losartan-potassium and Fetal-Hypoxia

Perinatal mortality has not decreased in type 1 diabetic pregnancies during the last 30 years. Fetal deaths are five times and neonatal deaths three times higher compared with the general population. Chronic intrauterine hypoxia caused by maternal diabetes is the most likely cause of stillbirths during the last weeks of pregnancy. Both fetal hyperglycemia and hyperinsulinemia can independently cause fetal chronic hypoxia by increasing fetal oxygen consumption. Fetal chronic hypoxia can be detected antenatally by measuring amniotic fluid erythropoietin concentration. Prepregnancy visits for advice and glycemic control should be increased among diabetic women. Furthermore, pregnancy surveillance should be enhanced and therapeutic strategies changed in order to improve perinatal outcome among diabetic pregnancies.

Topics: Amniotic Fluid; Diabetes, Gestational; Erythropoietin; Female; Fetal Death; Fetal Hypoxia; Humans; Infant Mortality; Infant, Newborn; Pregnancy; Pregnancy in Diabetics; Risk Factors

Perinatal mortality has not decreased over the last two decades in pregestational diabetic pregnancies. Stillbirth rate is 4-6 times and neonatal mortality 2-4 times higher in diabetic than in non-diabetic pregnancies despite modern electronic fetal surveillance methods. Majority of late stillbirths are "unexplained", many of which are presumably caused by fetal hypoxia. Both experimental and clinical studies have shown that fetal hyperglycaemia and hyperinsulinaemia can independently cause fetal hypoxia, which ultimately can lead to fetal death. Poor glycaemic control is associated with perinatal complications. Sharp increases in amniotic fluid erythropoietin levels indicate fetal hypoxia in diabetic pregnancy. Fetal erythropoietin concentrations correlate directly with maternal HbA(1c) levels. It is therefore important to maintain near-normal glycaemic level throughout pregnancy. Measurement of amniotic fluid erythropoietin level is a new way to detect fetal hypoxia antenatally. Sufficiently large controlled studies are needed before definitive answer of the clinical utility of amniotic fluid erythropoietin measurements in diabetic pregnancies can be determined.

Topics: Amniotic Fluid; Erythropoietin; Female; Fetal Hypoxia; Glycated Hemoglobin; Humans; Infant Mortality; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Stillbirth

Tissue hypoxia is the major stimulus of erythropoietin (EPO) synthesis in fetuses and adults. Since EPO does not cross the placenta and is not stored, fetal plasma and amniotic fluid levels indicate EPO synthesis and elimination. Acutely, the rate and magnitude of the increase in plasma EPO levels correlate with the intensity of hypoxia. Amniotic fluid EPO levels correlate with cord plasma levels in normal and abnormal pregnancies, with fetal plasma EPO levels in humans averaging 2.6 times higher than the corresponding amniotic fluid EPO levels. Recent experimental and clinical studies demonstrate that EPO has neuroprotective effects related to its anti-apoptotic and vascular growth-promoting properties. Although under basal conditions the fetal kidneys are the main site of EPO production, during hypoxia recent experimental data indicate an important role of the placenta. Amniotic fluid EPO levels have been shown to increase exponentially during fetal hypoxia in preeclamptic, diabetic and Rh-immunized pregnancies, to correlate inversely with cord blood pH, pO(2) and base excess and to predict neonatal morbidities and NICU admission. As an indicator of chronic intrauterine hypoxia, fetal EPO measurements have increased our knowledge about the pathogenesis and importance of intrauterine growth restriction, macrosomia, diabetic pregnancy, prolonged pregnancy, meconium staining, fetal hemorrhage, fetal anemia, maternal smoking and alcohol consumption, abnormal fetal heart rate and abnormal Doppler flow patterns. While the clinical utility of fetal amniotic fluid and plasma EPO measurements in the management of high-risk pregnancies and their offspring is promising, adequately powered clinical trials are urgently needed.

Topics: Adult; Amniotic Fluid; Biomarkers; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Pregnancy; Pregnancy Complications; Young Adult

Our objective was to discuss the role of erythropoietin in fetal erythropoiesis and to review its clinical uses in perinatal medicine. All relevant articles compiled through a MEDLINE search (years 1986-1997) were reviewed. Erythropoietin is essential for fetal erythropoiesis and is produced in response to hypoxia and anemia. Cord blood erythropoietin is purely fetal and reflects tissue oxygenation. It has been found to be increased in many complicated pregnancies with underlying fetal hypoxia. Erythropoietin could be used as a marker of fetal hypoxia because its concentration rises rapidly by increased production in response to hypoxia. Its measurement might enable more accurate timing of hypoxic injury. In addition, erythropoietin levels have been well correlated with perinatal brain damage and may facilitate treatment of high risk neonates. Erythropoietin has also been used successfully in anemia of prematurity, decreasing the transfusion requirement. However, studies are still needed to determine the optimal doses of erythropoietin and iron supplementations required for maximizing the red blood cell response. Erythropoietin has been examined as potential maternal therapy in various disorders during pregnancy. These include end-stage renal disease, severe antepartum iron deficiency anemia, and postpartum anemia. Erythropoietin has been found to be effective and well tolerated in these conditions. An additional promising use lies in the optimization of maternal red blood cell mass to allow autologous blood donation. This may be critical in cases where a large amount of bleeding might be anticipated, as with placenta previa. This would also minimize the donor transfusion-related hazards. Erythropoietin with its wide clinical applications could improve maternal and neonatal outcome.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Female; Fetal Diseases; Fetal Hypoxia; Fetus; Humans; Pregnancy; Recombinant Proteins

To investigate the relationship between erythropoietin concentration in umbilical venous blood and clinical signs of fetal hypoxia.. We measured erythropoietin concentrations in umbilical venous blood from 200 consecutively born neonates using an enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies. Results were available within 6 hours. Inter-assay variation was 8.5% and the mean intra-assay variation was 14.2%.. Using a multiple regression analysis, we found that the erythropoietin concentration correlated significantly (P < .01) with fetal growth retardation and umbilical acidosis but not with gestational age, meconium-stained amniotic fluid (AF), abnormal fetal heart rate (FHR) pattern, or Apgar score at 5 minutes. Median erythropoietin concentrations were 25.1 mU/mL in infants with no risk factors or complications during pregnancy and delivery (n = 19), 25.8 mU/mL after complicated pregnancy (n = 95), 50.6 mU/mL with meconium-stained AF (n = 12), 44.7 mU/mL with abnormal FHR pattern (n = 40), 47.8 mU/mL with both stained AF and abnormal FHR pattern (n = 10), and 72.6 mU/mL with umbilical acidosis (n = 24). The median erythropoietin concentration increased significantly with decreasing pH and with increasing base deficit in umbilical arterial blood. The erythropoietin concentration in umbilical venous blood (cutoff value 50 mU/mL) discriminated between infants with no clinical signs of fetal hypoxia and those with umbilical acidosis with a sensitivity of 75% and a specificity of 90%.. Elevated erythropoietin concentrations in umbilical venous blood indicate prolonged fetal hypoxia. The ELISA technique might be a useful tool for determining the exact time course of erythropoietin concentrations in fetal hypoxia.

Topics: Acidosis; Biomarkers; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Heart Rate, Fetal; Humans; Infant, Newborn; Pregnancy; Sensitivity and Specificity; Umbilical Veins

Erythropoietin is the primary hormone controlling erythropoiesis in both adults and fetuses. In extra-fetal life the main organ producing erythropoietin is the kidney which is responsible for producing about 90% of the total amount of this hormone. In fetal life erythropoietin is produced by the liver of the fetus. The erythropoietin production depends on the content of oxygen in blood. This is probably the only physiological stimulus which regulates the production of erythropoietin. The increase of erythropoietin concentration in the umbilical cord serum and in the amniotic fluid has been observed in the states of fetus anoxia. This mainly concerns such complications during pregnancy as the fetus hypotrophy, diabetes, serological conflict, and gestosis.

