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1.
PLoS One ; 15(2): e0229618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084244

RESUMO

Prenatal hypoxia is a gestational stressor that can result in developmental abnormalities or physiological reprogramming, and often decreases cellular capacity against secondary stress. When a developing fetus is exposed to hypoxia, blood flow is preferentially redirected to vital organs including the brain and heart over other organs including the kidney. Hypoxia-induced injury can lead to structural malformations in the kidney; however, even in the absence of structural lesions, hypoxia can physiologically reprogram the kidney leading to decreased function or increased susceptibility to injury. Our investigation in mice reveals that while prenatal hypoxia does not affect normal development of the kidneys, it primes the kidneys to have an increased susceptibility to kidney injury later in life. We found that our model does not develop structural abnormalities when prenatally exposed to modest 12% O2 as evident by normal histological characterization and gene expression analysis. Further, adult renal structure and function is comparable to mice exposed to ambient oxygen throughout nephrogenesis. However, after induction of kidney injury with a nephrotoxin (cisplatin), the offspring of mice housed in hypoxia exhibit significantly reduced renal function and proximal tubule damage following injury. We conclude that exposure to prenatal hypoxia in utero physiologically reprograms the kidneys leading to increased susceptibility to injury later in life.


Assuntos
Lesão Renal Aguda/etiologia , Hipóxia/metabolismo , Rim/metabolismo , Lesão Renal Aguda/embriologia , Animais , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Feminino , Hipóxia Fetal/fisiopatologia , Hemodinâmica , Hipóxia/fisiopatologia , Rim/embriologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo
2.
Ann Thorac Surg ; 109(3): 810-819, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31541634

RESUMO

BACKGROUND: Congenital heart disease (CHD) is associated with abnormal fetal brain development, a phenomenon that may be related to decreased cerebral oxygen delivery in utero. We used an artificial womb model to test the hypothesis that decreasing fetal oxygen delivery would reproduce physiologic changes identified in fetuses with CHD. METHODS: Experimental (hypoxemic) fetal lambs (mean gestational age, 111 ± 3 days; n = 4) and control animals (112 days; n = 5) were maintained in the artificial womb for a mean of 22 ± 6 days. Oxygen delivery was reduced to 15.6 ± 1.0 mL/kg/min in the hypoxemia animals versus 21.6 ± 2.0 mL/kg/min in the control animals. Blood chemistry analysis and sonographic evaluation were performed daily. An additional control group (n = 7) was maintained in utero and harvested for analysis at gestational age 134 ± 4 days. RESULTS: Physiologic variables were monitored continuously, and no statistical differences between the groups were identified. Fetal oxygen delivery and arterial partial pressure of oxygen were remarkably lower in the experimental group longitudinally. Increased umbilical artery and decreased middle cerebral artery resistance resulted in a lower cerebral to umbilical resistance ratio, similar to the brain sparing effect observed in human fetuses with CHD. Experimental brains were smaller than control brains in relation to the calvarium on magnetic resonance. CONCLUSIONS: Sustained hypoxemia in fetal sheep leads to altered cerebrovascular resistances and loss of brain mass, similar to human fetuses with CHD. This unique model provides opportunities to investigate the pathologic process underlying CHD-associated brain dysmaturity and to evaluate potential fetal neuroprotective therapies.


Assuntos
Encéfalo/patologia , Oxigenação por Membrana Extracorpórea/métodos , Hipóxia Fetal/terapia , Cardiopatias Congênitas/complicações , Oxigênio/sangue , Prenhez , Animais , Encéfalo/embriologia , Modelos Animais de Doenças , Feminino , Hipóxia Fetal/sangue , Hipóxia Fetal/etiologia , Idade Gestacional , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/diagnóstico , Imagem por Ressonância Magnética , Gravidez , Ovinos , Ultrassonografia Pré-Natal
3.
Am J Obstet Gynecol ; 222(1): 17-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351061

