Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Emerging therapies and management for neonatal encephalopathy—controversies and current approaches

Abstract

Neonatal encephalopathy (NE) continues to have a major impact on newborn survival and neurodevelopmental outcomes worldwide. In high-income settings, therapeutic hypothermia is the only established standard treatment for neonates with moderate-to-severe NE, with compelling evidence that cooling reduces mortality and major neurodevelopmental impairment in survivors. Despite therapeutic hypothermia, a significant proportion of cooled infants continue to suffer long-term disability from brain injury. Innovative therapies offer the possibility of further improving neurodevelopmental outcomes by working synergistically with therapeutic hypothermia to decrease hypoxia-ischemia-induced excitotoxicity, prevent progression to secondary energy failure, and in some cases, promote neuroregeneration in the developing neonatal brain. This review discusses emerging NE therapies currently under investigation, offers insight into controversies surrounding various approaches to clinical care during therapeutic hypothermia, and identifies ongoing knowledge deficits that hinder attainment of optimal outcomes for neonates with NE.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Obstet Gynecol. 2014;123:896–901.

    Google Scholar 

  2. Natarajan G, Laptook A, Shankaran S. Therapeutic hypothermia: how can we optimize this therapy to further improve outcomes? Clin Perinatol. 2018;45:241–55.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–88.

    Article  Google Scholar 

  4. Dammann O, Ferriero D, Gressens P. Neonatal encephalopathy or hypoxic-ischemic encephalopathy? Appropriate terminology matters. Pediatr Res. 2011;70:1–2.

    Article  PubMed  Google Scholar 

  5. Packer CH, Hersh AR, Sargent JA, Caughey AB. Therapeutic hypothermia in severe hypoxic-ischemic encephalopathy: a cost-effectiveness analysis. J Matern Fetal Neonatal Med. 2020;1–8. https://doi.org/10.1080/14767058.2020.1733519. [Epub ahead of print].

  6. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane database Syst Rev. 2013;1:CD003311.

    Google Scholar 

  7. Juul SE, Pet GC. Erythropoietin and neonatal neuroprotection. Clin Perinatol. 2015;42:469–81.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Patel S, Ohls RK. Darbepoetin administration in term and preterm neonates. Clin Perinatol. 2015;42:557–66.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Razak A, Hussain A. Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinat Med. 2019;47:478–89.

    Article  PubMed  Google Scholar 

  11. Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124:e218–226.

    Article  PubMed  Google Scholar 

  12. Baserga MC, Beachy JC, Roberts JK, Ward RM, DiGeronimo RJ, Walsh WF, et al. Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial. Pediatr Res. 2015;78:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. El Shimi MS, Awad HA, Hassanein SM, Gad GI, Imam SS, Shaaban HA, et al. Single dose recombinant erythropoietin versus moderate hypothermia for neonatal hypoxic ischemic encephalopathy in low resource settings. J Matern Fetal Neonatal Med. 2014;27:1295–1300.

    Article  CAS  PubMed  Google Scholar 

  14. Malla RR, Asimi R, Teli MA, Shaheen F, Bhat MA. Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. J Perinatol. 2017;37:596–601.

    Article  CAS  PubMed  Google Scholar 

  15. Avasiloaiei A, Dimitriu C, Moscalu M, Paduraru L, Stamatin M. High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns. Pediatr Int. 2013;55:589–93.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. Lv HY, Wu SJ, Wang QL, Yang LH, Ren PS, Qiao BJ, et al. Effect of erythropoietin combined with hypothermia on serum tau protein levels and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Neural Regen Res. 2017;12:1655–63.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, et al. Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res. 2013;23:267–300.

    Article  CAS  PubMed  Google Scholar 

  19. Hsu CN, Huang LT, Tain YL. Perinatal use of melatonin for offspring health: focus on cardiovascular and neurological diseases. Int J Mol Sci. 2019;20:5681.

    Article  CAS  PubMed Central  Google Scholar 

  20. Fulia F, Gitto E, Cuzzocrea S, Reiter RJ, Dugo L, Gitto P, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res. 2001;31:343–9.

    Article  CAS  PubMed  Google Scholar 

  21. Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015;35:186–91.

    Article  CAS  PubMed  Google Scholar 

  22. Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial. J Pak Med Assoc. 2018;68:1233–7.

    PubMed  Google Scholar 

  23. Gitto E, Reiter RJ, Cordaro SP, La Rosa M, Chiurazzi P, Trimarchi G, et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol. 2004;21:209–16.

