Chronic intrauterine hypoxia alters neurodevelopment in fetal sheep.

OBJECTIVE: We tested the hypothesis that chronic fetal hypoxia, at a severity present in many types of congenital heart disease, would lead to abnormal neurodevelopment. METHODS: Eight mid-gestation fetal sheep were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid-filled environment for 22 ± 2 days under normoxic or hypoxic conditions. Total parenteral nutrition was provided. Control fetuses (n = 7) were harvested at gestational age 133 ± 4 days. At necropsy, brains were fixed for histopathology. Neurons were quantified in white matter tracts, and the thickness of the external granular layer of the cerebellum was measured to assess neuronal migration. Capillary density and myelination were quantified in white matter. Data were analyzed with unpaired Student t tests or 1-way analysis of variance, as appropriate. RESULTS: Oxygen delivery was reduced in hypoxic fetuses (15.6 ± 1.8 mL/kg/min vs 24.3 ± 2.3 mL/kg/min, P < .01), but umbilical blood flow and caloric delivery were not different between the 2 groups. Compared with normoxic and control animals, hypoxic fetuses had reduced neuronal density and increased external granular layer thickness. Compared with normoxic and control animals, hypoxic fetuses had increased capillary density in white matter. Cortical myelin integrity score was lower in the hypoxic group compared with normoxic and control animals. There was a significant negative correlation between myelin integrity and capillary density. CONCLUSIONS: Chronic fetal hypoxia leads to white matter hyper-vascularity, decreased neuronal density, and impaired myelination, similar to the neuropathologic findings observed in children with congenital heart disease. These findings support the hypothesis that fetal hypoxia, even in the setting of normal caloric delivery, impairs neurodevelopment.

Gender-specific differences in fetal cardiac troponin T in pregnancies complicated by placental insufficiency.

BACKGROUND: Placental insufficiency and fetal growth restriction may lead to fetal hypoxia and acidemia, which result in fetal cardiac injury. OBJECTIVE: The goal of this study was to compare the levels of fetal cardiac troponin T (cTnT) at birth and fetal Doppler parameters according to fetal gender in pregnancies complicated by placental insufficiency before 34 weeks' gestation. METHODS: Between March 2007 and November 2010, singleton pregnancies with placental insufficiency characterized by abnormal umbilical artery Doppler results were prospectively studied. All the patients delivered by cesarean section, and Doppler examinations were performed up to 48 hours before birth. Immediately after delivery, umbilical artery blood samples were obtained for fetal cTnT measurements. RESULTS: Fifty high-risk pregnant women met the study criteria. The study groups were as follows: group 1 consisted of 23 male fetuses (46%) and group 2 consisted of 27 female fetuses (54%). cTnT levels were significantly higher in the group of male fetuses (median, 0.14; range, 0.01-0.85) compared with the group of female fetuses (median, 0.05; range, 0.01-0.27) (P = 0.039). In the group of male fetuses, Doppler results of the ductus venosus assessment revealed values of pulsatility index for veins ≥1.0 in 15 male fetuses (65.2%) and 9 female fetuses (33.3%) (P = 0.032). CONCLUSIONS: Fetal gender was associated with cTnT level at birth in pregnancies complicated by placental insufficiency before 34 weeks' gestation, although the Doppler findings did not support gender differences. The fetal cardiac compromise and cardiac injury may be influenced by fetal gender, suggesting differences in the cardiovascular response to fetal hypoxia.