RESUMO

Uterine contractions in labor result in a 60% reduction in uteroplacental perfusion, causing transient fetal and placental hypoxia. A healthy term fetus with a normally developed placenta is able to accommodate this transient hypoxia by activation of the peripheral chemoreflex, resulting in a reduction in oxygen consumption and a centralization of oxygenated blood to critical organs, namely the heart, brain, and adrenals. Providing there is adequate time for placental and fetal reperfusion between contractions, these fetuses will be able to withstand prolonged periods of intermittent hypoxia and avoid severe hypoxic injury. However, there exists a cohort of fetuses in whom abnormal placental development in the first half of pregnancy results in failure of endovascular invasion of the spiral arteries by the cytotrophoblastic cells and inadequate placental angiogenesis. This produces a high-resistance, low-flow circulation predisposing to hypoperfusion, hypoxia, reperfusion injury, and oxidative stress within the placenta. Furthermore, this renders the placenta susceptible to fluctuations and reduction in uteroplacental perfusion in response to external compression and stimuli (as occurs in labor), further reducing fetal capillary perfusion, placing the fetus at risk of inadequate gas/nutrient exchange. This placental dysfunction predisposes the fetus to intrapartum fetal compromise. In the absence of a rare catastrophic event, intrapartum fetal compromise occurs as a gradual process when there is an inability of the fetal heart to respond to the peripheral chemoreflex to maintain cardiac output. This may arise as a consequence of placental dysfunction reducing pre-labor myocardial glycogen stores necessary for anaerobic metabolism or due to an inadequate placental perfusion between contractions to restore fetal oxygen and nutrient exchange. If the hypoxic insult is severe enough and long enough, profound multiorgan injury and even death may occur. This review provides a detailed synopsis of the events that can result in placental dysfunction, how this may predispose to intrapartum fetal hypoxia, and what protective mechanisms are in place to avoid hypoxic injury.


Assuntos
Hipóxia Fetal/fisiopatologia , Feto/fisiologia , Placenta/fisiologia , Circulação Placentária/fisiologia , Contração Uterina/fisiologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/fisiopatologia , Feminino , Hipóxia Fetal/complicações , Feto/fisiopatologia , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Trabalho de Parto/fisiologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/fisiopatologia , Síndrome da Persistência do Padrão de Circulação Fetal/etiologia , Síndrome da Persistência do Padrão de Circulação Fetal/fisiopatologia , Placenta/fisiopatologia , Gravidez , Nascimento a Termo
6.
Clin Biochem ; 74: 69-72, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473201

RESUMO

BACKGROUND: S100B protein is one of the most accurate biomarkers for diagnosis of neuroapoptosis and brain damage. The aim was to evaluate the lactate concentration and acid-base balance (pH, pCO2, pO2, HCO3c and BEb) in umbilical cord blood to predict high risk of neuroapoptosis and analyze the relationship between the levels of these biomarkers and umbilical cord blood S100B protein concentration at birth. METHODS: Apparently healthy newborns were included. S100B protein and blood gas test (lactate and acid-base balance) were determined in umbilical cord blood at birth. Newborns were classified into two groups: with and without high risk of neuroapoptosis. Newborns with high umbilical cord blood S100B protein concentration were considered newborns at high risk of neuroapoptosis. RESULTS: Sixty-one newborns were included, 12 had high risk of neuroapoptosis and 49 did not. S100B protein concentration correlate directly with pCO2 levels (Rho: 0.286, p = .0321) and lactate concentration (Rho: 0.278, p = .0315); and indirectly with pH (Rho: -0.332, p = .01). The analysis of the ROC curves yielded significant curves for pH and pCO2 to predict high risk of neuroapoptosis, pH optimal cutoff value was 7.19 (sensitivity: 50%, specificity: 83.7%, AUC: 0.708); and pCO2 optimal cutoff value was 60 mmHg (sensitivity: 30%, specificity: 85.4%, AUC: 0.705). CONCLUSIONS: Respiratory acidosis is associated to high concentrations of S100B protein in umbilical cord blood at birth. Umbilical cord blood pH and pCO2 may be useful in differentiating newborns at high risk of neuroapoptosis. Umbilical cord blood gas test may be valuable as risk indicator for neuroapoptosis at birth.