Topics: Amniotic Fluid; Erythropoietin; Female; Fetal Hypoxia; Humans; Pregnancy; Pregnancy Complications

Topics: Animals; Blood Viscosity; Cardiovascular Diseases; Central Nervous System Diseases; Erythrocyte Deformability; Erythropoietin; Female; Fetal Hypoxia; Fetofetal Transfusion; Fetomaternal Transfusion; Fetus; Follow-Up Studies; Gastrointestinal Diseases; Genital Diseases, Male; Global Health; Growth Disorders; Hematocrit; Humans; Hyperbilirubinemia; Hypocalcemia; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Kidney Diseases; Male; Mental Disorders; Polycythemia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy in Diabetics; Prognosis; Respiration Disorders; Sheep; Thrombocytopenia

Background Normal development of the human placenta, referred to as villous tree maturation, entails formation of the vasculosyncytial membranes. These structures develop by the approximation of syncytiotrophoblasts with the villous capillary endothelium and constitute the most efficient sites of gaseous exchange in the placenta. Defective maturation of the villous tree can lead to deficient vasculosyncytial membranes, implicated in the high incidence of hypoxic complications. Hypoxia, in turn, can stimulate production of erythropoietin, whereby increased fetal plasma or amniotic fluid concentrations of this hormone reflect fetal hypoxemia. The current study was undertaken to determine whether delayed villous maturation is associated with changes in amniotic fluid erythropoietin concentrations. Methods Placental histologic examination was performed using hematoxylin and eosin. Subsequent to histologic assessment of delayed villous maturation, the diagnosis was confirmed with CD-15 immunohistochemistry. The controls (n = 61) were pregnancies without villous maturation abnormalities, and cases (n = 5) were pregnancies with delayed villous maturation. Amniotic fluid erythropoietin concentrations were measured using a specific immunoassay. Results Concentrations of erythropoietin in the amniotic fluid (1) of controls were less than the limit of detection and (2) of cases with delayed villous maturation were significantly higher than those of controls (P-value = 0.048). Conclusion Delayed villous maturation is associated with higher concentrations of amniotic fluid erythropoietin.

Topics: Amniotic Fluid; Chorionic Villi; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Placental Circulation; Placentation; Pregnancy; Trophoblasts

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

Topics: Adult; Amniocentesis; Amniotic Fluid; Brain Injuries; Cause of Death; Erythropoietin; Female; Fetal Death; Fetal Diseases; Fetal Hypoxia; Glial Fibrillary Acidic Protein; Heart Diseases; Humans; Immunohistochemistry; Placenta; Pregnancy; Random Allocation; Retrospective Studies; Stillbirth; Troponin I; United States

Erythropoietin - a hormone regulating erythropoiesis - is a biomarker of chronic fetal hypoxia. High erythropoietin levels in fetal plasma and amniotic fluid are associated with increased risk of adverse neonatal outcome. Since the risk of perinatal morbidity and mortality is increased in pregnancies beyond 41 gestational weeks, we evaluated erythropoietin levels in amniotic fluid and umbilical cord serum in apparently low-risk term (≥ 37 gestational weeks) and prolonged pregnancies (≥ 41 gestational weeks) with labor induction.. Amniotic fluid erythropoietin levels correlated with gestational age (r = 0.261, p = 0.012) and were higher among prolonged pregnancies as compared to term pregnancies (p = 0.005). There were 78 (83.9%) vaginal deliveries, and among these erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum (r = 0.513, p < 0.000). Umbilical cord serum erythropoietin levels correlated with gestational age among vaginal deliveries (r = 0.250, p = 0.027). Erythropoietin levels in amniotic fluid and umbilical cord serum did not correlate with umbilical artery pH or base excess, or other adverse pregnancy outcome.. In vaginal deliveries erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum. Erythropoietin levels correlated with gestational age, probably due to weakening placental function and relative hypoxemia occurring in advanced gestation. However, in this relatively low-risk study population erythropoietin was not related to adverse delivery outcome.

Topics: Adult; Amniotic Fluid; Biomarkers; Case-Control Studies; Delivery, Obstetric; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Pregnancy; Pregnancy Outcome; Pregnancy, Prolonged; Prospective Studies; Statistics, Nonparametric; Term Birth

Hypoxic-ischemic brain damage (HIBD) occurs due to intrauterine hypoxia ischemia influencing the energy supply for fetal brain cells, which affects the metabolism of the brain to make the brain suffer a severe damage. Erythropoietin (EPO), which regulates hemacytopoiesis, is a kind of cytokine. EPO is sensitive to hypoxia ischemia. In this study, we aimed to investigate the effect of EPO on the expression of Fas/FasL in brain tissues of neonatal rats with HIBD. Neonatal rats were assigned randomly to sham, HIBD, and EPO groups. Five time points for observation were 6, 12, 24, 48, and 72 h after the HIBD rat model had been established, respectively. In the HIBD group, Fas/FasL expression began to rise at 6 h, reached the peak at 12-24 h, and dropped from 24 h. In the EPO group, the expression of Fas/FasL was lower than those in HIBD group at 12, 24, and 48 h (P<0.05). Our findings suggest that EPO may reduce cell apoptosis after hypoxic-ischemic damage through reduction of the expression of Fas and FasL, and that optimal therapeutic time window is 6-24 h after HIBD.

Topics: Animals; Animals, Newborn; Brain; Erythropoietin; Fas Ligand Protein; fas Receptor; Female; Fetal Hypoxia; Hypoxia-Ischemia, Brain; Male; Random Allocation; Rats; Rats, Sprague-Dawley

Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1α and HIF-2α proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.

Topics: Animals; Astrocytes; Basic Helix-Loop-Helix Transcription Factors; Brain; Cells, Cultured; Disease Models, Animal; Erythropoietin; Female; Fetal Hypoxia; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice, Inbred BALB C; Midazolam; Pregnancy; RNA, Messenger; Up-Regulation

The time between onset of fetal hypoxia and first appearance of nucleated red blood cells (NRBCs) in the blood can conceptually be divided into two periods; (1) the 'erythropoietin (EPO) generation time', which previous fetal studies suggest is 4 to 5 h, and (2) the 'NRBC emergence time'. In this study, we estimated the latter as the time required for NRBC to appear in the blood after administering a dose of recombinant EPO.. This was a retrospective analysis of data from a multihospital healthcare system (Intermountain Healthcare). Data were included only for neonates born ≥34 weeks gestation between the dates 1 January 2005 and 31 October 2012 and only if they received a dose of darbepoetin during their neonatal intensive care unit stay and had one or more complete blood cell counts (CBCs) obtained during the 3-day period before the dose was given and one or more CBCs in the 7-day period after the dose.. The study involved 31 neonates who received 34 doses of darbepoetin. Seven doses were 4 μg kg(-1) and twenty-seven doses were 10 μg kg(-1). Twenty-six CBCs were obtained during the 24-h period following the darbepoetin dose and none had NRBC identified. NRBC first appeared in the blood between 24 and 36 h after the dose. Recipients of the higher dose generally had a higher peak NRBC count but the NRBC 'emergence time' did not appear to depend on dose.. Following fetal hypoxia, transcription and translation of the EPO gene result in an elevation in plasma EPO concentration. Previous fetal studies suggest this process requires 4 to 5 h. The present studies suggest that, following the increase in plasma EPO, NRBC emerge into the circulation in ≥24 h. If this model serves as a reasonable estimate, it suggests that neonates with an elevated NRBC count at birth had the onset of hypoxia at least 28 to 29 h before birth.

Topics: Blood Cell Count; Darbepoetin alfa; Erythrocytes; Erythropoietin; Fetal Hypoxia; Gestational Age; Humans; Infant, Newborn; Retrospective Studies; Time Factors

Topics: Darbepoetin alfa; Erythrocytes; Erythropoietin; Fetal Hypoxia; Humans

To investigate the effects of recombine human erythropoietin (rhEPO) on neural cells apoptosis and the expression of Caspase-3 protein in brain tissue of fetal rats after intrauterine hypoxic-ischemic brain injury.. Forty-four Sprague-Dawley rats on 19 days of pregnancy were divided into rhEPO treated group, ischemia-reperfusion group and sham-operated group. Intrauterine hypoxic-ischemic injury of fetal rats was induced by bilateral occlusion of the utero-ovarian artery for 20 min. rhEPO (5000 U/kg) was injected into rats through caudal vein in rhEPO treated group while saline was injected into rats in hypoxic-ischemic group 30 min before hypoxic-ischemic injury. The brain samples in rhEPO treated group and hypoxic-ischemic group were obtained at 30 min, 3 h, 6 h, 24 h and 48 h respectively after artery clamping. There was no hypoxic-ischemic injury in sham-operated group, so the brain samples were obtained at 24 hours after sham operation. Neuroapoptosis in brain tissue was measured by TdT mediated dUTP-biotin nick end labeling (Tunel) staining. The expression of Caspase-3 protein was observed by immunohistochemistry.. The number of apoptosis cells in fetal rat hippocampus after intrauterine hypoxic-ischemic increased progressively with reperfusion. Compared with the I/R group, the number of apoptosis cells decreased in rhEPO treated group (P < 0.01). The expression of Caspase-3 increased rapidly after 3 hours from the reperfusion in the I/R group. Compared with the I/R group, there was less expression of Caspase-3 in rhEPO treated group (P < 0.01).. rhEPO showed the effects to inhibit the apoptosis of fetal neural cells and the expression of Caspase-3 protein due to intrauterine hypoxic-ischemic brain injury.

Topics: Animals; Brain; Caspase 3; Erythropoietin; Female; Fetal Hypoxia; Humans; Hypoxia-Ischemia, Brain; Ischemic Preconditioning; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury

Topics: Blood Gas Analysis; Erythroblasts; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Male; Pregnancy; Pregnancy Complications; Umbilical Cord

In spite of improvement in obstetrical care, pregnancy in women with type 1 diabetes mellitus is associated with increased perinatal morbidity and mortality. Hyperglycemia during pregnancy causes excessive fetal growth and chronic fetal hypoxia as reflected in increased erythropoietin (EPO) levels in amniotic fluid (AF).. We hypothesized that the degree of fetal hypoxia would correlate with fetal oxidative and nitrosative stress as evidenced ty the concentration of specific biomarkers in AF.. 19 pregnant women with type 1 or insulin-treated gestational diabetes mellitus were studied. AF samples were collected and processed for EPO, meta-tyrosine, nitro-tyrosine and 8-hydroxy-2-deoxiguanosine by chemiluminescent immunoassay and high-performance liquid chromatography coupled to tandem mass spectrometry methods, respectively.. The mean (SD) of the last HbA1c concentration before delivery was 7.7% (1.1). Median gestational age was 258 days (range 231-268). Birth weight was 3,868 ± 695 g with a z-score >2 SD in 47% of the cases. A significant correlation was found between the concentrations of AF EPO and meta-tyrosine/phenylalanine ratio (p < 0.001), nitro-tyrosine (p < 0.01) and 8-oxo-dG/2dG ratio (p < 0.001).. We confirmed that fetuses of type 1 diabetes or insulin-treated gestational diabetes pregnancies experience chronic hypoxia as reflected by increased EPO concentrations in AF near term. Moreover, EPO levels significantly correlated with the concentration of oxidative and nitrosative stress biomarkers in AF. This pro-oxidant status may predispose newborn infants to poor postnatal adaptation and early neonatal complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amniocentesis; Amniotic Fluid; Biomarkers; Birth Weight; Chromatography, High Pressure Liquid; Chronic Disease; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes, Gestational; Erythropoietin; Female; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoassay; Infant, Newborn; Insulin; Male; Nitrosation; Oxidative Stress; Pilot Projects; Pregnancy; Pregnancy in Diabetics; Tandem Mass Spectrometry; Tyrosine; Young Adult

To evaluate the effect of maternal smoking during pregnancy on levels of umbilical cord erythropoietin.. Erythropoietin levels were measured in umbilical cord sera of 60 newborns who were delivered vaginally at term. There were 20 (33%) smoking and 40 (67%) nonsmoking mothers.. Mean cord serum erythropoietin levels were significantly lower in the nonsmokers (nonsmokers, 24 ± 9 IU/L; smokers, 61 ± 46 IU/L; P < .001). There was a significant positive correlation between the number of cigarettes smoked per day and cord serum erythropoietin levels (r, 0.58; P ≤ .05).. Smoking during pregnancy is associated with increased levels of umbilical cord erythropoietin at birth. This may indicate a risk of fetal hypoxia and growth restriction. Education and encouragement of cessation of smoking during pregnancy are important to avoid associated fetal and maternal morbidity and mortality.

Topics: Adult; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Fetal Hypoxia; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications; Prospective Studies; Smoking

To observe the permeability of recombinant human erythropoietin through placenta barrier and fetal blood-brain barrier after transient uteroplacental ischemia.. Rats on days 19 of pregnancy were divided into rhEPO treated group, ischemia-reperfusion group and sham operated group. Fetal ischemia in rhEPO treated group and ischemia-reperfusion group was induced by bilateral occlusion of the utero-ovarian artery for 20 minutes. Different dosage of 125I-rhEPO (2500 U/kg, 5000 U/kg, 7500 U/kg) was injected into the rats through caudal veins 30 min before injury in rhEPO treated group and sham-operated group. Saline was administered intravenously 30 min before the induction of hypoxic-ischemic injury in ischemia-reperfusion group. The amniotic fluid, placenta and fetal organs including brain, liver, heart, lung and kidney were collected to measure the radioactivity at 24h after injury.. 125I-rhEPO was detected in amniotic fluid, placenta and fetal organs. The radioactivity of 125I-rhEPO in these tissues increased gradually with the increased dose injected in rhEPO treated group and sham-operated group. There were significant differences in the radioactivity of 125I-rhEPO between rhEPO treated group and sham-operated group (P < 0.05).. The permeability of rhEPO through placental barrier and blood-brain barrier increased under the condition of fetal ischemia and hypoxia.

Topics: Animals; Blood-Brain Barrier; Erythropoietin; Female; Fetal Hypoxia; Maternal-Fetal Exchange; Permeability; Pregnancy; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury

Intrauterine infection is a common antecedent of preterm birth. Infants born very preterm are at increased risk for neurologic dysfunction, including visual deficits. With increasing survival of very preterm infants, there is a need for therapies that prevent adverse neurologic outcomes. Using an ovine model, the authors investigated the neuroprotective potential of recombinant human erythropoietin (rhEPO) on retinal injury induced by intrauterine inflammation.. At 107 ± 1 days of gestational age (DGA), chronically catheterized fetal sheep received either of the following on 3 consecutive days: intravenous (IV) bolus dose of lipopolysaccharide (LPS; ∼0.9 μg/kg; n = 8); IV bolus dose of LPS, followed at 1 hour by 5000 IU/kg rhEPO (LPS + rhEPO; n = 8); rhEPO alone (n = 5). Untreated fetuses (n = 8) were used for comparison with the three treatment groups. Fetal physiological parameters were monitored. At 116 ± 1 DGA, fetal retinas were assessed quantitatively for morphologic and neurochemical alterations.. Exposure to LPS alone, but not to rhEPO alone, resulted in fetal hypoxemia and hypotension (P < 0.05). Exposure to LPS alone caused retinal changes, including reductions in thickness of the inner nuclear layer (INL), somal areas of INL neurons, process growth in the plexiform layers, and numbers of ganglion and tyrosine hydroxylase immunoreactive (TH-IR) dopaminergic amacrine cells. Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but significantly reduced alterations in retinal layers and ganglion and TH-IR cell numbers.. rhEPO treatment was beneficial in protecting the developing retina after LPS-induced inflammation. Retinal protection could occur by the antiapoptotic or anti-inflammatory actions of EPO.

Topics: Amacrine Cells; Animals; Cell Count; Disease Models, Animal; Erythropoietin; Escherichia coli; Female; Fetal Hypoxia; Fluorescent Antibody Technique, Indirect; Gestational Age; Immunoenzyme Techniques; Lipopolysaccharides; Macrophages; Microglia; Pregnancy; Receptors, Erythropoietin; Recombinant Proteins; Retina; Retinal Diseases; Retinal Ganglion Cells; Sheep, Domestic; Tyrosine 3-Monooxygenase

To evaluate validity of biochemical diagnostic methods of fetal hypoxia.. A case-control study.. Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic.. We included 67 patients, and they were retrospectively divided into group of controls (n=36), and studied group (n=31) according to pH in umbilical artery (UA) <7.15. Acid-base parameters were assessed with Rapidlab 248, Bayer Healthcare LLC, East Walpole, USA. We determined criterion for metabolic acidosis (MAC) as pH UA <7.15, resp. base deficit (BD) UA >12 mmol/l. Postpartal lactate concentration in umbilical vein (UV) and UA was determined with lactatemeter Accutrend Lactate, Roche Diagnostics, Switzerland. Quantitative assessment of fetal human protein S100B was provided with ELISA (Sangtec 100 ELISA, DiaSorin Inc., Stillwater, Minnesota, USA). Fetal erythropoietin concentration in UV was examined with immunoenzymatic assessment Access EPO (Beckman Coulter, Inc., Fullerton, CA, USA).. histograms, Kolmogorov-Smirnov test, Mann-Whitney test, Spearman's rho; statistical significance: p<0.05, Receiver Operating Characteristic curves, Area Under the Curve.. The best correlation was between fetal acid-base parameters and lactate in UA (p<0.0005). Significant correlation was between EPO in UV, and protein S100B in UV (p<0.05). EPO in UV significantly correlated with lactate in UA (p<0.05). Correlation between EPO in UV and protein S100B was not significant. According to ROC curves in prediction of fetal hypoxia, we found an excellent accuracy (AUC>0.9) for lactate in UA, good accuracy (AUC>0.7) had EPO in UV. Results for protein S100B were not significant. The highest sensitivity had EPO in UV, while the highest specificity has had lactate in UA.. An indisputable evidence of labor management quality is the fetal metabolic status. On the basis of our results, the suitable clinical markers are lactate and EPO, in addition to acid-base parameters.

