Amniotic Fluid Erythropoietin Concentration Research Articles

Late-Pregnancy Fetal Hypoxia Is Associated With Altered Glucose Metabolism and Adiposity in Young Adult Offspring of Women With Type 1 Diabetes.

ObjectiveTo investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D).Methods156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration <14.0 mU/l, defined as normal, and were categorized into the low EPO (L-EPO) group. The remaining 29 OT1D had AF EPO ≥14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA1c, cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements.ResultsTwo OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters.ConclusionsHigh AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.

Placental delayed villous maturation is associated with evidence of chronic fetal hypoxia.

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.

Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks.

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.

Diabetic Pregnancy and Fetal Consequences

Perinatal morbidity and mortality, congenital malformations, abnormal fetal growth, both spontaneous and iatrogenic preterm birth, hypoxic complications, and trauma during delivery are increased in diabetic pregnancies. Perinatal mortality in diabetic pregnancies is still three to five times higher than the perinatal mortality in the general population. Stillbirths during the last weeks of pregnancy are often considered unexplained, although recent studies indicate that most of these stillbirths are caused by fetal chronic hypoxia. Importantly, perinatal mortality has not changed during the past 3 decades in diabetic pregnancies, which emphasizes the need to find new methods and strategies to improve perinatal outcome. Congenital malformations have decreased in pregestational diabetic pregnancies because of general improvement of glycemic control among diabetic women. However, the rate of fetal malformations is still two to four times higher in type 1 and type 2 diabetic pregnancies than in the general population. Prepregnancy counseling decreases the risk of fetal malformations. Efforts should be made to improve the attendance of diabetic women in prepregnancy clinics. Fetal overgrowth during the last trimester of pregnancy is the most common fetal complication in diabetic pregnancies. Accurate estimation of fetal weight by ultrasound is especially difficult in macrosomic fetuses. Magnetic resonance imaging can be used to assess fetal total volume, shoulder width, and fat amount in addition to obtaining accurate pelvic measurements. More studies on the clinical use of magnetic resonance imaging in obstetrics are urgently needed. Increased fetal erythropoietin (EPO) level is an indicator of fetal chronic hypoxia, which can be detected antenatally by measuring amniotic fluid EPO concentration. Sufficiently large controlled studies are needed before amniotic fluid EPO measurement can be recommended for clinical use.

Erythropoietin in amniotic fluid as a potential marker in distinction between growth restricted and constitutionally small fetuses

Objective: 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.Methods: 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.Results: 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%).Conclusion: 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.

OP23.02: Amniotic fluid erythropoietin like matter of distinction between IUGR and constitutionally small fetuses

To determine the possibilities of analysis of erythropoietin (EPO) in amniotic fluid as a parameter independent of gestational age and subjective interpretations upon making a distinction between IUGR and constitutionally small fetuses. Prospective clinical study was conducted on 38 pregnancies with fetuses small for gestational age. Small for gestational age fetuses (SGA) have been defined as both estimated fetal weight and neonatal body weight beyond 10th percentile for our population. The study group was divided into two subgroups: constitutionally small fetuses, n = 16 (42.11%) and growth restricted fetuses, n = 22 (57.89%). The diagnosis of both, constitutionally small and growth restricted fetuses, were based upon standard criteria (fetal biometry as well as AFI and Doppler evaluation). Amniotic fluid samples were collected in all pregnancies in order to evaluate EPO levels, by amniocenthesis for determination of lung maturity, maximum 48 hours before delivery EPO concentration was higher in growth restricted fetuses compared to constitutionally small fetuses showing high statistical significance (p < 0.01). ROC analysis for EPO values comparing growth restricted fetuses and constitutionally small fetuses has the best result at the level of 9.8 IU/L. This cut-off point has sensitivity of 81%, specificity of 80%, PPV 81.2% and NPV 88.4%. Neonates with EPO concentrations above 9.8 IU/l were more frequent admitted to the NICU and concentrations of EPO showed statistical significance (p < 0.05) comparing to those without admittance at NICU. There is a difference in amniotic fluid EPO concentrations between growth restricted and constitutionally small fetuses. Concerning the fact that EPO production is independent of gestational age, EPO concentrations may be used as a distinction between the pathologically and physiologically small for gestational age fetuses when amniocentesis is done for the detection of fetal lung maturity or rapid karyotypisation

Amniotic fluid S100B protein and erythropoietin in pregnancies at risk for fetal hypoxia

Objective 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. Study design 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. Results 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 (≥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%. Conclusion 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.

