Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

Ohls, Robin K.; Cannon, Daniel C.; Phillips, J. P.; Caprihan, Arvind; Patel, Shrena; Winter, Sarah; Steffen, Michael; Yeo, Ronald A.; Campbell, Richard A.; Wiedmeier, Susan E.; Baker, Shawna; Gonzales, Sean; Lowe, Jean

doi:10.1542/peds.2015-3859

Cited by 62 publications

(57 citation statements)

References 34 publications

(41 reference statements)

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“…Repeated low‐dose rhEpo treatment (500IU/kg, initiated within 72 hours, repeated every 48 hours for 2 weeks) significantly improved neurological outcomes in the Chinese RCT, indicating that continued treatment is essential, possibly because of successful stimulation of erythropoiesis and reduced red blood cell transfusions. This conclusion is in line with previous retrospective analyses of neurodevelopment in RCTs, which primarily aimed to reduce transfusions …”

supporting

confidence: 91%

Erythropoietin for Neuroprotection in preterm infants

Dame

2016

Annals of Neurology

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supporting

confidence: 91%

Erythropoietin for Neuroprotection in preterm infants

Dame

2016

Annals of Neurology

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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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“…Because Epo levels may predict neurocognitive outcomes in human premature infants after erythropoietic Epo dosing (Bierer et al, ; Ohls et al, ), we studied several relationships that may predict brain weight. Through stepwise modeling, total brain Fe (µg) was the stronger predictor of brain weight, and although potentially the relationship between Epo and brain size might be a statistical anomaly, plasma Epo levels also predicted brain weight.…”

Section: Discussionmentioning

confidence: 99%

“…Exogenous Epo also exerts neuroprotective effects and is being studied in term newborns with hypoxic brain damage and premature infants (Bierer, Peceny, Hartenberger, & Ohls, ). Anemic premature infants with higher plasma Epo levels exhibit improved neurodevelopmental outcomes (Bierer et al, ; Ohls et al, ). Although not completely understood, preliminary work shows that Epo promotes oligodendrocyte differentiation to myelin‐producing cells and improves hippocampal dependent memory by modulating plasticity, synaptic connectivity and activity of memory‐related neuronal networks (Adamcio et al, ; Sugawa, Sakurai, Ishikawa‐Ieda, Suzuki, & Asou, ).…”

Section: Introductionmentioning

confidence: 99%

The impact of erythropoietin and iron status on brain myelination in the newborn rat

Flores

Blohowiak

Winzerling

et al. 2018

J of Neuroscience Research

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Erythropoietin (Epo) drives iron (Fe) utilization for erythropoiesis, but the potentially resultant tissue iron deficiency (ID) can also impede brain development. Conversely, Epo binds to Epo receptors (EpoR) on immature brain oligodendrocytes and neurons, promoting growth and differentiation. The objective of the study was to examine the interaction between Epo and Fe on myelination in brain development during daily Epo treatment. Male and female Sprague-Dawley rats from postnatal day (P) P4-P12 modeled premature newborns. Dam-fed Fe-sufficient (IS) or postnatal ID groups were given daily subcutaneous sham or erythropoietic Epo injections (425 U kg d ), ± oral Fe (6 mg kg d ). Tissues and blood were collected and studied at P12. Epo in the ID groups, in the absence of oral Fe, stimulated microcytic ID anemia along with raising inflammatory markers. Both the microcytic anemia and inflammation improved in the ID + Epo + Fe group. Fe treatment positively impacted erythropoiesis and body Fe (µg/g) in all groups. Relative brain Fe (µg/g rat) was improved in the IS + Epo + Fe group. Brain Fe was not worsened in +Epo groups. Brain weight and brain Fe were related to plasma Epo levels. Amount of myelination was impacted by feeding type, but was not inhibited by Epo. Expression of a protein in myelin, mylein basic protein, was greater in all +Fe groups than -Fe groups. With therapeutic Epo, available body Fe was prioritized for erythropoiesis instead of brain, but Epo did not worsen brain Fe and potentially Epo improved myelination and maturation in the brain.

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Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

Abstract: BACKGROUND:We previously reported improved neurodevelopmental outcomes at 2 years among infants treated with the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa (darbepoetin) or erythropoietin. Here we characterize 4-year outcomes.

Cited by 62 publications

References 34 publications

Erythropoietin for Neuroprotection in preterm infants

Erythropoietin for Neuroprotection in preterm infants

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

The impact of erythropoietin and iron status on brain myelination in the newborn rat

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