Assuntos
Acidose Respiratória/sangue , Acidose Respiratória/patologia , Apoptose , Encéfalo/patologia , Sangue Fetal/química , Adolescente , Adulto , Biomarcadores/sangue , Gasometria , Dióxido de Carbono/sangue , Estudos Transversais , Feminino , Hipóxia Fetal/sangue , Humanos , Concentração de Íons de Hidrogênio , Recém-Nascido , Ácido Láctico/sangue , Masculino , Neurônios/patologia , Curva ROC , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Sensibilidade e Especificidade , Adulto Jovem
7.
J Dermatol ; 46(10): 849-852, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31418467

RESUMO

Infantile hemangioma is one of the most common tumors in infancy. Delivery may be a clue for the trigger of infantile hemangioma formation in the head and face areas. In this study, we tried to plot localization of infantile hemangioma as well as capillary malformation on the head and face, and compared them to identify their characteristics and risk factors. The distribution of 104 lesions in 100 patients with infantile hemangioma was as follows: 32 lesions on the head, 12 on the forehead, 57 on the cheek and three in the jaw area. We could not find a statistically significant correlation of the distribution with three clinical subtypes (superficial, deep and mixed), sex or size of the lesions. However, the lesions in the jaw or chin areas were significantly less frequent than other areas (P = 0.0008 or 0.03, respectively). This tendency was not found in 40 patients with capillary malformation. Mechanical stress to jaw or chin areas may be less than other areas in normal cephalic delivery. Considering the emergence after birth and age-dependent involution of infantile hemangioma, we speculate that physiological events including perinatal hypoxia or mechanical stress during delivery as the trigger of hemangioma formation. Taken together, our results may reveal the contribution of mechanical stress to the trigger of infantile hemangioma, not capillary malformation, and may facilitate clinical differentiation between the two diseases by their localization. Further studies with an increased number of patients will be necessary to validate the finding.


Assuntos
Capilares/anormalidades , Hemangioma/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Análise Espacial , Malformações Vasculares/diagnóstico por imagem , Capilares/diagnóstico por imagem , Parto Obstétrico/efeitos adversos , Face , Feminino , Hipóxia Fetal/complicações , Cabeça , Hemangioma/etiologia , Humanos , Lactente , Japão , Masculino , Fotografação , Pele/diagnóstico por imagem , Neoplasias Cutâneas/etiologia , Distribuições Estatísticas , Estresse Mecânico
8.
Arkh Patol ; 81(4): 73-77, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31407722

RESUMO

The paper considers one of the types of intranatal fetal hypoxia - circulatory hypoxia. It discusses the issues of fetal head configuration during childbirth and the compensatory-adaptive mechanisms when the fetal head passes through the maternal parturient canal. The relationships and differences between circulatory hypoxia and birth trauma are investigated.


Assuntos
Hipóxia Fetal , Feto , Feto/irrigação sanguínea , Humanos
9.
Oxid Med Cell Longev ; 2019: 7210249, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249648

RESUMO

Chronic intrauterine hypoxia is a programming stimulus of cardiovascular dysfunction. While the fetal heart adapts to the reduced oxygenation, the offspring heart becomes vulnerable to subsequent metabolic challenges as an adult. Cardiac mitochondria are key organelles responsible for an efficient energy supply but are subject to damage under hypoxic conditions. We propose that intrauterine hypoxia alters mitochondrial function as an underlying programming mechanism of contractile dysfunction in the offspring. Indices of mitochondrial function such as mitochondrial DNA content, Complex (C) I-V expression, and CI/CIV enzyme activity were measured in hearts of male and female offspring at 90 days old exposed to prenatal hypoxia (10.5% O2) for 14 d prior to term (65 d). Both left ventricular tissue and cardiomyocytes exhibited decreased mitochondrial DNA content, expression of CIV, and CI/CIV activity in male hearts. In female cardiomyocytes, hypoxia had no effect on protein expression of CI-CV nor on CI/CIV activity. This study suggests that chronic intrauterine hypoxia alters the intrinsic properties of select respiratory complexes as a programming mechanism of cardiac dysfunction in the offspring. Sex differences in mitochondrial function may underlie the increased vulnerability of age-matched males compared to females in cardiovascular disease and heart failure.