Topics: Acid-Base Equilibrium; Adult; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Lactic Acid; Nerve Growth Factors; Pregnancy; S100 Calcium Binding Protein beta Subunit; S100 Proteins

Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.

Topics: Animals; Brain; Brain Damage, Chronic; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endotoxins; Erythropoietin; Female; Fetal Diseases; Fetal Hypoxia; Injections, Intravenous; Lipopolysaccharides; Nerve Fibers, Myelinated; Neuroprotective Agents; Optic Nerve; Pregnancy; Sheep, Domestic; Treatment Outcome

To investigate whether recombine human erythropoietin can cross the placenta barrier in rats with transient uteroplacental ischemia.. Rats on day 19 of pregnancy were divided into ischemia-reperfusion group, sham-operated group and rhEPO treated group. Fetal ischemia was induced by bilateral occlusion of the utero-ovarian artery for 20 minutes. 125I-rhEPO or saline were administered intravenously 30 min before the induction of hypoxic-ischemic injury. Fetal rat organs were removed to measure the radioactivity post injury.. A small amount of radioactive activity (1.26 +/- 0.28) pg/g was detected in the fetal rats with ischemia-reperfusion. 125I-rhEPO radioactivity increased gradually with time in the placenta, amniotic fluid and fetal tissues of vital organs in the rats of sham-operated group and rhEPO treatment group. There were significant differences in 125I-rhEPO between placental organs and other organs (P < 0.05). The permeability of 125I-rhEPO through the blood brain barrier changed with reperfusion time and peaked about 6 h after reperfusion, and significant differences were found between rhEPO treatment group and sham operation group (P < 0.05).. Exogenous rhEPO can cross the placenta barrier and blood-brain barrier and reach hypoxic-ischemic fetal rats.

Topics: Animals; Blood-Brain Barrier; Capillary Permeability; Erythropoietin; Female; Fetal Hypoxia; Ischemia; Maternal-Fetal Exchange; Placenta; Pregnancy; Rats; Recombinant Proteins; Reperfusion Injury; Uterus

S100B protein is a biochemical marker for brain injury, and high serum S100B levels have been observed in newborns with birth asphyxia. We hypothesized that the concentration of amniotic fluid erythropoietin, which increases in chronic fetal hypoxia, correlates with amniotic fluid S100B concentration.. Amniotic fluid samples in 35 pregnancies at high risk for chronic fetal hypoxia were obtained at cesarean section or by amniocentesis done within a median of 2 days before delivery. S100B and erythropoietin concentrations were measured by chemiluminescent immunoassays.. A positive correlation existed between the concentrations of S100B and erythropoietin in the amniotic fluid (r=0.57, p<0.0001). Amniotic fluid S100B concentration was higher (70 ng/l; 33-469, n=17) (median; range) in pregnancies with elevated amniotic fluid erythropoietin (>or= 50 IU/l) than in pregnancies with normal erythropoietin (34 ng/l; 20-340, n=18) (p<0.0001, Mann-Whitney U-test). S100B predicted an elevated amniotic fluid erythropoietin concentration in the study population with the sensitivity of 94% and specificity of 83%.. A strong positive correlation exists between amniotic fluid S100B and erythropoietin concentrations in pregnancies at high risk for chronic fetal hypoxia. This suggests that chronic fetal hypoxia increases the intrauterine release of S100B.

Topics: Adult; Amniotic Fluid; Biomarkers; Erythropoietin; Female; Fetal Hypoxia; Humans; Infant, Newborn; Nerve Growth Factors; Pregnancy; Pregnancy, High-Risk; S100 Calcium Binding Protein beta Subunit; S100 Proteins

Reduced oxygen supply during the pre- and perinatal period often leads to acquired neonatal brain damage. So far, there are no reliable markers available to assess the hypoxic cerebral damage and the resulting prognosis during the immediate postnatal period. Thus we aimed to determine whether the hypoxia-inducible transcription factors (HIF-1 and HIF-2) and/or their target genes in the placenta represent reliable indicators of hypoxic distress of the developing brain during systemic hypoxia at the end of gestation. To this end, pregnant mice were exposed to systemic hypoxia (inspired O2 fraction: 6%, 6 h) at gestational day 20. This hypoxic exposure significantly increased HIF-1alpha and HIF-2alpha protein levels in brain and placental tissue. Compared with normoxic controls, an increase of HIF-1alpha-immunoreactive neurons and HIF-2alpha-positive glial cells and vascular endothelial cells was observed in hypoxic cerebral cortex and hippocampus. In placenta, HIF-1alpha and HIF-2alpha were expressed in labyrinthine layer with increased staining intensity during hypoxia compared with normoxia. Significant upregulation of VEGF mRNA and protein in brain and placenta, as well as erythropoietin protein in placenta, indicated activity of the HIF system upon fetal hypoxia. Notably, hypoxia did not affect expression of the HIF target genes inducible nitric oxide synthase and GLUT-1. Taken together, at gestational day 20, systemic hypoxia led to upregulation of HIF-alpha in mouse brain that was temporally paralleled in placenta, implying that alpha-subunits of both HIF-1 and HIF-2 are indeed early markers of hypoxic distress in vivo. If our data reflect the situation in humans, analysis of the placenta will allow early identification of the hypoxic brain distress occurring near birth.

Topics: Acute Disease; Animals; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Brain; Erythropoietin; Female; Fetal Hypoxia; Gene Expression Regulation; Gestational Age; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia, Brain; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Placenta; Pregnancy; Protein Stability; RNA, Messenger; Severity of Illness Index; Up-Regulation; Vascular Endothelial Growth Factor A

To evaluate the possible association between prenatal buprenorphine exposure and compromised early neonatal outcome in view of markers of perinatal hypoxia. DESIGN, SETTING AND SAMPLE: The study group consisted of 27 full-term neonates exposed to buprenorphine prenatally and prospectively followed up at a special tertiary outpatient clinic for pregnant drug abusers. Serving as controls were 27 full-term neonates exposed prenatally to illicit substances other than opioids and 38 full-term neonates from uncomplicated pregnancies of healthy parturients.. Apgar scores, cord pH and base excess were recorded. Cord serum samples were collected at birth for analysis of biochemical markers of fetal hypoxic stress: erythropoietin (EPO; chronic hypoxia), cardiac troponin T (cardiac involvement) and S100 (neural damage).. All infants were born in good condition according to Apgar scores and pH of cord blood. No statistically significant differences were found between the three groups in cord serum concentrations of EPO (33.0 median, range: 9.0-476.0 U/L in the buprenorphine-exposed group vs 27.0, range: 8.0-114.0 U/L in substance-abusing controls vs 28.1, range: 11.6-260.0 U/L in healthy controls) or S100 (0.47, range: 0.25-0.91 microg/L vs 0.40, range: 0.12-1.22 microg/L vs 0.47, range: 0.20-2.15 microg/L). No significant differences existed in cardiac TnT levels (0.017, range: 0.010-0.072 U/L vs 0.010, range: 0.010-0.075 U/L vs 0.024, range: 0.010-0.075 U/L).. While no significant differences in asphyxia markers were observed between the three groups, a tendency towards higher levels of EPO emerged in the buprenorphine-exposed group.

