Neonatal Med.  2022 Nov;29(4):123-129. 10.5385/nm.2022.29.4.123.

Erythropoietin Reduces Death and Neurodevelopmental Impairment in Neonatal Hypoxic-Ischemic Encephalopathy

Affiliations
  • 1Department of Pediatrics, Inha University Hospital, Incheon, Korea
  • 2Department of Pediatrics, Inha University College of Medicine, Incheon, Korea

Abstract

Purpose
Erythropoietin (EPO) is a promising neuroprotective drug. We investigated whether EPO has beneficial effects on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE).
Methods
We retrospectively reviewed the data of 56 infants with HIE born at or after 35 weeks of gestation who were admitted to Inha University Hospital between 2012 and 2021. Patients were divided into two groups based on EPO use and compared. In the EPO group, patients were administered 1,000 U/kg of EPO on days 1, 2, 3, 5, and 7, starting within 24 hours after birth. The primary outcome was death or neurodevelopmental impairment (NDI) at the age of 12 months.
Results
EPO was administered to 38 infants, and 18 did not receive EPO. Only 37.5% of patients with HIE (21/56) and 60% of patients with moderate-to-severe HIE (21/35) received therapeutic hypothermia. Among all patients with HIE, death or NDI (21.1 % vs. 50.0%; odds ratio [OR], 0.09; 95% confidence interval [CI], 0.01 to 0.78; P=0.029) and brain injury on imaging (42.1% vs. 83.3%; OR, 0.16; 95% CI, 0.03 to 0.92; P=0.040) were significantly lower in the EPO group than in the control group. Among patients with moderate-to-severe HIE, brain injury on imaging (54.2% vs. 90.9%; OR, 0.04; 95% CI, 0.002 to 0.700; P=0.027) was significantly lower in the EPO group than in the control group.
Conclusion
EPO administration significantly reduced mortality and NDI in infants with HIE. EPO can be considered an adjunctive therapeutic agent for neonatal HIE.

Keyword

Hypoxia-ischemia, brain; Erythropoietin; Asphyxia neonatorum

Figure

  • Figure 1. Study participants. Abbreviations: EPO, erythropoietin; HT, hypothermia.


Reference

1. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022; 6:106–15.
2. Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed. 2017; 102:F346–58.
3. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2012; 166:558–66.
4. Sung IK. Therapeutic hypothermia for hypoxic-ischemic encephalopathy in newborn infants. Neonatal Med. 2017; 24:145–56.
5. Sugawa M, Sakurai Y, Ishikawa-Ieda Y, Suzuki H, Asou H. Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res. 2002; 44:391–403.
6. Sun Y, Zhou C, Polk P, Nanda A, Zhang JH. Mechanisms of erythropoietin-induced brain protection in neonatal hypoxiaischemia rat model. J Cereb Blood Flow Metab. 2004; 24:259–70.
7. Oorschot DE, Sizemore RJ, Amer AR. Treatment of neonatal hypoxic-ischemic encephalopathy with erythropoietin alone, and erythropoietin combined with hypothermia: history, current status, and future research. Int J Mol Sci. 2020; 21:1487.
8. Razak A, Hussain A. Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinat Med. 2019; 47:478–89.
9. Juul SE, Comstock BA, Heagerty PJ, Mayock DE, Goodman AM, Hauge S, et al. High-dose erythropoietin for asphyxia and encephalopathy (HEAL): a randomized controlled trial: background, aims, and study protocol. Neonatology. 2018; 113:331–8.
10. Mulkey SB, Ramakrishnaiah RH, McKinstry RC, Chang T, Mathur AM, Mayock DE, et al. Erythropoietin and brain magnetic resonance imaging findings in hypoxic-ischemic encephalopathy: volume of acute brain injury and 1-year neurodevelopmental outcome. J Pediatr. 2017; 186:196–9.
11. Park SH. Clinical trials for preterm infants’ neurodevelopment to the norm: erythropoietin and nutritional interventions. Neonatal Med. 2017; 24:101–9.
12. Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016; 137:e20160191.
13. Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxicischemic encephalopathy. Pediatrics. 2009; 124:e218–26.
14. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol. 1976; 33:696–705.
15. Jacobs SE. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. J Pediatr. 2005; 147:122–3.
16. Hassell KJ, Ezzati M, Alonso-Alconada D, Hausenloy DJ, Robertson NJ. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed. 2015; 100:F541–52.
17. Linkenheimer WH, Grant WC, Berger H. Erythropoietin and known erythropoietic stimuli. Proc Soc Exp Biol Med. 1960; 104:230–2.
18. Halperin DS, Wacker P, Lacourt G, Felix M, Babel JF, Aapro M, et al. Effects of recombinant human erythropoietin in infants with the anemia of prematurity: a pilot study. J Pediatr. 1990; 116:779–86.
19. Ananthan A, Balasubramanian H, Rao S, Patole S. Clinical outcomes related to the gastrointestinal trophic effects of erythropoietin in preterm neonates: a systematic review and metaanalysis. Adv Nutr. 2018; 9:238–46.
20. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2012; 10:CD004865.
21. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2014; 4:CD004863.
22. Xiong Y, Mahmood A, Meng Y, Zhang Y, Qu C, Schallert T, et al. Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. J Neurosurg. 2010; 113:598–608.
23. Gonzalez FF, Larpthaveesarp A, McQuillen P, Derugin N, Wendland M, Spadafora R, et al. Erythropoietin increases neurogenesis and oligodendrogliosis of subventricular zone precursor cells after neonatal stroke. Stroke. 2013; 44:753–8.
24. Kaneko N, Kako E, Sawamoto K. Enhancement of ventricularsubventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives. Front Cell Neurosci. 2013; 7:235.
25. Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y, et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci. 2006; 26:5996–6003.
26. Villa P, van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, et al. Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab. 2007; 27:552–63.
27. Gonzalez FF, Abel R, Almli CR, Mu D, Wendland M, Ferriero DM. Erythropoietin sustains cognitive function and brain volume after neonatal stroke. Dev Neurosci. 2009; 31:403–11.
28. Fan X, Heijnen CJ, van der Kooij MA, Groenendaal F, van Bel F. Beneficial effect of erythropoietin on sensorimotor function and white matter after hypoxia-ischemia in neonatal mice. Pediatr Res. 2011; 69:56–61.
29. Elmahdy H, El-Mashad AR, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010; 125:e1135–42.
30. Ohls RK, Cannon DC, Phillips J, Caprihan A, Patel S, Winter S, et al. Preschool assessment of preterm infants treated with darbepoetin and erythropoietin. Pediatrics. 2016; 137:e20153859.
31. Song J, Sun H, Xu F, Kang W, Gao L, Guo J, et al. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol. 2016; 80:24–34.
32. Fischer HS, Reibel NJ, Buhrer C, Dame C. Prophylactic early erythropoietin for neuroprotection in preterm infants: a metaanalysis. Pediatrics. 2017; 139:e20164317.
33. Wu YW, Bauer LA, Ballard RA, Ferriero DM, Glidden DV, Mayock DE, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012; 130:683–91.
34. Juul SE, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, et al. A randomized trial of erythropoietin for neuroprotection in preterm infants. N Engl J Med. 2020; 382:233–43.
Full Text Links
  • NM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr