losartan-potassium and Fetal-Growth-Retardation

Oxidative stress is responsible for microvascular complications (hypertension, nephropathy, retinopathy, peripheral neuropathy) of diabetes, which during pregnancy increase both maternal and fetal complications. Chronic hypoxia and hyperglycemia result in increased oxidative stress and decreased antioxidant enzyme activity. However, oxidative stress induces also anti-oxidative reactions both in pregnant diabetes patients and in their fetuses. Not all type 1 diabetes patients with long-lasting disease develop microvascular complications, which suggests that some of these patients have protective mechanisms against these complications. Fetal erythropoietin (EPO) is the main regulator of red cell production in the mother and in the fetus, but it has also protective effects in various maternal and fetal tissues. This dual effect of EPO is based on EPO receptor (EPO-R) isoforms, which differ structurally and functionally from the hematopoietic EPO-R isoform. The tissue protective effects of EPO are based on its anti-apoptotic, anti-oxidative, anti-inflammatory, cell proliferative and angiogenic properties. Recent experimental and clinical studies have shown that EPO has also positive metabolic effects on hyperglycemia and diabetes, although these have not yet been fully delineated. Whether the tissue protective and metabolic effects of EPO could have clinical benefits, are important topics for future research in diabetic pregnancies.

Topics: Erythropoiesis; Erythropoietin; Female; Fetal Growth Retardation; Fetus; Humans; Hypoxia; Infant, Newborn; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Reactive Oxygen Species; Receptors, Erythropoietin

Iron sufficiency is critical for rapidly developing fetal and neonatal organ systems. The majority of iron in the third trimester fetus and the neonate is found in the red cell mass (as hemoglobin), with lesser amounts in the tissues as storage iron (e.g. ferritin) or functional iron (e.g. myoglobin, cytochromes). Iron is prioritized to hemoglobin synthesis in red cells when iron supply does not meet iron demand. Thus, non-heme tissues such as the skeletal muscle, heart and brain will become iron deficient before signs of iron-deficiency anemia. Gestational conditions that result in lower newborn iron stores include severe maternal iron deficiency, maternal hypertension with intrauterine growth retardation and maternal diabetes mellitus. Stable, very low birthweight premature infants are also at risk for early postnatal iron deficiency because they accrete less iron during gestation, grow more rapidly postnatally, are typically undertreated with enteral iron and receive fewer red cell transfusions. Conversely, iron overload remains a significant concern in multiply transfused sick preterm infants because they have low levels of iron-binding proteins and immature antioxidant systems.. The highly variable iron status of preterm infants combined with their risk for iron deficiency and toxicity warrants careful monitoring and support in the newborn and postdischarge periods.

Topics: Anemia, Iron-Deficiency; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Female; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Iron Compounds; Iron Metabolism Disorders; Iron Overload; Maternal-Fetal Exchange; Perinatology; Pregnancy; Recombinant Proteins; Risk Assessment; Risk Factors; Severity of Illness Index

Topics: Androgens; Animals; Erythropoietin; Female; Fetal Growth Retardation; Fetus; Growth Substances; Hormones; Humans; Insulin; Nerve Growth Factors; Peptides; Pregnancy; Receptors, Cell Surface; Somatomedins; Thyroid Hormones; Transforming Growth Factors; Vitamin D

This study was undertaken to determine the efficacy and safety of intravenously administered iron sucrose with versus without adjuvant recombinant human erythropoietin in the treatment of gestational iron-deficiency anemia resistant to therapy with orally administered iron alone.. Forty patients with gestational iron-deficiency anemia were randomly assigned to receive intravenously iron sucrose plus recombinant human erythropoietin or iron sucrose alone twice weekly. Target hemoglobin value was 11.0 g/dL. Efficacy measures were reticulocyte count, increase in hematocrit, and time to target hemoglobin level (treatment duration in weeks and need for continued therapy after 4 weeks).. Both regimens were effective, but with adjuvant recombinant human erythropoietin the reticulocyte counts were higher from day 4 (P<.01), increases in hematocrit were greater from day 11 (P <.01), and the median duration of therapy was shorter (18 vs 25 days), with more patients reaching the target hemoglobin level by 4 weeks of treatment (n = 19 vs. n = 15). The groups did not differ with respect to maternal-fetal safety parameters.. Adjuvant recombinant human erythropoietin safely enhanced the efficacy of iron sucrose in the treatment of gestational iron-deficiency anemia resistant to orally administered iron alone.

