Objective: The time between onset of fetal hypoxia and first appearance of nucleated red blood cells (NRBCs) in the blood can conceptually be divided into two periods; (1) the 'erythropoietin (EPO) generation time', which previous fetal studies suggest is 4 to 5 h, and (2) the 'NRBC emergence time'. In this study, we estimated the latter as the time required for NRBC to appear in the blood after administering a dose of recombinant EPO.
Study design: This was a retrospective analysis of data from a multihospital healthcare system (Intermountain Healthcare). Data were included only for neonates born ≥34 weeks gestation between the dates 1 January 2005 and 31 October 2012 and only if they received a dose of darbepoetin during their neonatal intensive care unit stay and had one or more complete blood cell counts (CBCs) obtained during the 3-day period before the dose was given and one or more CBCs in the 7-day period after the dose.
Result: The study involved 31 neonates who received 34 doses of darbepoetin. Seven doses were 4 μg kg(-1) and twenty-seven doses were 10 μg kg(-1). Twenty-six CBCs were obtained during the 24-h period following the darbepoetin dose and none had NRBC identified. NRBC first appeared in the blood between 24 and 36 h after the dose. Recipients of the higher dose generally had a higher peak NRBC count but the NRBC 'emergence time' did not appear to depend on dose.
Conclusion: Following fetal hypoxia, transcription and translation of the EPO gene result in an elevation in plasma EPO concentration. Previous fetal studies suggest this process requires 4 to 5 h. The present studies suggest that, following the increase in plasma EPO, NRBC emerge into the circulation in ≥24 h. If this model serves as a reasonable estimate, it suggests that neonates with an elevated NRBC count at birth had the onset of hypoxia at least 28 to 29 h before birth.