Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age

Leuchter, Russia Hà-Vinh; Gui, Laura; Poncet, Antoine; Hagmann, Cornelia; Lodygensky, Gregory A.; Martin, Ernst; Koller, Brigitte; Darqué, Alexandra; Bucher, Hans Ulrich; Hüppi, Petra Susan

doi:10.1001/jama.2014.9645

Cited by 126 publications

(112 citation statements)

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“…This high‐dose rhEPO in rodents was equivalent to that in preterm infants given at a high dose of 1,000 to 2,500U/kg 20. Based on those results from neonatal rodent brain injury models, clinical studies showed that high‐dose rhEPO (2,500–3,000U/kg) administered after birth was well tolerated in preterm and term infants14, 20, 33, 37, 42 and conferred neuroprotection 16, 36. In a previous study using low‐dose rhEPO to prevent anemia in preterm infants, it was observed that preterm infants with rhEPO treatment also had significant neurodevelopmental improvement 38.…”

Section: Discussionmentioning

confidence: 87%

“…EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection 8, 9, 10, 11. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models,12, 13 and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants 8, 14, 15, 16, 17. In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment 17, 18, 19, 20.…”

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confidence: 99%

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Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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ObjectiveTo evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants.MethodsA total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age.ResultsDeath and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed.InterpretationRepeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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“…58 Epo monotherapy, without hypothermia, may be useful for neonatal conditions other than HIE, such as perinatal stroke, 59 congenital heart disease, 60 and brain injury of prematurity. [61][62][63][64] This is the first clinical study of HIE that assesses biomarkers of efficacy to evaluate whether Epo provides additional neuroprotection to hypothermia. We found that Epo treatment was associated with significantly reduced severity of brain injury on MRI, specifically in the subcortical region (ie, the area that contains the basal ganglia, thalamus, and internal capsule).…”

Section: Sensitivity Analysesmentioning

confidence: 99%

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

Mathur²,

et al. 2016

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OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS:In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system. RESULTS:The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epotreated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05).CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

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“…Leuchter et al 17 reported decreased gray and white matter injury in 77 of the erythropoietin-treated infants compared with 88 placebo-treated infants, and O'Gorman et al 18 reported improved white matter development as assessed by diffusion tensor imaging and tract-based spatial statistics in 24 of the erythropoietin-treated infants compared with 34 placebotreated infants. A US multicenter trial of high-dose erythropoietin for neuroprotection in 960 extremely low gestational age infants (PENUT [Preterm Epo Neuroprotection Trial]; NCT01534481) is ongoing, and neurodevelopmental outcomes are expected in ∼3 years.…”

Section: Figurementioning

confidence: 99%

Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

Ohls

Cannon²,

Phillips

et al. 2016

Pediatrics

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Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age

Abstract: clinicaltrials.gov Identifier: NCT00413946.

Cited by 126 publications

References 39 publications

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

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