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Review
. 2020 Feb 21;21(4):1487.
doi: 10.3390/ijms21041487.

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

Dorothy E Oorschot  1 , Rachel J Sizemore  1 , Ashraf R Amer  1
Affiliations
Review

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

Dorothy E Oorschot et al. Int J Mol Sci. .

Abstract

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.

Keywords: anemia of prematurity; erythropoietin; moderate hypothermia; neonatal hypoxia-ischemia; perinatal hypoxic-ischemic encephalopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Timeline of the history of EPO in the context of its discovery, hypoxia-induced signalling processes (and the associated Nobel Prize), its use in animal studies on perinatal hypoxia-ischemia (HI) and its use in clinical trials on neonatal hypoxic-ischemic encephalopathy (HIE).
Figure 2
Figure 2
A summary of the immediate, neuroprotective, and restorative effects of EPO in the hypoxic-injured brain.
See this image and copyright information in PMC

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