóxia/fisiopatologia , Nefropatias/fisiopatologia , Doenças Metabólicas/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Neoplasias/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Doença Crônica , Endometriose/etiologia , Feminino , Cardiopatias/etiologia , Humanos , Hipóxia/complicações , Nefropatias/etiologia , Masculino , Doenças Metabólicas/etiologia , Isquemia Miocárdica/etiologia , Neoplasias/etiologia , Pré-Eclâmpsia/etiologia , Gravidez
14.
Nat Microbiol ; 5(7): 901-908, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367053

RESUMO

Pre-eclampsia (typically characterized by new-onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease1,2. Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction, but its role in placentally related disorders of human pregnancy is unknown3. We addressed this using RNA sequencing metagenomics4-6 of placental samples from normal and complicated pregnancies. Here, we show that human herpesvirus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of pre-eclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 pre-eclampsia cases and 3,854 controls and found an excess of iciHHV-6 in the cases (odds ratio of 2.8, 95% confidence intervals of 1.4-5.6, P = 0.008). We validated this finding by comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (odds ratio of 2.5, 95% confidence intervals of 1.4-4.4, P = 0.0013). We conclude that iciHHV-6 results in the transcription of viral RNA in the human placenta and predisposes the mother to pre-eclampsia.


Assuntos
Suscetibilidade a Doenças , Herpesvirus Humano 6/fisiologia , Herança Materna , Pré-Eclâmpsia/etiologia , Infecções por Roseolovirus/virologia , Integração Viral , Estudos de Casos e Controles , DNA Viral , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , RNA Viral , Análise de Sequência de DNA
16.
PLoS One ; 15(4): e0230955, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315307

RESUMO

INTRODUCTION: Prediction models for gestational hypertension and preeclampsia have been developed with data and assumptions from developed countries. Their suitability and application for low resource settings have not been tested. This review aimed to identify and assess the methodological quality of prediction models for gestational hypertension and pre-eclampsia with reference to their application in low resource settings. METHODS: Using combinations of keywords for gestational hypertension, preeclampsia and prediction models seven databases were searched to identify prediction models developed with maternal data obtained before 20 weeks of pregnancy and including at least three predictors (Prospero registration CRD 42017078786). Prediction model characteristics and performance measures were extracted using the CHARMS, STROBE and TRIPOD checklists. The National Institute of Health quality assessment tools for observational cohort and cross-sectional studies were used for study quality appraisal. RESULTS: We retrieved 8,309 articles out of which 40 articles were eligible for review. Seventy-seven percent of all the prediction models combined biomarkers with maternal clinical characteristics. Biomarkers used as predictors in most models were pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF). Only five studies were conducted in a low-and middle income country. CONCLUSIONS: Most of the studies evaluated did not completely follow the CHARMS, TRIPOD and STROBE guidelines in prediction model development and reporting. Adherence to these guidelines will improve prediction modelling studies and subsequent application of prediction models in clinical practice. Prediction models using maternal characteristics, with good discrimination and calibration, should be externally validated for use in low and middle income countries where biomarker assays are not routinely available.


Assuntos
Hipertensão Induzida pela Gravidez/etiologia , Pré-Eclâmpsia/etiologia , Biomarcadores/sangue , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/sangue , Hipertensão Induzida pela Gravidez/metabolismo , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Proteína Plasmática A Associada à Gravidez/metabolismo
17.
Curr Hypertens Rep ; 22(4): 28, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166454

RESUMO

PURPOSE OF REVIEW: Pathophysiology of hypertensive disorders of pregnancy (HDP), especially preeclampsia, has not been fully elucidated. Most trials aimed at the prevention of preeclampsia have failed to show significant benefit and investigation of novel, modifiable risk factors is sorely needed. Sleep disordered breathing (SDB), a group of disorders for which treatments are available, meets these criteria. SDB impacts about a third of all pregnancies and is associated with hypertension in the general non-pregnant population. RECENT FINDINGS: Recent studies have shown a high prevalence of SDB, especially in complicated pregnancies. Several studies have shown that pregnant women with SDB have a higher risk for developing HDP, and these two disorders are associated with similar maternal long-term cardiovascular outcomes. Based on limited animal models of gestational intermittent hypoxia and human studies, SDB and HDP share similar risk factors and some pathophysiological mechanisms. However, there is paucity of studies addressing causality of this association and identifying therapeutic targets for intervention. Maternal SDB represents a novel and modifiable risk factor of HDP. Further studies are needed in order to establish the exact mechanisms underlying this association and to identify specific areas for clinical interventions.