Conduta obstétrica na centralização da circulação fetal / Obstetric management in fetal brain sparing effect

A centralização do fluxo sanguíneo fetal é um fenômeno de compensação vascular bastante estudado na atualidade. Trata-se de alterações na resistência da circulação fetal, caracterizada pela redistribuição hemodinâmica do fluxo sanguíneo, com perfusão preferencial para órgãos nobres (cérebro, coração e glândulas adrenais) em detrimento dos pulmões, rins, baço e esqueleto, o que pode ser diagnosticado pelo estudo dopplervelocimétrico. O momento ideal para intervenção obstétrica ainda não é consenso. Uma das grandes preocupações, em relação à avaliação da vitalidade fetal, diz respeito ao momento ideal para interrupção da gravidez, uma vez que alguns dos métodos utilizados apresentam uma alta frequência de resultado falso-positivos, podendo ocasionar um nascimento prematuro, por vezes, desnecessário. Em fetos muito prematuros a opção pela interrupção da gravidez pode trazer consequências irreversíveis. Na tentativa de minimizar os danos, optou-se pela realização de uma revisão, baseada nas melhores evidências sobre a conduta nos fetos centralizados.

Fetal brain-sparing effect is a vascular compensation phenomenon widely studied today. Diagnosed by Doppler study it consists of changes on resistance in the fetal circulation characterized by hemodynamic redistribution of blood flow, with preferential perfusion to brain, heart and adrenal glands compared to the lungs, kidneys, spleen and skeleton. There is no consensus over ideal time for obstetric intervention. Ideal time for pregnancy termination is of major concern when assessing fetal vitality since methods used today have high false positives rate, leading to unnecessary prematurity. In extreme prematurity the decision to terminate pregnancy can lead to irreversible consequences. In an attempt to minimize damage, it was decided to carry out a review, based on the best evidence regarding conduct in fetal brain sparing effect.

Importância clínica da dosagem de lactato e contagem de eritroblastos no sangue colhido no segmento placentário da veia umbilical para o diagnóstico de hipóxia-isquemia em prematuros / Clinical value of lactate measurement and nucleated red blood cell counts in the placental segment of the umbilical vein of premature newborns for diagnosis of hypoxia-ischemia

OBJETIVO: Determinar a validade clínica das dosagens de lactato e contagem de eritroblastos quando comparados com o excesso de bases (EB) em sangue do segmento placentário da veia umbilical de prematuros. MÉTODOS: foram colhidas amostras de 25 prematuros, após ligadura e dequitação. Os prematuros foram seguidos até a alta. Estatística incluiu regressão linear, correlação de Spearman, curvas ROC, Teste de Fisher. RESULTADOS: Lactato mostrou boa correlação com pH e EB (p < 0,0001). Níveis de lactato de 4,04 mmol/L mostraram sensibilidade de 62,5 por cento e especificidade de 91,1 por cento em discriminar pH < 7,2 e EB < -10 mmol/L. Contagens de eritroblastos mostraram boa correlação com o EB (p = 0,0095), mas sensibilidade de 37,5 por cento e especificidade 82,4 por cento em discriminar EB < 10 mmol/L. CONCLUSÕES: Lactato é um marcador válido para hipóxia fetal, em amostras do segmento placentário das veias umbilicais. Contagens de eritroblastos apresentaram baixa sensibilidade na discriminação da acidose.

OBJECTIVE: To evaluate the clinical value of lactate measurement and nucleated red blood cell (NRBC) counts when compared to base excess (BE) in the blood collected from the placental segment of the umbilical vein. METHODS: 25 umbilical cords from premature babies were sampled after placental delivery and cord clamping. Babies were followed until discharge. Statistics involved linear regression, Spearman's correlation, ROC curves, and Fisher's exact test. RESULTS: The relationship between lactate in the umbilical vein blood and pH and BE was significant (p < 0.0001). A 4.04 mmol/L lactate level showed a sensitivity of 62.5 percent and a specificity of 94.1 percent in detecting pH <7.2 and BE < -10 mmol/L. NRBC counts were related to BE (p = 0.0095), but with a sensitivity of 37.5 percent and specificity of 82.4 percent in detecting BE < -10 mmol/L. CONCLUSIONS: Lactate is a valuable marker of fetal hypoxia when sampled from placental segment veins. NRBC counts demonstrated low sensitivity for the detection of acidosis.