Topics: Anemia, Iron-Deficiency; Erythrocyte Count; Erythrocyte Indices; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Fetal Growth Retardation; Glucaric Acid; Hematocrit; Humans; Placental Insufficiency; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Recombinant Proteins; Reticulocyte Count; Transferrin; Treatment Outcome; Ultrasonography

To investigate the toxic effect of tobacco smoke on the fetus, we measured in cord blood the concentrations of alpha-fetoprotein (AFP), the principal serum protein in early ontogenic development, and erythropoietin (EPO), as an index of chronic fetal hypoxia. A total of 103 consecutively enrolled term newborns of smoking mothers and 103 term infants of nonsmoking parents were studied. The mean +/- SD AFP concentrations in the newborns of the mothers who smoked 1-50, 5-50, and 10-50 cigarettes/day were 86.4 +/- 88.9, 96.3 +/- 91.9 and 118.7 +/- 103.7 ng/ml, respectively. The difference of all three groups from the control neonates (57.7 +/- 37.2) was significant. The EPO concentrations in the newborns of the mothers who smoked 1-50 (53.9 +/- 64.6 mU/ml) and 5-50 (56.3 +/- 68.5) cigarettes/day were significantly greater than in the control neonates (29.5 +/- 16.1). In the newborns of the smoking mothers there was a significant positive correlation between AFP concentrations and number of cigarettes smoked per day, and a negative correlation between AFP and birth weight or length. There was no correlation between AFP and EPO concentrations, as well as between EPO and birth weight, length or number of cigarettes smoked per day.. The absence of a correlation between erythropoietin and birth weight or length and the negative correlations between alpha-fetoprotein and these anthropometric parameters suggest that the intra-uterine growth retardation caused by maternal smoking is not due to tissue hypoxia, but that both growth retardation and elevated alpha-fetoprotein result from the direct or indirect toxic effect of a factor(s) present in tobacco smoke.

Topics: alpha-Fetoproteins; Analysis of Variance; Birth Weight; Body Height; Embryonic and Fetal Development; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Reference Values; Smoking

Topics: Animals; Cell Culture Techniques; Disease Models, Animal; Erythropoietin; Fetal Growth Retardation; Fetal Weight; Fetus; Hep G2 Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; In Vitro Techniques; Insulin-Like Growth Factor Binding Protein 1; Mechanistic Target of Rapamycin Complex 1; Microscopy, Fluorescence; Organ Size; Papio; Phosphorylation; Protein Kinase C-alpha; Receptors, Erythropoietin; Transcription Factors; Vascular Endothelial Growth Factor A

We previously reported that fetal plasma erythropoietin (EPO) concentrations are significantly increased in growth-restricted fetuses with abnormal umbilical artery (UA) Doppler. During hypoxia in an ovine model, the primary site of fetal EPO synthesis was switched from the kidneys to the placenta. Therefore, we designed this study to evaluate human placental EPO gene expression and the correlation to fetal serum EPO concentration in growth-restricted fetuses in a monochorionic (MC) twin model.. In MC twin pairs, selective intrauterine growth restriction (sIUGR) was defined as the presence of (i) birth weight discordance of > 20% and (ii) a smaller twin with a birth weight less than the 10th percentile. Fetal UA and middle cerebral artery (MCA) Doppler were checked within 1 week before delivery. An abnormal UA Doppler was defined as persistently absent or reverse end-diastolic flow. Cerebroplacental ratio (CPR) was defined as MCA-pulsatility index (PI)/UA-PI. Fetal plasma EPO concentrations were measured in cord blood, and EPO gene expression was assayed in each twin's placental territory. The intertwin plasma EPO ratio was calculated as the cord plasma EPO level of the smaller (or sIUGR) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin, and the intertwin placental EPO gene expression ratio was calculated similarly.. Twenty-six MC twins were analyzed, including normal twins (Group 1, n = 9), twins with sIUGR without UA Doppler abnormalities (Group 2, n = 9), and twins with sIUGR and UA Doppler abnormalities (Group 3, n = 8). The CPRs of smaller (sIUGR) fetuses were significantly decreased in Group 3 MC twins (p < 0.001), but not significantly different between Group 1 and Group 2. The highest fetal plasma EPO ratio and placental EPO gene expression ratio were identified in Group 3 MC twins (p < 0.001). The placental EPO gene expression ratios were significantly correlated with the fetal plasma EPO ratios (Pearson's correlation test, p = 0.004).. This study provides evidence of increased placental EPO expression in MC twin fetuses with sIUGR and abnormal UA Doppler. Future studies are needed to confirm the similar role of placental EPO in severe IUGR singletons.