Assuntos
Desenvolvimento Fetal , Coração Fetal/patologia , Hipóxia Fetal/fisiopatologia , Cardiopatias/patologia , Mitocôndrias Cardíacas/patologia , Proteínas Mitocondriais/metabolismo , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Caracteres Sexuais , Animais , Animais Recém-Nascidos , Feminino , Coração Fetal/metabolismo , Cobaias , Cardiopatias/metabolismo , Masculino , Mitocôndrias Cardíacas/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia
10.
Acta Obstet Gynecol Scand ; 98(10): 1258-1267, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31140581

RESUMO

INTRODUCTION: Studies indicate an association between errors in cardiotocography (CTG) management and hypoxic brain injuries among newborns. Continuing professional education is recommended. We aimed to examine whether the implementation of a national interprofessional CTG education program in Denmark was associated with a decrease in risk of fetal hypoxia measured by umbilical cord pH < 7.00, 5-minute Apgar score <7 or neonatal therapeutic hypothermia. As a secondary aim, we assessed whether the educational intervention was associated with an increase in operative deliveries. MATERIAL AND METHODS: We conducted a historical cohort study from 2009 to 2015 including all intended vaginal deliveries with liveborn singletons in cephalic presentation and gestational age ≥37 weeks. Data were retrieved from the Medical Birth Register and the National Patient Register. The study period was divided in three: pre-implementation (2009-2012), implementation (2013) and post-implementation (2014-2015). Using logistic regression we estimated odds ratios (OR) of fetal hypoxia outcomes using the pre-implementation period as reference. Analyses were adjusted for potential maternal, neonatal and delivery-associated confounders. Missing data were accounted for by multiple imputation. RESULTS: In all, 331 282 deliveries were included. Overall risks of pH < 7.00, Apgar score <7 and therapeutic hypothermia were respectively 0.45%, 0.58% and 0.06%. Adjusted OR in the post-implementation period were 1.12 (95% confidence interval [CI] 1.00-1.26), 0.99 (95% CI 0.90-1.10) and 1.34 (95% CI 0.99-1.82) for the three outcomes, respectively. The pH missingness equaled 12.4%. Odds of emergency cesarean section was unaltered, whereas the odds of assisted vaginal delivery decreased by 14% (0.86, 95% CI 0.84-0.89). CONCLUSIONS: Healthcare professionals are considered the weakest link of CTG technology. We did not find that increasing healthcare professionals' CTG interpretation skills affected the risk of fetal hypoxia. Missing data for pH values were substantial and represent a limitation of the study. We cannot with certainty rule out that missingness masked a true effect of the intervention. Our study indicates that assisted vaginal deliveries can be decreased without an increased risk of fetal hypoxia. Dilution of effect in a complex clinical setting, rare outcomes, insufficient intervention and a possible overestimation of the impact of errors in CTG management might explain the lack of effect.


Assuntos
Cardiotocografia/normas , Educação Continuada , Hipóxia Fetal/prevenção & controle , Obstetrícia/educação , Resultado da Gravidez , Adulto , Índice de Apgar , Dinamarca , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez
11.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137455

RESUMO

We investigated whether thrombin preconditioning of human Wharton's jelly-derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen-glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton's jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.


Assuntos
Hipóxia-Isquemia Encefálica/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Trombina/farmacologia , Animais , Apoptose , Hipóxia Celular , Células Cultivadas , Hipóxia Fetal/complicações , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido , Masculino , Ratos , Ratos Sprague-Dawley
12.
Am J Physiol Regul Integr Comp Physiol ; 317(1): R1-R13, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31017808