Clinical value of lactate measurement and nucleated red blood cell counts in the placental segment of the umbilical vein of premature newborns for diagnosis of hypoxia-ischemia.

OBJECTIVE: To evaluate the clinical value of lactate measurement and nucleated red blood cell (NRBC) counts when compared to base excess (BE) in the blood collected from the placental segment of the umbilical vein. METHODS: 25 umbilical cords from premature babies were sampled after placental delivery and cord clamping. Babies were followed until discharge. Statistics involved linear regression, Spearman's correlation, ROC curves, and Fisher's exact test. RESULTS: The relationship between lactate in the umbilical vein blood and pH and BE was significant (p < 0.0001). A 4.04 mmol/L lactate level showed a sensitivity of 62.5% and a specificity of 94.1% in detecting pH < 7.2 and BE < -10 mmol/L. NRBC counts were related to BE (p = 0.0095), but with a sensitivity of 37.5% and specificity of 82.4% in detecting BE < -10 mmol/L. CONCLUSIONS: Lactate is a valuable marker of fetal hypoxia when sampled from placental segment veins. NRBC counts demonstrated low sensitivity for the detection of acidosis.

Influencia de la altura en la eritropoyesis del recien nacido / Influence of the height in erythropoiesis newborn

Objetivo. Estudio de la influencia de la hipoxia de la altura sobre la eritropoyesis del recien nacido através del análisis de valores hematológicos. Población. Trescientas muestras de sangre venosa de cordon umbilical de niños nacidos vivos a término y 300 muestras de sangre venosa periférica de mujeres gestantes del Hospital de la Mujer de La Paz a 3600 msnm. Métodos. Los estudios se realizaron con contador automatico Micros 60 y por técnicas manuales. Resultados. Los valores hematológicos de las gestantes normales comparados con sus similares habitantes a nivel del mar son estadísticamente diferentes; mientras que los valores hematológicos de los recien nacidos en la altura comparados con los del nivel del mar, son estadísticamente similares. Conlusión. La eritropoyesis de los recien nacidos en la altura es independiente de los factores maternos y del ambiente hipóxico presente a 3600 msnm, probablemente por la función protectora que ejerce la placenta.

The role of neuropeptide Y in the ovine fetal cardiovascular response to reduced oxygenation.

This study investigated the role of neuropeptide Y (NPY) in mediating cardiovascular responses to reduced oxygenation in the late gestation ovine fetus by: (1) comparing the effects on the cardiovascular system of an exogenous infusion of NPY with those elicited by moderate or severe reductions in fetal oxygenation; and (2) determining the effect of fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist on the fetal cardiovascular responses to acute moderate hypoxaemia. Under general anaesthesia, 14 sheep fetuses (0.8-0.9 of gestation) were surgically prepared with vascular and amniotic catheters. In 5 of these fetuses, a Transonic flow probe was also implanted around a femoral artery. Following at least 5 days of recovery, one group of fetuses (n = 9) was subjected to a 30 min treatment period with exogenous NPY (17 microg kg(-1) bolus plus 0.85 microg kg(-1) min(-1) infusion). In this group, fetal blood pressure and heart rate were monitored continuously and the distribution of the fetal combined ventricular output was assessed via injection of radiolabelled microspheres before and during treatment. The second group of fetuses instrumented with the femoral flow probe (n = 5) were subjected to a 3 h experiment consisting of 1 h of normoxia, 1 h of hypoxaemia, and 1 h of recovery during a slow I.V. infusion of vehicle. One or two days later, the acute hypoxaemia protocol was repeated during fetal I.V. treatment with a selective NPY-Y(1) receptor antagonist (50 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion). In these fetuses, fetal arterial blood pressure, heart rate and femoral vascular resistance were recorded continuously. The results show that fetal treatment with exogenous NPY mimics the fetal cardiovascular responses to asphyxia, and that treatment of the sheep fetus with a selective NPY-Y(1) receptor antagonist does not affect the fetal cardiovascular response to acute moderate hypoxaemia. These results support a greater role for NPY in mediating the fetal cardiovascular responses to acute asphyxia than to acute moderate hypoxaemia.