    Article  PubMed  Google Scholar 

  24. Gitto E, Reiter RJ, Amodio A, Romeo C, Cuzzocrea E, Sabatino G, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res. 2004;36:250–5.

    Article  CAS  PubMed  Google Scholar 

  25. Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, et al. Effects of melatonin treatment in septic newborns. Pediatr Res. 2001;50:756–60.

    Article  CAS  PubMed  Google Scholar 

  26. Okatani Y, Okamoto K, Hayashi K, Wakatsuki A, Tamura S, Sagara Y. Maternal-fetal transfer of melatonin in pregnant women near term. J Pineal Res. 1998;25:129–34.

    Article  CAS  PubMed  Google Scholar 

  27. Ruegger CM, Davis PG, Cheong JL. Xenon as an adjuvant to therapeutic hypothermia in near-term and term newborns with hypoxic-ischaemic encephalopathy. Cochrane database Syst Rev. 2018;8:CD012753.

    PubMed  Google Scholar 

  28. Azzopardi D, Robertson NJ, Bainbridge A, Cady E, Charles-Edwards G, Deierl A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol. 2016;15:145–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Koziakova M, Harris K, Edge CJ, Franks NP, White IL, Dickinson R. Noble gas neuroprotection: xenon and argon protect against hypoxic-ischaemic injury in rat hippocampus in vitro via distinct mechanisms. Br J Anaesth. 2019;123:601–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Htun Y, Nakamura S, Kusaka T. Hydrogen and therapeutic gases for neonatal hypoxic-ischemic encephalopathy: potential neuroprotective adjuncts in translational research. Pediatr Res. 2020. https://doi.org/10.1038/s41390-020-0998-z. [Epub ahead of print].

  31. Annink KV, Franz AR, Derks JB, Rudiger M, Bel FV, Benders M. Allopurinol: old drug, new indication in neonates? Curr Pharm Des. 2017;23:5935–42.

    Article  CAS  PubMed  Google Scholar 

  32. Kaandorp JJ, Benders MJ, Schuit E, Rademaker CM, Oudijk MA, Porath MM, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100:F216–223.

    Article  PubMed  Google Scholar 

  33. Chaparro-Huerta V, Flores-Soto ME, Merin Sigala ME, Barrera de Leon JC, Lemus-Varela ML, Torres-Mendoza BM, et al. Proinflammatory cytokines, enolase and S-100 as early biochemical indicators of hypoxic-ischemic encephalopathy following perinatal asphyxia in newborns. Pediatr Neonatol. 2017;58:70–76.

    Article  PubMed  Google Scholar 

  34. Kaandorp JJ, van Bel F, Veen S, Derks JB, Groenendaal F, Rijken M, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97:F162–166.

    Article  PubMed  Google Scholar 

  35. Van Bel F, Shadid M, Moison RM, Dorrepaal CA, Fontijn J, Monteiro L, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;101:185–93.

    Article  PubMed  Google Scholar 

  36. Benders MJ, Bos AF, Rademaker CM, Rijken M, Torrance HL, Groenendaal F, et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91:F163–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol. 2007;36:17–24.

    Article  PubMed  Google Scholar 

  38. Maiwald CA, Annink KV, Rudiger M, Benders M, van Bel F, Allegaert K, et al. Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). BMC Pediatr. 2019;19:210.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984;307:462–5.

    Article  CAS  PubMed  Google Scholar 

  40. Tagin M, Shah PS, Lee KS. Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinatol. 2013;33:663–9.

    Article  CAS  PubMed  Google Scholar 

  41. El Farargy MS, Soliman NA. A randomized controlled trial on the use of magnesium sulfate and melatonin in neonatal hypoxic ischemic encephalopathy. J Neonatal Perinat Med. 2019;12:379–84.

    Article  CAS  Google Scholar 

  42. Ichiba H, Yokoi T, Tamai H, Ueda T, Kim TJ, Yamano T. Neurodevelopmental outcome of infants with birth asphyxia treated with magnesium sulfate. Pediatr Int. 2006;48:70–5.

    Article  CAS  PubMed  Google Scholar 

  43. Zitta K, Peeters-Scholte C, Sommer L, Gruenewald M, Hummitzsch L, Parczany K, et al. 2-Iminobiotin superimposed on hypothermia protects human neuronal cells from hypoxia-induced cell damage: an in vitro study. Front Pharm. 2017;8:971.

    Article  Google Scholar 

  44. Biselele T, Bambi J, Betukumesu DM, Ndiyo Y, Tabu G, Kapinga J, et al. A phase IIa clinical trial of 2-iminobiotin for the treatment of birth Asphyxia in DR Congo, a low-income country. Paediatr Drugs. 2020;22:95–104.

    Article  PubMed  Google Scholar 

  45. Favie LMA, Peeters-Scholte C, Bakker A, Tjabbes H, Egberts TCG, van Bel F, et al. Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia. Pediatr Res. 2020;87:689–96.

    Article  CAS  PubMed  Google Scholar 

  46. Archambault J, Moreira A, McDaniel D, Winter L, Sun L, Hornsby P. Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: a systematic review and meta-analysis of preclinical studies. PloS one. 2017;12:e0189895.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bruschettini M, Romantsik O, Moreira A, Ley D, Thebaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Cochrane database Syst Rev. 2020;8:CD013202.

    PubMed  Google Scholar 

  48. Donega V, van Velthoven CT, Nijboer CH, van Bel F, Kas MJ, Kavelaars A, et al. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PloS One. 2013;8:e51253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. van Velthoven CT, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 2012;71:474–81.

    Article  PubMed  Google Scholar 

  50. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Verina T, Fatemi A, Johnston MV, Comi AM. Pluripotent possibilities: human umbilical cord blood cell treatment after neonatal brain injury. Pediatr Neurol. 2013;48:346–54.

    Article  PubMed  Google Scholar 

  52. McDonald CA, Penny TR, Paton MCB, Sutherland AE, Nekkanti L, Yawno T, et al. Effects of umbilical cord blood cells, and subtypes, to reduce neuroinflammation following perinatal hypoxic-ischemic brain injury. J Neuroinflammation. 2018;15:47.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Javed MJ, Mead LE, Prater D, Bessler WK, Foster D, Case J, et al. Endothelial colony forming cells and mesenchymal stem cells are enriched at different gestational ages in human umbilical cord blood. Pediatr Res. 2008;64:68–73.

    Article  PubMed  Google Scholar 

  54. Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, Smith PB, Goldstein RF, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatrics. 2014;164:973–9 e971.

    Article  Google Scholar 

  55. Tsuji M, Sawada M, Watabe S, Sano H, Kanai M, Tanaka E, et al. Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety. Sci Rep. 2020;10:4603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cotten CM, Fisher K, Kurtzberg J, Simmons R. Phase I trial of allogeneic umbilical cord tissue-derived mesenchymal stromal cells in neonates with hypoxic-ischemic encephalopathy. Cytotherapy. 2020;22:S192.

    Article  Google Scholar 

  57. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatrics. 2009;155:318–23.

    Article  Google Scholar 

  58. Yozawitz E, Stacey A, Pressler RM. Pharmacotherapy for seizures in neonates with hypoxic ischemic encephalopathy. Paediatr Drugs. 2017;19:553–67.

    Article  PubMed  Google Scholar 

  59. Filippi L, Fiorini P, Catarzi S, Berti E, Padrini L, Landucci E, et al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study. J Matern Fetal Neonatal Med. 2018;31:973–80.

    Article  CAS  PubMed  Google Scholar 

  60. Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010;8:254–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nunez-Ramiro A, Benavente-Fernandez I, Valverde E, Cordeiro M, Blanco D, Boix H, et al. Topiramate plus cooling for hypoxic-ischemic encephalopathy: a randomized, controlled, multicenter, double-blinded trial. Neonatology. 2019;116:76–84.

    Article  CAS  PubMed  Google Scholar 

  62. Bonifacio SL, McDonald SA, Chock VY, Wusthoff CJ, Hintz SR, Laptook AR, et al. Differences in patient characteristics and care practices between two trials of therapeutic hypothermia. Pediatr Res. 2019;85:1008–15.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Festekjian A, Ashwal S, Obenaus A, Angeles DM, Denmark TK. The role of morphine in a rat model of hypoxic-ischemic injury. Pediatr Neurol. 2011;45:77–82.

    Article  PubMed  Google Scholar 

  64. Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res. 2001;50:405–11.

    Article  CAS  PubMed  Google Scholar 

  65. McPherson C, Miller SP, El-Dib M, Massaro AN, Inder TE. The influence of pain, agitation, and their management on the immature brain. Pediatr Res. 2020;88:168–75.

    Article  PubMed  Google Scholar 

  66. Durrmeyer X, Vutskits L, Anand KJ, Rimensberger PC. Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data. Pediatr Res. 2010;67:117–27.

    Article  PubMed  Google Scholar 

  67. Frymoyer A, Bonifacio SL, Drover DR, Su F, Wustoff CJ, Van Meurs KP. Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia. J Clin Pharm. 2017;57:64–76.