RESUMO

The availability of oxygen to the fetus is limited by the route taken by oxygen from the atmosphere to fetal tissues, aided or diminished by pregnancy-associated changes in maternal physiology and, ultimately, a function of atmospheric pressure and composition of the mother's inspired gas. Much of our understanding of the fetal physiological response to hypoxia comes from experiments designed to elucidate the cardiovascular and endocrine responses to transient hypoxia. Complementing this work is equally impactful research into the origins of intrauterine growth restriction in which animal models designed to restrict the transfer of oxygen from the maternal to the fetal circulation were used. A common assumption has been that outcomes measured after a period of hypoxia are related to cellular deprivation of oxygen and reoxygenation: an assumption based on a focus on what we can see "under the streetlights." Recent studies demonstrate that availability of oxygen may not tell the whole story. Transient hypoxia in the fetal sheep stimulates transcriptomics responses that mirror inflammation. This response is accompanied by the appearance of bacteria in the fetal brain and other tissues, likely resulting from a hypoxia-stimulated release of bacteria from the placenta. The appearance of bacteria in the fetus after transient hypoxia complements the recent discovery of bacterial DNA in the normal human placenta and in the tissues of fetal sheep. An understanding of the mechanism of the physiological, cellular, and molecular responses to hypoxia requires an appreciation of stimuli other than cellular oxygen deprivation: stimuli that we would have never known about without looking "between the streetlights," illuminating direct responses to the manipulated variables.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Desenvolvimento Fetal , Hipóxia Fetal/fisiopatologia , Consumo de Oxigênio , Animais , Feminino , Troca Materno-Fetal , Modelos Biológicos , Gravidez , Ovinos
13.
Dev Neurosci ; 41(1-2): 56-66, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30904914

RESUMO

Using electrocorticogram (ECoG) analysis, we compared age-related dynamics of general neuronal activity and convulsive epileptiform responsiveness induced by intracortical microinjections of 4-aminopyridine (4-AP) in control Wistar rats and those subjected to prenatal hypoxia (Hx; E14; 7% O2, 3 h). The studies were carried out in three age periods roughly corresponding to childhood (P20-27), adolescence (P30-45), and adulthood (P90-120). It was found that in the process of postnatal development of the control rats, the peak of the ECoG power spectrum density (PSD) of the theta rhythm during wakefulness shifted from the low to the higher frequency, while in the Hx rats this shift had the opposite direction. Moreover, the Hx rats had different frequency characteristics of the ECoG PSD and longer episodes of spike-and-wave discharges caused by 4-AP injections compared to the controls. The total ECoG PSD of slow-wave sleep (1-5 Hz) was also dramatically decreased in the process of development of the Hx rats. Such alterations in PSD could be explained by the changes in balance of the excitation and inhibition processes in the cortical networks. Analyzing protein levels of neurotransmitter transporters in the brain structures of the Hx rats, we found that the content of the glutamate transporter EAAT1 was higher in the parietal cortex in all age groups of Hx rats while in the hippocampus it decreased during postnatal development compared to controls. Furthermore, the content of the vesicular acetylcholine transporter in the parietal cortex, and of the inhibitory GABA transporter 1 in the hippocampus, was also affected by prenatal Hx. These data suggest that prenatal Hx results in a shift in the excitatory and inhibitory balance in the rat cortex towards excitation, making the rat's brain more vulnerable to the effects of proconvulsant drugs and predisposing animals to epileptogenesis during postnatal life.


Assuntos
Hipóxia Fetal/metabolismo , Hipóxia Fetal/fisiopatologia , Proteínas de Transporte de Neurotransmissores/metabolismo , 4-Aminopiridina/toxicidade , Animais , Convulsivantes/toxicidade , Eletrocorticografia , Feminino , Bloqueadores dos Canais de Potássio/toxicidade , Gravidez , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
14.
Am J Obstet Gynecol ; 221(1): 65.e1-65.e18, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30878322

