A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants

Juul, Sandra E.; Comstock, Bryan A.; Wadhawan, Rajan; Mayock, Dennis E.; Courtney, Sherry E.; Robinson, Tonya; Ahmad, Kaashif A.; Bendel-Stenzel, Ellen; Baserga, Mariana; LaGamma, Edmund F.; Downey, L. Corbin; Rao, Raghavendra; Fahim, Nancy; Lampland, Andrea; Frantz, Ivan D.; Khan, Janine Y.; Weiss, Michael; Gilmore, Maureen; Ohls, Robin K.; Srinivasan, Nishant; Pérez, Jorge Enrique; McKay, Victor; Vu, Phuong T.; Lowe, Jean; Kuban, Karl; O’Shea, T. Michael; Hartman, Adam L.; Heagerty, Patrick J.

doi:10.1056/nejmoa1907423

Cited by 249 publications

(280 citation statements)

References 41 publications

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“…For extremely preterm infants born at 24 to 27 weeks-of-gestation, Juul et al 2020 [147] published a Phase III Preterm EPO Neuroprotection (PENUT) clinical trial [NCT01378273] involving 936 subjects. It aimed to evaluate the effect of treatment with EPO on the combined effect of death or severe neurodevelopmental impairment at 24 months-of-age.…”

Section: Effects Of Epo In Clinical Trials For Preterm Infantsmentioning

confidence: 99%

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Oorschot

Sizemore

Amer

2020

IJMS

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Perinatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of morbidity and mortality. Moderate hypothermia (33.5 °C) is currently the sole established standard treatment. However, there are a large number of infants for whom this therapy is ineffective. This inspired global research to find neuroprotectants to potentiate the effect of moderate hypothermia. Here we examine erythropoietin (EPO) as a prominent candidate. Neonatal animal studies show that immediate, as well as delayed, treatment with EPO post-injury, can be neuroprotective and/or neurorestorative. The observed improvements of EPO therapy were generally not to the level of control uninjured animals, however. This suggested that combining EPO treatment with an adjunct therapeutic strategy should be researched. Treatment with EPO plus hypothermia led to less cerebral palsy in a non-human primate model of perinatal asphyxia, leading to clinical trials. A recent Phase II clinical trial on neonatal infants with HIE reported better 12-month motor outcomes for treatment with EPO plus hypothermia compared to hypothermia alone. Hence, the effectiveness of combined treatment with moderate hypothermia and EPO for neonatal HIE currently looks promising. The outcomes of two current clinical trials on neurological outcomes at 18–24 months-of-age, and at older ages, are now required. Further research on the optimal dose, onset, and duration of treatment with EPO, and critical consideration of the effect of injury severity and of gender, are also required.

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Section: Effects Of Epo In Clinical Trials For Preterm Infantsmentioning

confidence: 99%

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Oorschot

Sizemore

Amer

2020

IJMS

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“…On this background a recent multicenter (19 sites, 30 hospitals), randomized, double-blind trial of EPO was undertaken in 741 infants (24 to 27 6/7 weeks' 150 J.J. Volpe / Erythropoertin for premature brain gestation) [PENUT trial], i.e., preterm EPO Neuroprotection] [11]. Infants were administered EPO or placebo within 24 hours of birth and continued through 32 weeks' gestational age.…”

Section: Penut Trialmentioning

confidence: 99%

“…Thus, no differences between the EPO and placebo groups were observed at 22 to 26 months of age in the primary outcome of death or severe neurological impairment (26% vs. 26%), or in the key secondary outcome of death or moderate to severe neurodevelopmental impairment (48% vs. 47%). A limitation of the study, explicitly acknowledged by the investigators [11], is that cognitive testing at two years of age is not so reliable as testing at later ages [13]. Thus, a metaanalysis of 24 studies in which early assessments (by Bayley Scales of Infant Development-III or Griffiths Scales of Mental Development) performed at 1 1/2 to 3 years of age were compared with later cognitive tests carried out at school age showed that the pooled sensitivity of early assessments for identifying school-age cognitive deficits was only 55%.…”

Section: Penut Trialmentioning

confidence: 99%

“…The duration of treatment in the PENUT trial (onset 24-28 weeks' gestational age and continued to 32 weeks' postconceptional age) "was determined on the basis of the period of oligodendrocyte vulnerability" [11]. Indeed, this period is the peak time for the occurrence of overt periventricular leukomalacia [3].…”

Section: Critical Importance Of Duration Of Epo Treatmentmentioning

confidence: 99%

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Commentary – Do the negative results of the PENUT trial close the book on erythropoietin for premature infant brain?

Volpe

2020

NPM

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“…Similarly, high-dose EPO administration prompts newly differentiating neurons in the adult mouse brain [2]. Instead, it was recently showed that high-dose EPO treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age [3]. Nevertheless, the primary cause of this discrepant phenomenon is still puzzling.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Promotes the Differentiation of Fetal Neural Stem Cells into Glial Cells Partly via EPOR-βCR/Syne-1/H3K9me3 Pathway

Zhang

Wang

et al. 2020

Preprint

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Abstract Erythropoietin (EPO) treatment has achieved a remarkable improvement of cognition in neonatal hypoxic-ischae mic encephalopathy (HIE) in clinical settings, however, it did not lower the severe neurodevelopmental impairment to extremely preterm infants, however, the primary cause of this discrepant phenomenon is still puzzling. Here, we explore the effect of EPO on post-hypoxic neurogenesis using fetal neural stem cells (NSCs)/neural progenitors (NPs) and whether the effect is mediated by EPOR/βCR heteromimer. Fetal NSCs/NPs was treated with EPO at different time point after oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability, proliferation, and differentiation of NSCs/NPs were detected by CellTiter-Glo, Edu assay, flow cytometry and RT-PCR. We found that EPO treatment at different time point increased the cell viability without affecting the proliferation. EPO treatment immediately after OGD/R promoted the oligodendrocyte and astrocyte differentiation, while decreased neuronal differentiation of NSCs/NPs. Furthermore, immunofluorescence and co-immunoprecipitation proved the existence of EPOR/βCR heterodimer on NSCs/NPs, and EPO treatment significantly increase the mRNA expression of βCR and elevated the correlation between levels of EPOR and βCR. Moreover, EPOR and βCR receptors were both correlated with markers of oligodendrocytes. In addition, mass spectrometer analysis identified Syne-1 as one downstream signaling of EPOR/βCR heterodimer. Immunofluorescence and western blot indicated that βCR/Syne-1/H3K9me3 pathway was possibly involved in the function of EPO. Collectively, our data revealed that EPO treatment immediately after OGD/R was not a good time point for neurogenesis, and EPO could promote the formation of EPOR/βCR on fetal NSCs/NPs which mediates its function on glia differentiation.

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A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants

Cited by 249 publications

References 41 publications

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

Commentary – Do the negative results of the PENUT trial close the book on erythropoietin for premature infant brain?

Erythropoietin Promotes the Differentiation of Fetal Neural Stem Cells into Glial Cells Partly via EPOR-βCR/Syne-1/H3K9me3 Pathway

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