    Article  CAS  Google Scholar 

  68. Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844–9.

    Article  PubMed  Google Scholar 

  69. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N. Engl J Med. 2009;361:1349–58.

    Article  CAS  PubMed  Google Scholar 

  70. Montaldo P, Vakharia A, Ivain P, Mendoza J, Oliveira V, Markati T, et al. Pre-emptive opioid sedation during therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2020;105:108–9.

    Article  PubMed  Google Scholar 

  71. Berube MW, Lemmon ME, Pizoli CE, Bidegain M, Tolia VN, Cotten CM, et al. Opioid and benzodiazepine use during therapeutic hypothermia in encephalopathic neonates. J Perinatol. 2020;40:79–88.

    Article  CAS  PubMed  Google Scholar 

  72. Natarajan G, Shankaran S, Laptook AR, McDonald SA, Pappas A, Hintz SR, et al. Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. J Perinatol. 2018;38:1060–7.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Pichot C, Ghignone M, Quintin L. Dexmedetomidine and clonidine: from second- to first-line sedative agents in the critical care setting? J Intensive Care Med. 2012;27:219–37.

    Article  CAS  PubMed  Google Scholar 

  74. Giovannitti JA Jr., Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62:31–9.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Lewis SR, Nicholson A, Smith AF, Alderson P. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia. Cochrane Database Syst Rev. 2015;8:CD011107.

    Google Scholar 

  76. Wassink G, Lear CA, Gunn KC, Dean JM, Bennet L, Gunn AJ. Analgesics, sedatives, anticonvulsant drugs, and the cooled brain. Semin Fetal Neonatal Med. 2015;20:109–14.

    Article  PubMed  Google Scholar 

  77. O’Mara K, Weiss MD. Dexmedetomidine for sedation of neonates with HIE undergoing therapeutic hypothermia: a single-center experience. AJP Rep. 2018;8:e168–73.

    Article  PubMed  PubMed Central  Google Scholar 

  78. McAdams RM, Pak D, Lalovic B, Phillips B, Shen DD. Dexmedetomidine pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Anesthesiol Res Pr. 2020;2020:2582965.

    Google Scholar 

  79. Chrysostomou C, Schulman SR, Herrera Castellanos M, Cofer BE, Mitra S, da Rocha MG, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J Pediatrics. 2014;164:276–82 e271-273.

    Article  CAS  Google Scholar 

  80. Greenberg RG, Wu H, Laughon M, Capparelli E, Rowe S, Zimmerman KO, et al. Population pharmacokinetics of dexmedetomidine in infants. J Clin Pharm. 2017;57:1174–82.

    Article  CAS  Google Scholar 

  81. Potts AL, Anderson BJ, Warman GR, Lerman J, Diaz SM, Vilo S. Dexmedetomidine pharmacokinetics in pediatric intensive care-a pooled analysis. Paediatr Anaesth. 2009;19:1119–29.

    Article  PubMed  Google Scholar 

  82. Badjatia N, Strongilis E, Gordon E, Prescutti M, Fernandez L, Fernandez A, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke. 2008;39:3242–7.

    Article  PubMed  Google Scholar 

  83. O’Dea M, Sweetman D, Bonifacio SL, El-Dib M, Austin T, Molloy EJ. Management of multi organ dysfunction in neonatal encephalopathy. Front Pediatr. 2020;8:239.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Li B, Concepcion K, Meng X, Zhang L. Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Prog Neurobiol. 2017;159:50–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Davidson JO, Dean JM, Fraser M, Wassink G, Andelius TC, Dhillon SK, et al. Perinatal brain injury: mechanisms and therapeutic approaches. Front Biosci. 2018;23:2204–26.

    Article  Google Scholar 

  87. Cikla U, Chanana V, Kintner DB, Covert L, Dewall T, Waldman A, et al. Suppression of microglia activation after hypoxia-ischemia results in age-dependent improvements in neurologic injury. J Neuroimmunol. 2016;291:18–27.