RESUMO

BACKGROUND: Third-trimester studies in selected high-risk pregnancies have reported that low cerebroplacental ratio, due to high pulsatility index in the umbilical artery, and or decreased pulsatility index in the fetal middle cerebral artery, is associated with increased risk of adverse perinatal outcomes. OBJECTIVE: To investigate the predictive performance of screening for adverse perinatal outcome by the cerebroplacental ratio measured routinely at 35-37 weeks' gestation. STUDY DESIGN: This was a prospective observational study in 47,211 women with singleton pregnancies undergoing routine ultrasound examination at 35+6 to 37+6 weeks' gestation, including measurement of umbilical artery-pulsatility index and middle cerebral artery-pulsatility index. The measured umbilical artery-pulsatility index and middle cerebral artery-pulsatility index and their ratio were converted to multiples of the median after adjustment for gestational age. Multivariable logistic regression analysis was used to determine whether umbilical artery-pulsatility index, middle cerebral artery-pulsatility index, and cerebroplacental ratio improved the prediction of adverse perinatal outcome that was provided by maternal characteristics, medical history, and obstetric factors. The following outcome measures were considered: (1) adverse perinatal outcome consisting of stillbirth, neonatal death, or hypoxic-ischemic encephalopathy grades 2 and 3; (2) presence of surrogate markers of perinatal hypoxia consisting of umbilical arterial or venous cord blood pH ≤7 and ≤7.1, respectively, 5-minute Apgar score <7, or admission to the neonatal intensive care unit for >24 hours; (3) cesarean delivery for presumed fetal compromise in labor; and (4) neonatal birthweight less than the third percentile for gestational age. RESULTS: First, the incidence of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, and cesarean delivery for presumed fetal compromise in labor was greater in pregnancies with small for gestational age neonates with birthweight <10th percentile compared with appropriate for gestational age neonates; however, 80%-85% of these adverse events occurred in the appropriate for gestational age group. Second, low cerebroplacental ratio <10th percentile was associated with increased risk of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, cesarean delivery for presumed fetal compromise in labor, and birth of neonates with birthweight less than third percentile. However, multivariable regression analysis demonstrated that the prediction of these adverse outcomes by maternal demographic characteristics and medical history was only marginally improved by the addition of cerebroplacental ratio. Third, the performance of low cerebroplacental ratio in the prediction of each adverse outcome was poor, with detection rates of 13%-26% and a false-positive rate of about 10%. Fourth, the detection rates of adverse outcomes were greater in small for gestational age than in appropriate for gestational age babies and in pregnancies delivering within 2 weeks rather than at any stage after assessment; however, such increase in detection rates was accompanied by an increase in the false-positive rate. Fifth, in appropriate for gestational age neonates, the predictive accuracy of cerebroplacental ratio was low, with positive and negative likelihood ratios ranging from 1.21 to 1.82, and 0.92 to 0.98, respectively; although the accuracy was better in small for gestational age neonates, this was also low with positive likelihood ratios of 1.31-2.26 and negative likelihood ratios of 0.69-0.92. Similar values were obtained in fetuses classified as small for gestational age and appropriate for gestational age according to the estimated fetal weight. CONCLUSIONS: In pregnancies undergoing routine antenatal assessment at 35-37 weeks' gestation, measurement of cerebroplacental ratio provides poor prediction of adverse perinatal outcome in both small for gestational age and appropriate for gestational age fetuses.


Assuntos
Hipóxia Fetal/epidemiologia , Hipóxia-Isquemia Encefálica/epidemiologia , Artéria Cerebral Média/diagnóstico por imagem , Fluxo Pulsátil , Natimorto/epidemiologia , Artérias Umbilicais/diagnóstico por imagem , Adulto , Índice de Apgar , Cérebro/irrigação sanguínea , Cesárea/estatística & dados numéricos , Feminino , Sangue Fetal/química , Humanos , Concentração de Íons de Hidrogênio , Lactente , Mortalidade Infantil , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Modelos Logísticos , Análise Multivariada , Placenta/irrigação sanguínea , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Medição de Risco , Ultrassonografia Doppler em Cores , Ultrassonografia Pré-Natal
15.
Bull Exp Biol Med ; 166(5): 617-621, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30903499

RESUMO

The contribution of prenatal hypoxic damage to the CNS to the formation of high sensitivity of the body to lead acetate was studied. Prenatal fetal hypoxia was modeled by the administration of sodium nitrite in doses of 5, 25, and 50 mg/kg to pregnant female rats. Cognitive capacities of mature offspring were evaluated in the radial maze test and Morris water maze test. After attaining learning criterion in the radial maze, lead acetate in a dose of 80 mg/kg was added to the drinking water of all animals over 2 weeks. Testing was performed during the exposure to the agent until disruption of the conditioned behavior. It was found that severe prenatal hypoxia (induced by the administration of 50 mg/kg sodium nitrite) impaired spatial memory, increased latency of funding the platform in Morris water maze test, and serves as a factor contributing to earlier manifestations of the neurotoxic effects of lead acetate.