Topics: Case-Control Studies; Chorion; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Gene Expression; Humans; Infant, Newborn; Male; Middle Cerebral Artery; Placenta; Pregnancy; Pulsatile Flow; Twins; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries

BackgroundWe determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney, and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and vascular endothelial growth factor (VEGF) protein levels, and for HP-1 immunoreactivity (IR).ResultsFGR-MNR fetuses were 36% smaller with asymmetrical growth restriction compared to controls. EPO and VEGF protein levels were increased in the female FGR-MNR fetuses, providing support for hypoxic stimulus and linkage to increased erythropoiesis, but not in the male FGR-MNR fetuses, possibly reflecting a weaker link between oxygenation and erythropoiesis. HP-1 IR was increased in the liver and kidneys of both male and female FGR-MNR fetuses as an index of local tissue hypoxia, but with no changes in the placenta.ConclusionChronic hypoxia is likely to be an important signaling mechanism for the decreased fetal growth seen with maternal undernutrition and appears to be post-placental in nature.

Topics: Animals; Cohort Studies; Erythropoietin; Female; Fetal Development; Fetal Growth Retardation; Guinea Pigs; Hypoxia; Immunohistochemistry; Male; Maternal Nutritional Physiological Phenomena; Maternal-Fetal Exchange; Nitroimidazoles; Placenta; Pregnancy; Signal Transduction; Vascular Endothelial Growth Factor A

Erythropoietin seems to play an important role in the regulation of fetal hypoxemia. The present prospective study was designed to determine if changes in erythropoietin levels can be found in fetuses with severe early-onset growth restriction and hemodynamic compromise.. Erythropoietin, hemoglobin, hematocrit, platelet counts, normoblasts, lacate, arterial and venous blood gasses in the umbilical cord were determined in 42 fetuses with fetal growth restriction (IUGR) with absent (zero-flow) and 26 IUGR fetuses with retrograde end-diastolic flow (reverse-flow) in the umbilical artery. Color Doppler measurements were performed on the middle cerebral artery (PI) and ductus venosus [(S-a)/D and (S-a)/Vmean]. Erythropoietin concentrations were significantly lower in the zero-flow group (median: 128.0 mU/mL; range: 60.3-213 mU/mL) compared with the reverse-flow group (median: 202.5 mU/mL; range: 166-1182 mU/mL). Significant differences in median lactate concentrations were observed between the zero-flow group: 3.28 mmol/L (range; 2.3-4.7 mmol/L), and reverse-flow group: 5.6 mmol/L (range: 3.8-7.5 mmol/L). Fetuses with reverse-flow had significantly lower median platelet counts than fetuses with zero-flow (74 vs. 155/μL) and significantly lower normoblast counts (63 vs. 342/100 WBC).. Fetuses with severe IUGR due to chronic placental insufficiency and absent or reversed flow in the umbilical artery show increased erythropoietin levels.

Topics: Blood Flow Velocity; Erythropoietin; Female; Fetal Growth Retardation; Humans; Hypercapnia; Hypoxia; Platelet Count; Pregnancy; Prospective Studies; Thrombocytopenia; Ultrasonography, Doppler, Color; Ultrasonography, Prenatal; Umbilical Arteries