Increased Fetal Plasma and Amniotic Fluid Erythropoietin Concentrations: Markers of Intrauterine Hypoxia

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, pO₂ 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.

Sources of amniotic fluid erythropoietin during normoxia and hypoxia in fetal sheep

Erythropoietin is present in human amniotic fluid and has been suggested as a marker of fetal hypoxia. The objectives of the present study were to determine whether erythropoietin is present in ovine amniotic fluid, fetal urine, and/or lung liquid and whether concentrations in these compartments change in parallel with endogenous fetal plasma erythropoietin concentration when the latter is increased experimentally. In late gestation chronically catheterized fetal sheep, samples of amniotic fluid and plasma, urine and plasma, lung liquid, amniotic fluid, and plasma were collected before and up to 7 days after induction of 4 types of fetal hypoxia: (1) acute anemic hypoxia that was induced by a single fetal hemorrhage, (2) progressive anemic hypoxia that was induced by daily exchange transfusion, (3) acute hypoxic hypoxia that was induced by the reduction of maternal inspired oxygen content, or (4) chronic placental insufficiency that was induced by daily umbilicoplacental embolization for 4 days. Erythropoietin concentrations were determined by radioimmunoassay. Statistical testing included analysis of variance and least squares regression. Under basal, nonhypoxic conditions, amniotic fluid erythropoietin concentration averaged 33.2% +/- 1.6% (SE) of fetal plasma erythropoietin concentration, and basal fetal urine and lung liquid erythropoietin concentrations ranged from low (<10% of plasma concentration) to nondetectable. Unlike the strong correlation in humans, basal amniotic fluid and plasma erythropoietin concentrations were correlated only weakly (r = 0.259; r2 = 6.7%; P = .0027; n = 132). Amniotic fluid erythropoietin concentration approximately doubled after 12 hours of severe hypoxic hypoxia or after 24 hours of embolization-induced severe hypoxia but was unchanged after 12 hours of mild-moderate hypoxic hypoxia or 24 hours of anemic hypoxia. Concomitant fetal plasma erythropoietin concentrations increased to 28.1 +/- 5.3, 12.5 +/- 2.7, 10.8 +/- 4.6, and 10.0 +/- 1.3 times basal values, respectively. During progressive fetal anemia, urinary erythropoietin concentration increased almost 10-fold (P = .0023) but remained a small fraction (3.7% +/- 0.4%) of plasma concentration; at 12 hours of hypoxic hypoxia, lung liquid erythropoietin concentration did not vary with the severity of the hypoxia and remained low relative to plasma concentration (4.2% +/- 2.1%). Erythropoietin is present in ovine amniotic fluid, urine, and lung liquid. With only 3 potential sources, the fetal membranes appear to be the primary source of amniotic fluid erythropoietin in the nonhypoxic ovine fetus because basal urine and lung liquid erythropoietin concentrations are much lower than amniotic fluid concentrations. Although unchanged during mild-to-moderate fetal hypoxia, amniotic fluid erythropoietin concentration increases modestly during severe fetal hypoxia. In sheep, fetal urinary erythropoietin may contribute to this rise in amniotic fluid erythropoietin concentration during severe hypoxia, because fetal urinary and plasma concentrations increase in parallel during anemia.

Concentration of cord serum placenta growth factor in normal and diabetic pregnancies

To investigate whether maternal diabetes or diabetes-related complications, such as macrosomia and chronic fetal hypoxia, are associated with altered placenta growth factor (PlGF) levels in cord serum. Case-control study. Helsinki University Central Hospital, Helsinki, Finland. Sixty-two normal pregnancies, 67 pregnancies complicated by type 1 diabetes and 28 pregnancies complicated by insulin-treated gestational diabetes. Cord serum PlGF concentration was measured by an enzyme-linked immunosorbent assay. Amniotic fluid erythropoietin concentration was measured by a chemiluminescent immunologic method. Umbilical artery gas variables were analysed with standard blood gas and pH electrodes. PlGF concentration in cord serum at birth. Cord serum PlGF concentration was similar in normal pregnancies [13.4 (1.0) ng/L], in pregnancies complicated by type 1 diabetes [15.1 (1.8) ng/L, P= 0.583 vs controls] and in pregnancies complicated by insulin-treated gestational diabetes [13.6 (0.9) ng/L, P= 0.991 vs controls]. Cord serum PlGF did not correlate with relative birthweight. In diabetic pregnancies, cord serum PlGF correlated negatively with amniotic fluid erythropoietin (r=-0.449, P < 0.0001) and positively with umbilical artery Po(2) (r= 0.333, P= 0.001). There was a trend toward lower cord serum PlGF levels in diabetic pregnancies with pre-eclampsia compared with those without any hypertensive disorders. Maternal diabetes per se is not associated with altered PlGF levels in cord serum. The correlation between PlGF and indices of fetal hypoxia in diabetic pregnancies may be related to the role of PlGF in potentiating the angiogenic response to vascular endothelial growth factor in ischaemia.

