What are Nucleated Red Blood Cells (NRBCs)?

What are Nucleated Red Blood Cells (NRBCs)?

Nucleated red blood cells (NRBCs) are immature erythrocyte precursors that normally reside in the bone marrow as part of erythropoiesis and rarely circulate in healthy adults, though they are physiologically present in fetuses and neonates. 1

Definition and Normal Physiology

• NRBCs are normoblastic cells that failed to extrude their nuclei before exiting from bone marrow or liver 2
• In healthy term fetuses, the median NRBC count in umbilical cord blood is 3.05 per 100 white blood cells (range 0-11.6), with a median absolute count of 0.39 x10⁹/L (range 0-1.8) 3
• These cells are normally observed in peripheral blood of neonates and during pregnancy, but their presence in other circumstances indicates a disorder in the blood-producing mechanism 4

Clinical Significance as Biomarkers

In Neonatal Populations

NRBCs serve as fetal hematologic markers for placental dysfunction, hypoxemia, and asphyxia 5:

• NRBC counts are frequently elevated in umbilical cord blood after fetal distress, though counts typically drop rapidly after birth 2
• In preterm infants (<32 weeks gestation, <1500g birth weight), an increase of 10/nL in mean NRBC count on postnatal days 2-5 carries an odds ratio for mortality of 6.95 (95% CI 2.21-21.86) 2
• The optimal cut-off value for predicting death is NRBC >2/nL with 85% sensitivity and 75% specificity 2
• Persistent NRBC elevation beyond day 3-4 is an independent predictor of adverse outcome: 80% of survivors achieve clearance by day 4, compared to only 35% of neonatal deaths 5
• Day-4 NRBC counts >70 per 100 white blood cells predict morbidity with 82% sensitivity and 96% specificity 5

In Adult Populations

• NRBCs can predict clinical deterioration and mortality in critically ill adults, including those with sepsis, trauma, ARDS, acute pancreatitis, or severe cardiovascular disease 1
• The presence of circulating NRBCs in adults indicates significant physiologic stress or hematologic dysfunction 1

Laboratory Considerations

Elevated NRBC counts falsely increase automated white blood cell counts, requiring manual correction 4:

• Most automated hematology analyzers cannot distinguish NRBCs from leukocytes 4
• Common cutoff values for correction vary between laboratories (1,5,10,20, or 50 per 100 WBCs), with 5 and 10 being most frequently used 4
• Automated NRBC counting methods correlate well with manual microscopic evaluation (r² = 0.988), offering a more efficient and reproducible approach 3

Pathophysiologic Mechanisms

• NRBC elevation reflects bone marrow stress response to hypoxia, anemia, or hemolysis 1
• In neonates, persistent elevation suggests ongoing placental dysfunction or inadequate postnatal adaptation 5
• The magnitude and duration of NRBC elevation correlate with severity of underlying pathology 5