Hypoxia is the primary stimulus for the production of erythropoietin (EPO) in both fetal and adult life. Here, we investigated fetal plasma EPO concentrations in monochorionic (MC) twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery (UA) Doppler. We diagnosed sIUGR in presence of (1) birth-weight discordance >20% and (2) either twin with a birth weight <10th percentile. An abnormal UA Doppler was defined as a persistent absent-reverse end diastolic flow (AREDF). The intertwin EPO ratio was calculated as the plasma EPO level of the smaller (or small-for-gestational-age) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin. Thirty-two MC twin pairs were included. Of these, 17 pairs were normal twins (Group 1), seven pairs were twins with sIUGR without UA Doppler abnormalities (Group 2), and eight pairs were twins with sIUGR and UA Doppler abnormalities (Group 3). The highest EPO ratio was identified in Group 3 (p < .001) but no significant differences were observed between Groups 1 and 2. Fetal hemoglobin levels did not differ significantly in the three groups, and fetal EPO concentration did not correlate with gestational age at birth. We conclude that fetal plasma EPO concentrations are selectively increased in MC twin pregnancies with sIUGR and abnormal UA Doppler, possibly as a result of uncompensated hypoxia.

Topics: Chorion; Diseases in Twins; Erythropoietin; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy, Twin; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries

High amniotic fluid erythropoietin concentration reflects chronic fetal hypoxia. Our aim was to study amniotic fluid erythropoietin concentration in relation to neonatal outcome in pregnancies complicated by intrauterine growth restriction.. Retrospective case series.. Helsinki University Hospital, Finland.. A total of 66 singleton pregnancies complicated by intrauterine growth restriction.. Amniocentesis or amniotic fluid sampling at cesarean section was performed between 24 and 34 gestational weeks. Values of amniotic fluid erythropoietin were quantitated with immunochemiluminometric assay. Normal amniotic fluid erythropoietin was defined as <3 IU/L, intermediate as 3-27 IU/L, and abnormal as >27 IU/L.. Adverse neonatal outcome.. Abnormal biophysical profile and reversed end-diastolic flow in umbilical artery were associated with abnormal amniotic fluid erythropoietin (p < 0.001 and p = 0.042, respectively). Abnormal amniotic fluid erythropoietin was not associated with absent end-diastolic flow in umbilical artery or with oligohydramnios (p = 0.404 and p = 0.080, respectively). Decreased umbilical artery pH and base excess values were associated with abnormal amniotic fluid erythropoietin (p = 0.027 and p = 0.007, respectively). Composite adverse neonatal outcome defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction and/or necrotizing enterocolitis was associated with abnormal amniotic fluid erythropoietin (p < 0.001).. High amniotic fluid erythropoietin concentrations are associated with decreased umbilical artery pH and base excess and with adverse neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. In selected pregnancies complicated by intrauterine growth restriction, determining amniotic fluid erythropoietin could be a useful additional tool in fetal surveillance and possibly in optimizing timing of delivery.

Topics: Amniotic Fluid; Biomarkers; Cesarean Section; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Finland; Humans; Immunoassay; Luminescent Measurements; Pregnancy; Pregnancy Outcome; Prenatal Diagnosis

To determine if there is any difference in amniotic fluid erythropoietin (EPO) concentration between fetuses small for gestational age (SGA) and appropriate for gestational age (AGA), and between the constitutionally small (CSF) and growth-restricted (GRF) fetuses.. EPO concentrations in the amniotic fluid samples were determined by EpoELISA test in 38 pregnancies with SGA and 15 pregnancies with AGA fetuses. In the SGA group we measured Ponderal index (PI) and skin-fold thickness (SFT). If PI and/or SFT were below 10th percentile the neonate was GRF. If both PI and SFT were above 10th percentile the neonate was CSF.. Higher levels of EPO were detected in the SGA in comparison to the AGA fetuses (p < 0.01). EPO concentration was higher in GRF compared to CSF (p < 0.05). The EPO cut-off level between SGA and AGA was 6.81 IU/L (sensitivity 92.3%; specificity 73.3%), and between GRF and CSF was 9.8 IU/L (sensitivity 81%; specificity 80%).. The preliminary results of this study suggest that amniotic fluid erythropoietin concentration is elevated in growth-restricted fetuses and could potentially be used for distinction between growth restricted and constitutionally small fetuses. Confirmation of these results on a larger group of pregnant women is needed.