Assuntos
Disfunção Cognitiva/fisiopatologia , Intoxicação por Chumbo/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Animais , Feminino , Desenvolvimento Fetal/fisiologia , Hipóxia Fetal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos
17.
Am J Physiol Cell Physiol ; 316(6): C815-C827, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30917030

RESUMO

We studied the role of bone marrow mesenchymal stem cells (MSCs) in our established model of bronchopulmonary dysplasia (BPD) induced by intrauterine hypoxia in the rat. First, we found that intrauterine hypoxia can reduce the number of MSCs in lungs and bone marrow of rat neonates, whereas the administration of granulocyte colony-stimulating factor or busulfan to either motivate or inhibit bone marrow MSCs to lungs altered lung development. Next, in vivo experiments, we confirmed that intrauterine hypoxia also impaired bone marrow MSC proliferation and decreased cell cycling activity. In vitro, by using the cultured bone marrow MSCs, the proliferation and the cell cycling activity of MSCs were also reduced when N-methyl-d-aspartic acid (NMDA) was used as an NMDA receptor (NMDAR) agonist. When MK-801 or memantine as NMDAR antagonists in vitro or in vivo was used, the reduction of cell cycling activity and proliferation were partially reversed. Furthermore, we found that intrauterine hypoxia could enhance the concentration of glutamate, an amino acid that can activate NMDAR, in the bone marrow of neonates. Finally, we confirmed that the increased concentration of TNF-ɑ in the bone marrow of neonatal rats after intrauterine hypoxia induced the release of glutamate and reduced the cell cycling activity of MSCs, and the latter could be partially reversed by MK-801. In summary, intrauterine hypoxia could decrease the number of bone marrow MSCs that could affect lung development and lung function through excessive activation of NMDAR that is partially caused by TNF-ɑ.


Assuntos
Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/prevenção & controle , Citoproteção/fisiologia , Células-Tronco Mesenquimais/metabolismo , Alvéolos Pulmonares/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Células da Medula Óssea/metabolismo , Displasia Broncopulmonar/patologia , Células Cultivadas , Feminino , Hipóxia Fetal/complicações , Hipóxia Fetal/metabolismo , Hipóxia Fetal/patologia , Masculino , Gravidez , Alvéolos Pulmonares/crescimento & desenvolvimento , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
18.
Am J Obstet Gynecol ; 221(1): 63.e1-63.e13, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30826340

RESUMO

BACKGROUND: Although the evidence regarding the benefit of using ST waveform analysis of the fetal electrocardiogram is conflicting, ST waveform analysis is considered as adjunct to identify fetuses at risk for asphyxia in our center. Most randomized controlled trials and meta-analyses have not shown a significant decrease in umbilical metabolic acidosis, while some observational studies have shown a gradual decrease of this outcome over a longer period of time. Observational studies can give more insight into the effect of implementation of the ST technology in daily clinical practice. OBJECTIVE: To evaluate the change in frequency of perinatal intervention and adverse neonatal outcome after the implementation of ST waveform analysis of the fetal electrocardiogram from 2000 to 2013. STUDY DESIGN: This retrospective longitudinal study was conducted in a tertiary referral center. A total of 19,664 medium- and high-risk singleton pregnancies with fetuses in cephalic presentation, a gestational age of ≥36 weeks, and the intention to deliver vaginally were included. ST waveform analysis of the fetal electrocardiogram was implemented in the year 2000 and by 2010 all deliveries were monitored using this technology. Data were collected on the following perinatal outcomes: fetal blood sampling, mode of delivery, umbilical cord blood gases, Apgar scores, neonatal encephalopathy, and perinatal death. Longitudinal trend analysis was used to detect changes over time in all deliveries monitored by cardiotocography either alone or in adjunct to ST waveform analysis of the fetal electrocardiogram. Logistic regression was used to correct for possible confounders. RESULTS: The umbilical artery metabolic acidosis rate declined from 2.5% (average rate of 2000 + 2001 + 2002) to 0.4% (average of 2011 + 2012 + 2013) (P < .001), which represents an 84% decrease. This decrease largely occurred between 2006 and 2008, during the Dutch randomized trial on fetal electrocardiogram ST waveform analysis. At this time, approximately 20% of deliveries were monitored using this method. Furthermore, there were significant reductions in fetal blood sampling rate (P < .001). Overall cesarean and vaginal instrumental deliveries decreased significantly (P < .001), but not for fetal distress. There were no changes in the Apgar scores. The incidence of neonatal encephalopathy was significantly lower in the second part of the study (odds ratio 0.39, 95% confidence interval 0.17-0.89). CONCLUSION: There was an 84% decrease in the incidence of umbilical artery metabolic acidosis in all deliveries between 2000 and 2013. The neonatal encephalopathy rate, fetal blood sampling rate, and the total number of cesarean and vaginal instrumental deliveries also decreased.


