Increased fetal plasma and amniotic fluid erythropoietin concentrations: markers of intrauterine hypoxia

Abstract

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.

Fig. 1

Fifty-eight pregnancies complicated by preeclampsia or hypertension grouped into low (<20 mU/ml, regression line A, r = 0.87, p < 0.0001, n = 28) and high (>50 mU/ml, regression line C, r = 0.86, p < 0.0001, n = 17) amniotic fluid EPO levels correlate with cord plasma EPO levels obtained simultaneously at cesarean section. Slightly elevated amniotic fluid EPO levels (20-50 mU/ ml, regression line B, r = −0.10, n = 13) do not correlate with cord plasma EPO levels. Reproduced with permission from Teramo [30].

Fig. 2

Seventy-five pregnancies complicated by hypertension grouped into low amniotic fluid (<20 mU/ml, n = 38, group 1), intermediate amniotic fluid (20.0-71.2 mU/ml, n = 19, group 2) and high amniotic fluid EPO levels (>71.2 mU/ml, n = 18, group 3). The lower horizontal dotted line represents the upper range of healthy control pregnancies (19.1 mU/ml) and the upper horizontal dotted line represents 8X the median of controls (71.2 mU/ml). Serial amniotic fluid samples from the same patient are connected by lines. Fetal and neonatal data of group 1 (normal EPO) and group 3 (high EPO) are given in table 1 under Hypertensive pregnancies. Reproduced with permission from Teramo et al. [29].

Fig. 3

Logarithmically transformed last amniotic fluid EPO concentration obtained 1 day (median) before delivery by cesarean section correlates negatively with umbilical artery p0₂ in type-1 diabetic pregnancies. Reproduced with permission from Teramo et al. [28].

Fig. 4

Exponentially increasing amniotic fluid EPO level in a White's class C diabetic with poor glycémie control during the last trimester (HbA1c ranged from 8.4 to 8.8%). The patient was hospitalized for preeclampsia during the 34th gestational week. She had two amniocenteses done for fetal lung maturity evaluation at 34²/₇ and 35²/₇ gestational weeks. Amniotic fluid EPO levels were not known to the clinicians. An emergency cesarean section was performed at 36³/₇ weeks of gestation because of late decelerations in the fetal heart rate recording. Umbilical artery pH was 7.18 at birth. L/S = Lecithin/sphingomyelin ratio; PG = phosphatidylglycerol; C/S = cesarean section; CTG = cardiotocography

Fig. 5

Negative correlation between fetal hemoglobin concentration and logarithmically transformed amniotic fluid EPO level is the same in fetuses with a gestational age of <27 weeks (∘; r = −0.57, p = 0.027, n = 15) and in fetuses with a gestational age above 27 weeks (•; r = −0.49, p = 0.039, n = 17). The regression slopes do not differ from each other. The fetal blood samples were obtained by cordocentesis before the first intrauterine red cell transfusion done for maternal Rh immunization. Amniotic fluid samples were obtained at the same time as the first cordocentesis.