Topics: Adult; Amniotic Fluid; Biomarkers; Birth Weight; Case-Control Studies; Diagnosis, Differential; Erythropoietin; Female; Fetal Growth Retardation; Humans; Infant, Small for Gestational Age; Pregnancy; Prenatal Diagnosis; Somatotypes; Young Adult

Topics: Amniotic Fluid; Biomarkers; Erythropoietin; Female; Fetal Growth Retardation; Humans; Infant, Small for Gestational Age; Pregnancy; Prenatal Diagnosis

Our patient is a 26-week-old preterm female infant delivered by caesarean section secondary to severe maternal preeclampsia who had been receiving subcutaneous recombinant erythropoietin (r-EPO) for anemia of prematurity. At 8 weeks of age after 8 doses of r-EPO, the infant developed numerous non-blanching erythematous macules and patches located on the back, posterior shoulder, and posterior arms, concerning for late-onset blueberry muffin lesions. Biopsy of the lesions confirmed dermal hematopoiesis. After r-EPO was discontinued all skin lesions gradually resolved over a period of 2 weeks and never recurred.

Topics: Anemia; Dermis; Erythroblasts; Erythropoietin; Female; Fetal Growth Retardation; Hematopoiesis, Extramedullary; Humans; Infant; Infant, Premature; Infant, Premature, Diseases; Intracranial Hemorrhages; Recombinant Proteins; Respiratory Distress Syndrome, Newborn; Skin Diseases

The benefit to risk ratio of the treatment with erythropoietin (EPO) as a means of limiting the number of transfusions in very preterm infants during hospitalization, seems to be modest since the adoption of restrictive transfusion criteria and of policy limiting phlebotomy losses. We therefore aim to evaluate the factors associated with the number of late blood transfusion in very preterm infants in a unit where the routine use of EPO has been discontinued.. A comparative "before-after" study was carried out in premature infants born before 32 weeks postmenstrual age (PMA), over a period of one year before (EPO group) and one year after (non-EPO group) the discontinuation of EPO therapy.. A total of 48 infants were included in the study (EPO = 21; non-EPO = 27). The number of infants transfused after the 15 day of life (D15) and the number of transfusions per infant after D15 were not significantly different between the two groups. In a multivariate analysis, the gestational age and the volume of blood drawn off during the first month of life significantly influenced the need for transfusions after the 15th day of life, independently of the treatment with EPO. The hemoglobin levels measured at different times of hospitalization (median postnatal age: 16, 33 and 67 days) were not significantly different between the two groups.. Our study shows that the discontinuation of EPO did not change the number of late transfusions. Even when a policy limiting phlebotomy losses is used, blood loss is an important and independent risk factor for late transfusion of very preterm infants.

Topics: Anemia; Blood Transfusion; Edetic Acid; Erythropoietin; Female; Ferric Compounds; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Male; Phlebotomy; Retrospective Studies; Risk Assessment; Unnecessary Procedures

To prospectively investigate iron homeostasis in full-term intrauterine growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) infants at birth, by evaluating cord blood concentrations of hepcidin (a bioactive molecule, principal regulator of iron metabolism, downregulated by hypoxia/iron deficiency and upregulated by inflammation), erythropoietin (EPO, a marker of prolonged fetal hypoxia), soluble transferrin receptor (sTfR, a marker of increased erythropoiesis and tissue iron deficiency), iron, ferritin, and unsaturated iron-binding capacity (UIBC).. Serum cord blood samples from 47 well-defined IUGR and 104 AGA singleton, full-term infants were analyzed for concentrations of all the aforementioned parameters by enzyme immunoassays and spectrophotometry.. Hepcidin concentrations were similar, while EPO concentrations were higher in IUGR cases than in AGA controls (P = 0.047). Cord blood sTfR concentrations were increased in IUGR, compared to AGA infants (P = 0.004), and negatively correlated with their customized centiles and birth weight (r = -0.238, P = 0.003 and r = -0.157, P = 0.050, respectively). Ferritin concentrations were lower in IUGR cases than in AGA controls (P = 0.039). In both groups, no correlations were observed between cord blood hepcidin concentrations and iron status indices.. Cord blood hepcidin concentrations in term IUGRs may remain unaffected, possibly due to a balance between hepcidin downregulation by chronic fetal hypoxia (indicated by higher EPO concentrations) and impaired iron metabolism (indicated by lower ferritin and higher sTfR concentrations) on the one hand, and hepcidin upregulation by the inflammatory state characterizing IUGRs, on the other. Furthermore, our findings may possibly indicate the need for regular follow-up for detection of iron-deficient anemia, not only in preterm but also in full-term IUGR neonates.