Assuntos
Acidose/epidemiologia , Cardiotocografia/métodos , Eletrocardiografia/métodos , Hipóxia Fetal/epidemiologia , Adulto , Índice de Apgar , Gasometria , Cesárea/estatística & dados numéricos , Parto Obstétrico , Extração Obstétrica/estatística & dados numéricos , Feminino , Sangue Fetal/química , Idade Gestacional , Humanos , Incidência , Modelos Logísticos , Estudos Longitudinais , Países Baixos , Gravidez , Gravidez de Alto Risco , Estudos Retrospectivos , Medição de Risco , Artérias Umbilicais
19.
Arterioscler Thromb Vasc Biol ; 39(4): 653-664, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30727752

RESUMO

In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.


Assuntos
Epigênese Genética , Hipertensão Arterial Pulmonar/genética , Remodelação Vascular/genética , Adulto , Biomarcadores , Diagnóstico Precoce , Feminino , Hipóxia Fetal/complicações , Estudos de Associação Genética , Humanos , MicroRNAs/genética , Medicina de Precisão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/prevenção & controle , RNA Longo não Codificante/genética , Fatores de Risco
20.
BMC Pregnancy Childbirth ; 19(1): 71, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760224

RESUMO

BACKGROUND: Hypoxia during labor contributes to 2.2 million intrapartum and early neonatal deaths each year. An additional 0.6-1.0 million cases of life-long disability occur because of fetal hypoxia during labor. It is known that fetal heart rate changes in labor correspond to hypoxia and neurologic compromise, but a reliable, low-cost method for detecting these changes is not available. In this study we sought to compare the ability of a handheld Doppler device to detect accelerations as part of the fetal scalp stimulation test and to compare the diagnostic performance of routine intermittent auscultation with auscultation that is augmented with fetal scalp stimulation. METHODS: This non-randomized, pre- and post-diagnostic trial was conducted with 568 maternal-fetus pairs at Kilimanjaro Christian Medical Center in Moshi, Tanzania. The first objective was to determine whether a handheld Doppler device could detect fetal accelerations in labor with reasonable accuracy as compared with a cardiotocography machine. We performed the fetal scalp stimulation test on 50 fetuses during labor using both a handheld Doppler and a cardiotocography machine and compared the outcomes for correlation using the kappa correlation coefficient. During the second objective, two groups of laboring women were monitored either with intermittent auscultation alone per routine protocol (N = 251) or with intermittent auscultation augmented with fetal scalp stimulation per study protocol(N = 267). Diagnostic accuracy of the monitoring method was determined by comparing umbilical cord blood gases immediately after birth with the predicted state of the baby based on monitoring. The analyses included sensitivity, specificity, and positive and negative predictive values. RESULTS: The prevalence of fetal acidemia ranged from 15 to 20%. Adding the fetal scalp stimulation test to intermittent auscultation protocols improved the performance of intermittent auscultation for detecting severe acidemia (pH < 7.0) from 27 to 70% (p = 0.032). The negative predictive value of intermittent auscultation augmented with the fetal scalp stimulation test ranged from 88 to 99% for mild (pH < 7.2) to severe fetal acidemia. CONCLUSIONS: The fetal scalp stimulation test, conducted with a handheld Doppler, is feasible and accurate in a limited resource setting. It is a low-cost solution that merits further evaluation to reduce intrapartum stillbirth and neonatal death in low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02862925 ).


Assuntos
Hipóxia Fetal/diagnóstico , Monitorização Fetal/métodos , Auscultação Cardíaca/métodos , Frequência Cardíaca Fetal/fisiologia , Ultrassonografia Doppler/instrumentação , Ecocardiografia Doppler/métodos , Feminino , Humanos , Trabalho de Parto/fisiologia , Gravidez , Couro Cabeludo , Tanzânia
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