Topics: Acid-Base Equilibrium; Adolescent; Adult; Apgar Score; Biomarkers; Buprenorphine; Case-Control Studies; Dose-Response Relationship, Drug; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Follow-Up Studies; Humans; Infant, Newborn; Narcotics; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Prospective Studies; S100 Proteins; Troponin T; Young Adult

Previous studies have established the association between fetal hypoxia and elevated nucleated red blood cells (NRBCs). Animal studies have demonstrated that a rise in plasma erythropoietin (EPO) is not detectable until 4 to 6 hours after the initiation of hypoxia. In contrast, interleukin-6 (IL-6) has the capacity to directly induce erythroid maturation. Therefore, we set forth to evaluate the role of EPO and IL-6 as potential mediators of elevated fetal NRBCs in response to acute hypoxia.. Low-risk pregnancies with a normal fetal heart rate at admission to labor and delivery were eligible for participation. Deliveries for "nonreassuring fetal status" comprised the study group. All other deliveries served as controls. Umbilical cord blood was prospectively collected for blood gas analysis, NRBC counts, EPO, and IL-6.. One hundred women participated in the study. Nonparametric univariate analysis demonstrated a significant association between elevated NRBC counts and Apgar scores, arterial cord blood pH, base excess, EPO, and IL-6 levels (all P values <.01). Stepwise regression analysis identified only pH, IL-6, and EPO as independent variables associated with elevated NRBC counts at birth (all P values <.0001 with R2 of 0.27, 0.42, and 0.46, respectively). A significant increase in NRBC counts was noted in study patients. IL-6 was significantly increased in study patients, whereas there was no difference in EPO between groups.. The fact that NRBC counts were elevated in fetuses who were delivered for "nonreassuring fetal status" with EPO being normal and IL-6 being elevated implies that IL-6 may have a unique, short-term role in elevating fetal NRBC counts.

Topics: Apgar Score; Arteries; Case-Control Studies; Erythroblasts; Erythrocyte Count; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Interleukin-6; Parturition; Pregnancy; Regression Analysis

To determine if prenatally measured cardiac troponin T in the amniotic fluid (Am-TnT) could be used as a marker of fetal myocardial hypoxia and necrosis in pathological pregnancy characterized by increased concentration of amniotic fluid erythropoietin (Am-EPO) as a sign of chronic fetal hypoxia.. We measured Am-TnT and Am-EPO in 29 pathological and 5 uncomplicated pregnancies. Samples of amniotic fluid were collected prospectively during elective amniocentesis (n=15), cesarean sections (n=17), and before elective induction of labor in two pregnancies with stillbirth. Am-TnT and Am-EPO were determined by chemiluminescent immunological method.. Am-TnT was undetectable in normal pregnancies, but it was detectable in 9 of 29 amniotic fluid samples from pathological pregnancies, with a median value of 0.030 microg/L (range, 0.010-111.6 microg/L). Am-EPO values were above normal values (>11 U/L) in all pathological pregnancies. Am-EPO concentration showed positive correlation with the Am-TnT concentration (r=0.526, P=0.003). Median concentration of Am-EPO in 9 pregnancies with detectable Am-TnT was 198 U/L (range, 16-3,378 U/L). In 20 pathologic pregnancies with undetectable Am-TnT, the median concentration of Am-EPO was 39 U/L (range, 12-293 U/L). There was no statistically significant difference between the groups (P=0.051).. Am-TnT is measurable in some pathological pregnancies with signs of fetal chronic hypoxia and myocardial involvement and could be potentially used as a biochemical marker of fetal myocardial injury.

Topics: Amniocentesis; Amniotic Fluid; Biomarkers; Cardiomyopathy, Hypertrophic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Humans; Pregnancy; Prospective Studies; Troponin T

Topics: Amniocentesis; Amniotic Fluid; Chronic Disease; Erythropoietin; Fetal Hypoxia; Humans; Immunoassay; Troponin I; Troponin T

Maternal diabetes increases the risk of intrauterine hypoxia. Inflammation may play a role in the pathogenesis of hypoxia-related neonatal complications. We studied correlations between levels of cord serum C-reactive protein (CRP), measured by a highly sensitive immunofluorometric assay, and indices of fetal hypoxia in diabetic pregnancies. Cord serum CRP correlated positively with amniotic fluid erythropoietin and umbilical artery pCO2. A negative correlation existed between cord serum CRP and umbilical artery pH and pO2. Amniotic fluid erythropoietin showed an independent effect on cord serum CRP in multiple regression analysis. These data suggest that the fetus responds to hypoxia by an inflammatory reaction.

Topics: Adult; Amniotic Fluid; Body Mass Index; C-Reactive Protein; Carbon Dioxide; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Fluoroimmunoassay; Humans; Hydrogen-Ion Concentration; Inflammation; Oxygen; Pregnancy; Pregnancy in Diabetics; Regression Analysis; Umbilical Arteries

Animal and human studies demonstrated elevated erythropoietin (EPO) levels in response to intrauterine hypoxic events. Other studies documented an association between fetal hypoxia and elevated nucleated red blood cell (NRBC) counts and have speculated that it is the elevation of EPO that results in an increase in NRBC counts. Thus, the purpose of our study was to determine the correlation between EPO levels and NRBC counts in the human fetus.. Data were collected prospectively between April and July of 2003. Term singleton pregnancies were eligible to participate in the study. Umbilical cord blood was collected immediately after birth for determination of fetal EPO levels and NRBC counts.. Forty pregnancies formed the study population. The mean gestational age at delivery was 39.5 +/- 1.2 weeks (+/-SD) and the mean birth weight was 3500 +/- 372 g. The median EPO (mU/mL) was 34 (range 13-427). The median NRBC/100 white blood cells was 10 (range 0-150). A simple regression analysis indicated that NRBC counts are significantly and positively correlated with EPO (P=.0004, R(2)=0.287).. Our results suggest a significant association between EPO and NRBC counts in term singleton fetuses. These results support the hypothesis that fetal NRBC and EPO are interrelated. However, the relatively low R(2) indicates that there are other (yet to be determined) hypoxia-derived mediators that result in an elevation of fetal NRBC counts.

Topics: Adult; Biomarkers; Birth Weight; Erythroblasts; Erythrocyte Count; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Infant, Newborn; Postpartum Period; Predictive Value of Tests; Pregnancy; Probability; Prospective Studies; Regression Analysis; Sampling Studies; Sensitivity and Specificity

The purpose of the present study was to compare fetal and neonatal outcomes with amniotic fluid erythropoietin (EPO) levels obtained in the antepartum period in pregnancies complicated by preeclampsia, pregnancy-induced hypertension or chronic hypertension.. Erythropoietin concentrations were measured in amniotic fluid within 2 days before delivery and in cord blood at birth in 75 hypertensive women and in 23 healthy controls delivered by cesarean section before labor contractions. Erythropoietin levels did not influence clinical decisions.. Amniotic fluid erythropoietin levels correlated highly significantly with cord plasma EPO levels and were significantly higher in pregnancies complicated by hypertension than in control pregnancies. Umbilical arterial pH, acid-base and blood gas values at birth were not different from controls. Both cord plasma and amniotic fluid erythropoietin levels correlated with cord blood pH, acid-base and blood gas values at birth in the study group. Newborn infants admitted to the newborn intensive care unit had significantly higher fetal erythropoietin levels and were more acidotic, hypoxemic and hypoglycemic than infants admitted to the normal care nursery.. Our findings suggest that elevated amniotic fluid erythropoietin levels are markers of chronic or subchronic fetal hypoxia and are associated with neonatal morbidity in pregnancies complicated by hypertension.

Topics: Adult; Amniotic Fluid; Biomarkers; Case-Control Studies; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; ROC Curve

Our data in rats suggest that an elevated amniotic fluid erythropoietin (EPO) level at birth indicates antepartum fetal hypoxia. However, the short gestation period in rats does not permit a direct comparison of our data with humans.. We conducted a retrospective study of the relationship between EPO levels at birth and abnormal fetal heart rate (FHR) records in 113 infants.. Among the cesarean section group, the cord serum and amniotic fluid EPO levels in the infants with antepartum abnormal FHR records were significantly higher than those in the control infants. Among the vaginal delivery group, the cord serum EPO levels in the infants with intrapartum abnormal FHR records was significantly higher than that in the control infants. The EPO levels in either cord serum and amniotic fluid discriminated between infants with antepartum abnormal FHR records. The control infants had a sensitivity of 83% and a specificity of 96%. Six of the seven infants with abnormal EPO levels in both cord serum and amniotic fluid had symptoms of prolonged fetal hypoxia. Five infants with abnormal EPO levels in only cord serum had symptoms of acute fetal hypoxia before birth. Four of the 14 infants with abnormal EPO levels at birth had poor outcomes in the neonatal period.. We concluded that EPO levels in both cord serum and amniotic fluid at birth are valuable for determining the timing of fetal hypoxia and may predict the outcome in the neonatal period.