Reavaliaçäo da cardiotocografia basal, na gestaçäo de alto-risco, à luz da gasometria do sangue fetal obtido por cordocentese / Re-evaluation of basal cardiotocography, in high-risk pregnancy, by fetal blood gasometry obtained by cordocentesis

Em 57 pacientes de alto-risco foram realizados 60 exames de cardiotocografia (CTG) basal e determinado o equilíbrio cido-b sico do sangue da veia umbilical, obtido por cordocentese. Os resultados da CTG foram realcionados com os resultados do pH, pO2 e asfixia fetal. Observou-se relaçäo significante entre os parâmetros bioquímicos estudados do sangue da veia umbilical e os exames de CTG basal. Relevante é o comprometimento do concepto (asfixia) quando presente a CTG basal grave terminal (85 por cento).

[Correlation of creatine phosphokinase blood level with prenatal fetal heart rate as a prognostic factor in tissue hypoxia]. / Correlación del nivel sanguíneo de creatin fosfoquinasa con los registros de la frecuencia cardiaca fetal anteparto, como un predictor clínico de hipoxia tisular.

The presence of a high serum activity of the creatinine phosphokinase enzyme (CPK) could be the result of an hypoxic tissue event. The existence of an ominous fetal heart rate tracing is a reliable method which indicates the presence of an hypoxic state in variable degrees. Thirty-five pregnancies between 34 and 41 weeks of gestation were prospectively studied to correlate both, CPK activity and cardiotocography, with perinatal morbidity and mortality. All the patients had antepartum fetal heart rate testing and pregnancy was terminated by cesarean section within seven days to the last fetal heart tracing. As soon as the baby was born, we took an umbilical cord sample to measure CPK activity and a second sample was also taken at 36 hours of life. All the neonates had pediatric, neurologic, electrocardiographic and sonographic evaluation within their 48 hours of extrauterine life. Two groups were created: Group A included 14 neonates with normal cardiotocographic tracings (control group) and Group B had 21 infants with abnormal tracings (study group). We found an elevated serum CPK activity with statistic significance in the next three conditions: a) In the sample at 36 hours of life when compared to the cord sample in the control group, p less than 0.001; b) In the neonatal sample at 36 hours of age when compared to the cord sample in the study group, p less than 0.001; c) In the neonates of the study group compared to the neonates of the control group at 36 hours of extrauterine life, p less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents.

Because chronic hypoxemia causes a redistribution of iron from serum and storage pools into an expanding erythrocyte mass, and because infants of diabetic mothers are often hypoxemic in utero and have a high prevalence of polycythemia at birth, we studied iron distribution in 43 term infants of diabetic mothers. Twenty-four infants were at an appropriate size for gestational age; 19 were large for gestational age. At birth, 28 infants (65%) had abnormal serum iron profiles; eight had decreased ferritin concentrations only (stage 1), nine had decreased ferritin and increased total iron-binding capacity values (stage 2), and 11 had these serum findings plus elevated free erythrocyte protoporphyrin concentrations (stage 3). The hypoglycemic infants who were large for gestational age (n = 14) had a higher prevalence of abnormal iron profiles than euglycemic infants who were appropriate in size for gestational age (n = 20; 93% vs 50%; p = 0.009). Progressively abnormal iron profiles were associated with higher glycosylated fetal hemoglobin values, greater degrees of macrosomia, increased hemoglobin and erythropoietin concentrations, and increased erythrocyte/storage iron ratios. Erythropoietin concentrations were inversely linearly correlated with serum iron values (n = 32, r = -0.54; p = 0.003). The combined erythrocyte and storage iron pools were significantly lower in infants with abnormal iron values whose mothers were diabetic, particularly in infants of women with confirmed diabetic vasculopathy. We speculate that these findings are likely due to (1) increased fetal iron utilization during compensatory hemoglobin synthesis in response to chronic hypoxemia and (2) reduced iron transfer during late gestation complicated by diabetes.