Topics: Antimicrobial Cationic Peptides; Erythropoietin; Ferritins; Fetal Blood; Fetal Growth Retardation; Hepcidins; Homeostasis; Humans; Iron; Receptors, Transferrin

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

Prohepcidin (Pro-Hep), synthesized in the liver, is the prohormone of hepcidin (Hep), which reduces iron absorption in the gut; its synthesis is enhanced by inflammation and is reduced during hypoxia. We aimed to study the hypothesis that infants born small for gestational age (SGA) have reduced cord blood concentrations of Pro-Hep.. Cord blood was collected from 20 SGA (term and near term >35 week gestation) infants and 20 appropriate for gestational age (AGA) controls. We excluded infants exposed to maternal chronic diseases, smoking, diabetes, alcohol or drug use. Both groups had a 1 min Apgar score above or equal to 7 and had normal cord blood pH (above 7.25). ELISA was used to determine serum concentrations of Pro-Hep and erythropoietin (EPO). Circulating CD71(+)/CD45(-)/SSC(low) cells were measured by flow cytometry as an index of erythroid progenitors.. There were no significant differences between groups in terms of hemoglobin concentrations, and Pro-Hep. In contrast, EPO levels and circulating CD71(+)/CD45(-)/SSC(low) erythroid progenitors were significantly higher in the SGA group. These differences remained significant even after controlling for gestational age and gravidity.. Contrary to EPO upregulation during intrauterine growth restriction (IUGR), and higher concentrations of circulating erythroid progenitors, Pro-Hep concentration is not affected by IUGR.

Topics: Adult; Antimicrobial Cationic Peptides; Erythrocyte Count; Erythroid Cells; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Hepcidins; Humans; Infant, Newborn; Infant, Small for Gestational Age; Prospective Studies; Protein Precursors; Stem Cells

We hypothesized that in growth restricted fetuses, erythropoietin (EPO) secretion is increased in proportion to the severity of cardiovascular compromise.. Thirty-eight growth restricted fetuses underwent Doppler ultrasonography of cardiovascular hemodynamics. An umbilical artery (UA) blood sample was taken at delivery for EPO analysis. Group 1 fetuses (n=9) had normal UA and ductus venosus (DV) velocimetries. Group 2 fetuses (n=18) showed an abnormal UA and a normal DV velocimetry. Group 3 fetuses (n=11) had abnormal UA and DV velocimetries. Normal EPO values were determined in 19 uncomplicated pregnancies (control group).. In group 3, EPO levels were higher (P<.05) than in groups 1 and 2. All fetuses in group 3 had EPO concentrations above the 90th percentile EPO value in the control group. The corresponding incidences were 44% and 50% in groups 1 and 2. Fetuses with retrograde aortic isthmus net blood flow had greater (P<.001) EPO levels than fetuses with antegrade net blood flow. Descending aorta, UA, DV and left hepatic vein pulsatility index values correlated significantly with EPO concentrations.. In fetal growth restriction, serum EPO concentration is increased in proportion to the severity of fetal cardiovascular compromise. Furthermore, in fetuses with retrograde aortic isthmus net blood flow, EPO levels are increased.

Topics: Adult; Cardiovascular Diseases; Erythropoietin; Female; Fetal Diseases; Fetal Growth Retardation; Humans; Pregnancy; Ultrasonography, Prenatal