Topics: Amniotic Fluid; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Heart Rate, Fetal; Humans; Pregnancy; Retrospective Studies; Sensitivity and Specificity

We have examined whether endothelin-1 (ET-1) and erythropoietin (EPO) in amniotic fluid, and EPO in fetal serum obtained by cordocentesis from fetuses with signs of intrauterine growth retardation (IUGR), were correlated to fetal growth and/or chronic fetal hypoxia.. Amniotic fluid and fetal serum were obtained by cordocentesis from 28 fetuses suspected to have IUGR and subsequently analyzed for EPO and ET-1 by ELISA. These data were correlated to blood gas results and fetal/maternal parameters at delivery.. A novel finding was that ET-1 correlated to PO2 in amniotic fluid. The average level of ET-1 in amniotic fluid was 48.3+/-4.7 pmol/L. The results also showed a correlation between EPO levels in amniotic fluid and EPO in fetal serum. Furthermore, EPO correlated weakly to birth weight at delivery. Children with the lowest birth weights had the highest EPO levels. High EPO values, similarly to ET-1, correlated to low pO2 values. The level of EPO in amniotic fluid was 8.0+/-1.6 mIU/ml and in cord blood 29.5+/-9.6 mIU/ml.. The results indicate that ET-1 levels may be a marker for short-term hypoxia, but not for fetal growth, since ET-1 in amniotic fluid was correlated to PO2 at the time of cordocentesis, but not to birth weight. The results also indicate that EPO levels in amniotic fluid and in fetal cord serum are highly correlated, and thus both can be used as markers for fetal growth and chronic hypoxia before the onset of labor.

Topics: Adult; Amniotic Fluid; Biomarkers; Blood Gas Analysis; Embryonic and Fetal Development; Endothelin-1; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Humans; Pregnancy

The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus.. We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 +/- 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic.. The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5-135.1 vs median 16.2; range, 3.7-52.2 micrograms/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = -0.440, p = 0.032), and pH (r = -0.414, p = 0.040).. Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia.

Topics: Amniotic Fluid; Birth Weight; Body Constitution; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy in Diabetics; Reference Values; Regression Analysis

We sought to determine whether umbilical cord plasma erythropoietin levels were different in deliveries complicated by meconium passage and to determine whether this response is influenced by gestational age.. Fetal erythropoietin levels were measured in 203 appropriately grown neonates at 37 to 43 weeks of gestation; among those, 70 had passed meconium.. Meconium passage in the entire population was associated with elevated fetal erythropoietin levels (68 vs 31 mIU/mL; P <.001). Cord blood gases, pH, base deficit, and PO (2), as well as the 1- and 5-minute Apgar scores, were not different between the meconium and no-meconium groups. Gestational age and birth weights were significantly higher in the meconium group. Stepwise multiple regression analysis with meconium and gestational age used as the independent variables showed both meconium and gestational age to be independently associated with fetal erythropoietin levels (r = 0.356, F = 14.5; meconium, P <.001; gestational age, P <.01).. These results suggest that meconium passage can be associated with chronic fetal hypoxia as demonstrated by elevated fetal erythropoietin levels, independent of gestational age.

Topics: Apgar Score; Birth Weight; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Logistic Models; Meconium; Odds Ratio; Oxygen; Pregnancy; Regression Analysis

Our goal was to determine whether maternal smoking was associated with elevated umbilical cord erythropoietin, a marker for chronic hypoxia.. Plasma erythropoietin levels were measured in umbilical cord plasma of 222 newborns. There were 48 mothers who smoked and 174 nonsmokers.. When all pregnancies were included, mean cord plasma erythropoietin levels were significantly higher in the smokers (78.0 +/- 15.3 mIU/ml) compared with the nonsmoking group (35.2 +/- 4.0 mIU/ml; p < 0.005). Regression analysis showed a significant positive correlation between the number of cigarettes smoked per day and cord plasma erythropoietin levels (r = 0.26, p < 0.0001). Smoking was associated with a significantly elevated risk (relative risk = 2.6, 95% confidence interval 1.7 to 10.9, p < 0.005) of fetal growth restriction. When pregnancies with fetal growth restriction were excluded from the analysis, the difference between the two groups remained significant (smokers 81.3 +/- 18.6, n = 38; nonsmokers 24.3 +/- 1.4, n = 164; p < 0.03).. These results illustrate that smoking during pregnancy is associated with fetal growth restriction and significantly elevated umbilical cord erythropoietin levels.

Topics: Adolescent; Adult; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Fetal Hypoxia; Humans; Infant, Newborn; Male; Maternal Age; Pregnancy; Pregnancy Complications; Risk Factors; Smoking; Statistics as Topic

To determinate the erythropoietin concentration in amniotic fluid in normal pregnancies and pregnancies with suspected hypoxia.. The erythropoietin concentration of 164 samples of amniotic fluid was determined by ELISA. The samples were taken by amniotomy during birth, as well as amniocentesis conducted during prenatal care.. A distribution of 1.07-7.29 U/l (10th-90th percentile) within the normal group (n = 106) was determined. Significantly elevated erythropoietin levels in amniotic fluid were determined in maternal hypertension (P = 0.039) and low birth-weight children (P = 0.0032). A correlation with the child's sex could be excluded.. Elevated erythropoietin levels in amniotic fluid indicated chronic fetal hypoxia.

Topics: Adolescent; Adult; Amniotic Fluid; Biomarkers; Chronic Disease; Erythropoietin; Female; Fetal Hypoxia; Humans; Pregnancy; Prenatal Diagnosis; Risk Factors

To determine if diabetes and preeclampsia are independent stimulators of erythropoietin, distinct from hypoxia, we measured umbilical cord plasma erythropoietin in 239 deliveries from 24 to 40 weeks of gestation. Mean plasma erythropoietin levels were not different between normal, diabetic, and preeclamptic women when all deliveries were analyzed. When infants with suspected intrauterine hypoxia were excluded, the mean erythropoietin level was considerably lower within all three groups but there was no difference among the groups. In suspected hypoxia, the mean fetal erythropoietin was elevated, but there was no difference between control, diabetic, or preeclamptic pregnancies. These results provide further support that hypoxia remains the only known stimulator of erythropoietin production in the fetus.

Topics: Erythropoietin; Female; Fetal Hypoxia; Fetus; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics

Topics: Amniocentesis; Amniotic Fluid; Erythropoietin; Female; Fetal Hypoxia; Humans; Hypertension; Infant, Newborn; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Erythropoietin (EPO) levels in amniotic fluid and serum were measured in hypoxic (fraction of inspired oxygen, FiO2, 0.09) and posthypoxic (following a 24-hour period of hypoxia, FiO2 0.09) fetal rats on day 21 of gestation. Each of the study groups comprised 12-20 fetuses. Each of the control groups consisted of 21 or 22 fetuses. Fetal serum EPO levels at 3, 6, 9, 12, and 24 h of hypoxia were significantly higher than the control level. Amniotic fluid EPO levels at 9, 12, and 24 h of hypoxia were also significantly increased compared to the control level. Fetal serum EPO levels returned to baseline during the 12- to 48-hour period after hypoxia. During the 0- to 48-hour posthypoxic period, amniotic fluid EPO levels were significantly higher than the control level. These data demonstrate that rates of appearance and turnover of amniotic fluid EPO are different from those of fetal serum EPO.

Topics: Amniotic Fluid; Animals; Erythropoietin; Female; Fetal Hypoxia; Gestational Age; Pregnancy; Rats; Rats, Sprague-Dawley

Topics: Amniotic Fluid; Biomarkers; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Pregnancy; Sensitivity and Specificity

Prenatal plasma concentrations of erythropoietin in fetuses with Rh disease should contribute information to the clinical course and therapeutic control of this disease.. Fetal plasma erythropoietin (Epo) and haemoglobin (Hb) concentrations were measured in 145 umbilical venous blood samples of 30 fetuses with Rh disease at 20 to 38 weeks' gestation.. Both Epo and Hb concentrations were independent of the gestational age in red blood cell-isoimmunised pregnancies. The Hb concentration correlated significantly with Epo concentration without intrauterine transfusion (IUT) (r = -0.519, p = 0.005) and after IUT (i = -0.212, p = 0.01). A haemoglobin deficit of 3 g/dl at 20 weeks' gestation increased to 6 g/dl at 38 weeks' gestation in spite of IUT (p = -0.354, p < 0.001).. Even with IUT, Epo concentrations increase with gestational age during these pregnancies. This is due to increasing Hb deficits indicating fetal hypoxia which might be prevented by increasing volumes of transfusion.

Topics: Adult; Blood Transfusion, Intrauterine; Erythroblastosis, Fetal; Erythropoietin; Female; Fetal Hypoxia; Gestational Age; Hemoglobinometry; Humans; Infant, Newborn; Pregnancy; Rh Isoimmunization; Ultrasonography, Prenatal

To assess a correlation between the erythropoietin (Epo) level in umbilical blood during delivery and three "classical" markers of hypoxia: the Apgar score, pH in the umbilical artery and lactate concentration.. The above parameters were assessed in 109 deliveries divided into three groups-normal deliveries, deliveries with neonatal pathology at term and premature deliveries.. Based on calculation of Spearman correlations which seemed most suitable with regard to the nature of the experimental data no significant relations were found between Epo and any of the mentioned parameters, while the mutual correlations between the Apgar score, pH of the umbilical artery and lactate were highly significant.. Epo is an independent marker of foetal hypoxia and supplementation of "classical" markers by this examination could be an asset to the evaluation of the prognosis of postnatal development.