Assuntos
Hipertensão Induzida pela Gravidez/etiologia , Síndromes da Apneia do Sono/complicações , Feminino , Humanos , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipertensão Induzida pela Gravidez/prevenção & controle , Hipertensão Induzida pela Gravidez/terapia , Placenta/fisiopatologia , Polissonografia , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/terapia , Gravidez , Fatores de Risco , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/fisiopatologia , Síndromes da Apneia do Sono/terapia
18.
Am J Physiol Heart Circ Physiol ; 318(4): H1018-H1027, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167780

RESUMO

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of ß-epithelial Na+ channel (ßENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, ßENaC is an essential signaling element in transduction of pressure-induced (aka "myogenic") constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular ßENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular ßENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of ßENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell ßENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1-100 ng/mL) for 16-24 h. TNF-α reduced ßENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated ßENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced ßENaC-mediated vascular function.NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular ß-epithelial sodium channel (ßENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced ßENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.


Assuntos
Circulação Cerebrovascular , Canais Epiteliais de Sódio/metabolismo , Músculo Liso Vascular/metabolismo , Pré-Eclâmpsia/etiologia , Fator de Necrose Tumoral alfa/sangue , Animais , Pressão Sanguínea , Linhagem Celular , Células Cultivadas , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Canais Epiteliais de Sódio/genética , Feminino , Homeostase , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/efeitos dos fármacos , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/farmacologia
19.
Pregnancy Hypertens ; 20: 27-35, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145525

RESUMO

OBJECTIVE: To determine the rate of sonographic placental markers and their predictive value for preeclampsia and fetal growth restriction in women with chronic kidney disease (CKD). STUDY DESIGN: A retrospective cohort study of women with CKD followed at a tertiary referral center between 2016 and 2019 (n = 86). All women underwent 2nd trimester sonographic placental examinations that included assessment of placental morphology, umbilical cord, and uterine artery Doppler. Continuous placental markers were converted to multiples on medians (MoM). MAIN OUTCOME MEASURES: Predictive value of sonographic markers for preeclampsia and birthweight < 10th percentile. RESULTS: Women in the cohort had a high rate of preeclampsia (24.4%), birthweight < 10th% (26.7%), and preterm birth (30.2%). The most important markers were placental volume and uterine artery Doppler: the risk of preeclampsia was elevated in women with low placental volume (51.7% vs. 10.9%; OR = 8.79 [2.70-28.59] for preeclampsia; and 40.0% vs. 9.1%; OR = 6.67 [1.85-24.04] for preterm preeclampsia), and in women with bilateral uterine artery notching (62.5% vs. 20.8%; OR = 6.35 [1.37-29.45] for preeclampsia; and 62.5% vs. 10.4%; OR = 14.38 [1.29-71.75] for preterm preeclampsia). The combination of both markers had the strongest predictive value for preeclampsia (positive likelihood ratio = 8.25 [6.84-9.95]). Low placental volume and bilateral uterine notching were also associated with birthweight < 10th percentile. CONCLUSION: A 2nd-trimester sonographic placental study can identify a subgroup of women with CKD who are at most risk of preeclampsia and fetal growth restriction. Such data may inform their subsequent perinatal care and assist care providers in the often challenging distinction between preeclampsia flare of underlying CKD.


Assuntos
Retardo do Crescimento Fetal/diagnóstico por imagem , Placenta/diagnóstico por imagem , Pré-Eclâmpsia/diagnóstico por imagem , Insuficiência Renal Crônica/complicações , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Adulto , Peso ao Nascer , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Pré-Eclâmpsia/etiologia , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Segundo Trimestre da Gravidez , Nascimento Prematuro/etiologia , Insuficiência Renal Crônica/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Cordão Umbilical/diagnóstico por imagem , Artéria Uterina/diagnóstico por imagem
20.
Curr Hypertens Rep ; 22(4): 31, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32172383

RESUMO

PURPOSE OF REVIEW: This manuscript aims to review (for the first time) studies describing NGS sequencing of preeclampsia (PE) women's DNA. RECENT FINDINGS: Describing markers for the early detection of PE is an essential task because, although associated molecular dysfunction begins early on during pregnancy, the disease's clinical signs usually appear late in pregnancy. Although several biochemical biomarkers have been proposed, their use in clinical environments is still limited, thereby encouraging research into PE's genetic origin. Hundreds of genes involved in numerous implantation- and placentation-related biological processes may be coherent candidates for PE aetiology. Next-generation sequencing (NGS) offers new technical possibilities for PE studying, as it enables large genomic regions to be analysed at affordable cost. This technique has facilitated the description of genes contributing to the molecular origin of a significant amount of monogenic and complex diseases. Regarding PE, NGS of DNA has been used in familial and isolated cases, thereby enabling new genes potentially related to the phenotype to be proposed. For a better understanding of NGS, technical aspects, applications and limitations are presented initially. Thereafter, NGS studies of DNA in familial and non-familial cases are described, including pitfalls and positive findings. The information given here should enable scientists and clinicians to analyse and design new studies permitting the identification of novel clinically useful molecular PE markers.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Hipertensão , Pré-Eclâmpsia , DNA , Feminino , Humanos , Hipertensão/genética , Fenótipo , Pré-Eclâmpsia/etiologia , Gravidez
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