Nucleated red blood cells (NRBCs) in fetal circulation have been proposed as a marker of chronic hypoxia in fetuses with intrauterine growth restriction (IUGR). We sought to determine the effects of chronic hypoxia, chronic nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME), or both on NRBC counts, erythropoietin levels, and pathologic changes in an animal model of IUGR.. We assigned timed pregnant adult Sprague Dawley rats to the following groups: (1) 21% oxygen + saline solution (n = 7); (2) 21% oxygen + L-NAME (n = 8); (3) 10% oxygen + saline solution (n = 6); and (4) 10% oxygen + L-NAME (n = 6). We inserted osmotic pumps that were prefilled with saline solution or L-NAME subcutaneously on day 17 of gestation. The animals were placed in a Plexiglas hypoxic chamber, which ensured a constant hypoxic environment. The animals were killed on day 21 of gestation before the onset of spontaneous labor. We collected maternal and fetal blood for measurement of NRBC and erythropoietin levels. The results were interpreted in relationship to maternal arterial blood gases and hemoglobin and hematocrit levels. Fetuses were examined for gross abnormalities and histological abnormalities that are characteristic of vascular disruptions by a blind examiner to experimental manipulation.. Nitric oxide inhibition induced IUGR with maximal effect when both L-NAME and hypoxia treatments were combined. Inhibition of nitric oxide synthesis, but not chronic hypoxia, increased the number of fetal NRBCs and generalized hemorrhagic diathesis in utero. These features were aggravated significantly when the treatments were combined. Moreover, chronic hypoxia induced significant maternal metabolic acidosis and increased hematocrit and erythropoietin levels in maternal and fetal blood. Nitric oxide inhibition increased maternal hematocrit levels while decreasing maternal erythropoietin levels without significantly altering the maternal acid-base status. In contrast with chronic hypoxia, nitric oxide inhibition increased fetal NRBCs without affecting erythropoietin levels.. Our findings indicate that the number of NRBCs in fetal circulation does not serve as a specific marker of chronic hypoxia that accompanies IUGR or of elevated erythropoietin levels but are an epiphenomenon that is related to the inhibition of nitric oxide.

Topics: Animals; Chronic Disease; Disease Models, Animal; Erythroblasts; Erythrocyte Count; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Hypoxia; Nitric Oxide Synthase; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley

To examine the utility of red blood cell (RBC) zinc protoporphyrin/heme ratio (ZnPP/H) as an indicator of fetal iron status, because unfavorable neurodevelopmental outcomes have been associated with poor iron status at birth, as indicated by low serum ferritin, and because few reliable indicators of fetal and early neonatal iron status exist.. Consecutively studied preterm and term fetuses at delivery included the following groups: (1) control nonhypoxic, (2) fetuses with intrauterine growth retardation (IUGR), and (3) fetuses of insulin-treated mothers (FDM). We hypothesized (1) that rapid growth velocity associated with an accelerated erythropoiesis among normal fetuses will lead to reduced iron delivery to a rapidly expanding RBC mass and higher umbilical cord blood RBC ZnPP/H and (2) that fetuses that are exposed to pathologic hypoxemia will experience an additional increase in erythropoiesis and higher cord ZnPP/H. ZnPP/H was determined on saline-washed cord blood erythrocytes by hematofluorometry and was examined for its relationship with clinical factors and cord blood laboratory measurements indicative of tissue oxygenation (plasma erythropoietin [EPO] and reticulocyte count) and iron status (plasma ferritin and erythrocyte indices). Statistical testing included 1-way analysis of variance, 2-way analysis of variance with covariates, simple linear regression, and multiple regression analysis.. Among control group subjects, gestational age at birth was inversely correlated with RBC ZnPP/H and reticulocyte count and positively correlated with ferritin and EPO. Relative to control subjects, IUGR and FDM fetuses at specified gestational age groupings had higher ZnPP/H, lower plasma ferritin, and higher plasma EPO. Statistical modeling of the relationship between ZnPP/H and plasma ferritin among all study groups demonstrated significant impacts of gestational age, plasma EPO, maternal hypertension, and maternal smoking.. The inverse association of fetal ZnPP/H with gestational age at birth among control subjects is attributable to erythropoietic stimulation likely as a result of increasing growth velocity at the earliest gestational ages. The relatively higher ZnPP/H observed among fetuses in the IUGR and FDM groups likely is attributable to increased erythropoietic activity secondary to pathologic hypoxemia. Decreased placental iron transfer may also have limited iron availability and contributed to elevated ZnPP/H in the IUGR group. These data support the concept that increased erythropoietic activity and/or limited iron transport may place infants of diabetic mothers and infants with growth retardation at risk for developing systemic iron deficiency later in infancy and in early childhood.