Topics: Asphyxia Neonatorum; Biomarkers; Erythropoietin; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Umbilical Arteries

To investigate the concentrations of amniotic fluid erythropoietin in normal and risk pregnancies.. The concentrations of erythropoietin were measured in 150 samples of amniotic fluid. The samples were obtained by amniocentesis and amniotomia and were analysed using an enzyme-linked immunosorbent assay (ELISA). Results were available within 6 hours. The intra-assay variation was 6.4%, the inter-assay variation 7.2%.. The range of erythropoietin concentration in all samples was between 0.23 and 80 U/L and in a defined group of normal pregnancies between 1.20 and 6.53 U/L (10%-90% percentile). Correlation was found between the concentration of erythropoietin and maternal hypertension (p = 0.0159), amnion infection syndrome in combination with premature birth (p = 0.0593), fetal growth retardation (p = 0.784), and base-excess (p = 0.0487). Elevated erythropoietin concentrations were found in a defined risk group with Apgar scores below 7 after 1 minute (p = 0.072) and after 5 minutes (p = 0.0037). There is a connection between postpartal transfer to the intensive-care unit and elevated erythropoietin concentrations (p = 0.073). No influence is exercised by the child's sex on the concentration of erythropoietin. No significant connection was found between the level of erythropoietin and smoking during pregnancy, volume of amniotic fluid and maturity at birth. A critical erythropoietin concentration could be postulated at 12 U/L. Children with higher levels showed heavy and severe disorders.. Elevated erythropoietin levels in amniotic fluid indicate prolonged fetal hypoxaemia. Using the ELISA-technique a rapid prepartal determination of such situations is possible and might be helpful in the clinical procedure.

Topics: Adolescent; Adult; Amniocentesis; Amniotic Fluid; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Pregnancy, High-Risk; Reference Values

To assess the risk for acute and chronic fetal hypoxia in twin pregnancies.. We investigated 50 sets of twins (24-38 weeks' gestation, 660-3200 g birth weight) admitted consecutively to our neonatal intensive care unit. Seventy-six infants were appropriate for gestational age (AGA; tenth to 90th percentile), 20 were small for gestational age (SGA; below the tenth percentile), and four were large for gestational age (above the 90th percentile). Twenty-six singleton AGA term newborns served as controls. Umbilical arterial pH was used as a marker for acute and umbilical venous erythropoietin concentration for chronic fetal hypoxia. The results are given as median followed by quartiles.. We identified 40 sets of diamniotic-dichorionic twins and ten sets of diamniotic-monochorionic twins with transplacental vascular shunts. In the second-born twin, umbilical arterial pH was lower (7.29, 7.23-7.33) than in the firstborn (7.31, 7.25-7.34) (P = .03), and the incidence of a low pH (less than 7.20) was higher (19 versus 11%). Two second-born twins and none of the firstborn twins had an umbilical arterial pH less than 7.05. In SGA twins, the erythropoietin concentration was elevated (34.8, 22.8-325 mU/mL) compared with that in AGA twins (16.2, 8.2-26.6 mU/mL) (P < .01). In AGA twins, erythropoietin concentration did not differ from that in AGA singleton newborns (19.6, 14.7-31.6 mU/mL). In 12 of 17 twin sets with weight discordancy greater than 15% and in all five twin sets with weight difference greater than 25%, erythropoietin concentration was higher in the smaller twin. The proportion of infants and of complete sets with elevated erythropoietin levels was higher (P < .01) in monochorionic than in dichorionic pregnancies.. The second-born twin is at increased risk for acute birth asphyxia. Fetal growth restriction in twin pregnancies is associated with chronic fetal hypoxia. Monochorionic twins are at higher risk for chronic fetal hypoxia than are dichorionic twins.

Topics: Acute Disease; Chronic Disease; Erythropoietin; Fetal Hypoxia; Humans; Infant, Newborn; Infant, Newborn, Diseases; Risk Factors; Twins, Dizygotic; Twins, Monozygotic

To investigate the relation between the biochemical markers of umbilical venous erythropoietin and umbilical arterial pH and morphologic placental abnormalities in fetal hypoxia.. Placentas from 300 high-risk newborn infants (gestational age 24-42 weeks) were examined macroscopically and microscopically following standardized criteria. The morphologic findings were correlated with the erythropoietin concentration in umbilical venous blood and with umbilical arterial pH at birth. Venous hematocrit and circulating nucleated red blood cells were measured in 112 of these infants during the first 6 hours of life.. The umbilical venous erythropoietin concentration correlated significantly (r = 0.74) with the number of circulating nucleated red blood cells. In 26 placentas without morphologic abnormalities, the median (and 25th and 75th percentiles) erythropoietin concentration was 35.2 mU/mL (19.2-48.7) and umbilical arterial pH was 7.30 (7.20-7.33). The erythropoietin concentration was elevated significantly when placental examination showed evidence of acute villous circulatory disturbance (61.3 mU/mL; 24.2-125.1), fetal vasculopathy (85.6 mU/mL; 23.7-119.7), or chorioamnionitis with fetal reaction (51.3 mU/mL; 27.7-118.7). The erythropoietin concentration varied significantly with the stage of placental meconium phagocytosis; it was 62.7 mU/mL (16.3-125.9) if meconium phagocytosis was classified as recent, 128.2 mU/mL (44.4-1483.2) if it was classified as a few hours old, and 66.2 mU/mL (46.3-140.1) if it was classified as a few days old. Umbilical arterial pH was not altered significantly with different morphologic placental abnormalities.. Fetal erythropoietin production is stimulated by hypoxia after a few hours' delay and leads to increased erythropoiesis. Placental examination combined with measurement of umbilical venous erythropoietin and umbilical arterial pH provides information about earlier fetal hypoxia.

Topics: Age Factors; Biomarkers; Blood Gas Analysis; Congenital Abnormalities; Delivery, Obstetric; Erythrocyte Count; Erythropoiesis; Erythropoietin; Evaluation Studies as Topic; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Hematocrit; Humans; Hydrogen-Ion Concentration; Linear Models; Male; Meconium; Phagocytosis; Placenta; Pregnancy; Risk Factors; Time Factors; Umbilical Arteries; Umbilical Veins

1. Fetal sheep at 120 days gestation were fitted with upper and lower body arterial and venous catheters in addition to a flow sensor and occluder placed around the aorta below the renal arteries. 2. After 7 days of recovery, the occluder was partially inflated to reduce aortic blood flow to 70% of control. Blood flow reduction was maintained at this level for the remainder of the experiment. 3. Blood samples were taken after 60 min of blood flow reduction and again after 3 or more days of blood flow reduction. 4. There was no change in upper body arterial or venous blood pressure. Lower body arterial blood pressure decreased, as expected. Arterial PO2 decreased while packed cell volume and haemoglobin concentration increased. There was no change in plasma erythropoietin concentrations or plasma renin activity. 5. While both red cell mass and haemoglobin mass increased during the period of the study, the rate of increase was no different from the rate of blood volume increase.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Blood Volume; Erythrocytes; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Heart Rate; Hematocrit; Hemoglobins; Hypoxia; Pregnancy; Sheep

We have investigated the relationship between erythropoietin (Epo) and pH, PaO2 and haematocrit in 100 cord blood samples obtained at Caesarean section prior to labour. Of 82 term (> 37 weeks) infants, 64 were appropriately grown (10th-90th centiles), and their mean cord serum Epo and cord blood Epo was 23 +/- 8 mU/ml (mean +/- SD). Strong inverse correlations were found between cord serum Epo and cord blood pH (r = -0.74; p < 0.0001), and between cord serum Epo and cord blood PaO2 (r = -0.55; p < 0.0001), but not between cord serum Epo and cord haematocrit (r = 0.02; p < 0.9). For the 18 preterm babies (gestation 32.4 +/- 4.1 weeks, birth weight 1,820 +/- 476 g), the Epo level was 36 +/- 8 mU/ml, which was not significantly greater than for the term babies. Strong inverse correlations were again found between Epo and pH (r = -0.87; p < 0.0001) and Epo and PaO2 (r = -0.69; p < 0.002). Babies from complicated pregnancies (intra-uterine growth retardation, pre-eclampsia, antepartum haemorrhage, diabetes mellitus and fetal distress) tended to have higher Epo levels. Thirteen babies had Epo levels > 40 mU/ml, and 11 (85%) of these required neonatal intensive care. Cord serum Epo correlates better with oxygen tension and pH at birth than with fetal growth and haematocrit, which are measures of chronic stress to the fetus.