Postnatal changes in serum immunoreactive erythropoietin in relation to hypoxia before and after birth.

To assess the immediate postnatal changes of serum immunoreactive erythropoietin (EP) in infants born after acute or chronic fetal hypoxia, and to estimate the rate of EP disappearance, we studied EP concentration, measured by double-antibody radioimmunoassay, in cord venous plasma and in serum at a mean age of 8 hours in a control group (n = 9) and in three patient groups: (1) infants with polycythemia (n = 10), (2) infants born to mothers with preeclampsia of pregnancy, without (n = 22) or with (n = 11) acidosis at birth, and (3) infants with acute birth asphyxia (n = 19), seven of whom had postnatal hypoxia. In all patient groups, cord venous EP was elevated in comparison with values in control infants. No change was found in EP level between birth and 8 hours in control infants (geometric mean in cord and 8-hour sample: 20 and 16 mU/ml, not significant) or in acutely asphyxiated infants with postnatal hypoxia (122 and 72 mU/ml, not significant), whereas the EP level decreased in all other groups: infants with polycythemia (123 to 24 mU/ml, p less than 0.001), nonacidotic infants (78 to 26 mU/ml, p less than 0.001) and acidotic infants (176 to 38 mU/ml, p less than 0.001) of the preeclampsia group, and acutely asphyxiated infants without postnatal hypoxia (58 to 30 mU/ml, p less than 0.001). The mean (+/- SD) half-time of EP disappearance was 2.6 +/- 0.5 hours in infants with polycythemia and 3.7 +/- 0.9 hours in infants of the preeclampsia group.

Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.

We measured cord transferrin and ferritin levels in 50 newborn infants with fetal conditions associated with either uteroplacental vascular insufficiency or chronic hypoxia. Sixteen small for gestational age infants, 21 infants of mothers with preeclampsia, and 13 symptomatic infants of diabetic mothers had significantly higher transferrin levels and lower ferritin levels and calculated iron stores than did asymptomatic gestational age-matched control infants without these conditions. Cord ferritin levels and calculated iron stores were significantly lower in the infants of diabetic mothers than in any other group of infants. Cord transferrin levels were inversely correlated with ferritin levels (r = -0.59, P less than 0.001) and were unrelated to transthyretin levels and birth weight in the high-risk infants, but were positively correlated with ferritin levels (r = 0.50, P less than 0.001), transthyretin levels (r = 0.65, P less than 0.001), and birth weight (r = 0.75, P less than 0.001) in the control infants. We conclude that cord transferrin levels do not reflect protein-energy status in newborn infants with prenatal histories suggesting uteroplacental insufficiency or chronic hypoxia, and that when associated with decreased cord ferritin levels, indicate possible impaired iron stores in these infants.

Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia.

The reduced birth weight widely reported for high-altitude infants has been attributed to intrauterine hypoxia. This assertion may be tested by comparing hematologic values of high-altitude and low-altitude newborn infants, since the human fetus can respond to intrauterine hypoxia with enhanced erythropoiesis. This report presents cord blood values of term Bolivian infants classified by altitude, ethnic group, and parity: 105 from La Paz (3600 m) and 46 from Santa Cruz (400 m). Hematocrit, hemoglobin concentration, and the proportion of hemoglobin F are higher among newborn infants at high altitude. Ethnic group and parity interact with altitude in effect on hematocrit and hemoglobin concentration. Gestational age, birth weight, maternal hematologic variables, and socioeconomic indicators are not significantly associated with cord blood values. The high-altitude newborn infant displays evidence of enhanced erythropoiesis, which supports the suggestion that the high-altitude fetus experiences a greater degree of hypoxia in utero than does the low-altitude fetus.