Topics: Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Ferritins; Fetal Blood; Fetal Diseases; Fetal Growth Retardation; Gestational Age; Heme; Humans; Hypoxia; Infant, Newborn; Infant, Premature; Insulin; Pregnancy; Pregnancy in Diabetics; Protoporphyrins; Reticulocyte Count

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

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

To determine if umbilical cord plasma erythropoietin (EPO) levels in combination with cord blood gases and Apgar scores can distinguish between subacute and chronic uteroplacental insufficiency.. A total of 184 neonates delivered between 1993 and 1997 at Tampa General Hospital were studied. Cord plasma EPO levels, cord blood gases, and Apgar scores were determined prospectively and compared in four subgroups that were defined based on the presence or absence of fetal growth restriction (FGR; chronic fetal hypoxia), abnormal fetal heart rate tracings during labor (FHR; subacute/acute fetal hypoxia), or both.. Both growth-restricted and appropriately grown newborns with abnormal intrapartum FHR tracing had elevated umbilical cord plasma EPO (183.5 and 135.2 mIU/ml, respectively; normal = 20.7 mIU/ml) and base deficit, whereas pH, Po2, and 1-minute and 5-minute Apgar scores were significantly lower, compared with appropriately grown newborns with a normal intrapartum course. Among newborns with normal heart rate tracings and FGR, the mean plasma EPO levels were elevated (89.5 mIU/ml), whereas the other parameters were not different from normal.. Our findings suggest that, although cord blood gases and Apgar scores may reflect subacute and acute events, they are not good predictors of chronic uteroplacental insufficiency. The supplemental use of umbilical cord plasma EPO levels may improve our ability to identify chronic uteroplacental insufficiency.

Topics: Apgar Score; Blood Gas Analysis; Chronic Disease; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Heart Rate, Fetal; Humans; Infant, Newborn; Placental Insufficiency; Pregnancy

The fetal liver is the main hematopoietic organ during intrauterine life. Morphometrical studies were performed on liver sections to detect changes occurring with intrauterine growth retardation and preeclampsia. Compared with the controls (n = 10), fetuses from preeclamptic mothers showed a severe reduction of erythroid cells by 60% on average (n = 18). Closer examination revealed that the erythroid cells at early stages of differentiation were more affected (80% reduction) than at later stages (55%). Seven out of 18 fetuses from preeclamptic mothers did not show growth retardation but exhibited severely reduced hepatic erythropoiesis. We suggest that the prime factor for impaired red blood cell production is preeclampsia itself rather than intrauterine growth retardation. Regulation of erythropoiesis in utero might depend on the interaction of many hematopoietic growth factors, and preeclampsia might alter the balance. To test this notion, we quantitated erythropoietin in fetal blood and various cytokines in the amniotic fluid. An elevation of erythropoietin and interleukin (IL)-3 levels was seen in babies born under the conditions of preeclampsia, whereas the concentrations of granulocyte/macrophage-colony-stimulating factor (CSF), granulocyte-CSF, and IL-1 beta were reduced, and the levels of IL-6 and IL-8 remained constant. With preeclampsia, a discrepancy between elevation of erythrocyte numbers in peripheral blood and depression of hematopoiesis at the main production site, the fetal liver, is seen. Concomitantly, there is elevation of some but reduction of other hematopoietic cytokines. We envision that during the course of preeclampsia quantitation of hematopoietic growth factors might allow to predict the deterioration of in utero life conditions.

Topics: Amniotic Fluid; Case-Control Studies; Cytokines; Erythropoiesis; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Fetus; Hematopoietic Cell Growth Factors; Humans; Liver; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy

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 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

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

The aim of this study was to determine whether hypoxemia induces an increase in plasma erythropoietin concentration in human fetal life and, if so, whether this response stimulates fetal erythropoiesis.. The plasma erythropoietin concentration in blood samples from 33 small-for-gestational-age fetuses at 26 to 38 weeks' gestation was measured. Measurements were compared with the reference range for gestation, and associations with PO2, pH, and erythroblast and erythrocyte counts were examined.. The mean plasma erythropoietin concentration in the small-for-gestational-age fetuses was significantly increased, and the degree of increase was significantly associated both with fetal acidemia and, more strongly, with fetal erythroblastosis.. Erythropoietin production in response to tissue hypoxia occurs from at least 26 weeks' gestation with measurable physiologic effects on erythropoiesis. Furthermore, more accurate assessment of tissue oxygenation may be obtained by measuring the erythroblast count rather than the blood pH.

Topics: Erythrocyte Count; Erythropoietin; Fetal Blood; Fetal Growth Retardation; Humans; Hydrogen-Ion Concentration; Osmolar Concentration; Oxygen; Partial Pressure; Regression Analysis