Topics: Cesarean Section; Cordocentesis; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Distress; Fetal Growth Retardation; Fetal Hypoxia; Hematocrit; Humans; Hydrogen-Ion Concentration; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Oxygen; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Uterine Hemorrhage

Chronic fetal hypoxemia stimulates erythropoiesis and may result in a redistribution of fetal iron from plasma into erythrocytes. We studied the response of fetal plasma erythropoietin (Ep) to hypoxemia, the role of Ep in stimulating erythropoiesis in utero, and the effect of augmented erythropoiesis on fetal plasma Ep and iron and tissue cytochrome c concentrations in 19 chronically instrumented late-gestation fetal sheep. The fetuses were stimulated to produce 28 erythropoietic responses after exposure to 1) acute hypoxemia (1-5 days), 2) chronic hypoxemia (greater than 7 days), and/or 3) administration of 1,500 U recombinant human Ep concurrently during normoxemia. Plasma Ep peaked less than 12 h after the onset of hypoxemia or Ep bolus. Plasma iron decreased 24-48 h later and returned to baseline 48-96 h after normalization of Ep levels to baseline. The plasma iron response was directly related to the erythropoietin stimulus (r = 0.79, P less than 0.001) and inversely related to liver iron concentration at death (r = -0.84, P less than 0.001). Nine fetuses with depleted liver iron concentrations at autopsy had significantly lower heart and skeletal muscle iron concentrations compared with animals with 10% of control liver iron remaining. Skeletal muscle and heart iron and cytochrome c concentrations were significantly correlated. Ep has a potent biological effect on fetal erythropoiesis and iron metabolism. Augmented fetal erythropoiesis, mediated by Ep, results in decreased plasma iron, hepatic storage iron, and skeletal and cardiac muscle iron and cytochrome c. The model potentially explains the iron abnormalities found in newborn infants after fetal hypoxia.

Topics: Animals; Brain; Cytochrome c Group; Erythropoietin; Female; Fetal Hypoxia; Heart; Hemoglobins; Iron; Liver; Muscles; Myocardium; Oxygen; Pregnancy; Recombinant Proteins; Sheep

A sensitive assay was used to compare the biological activity of cord serum erythropoietin in two groups of infants born with or without labor-induced hypoxia. The mean cord serum erythropoietin activity in 161 infants delivered after vaginal labor was 116 +/- 36 mU/mL, and was indistinguishable from that observed in 23 infants delivered by preplanned, elective cesarean section, 114 +/- 12 mU/mL (P = .75). The bioassay measured effective erythropoietin activity, including the contribution of potentiators in serum. These results indicate that duration and intensity of labor are insufficient to cause a significant increase in effective erythropoietin activity.

Topics: Cesarean Section; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Infant, Newborn; Labor, Obstetric; Pregnancy; Stress, Physiological

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.

Topics: Acidosis; Apgar Score; Asphyxia Neonatorum; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Polycythemia; Pre-Eclampsia; Pregnancy; Time Factors

Acute hypoxemia was produced in chronically catheterized sheep fetuses to determine the response time necessary to increase plasma immunoreactive erythropoietin (Ep) concentration. Sodium nitrite (0.2 mM) was infused via a fetal vein to induce fetal hypoxemia. The resultant fetal methemoglobinemia was associated with a predictable, incremental decrease in arterial oxygen content. Twelve nitrite infusions were performed in eight fetal sheep preparations (gestational ages 115-146 days). Mean methemoglobin level increased to 33% of total Hb after 1-2 h of NaNO2 infusion. These results were compared to those obtained in nine control studies in eight fetuses in which no change was observed for plasma Ep, arterial oxygen content, PaO2, pHa, or whole blood lactate. In the nitrite infused group, however, a significant and progressive increase in mean plasma Ep level over baseline levels was observed during the 4th and 5th h of hypoxemia (p less than 0.01). This change in Ep was significantly greater compared to the control group. These results, however, were confounded by the concomitant development of a lactic acidemia secondary to the fetal hypoxemia. To examine the theoretic possibility that lactic acidemia may primarily affect fetal Ep levels, an additional group of five fetuses was infused with L-lactic acid for the same time period. Although the decrements in pHa and whole blood lactate levels achieved in these fetuses were in excess of those observed during the nitrite infusions, this possibility was ruled out since no change in fetal plasma Ep levels occurred. We conclude that during the 4th h of acute fetal hypoxemia a predictable, progressive increase in plasma Ep level is observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animals; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Hemodynamics; Lactates; Lactic Acid; Methemoglobinemia; Oxygen; Pregnancy; Radioimmunoassay; Sheep; Sodium Nitrite

Nonhuman primate models of gestational diabetes have produced fetopathies most similar to those of the human infant of the mother with gestational diabetes (IGDM). Fetal hyperglycemia, hyperinsulinemia, macrosomia, selective organomegaly, intrauterine death, and placental hyperplasia are hallmarks of the fetopathy of the IGDM. The chronic infusion of insulin into the fetus of a normal pregnant rhesus monkey results in fetal hyperinsulinemia with normal to low plasma metabolic substrate concentrations. Under these conditions, fetal hyperinsulinemia is sufficient to cause fetal growth and hormone changes observed in the human IGDM. Our studies provide evidence that the soft tissue hyperplasia in the fetal macrosomia syndromes in humans and nonhuman primates in which fetal hyperinsulinemia is observed is the direct result of that chronic in utero hyperinsulinemia.

Topics: Adipose Tissue; Amino Acids; Animals; Birth Weight; Blood Glucose; C-Peptide; Disease Models, Animal; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Fetus; Glucagon; Hydrocortisone; Insulin; Macaca mulatta; Pregnancy; Pregnancy in Diabetics

Topics: Erythropoiesis; Erythropoietin; Female; Fetal Hypoxia; Fetus; Humans; Infant, Newborn; Pregnancy

Since several hours of hypoxemia in fetal animals is sufficient to cause an increase in the plasma erythropoietin level and since labor may be associated with fetal hypoxemia, this study was undertaken to determine if erythropoietin levels in cord blood were higher in fetuses subjected to labor. Two groups of term (37 to 41 weeks) singleton pregnancies were compared: (1) those delivered by elective repeat cesarean section without prior labor (n = 18) and (2) those delivered vaginally (n = 23). Erythropoietin was measured by a radioimmunoassay in which a highly purified human erythropoietin (70,000 U/mg of protein) was used and which has a sensitivity limit of 4 to 5 mU/ml. The mean cord serum erythropoietin level was higher in pregnancies with labor (46 +/- 34 mU/ml, mean +/- SD) compared to those without (26 +/- 10, p less than 0.02). There were no differences between the two groups for maternal age, gestational age, birth weight, infant sex, or Apgar scores. No association of erythropoietin with either gestational age or sex was found. In 11 pregnancies without labor, comparisons were made among simultaneously obtained samples of umbilical arterial plasma, umbilical venous plasma, and mixed cord serum. Although there were no differences between umbilical arterial and umbilical venous plasma erythropoietin levels (21.3 +/- 9.3 versus 19.0 +/- 7.8 mU/ml), mixed cord serum was inexplicably higher (24.4 +/- 9.5 mU/ml, p less than 0.01). We concluded that in uncomplicated pregnancies the duration and intensity of labor are sufficient to cause an increase in the fetal erythropoietin level at delivery.

Topics: Adolescent; Adult; Apgar Score; Birth Weight; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Infant, Newborn; Labor, Obstetric; Male; Pregnancy; Radioimmunoassay

Using a fetal rat liver cell bioassay, serum erythropoietic activity was tested in non-suckled newborn rats comparatively to 21-day-old rat fetuses at time 0 or after 2 h of surviving. The number of erythroid colonies (CFUe) is significantly greater in cultures with neonatal and fetal rat serum after 2 h of surviving than in cultures with fetal rat serum sampled at time 0. These results suggest a release of erythropoietin or erythropoietin-like substances in response to a short hypoxic phase following the parting of the fetus with the mother and preceding the autonomous oxygenation of the newborn by breathing.

Topics: Animals; Animals, Newborn; Biological Assay; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Fetus; Liver; Pregnancy; Rats; Rats, Inbred Strains