High amniotic fluid erythropoietin levels are associated with an increased frequency of fetal and neonatal morbidity in Type 1 diabetic pregnancies

In this study we investigated whether chronic fetal hypoxia, as indicated by amniotic fluid erythropoietin levels, is associated with perinatal morbidity in type 1 diabetic pregnancies. A total of 331 women with type 1 diabetes had at least one childbirth between 1995 and 2000. The amniotic fluid erythropoietin concentration was measured in 156 diabetic singleton pregnancies at a median time of 1 day before Caesarean section without labour contractions and in 19 healthy control subjects at Caesarean section. The median amniotic fluid erythropoietin level was 14.0 mU/ml (range 2.0-1975.0) in diabetic pregnancies and 6.3 mU/ml (range 1.7-13.7) in controls (p<0.0001). Of the 156 diabetic patients, 21 (13.5%) had amniotic fluid erythropoietin levels higher than 63.0 mU/ml. Amniotic fluid erythropoietin levels correlated negatively with umbilical artery pH (r=-0.49, p<0.0001) and pO2 (r=-0.62, p<0.0001) at birth and neonatal lowest blood glucose level (r=-0.47, p<0.0001). Positive correlations were found between amniotic fluid erythropoietin levels and umbilical artery pCO2 (r=0.49, p<0.0001) and last maternal HbA1c (r=0.43, p<0.0001). Furthermore, a U-shaped correlation was demonstrated between amniotic fluid erythropoietin levels and birthweight z score (z score below -0.6 SD units: r=-0.63, p=0.0007; z score above +1.0 SD units: r=0.32, p=0.0014). Neonatal hypoglycaemia, hypertrophic cardiomyopathy and admission to the neonatal intensive care unit occurred significantly more often in cases with high amniotic fluid erythropoietin levels (>63.0 mU/ml) than in those with normal levels. Multivariate logistic regression analysis revealed that amniotic fluid erythropoietin was the only variable independently related to low umbilical artery pH (<7.21; p<0.0001) and neonatal hypoglycaemia (p=0.002). Low umbilical artery pO2 (<15.0 mm Hg) was explained by amniotic fluid erythropoietin (p<0.0001) and birthweight z score (p=0.004). Antenatal high amniotic fluid erythropoietin levels can identify type 1 diabetic pregnancies at increased risk of severe perinatal complications.

Amniotic fluid erythropoietin concentrations differentiate between acute and chronic causes of fetal death.

Increased fetal plasma erythropoietin concentration is an indicator of chronic fetal hypoxia. Amniotic fluid erythropoietin levels correlate highly significantly with fetal erythropoietin levels before labor. We studied AF erythropoietin levels after fetal death in order to determine whether this could differentiate between stillbirths from acute or chronic causes. Amniotic fluid was obtained after fetal death for erythropoietin measurement following fetal death in 21 pregnancies. Two of the pregnancies had twins, of which one infant was born alive. All 22 stillborn fetuses had an autopsy. None had malformations. Without prior knowledge of the results of the erythropoietin analyzes, the causes of fetal death were divided into acute, chronic or unknown groups. Eight pregnancies had an acute cause of fetal death (e.g. cord complication or placental abruption), eight pregnancies had a chronic cause (intrauterine growth restriction or erythroblastosis) and in five pregnancies the cause of fetal death could not be determined. In all eight pregnancies with an acute cause of fetal death, AF erythropoietin levels were normal (< 20 mU/mL). In contrast, six of the eight pregnancies with a chronic cause had AF erythropoietin levels above normal (range from 49.9 mU/mL to 391 mU/mL). In the five pregnancies with an unknown cause of fetal death, AF erythropoietin levels were normal in three and elevated in two. Elevated AF erythropoietin levels, identified after fetal death, suggest that the fetus died from a chronic hypoxic event, whereas normal AF erythropoietin levels suggest that the fetus died from an acute event.

Amniotic fluid erythropoietin concentrations differentiate between acute and chronic causes of fetal death

Amniotic fluid erythropoietin concentrations differentiate between acute and chronic causes of fetal death