Are high cumulative doses of erythropoietin neuroprotective in preterm infants? A two year follow-up report

Abstract

BackgroundPreterm infants are at risk for neurodevelopmental sequelae even in absence of major cerebral lesions. The hypothesis that Human Recombinant Erythropoietin (rEpo) could improve the neurodevelopmental outcome in risk neonates has raised the highest interest in recent years.MethodsA group of preterm neonates born at a gestational age ≤ 30 weeks and free from major cerebral lesions or major visual impairment, were included in the study if they had a complete neurologic evaluation for at least 24 months of postmenstrual age. They were assigned to group I in the case they had been treated with rEpo or group II if untreated. The aim was to evaluate whether rEpo, given at the high cumulative doses utilized for hematologic purposes, is able to improve the neurodevelopmental outcome in preterm infants born at a gestational age ≤ 30 weeks. A group of 104 preterm neonates were studied: 59 neonates who received rEpo for 6.9 ± 2.4 weeks at a median cumulative dose of 6300 UI/Kg (6337 ± 2434 UI/Kg), starting at a median age of 4 days and 45 neonates who were born in the period preceding the routine use of rEpo. The neurodevelopmental quotient at 24 month postmenstrual age was assessed utilizing the Griffiths’ Mental Developmental Scales.ResultsOur results failed to show any difference in the Developmental Quotient at 24 month. Bronchopulmonary dysplasia, minor intraventricular hemorrhages and blood transfusions were the clinical features significantly related to the Developmental Quotient.ConclusionsOur results do not support the hypothesis that rEpo, administered with the schedule utilized for hematologic purposes, improve the neurodevelopmental outcome of preterm neonates, at least those preterm infants free from major impairments.

Neuroimaging in former preterm children who received erythropoiesis stimulating agents

“…ESAs are essential for normal brain development and augment a variety of potential neuroprotective mechanisms including promoting neurogenesis and angiogenesis ( 3 – 4 ) and inhibiting apoptotic, excitotoxic and oxidative injury to neurons and oligodendroglia ( 5 – 11 ). ESAs may improve neurologic outcome of term infants with hypoxic ischemic encephalopathy ( 12 ), and appear safe in premature infants as well ( 13 ), decreasing major morbidity ( 14 ) and possibly improving cognitive outcome at 18–22 months ( 15 ), 3.5–4 years ( 16 ) and at 10 years ( 17 ), though some trials reporting no difference have been published ( 18 – 19 ).…”

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis

“…16 Most clinical follow-up studies on preterm infants primarily treated with rhEPO (or its higherglycosylated derivate darbepoetin) for anemia of prematurity indicated improved neurodevelopmental outcomes, 17 -21 whereas only a few studies have shown no effect. 22,23 In 2005, the first phase I and II trials were initiated to establish the safety of early high-dose rhEPO for neuroprotection. 24,25 So far, only a limited number of randomized controlled trials (RCTs) have reported data on the neuroprotective effects of rhEPO in preterm infants.…”

Efficacy and safety of high and low dose recombinant human erythropoietin on neurodevelopment of premature infants

“…Detailed characteristics of the included studies were presented in Table 1 [13–22] . All these studies were published from 2010 to 2020.…”

“…Detailed characteristics of the included studies were presented in Table 1. [13][14][15][16][17][18][19][20][21][22] All these studies were published from 2010 to 2020. The sample size ranged from 53 to 1285.…”

“…Fauchere [13] 2015 English Switzerland 3000 U/kg 29 ± 1.1 rhEPO 229 September 2005 to December 2012 29 ± 1.2 Placebo 214 Juul [14] 2020 English America 6000 U/kg 29.1 ± 6.2 rhEPO 476 December 2013 to September 2016 28.8 ± 6. 2 Placebo 460 Leuchter [15] 2014 English Switzerland 3000 U/kg 29.5 ± 1.5 rhEPO 256 2005 to 2012 29 ± 1.6 Placebo 239 Luciano [16] 2015 English Italy 6300 U/kg 28.1 ± 1. Placebo 45 Natalucci [17] Placebo 174 Neubauer [18] 2010 English Germany 8574 U/kg 27.1 ± 1.9 rhEPO 89 January 1993 to December 1998 27.2 ± 2.…”