Although nucleated red blood cells (nRBCs) are rarely found circulating in older children,1 they are commonly seen in the blood of newborns. They are primarily produced in the fetal bone marrow in response to erythropoietin and are stored in the marrow as precursors to reticulocytes and mature erythrocytes. Many acute and chronic stimuli cause increases in the number of circulating nRBCs from either increased erythropoietic activity or a sudden release from the marrow storage pools. This paper reviews the various pathological processes associated with increased production and release of nRBCs. It emphasises the effects of acute, subacute, and chronic asphyxia on nRBC counts.#### Key message

1

Common causes of increased nucleated red blood cells include prematurity, increased erythropoiesis from chronic hypoxia, anaemia, and maternal diabetes, from acute stress mediated release from the marrow stores, and from postnatal hypoxia. Extreme increases may occasionally be idiopathic.

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2

When increased nRBC counts are seen with acute and subacute asphyxia, the magnitude of the increase is a function of the severity and duration of the asphyxia. However, there is a large overlap between the nRBC values found after acute, subacute, and chronic asphyxia; asphyxia of any duration does not always cause an increased nRBC count, and extreme increases may be found without asphyxia.

Nucleated red blood cells are sometimes called erythroblasts, normoblasts, or normocytes. For this review, the term “normoblasts” will be used to refer to the cells when they are in the bone marrow and “nRBCs” when they are in circulating blood.

Clinically it is best to express nRBCs as an absolute number of cells per unit volume, either “nRBCs/mm3” or “nRBCs/l”. However, most clinical laboratories and many research publications report nRBCs relative to 100 white blood cells (WBCs). Unfortunately the extreme variability in the number of leucocytes …

https://fn.bmj.com/content/fetalneonatal/84/3/F211.full.pdf

Nucleated red blood cells in the fetus and newborn.

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.

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

Fetal plasma erythropoietin concentration in severe growth retardation

Nucleated red blood cell count at birth as an index of perinatal brain damage.

Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (11.9 +/- 0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial O2 content difference by 24 h of infusion (P less than 0.01). Calculated fetal O2 consumption increased from 8.1 +/- 0.4 ml/kg per min in the control period to a maximum value of 10.6 +/- 0.3 ml/kg per min by third infusion day (P less than 0.01), which is an increase of approximately 30%. The degree of stimulation of fetal O2 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal O2 consumption was accompanied by a significant increase in fetal O2 extraction with no change in either fetal O2 delivery or fetal blood O2 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial PCO2 was linearly related (P less than 0.001) to the magnitude of increase in fetal O2 consumption. These studies suggest that chronic fetal hyperglycemia induces a state of accelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

/pdf/effects-of-chronic-fetal-hyperglycemia-upon-oxygen-55envkesj3.pdf

Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus

. 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<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. This response of plasma Ep to hypoxemia in late gestation fetal sheep is qualitatively similar to that observed in adult animals, thus demonstrating developmental maturity of the fetus.

/pdf/temporal-response-of-immunoreactive-erythropoietin-to-acute-13sjep0j2r.pdf

Benjamin T Jackson

Papers

Temporal response of immunoreactive erythropoietin to acute hypoxemia in fetal sheep.