    Article  CAS  PubMed  Google Scholar 

  88. Faustino JV, Wang X, Johnson CE, Klibanov A, Derugin N, Wendland MF, et al. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci. 2011;31:12992–3001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ma Q, Dasgupta C, Li Y, Bajwa NM, Xiong F, Harding B, et al. Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats. Neurobiol Dis. 2016;89:202–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang Y, Xu N, Ding Y, Doycheva DM, Zhang Y, Li Q, et al. Chemerin reverses neurological impairments and ameliorates neuronal apoptosis through ChemR23/CAMKK2/AMPK pathway in neonatal hypoxic-ischemic encephalopathy. Cell Death Dis. 2019;10:97.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Janowska J, Gargas J, Ziemka-Nalecz M, Zalewska T, Sypecka J. Oligodendrocyte response to pathophysiological conditions triggered by episode of perinatal hypoxia-ischemia: role of IGF-1 secretion by glial cells. Mol Neurobiol. 2020;57:4250–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Favie LMA, Cox AR, van den Hoogen A, Nijboer CHA, Peeters-Scholte C, van Bel F, et al. Nitric oxide synthase inhibition as a neuroprotective strategy following hypoxic-ischemic encephalopathy: evidence from animal studies. Front Neurol. 2018;9:258.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Charriaut-Marlangue C, Besson VC, Baud O. Sexually dimorphic outcomes after neonatal stroke and hypoxia-ischemia. Int J Mol Sci. 2017;19:61.

    Article  PubMed Central  Google Scholar 

  94. Peebles PJ, Duello TM, Eickhoff JC, McAdams RM. Antenatal and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy. J Perinatol. 2020;40:63–9.

    Article  CAS  PubMed  Google Scholar 

  95. Popescu MR, Panaitescu AM, Pavel B, Zagrean L, Peltecu G, Zagrean AM. Getting an early start in understanding perinatal asphyxia impact on the cardiovascular system. Front Pediatr. 2020;8:68.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PloS One. 2013;8:e58834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Thayyil S. Cooling therapy for the management of hypoxic-ischaemic encephalopathy in middle-income countries: we can, but should we? Paediatr Int Child Health. 2019;39:231–3.

    Article  PubMed  Google Scholar 

  98. Qin X, Cheng J, Zhong Y, Mahgoub OK, Akter F, Fan Y, et al. Mechanism and treatment related to oxidative stress in neonatal hypoxic-ischemic encephalopathy. Front Mol Neurosci. 2019;12:88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mutlu M, Sariaydin M, Aslan Y, Kader S, Dereci S, Kart C, et al. Status of vitamin D, antioxidant enzymes, and antioxidant substances in neonates with neonatal hypoxic-ischemic encephalopathy. J Matern Fetal Neonatal Med. 2016;29:2259–63.

    CAS  PubMed  Google Scholar 

  100. Thornton C, Baburamani AA, Kichev A, Hagberg H. Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic-ischaemic brain injury. Biochem Soc Trans. 2017;45:1067–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, et al. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2018;38:80–5.

    Article  CAS  PubMed  Google Scholar 

  102. Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S, et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res. 2018;84:861–8.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Oliveira V, Martins R, Liow N, Teiserskas J, von Rosenberg W, Adjei T, et al. Prognostic accuracy of heart rate variability analysis in neonatal encephalopathy: a systematic review. Neonatology. 2019;115:59–67.

    Article  PubMed  Google Scholar 

  104. Chalak LF, Adams-Huet B, Sant’Anna G. A total sarnat score in mild hypoxic-ischemic encephalopathy can detect infants at higher risk of disability. J Pediatr. 2019;214:217–21 e211.

    Article  PubMed  Google Scholar 

  105. Harbert MJ, Tam EW, Glass HC, Bonifacio SL, Haeusslein LA, Barkovich AJ, et al. Hypothermia is correlated with seizure absence in perinatal stroke. J Child Neurol. 2011;26:1126–30.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates who do not fulfil the standard cooling criteria - short- and long-term outcomes. Acta Paediatr. 2015;104:138–45.

    Article  PubMed  Google Scholar 

  107. Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of therapeutic hypothermia initiated after 6 h of age on death or disability among newborns with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA. 2017;318:1550–60.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Walloe L, Hjort NL, Thoresen M. Why results from Bayesian statistical analyses of clinical trials with a strong prior and small sample sizes may be misleading The case of the NICHD Neonatal Research Network Late Hypothermia Trial. Acta Paediatr. 2019;108:1190–1.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Califf RM. Biomarker definitions and their applications. Exp Biol Med. 2018;243:213–21.

    Article  CAS  Google Scholar 

  110. Sanchez Fernandez I, Morales-Quezada JL, Law S, Kim P. Prognostic value of brain magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2017;32:1065–73.

    Article  PubMed  Google Scholar 

  111. Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312:2629–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018;16:29.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Dr. Pamela Kling for her valuable editing advice.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ryan M. McAdams.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McAdams, R.M., Berube, M.W. Emerging therapies and management for neonatal encephalopathy—controversies and current approaches. J Perinatol 41, 661–674 (2021). https://doi.org/10.1038/s41372-021-01022-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-021-01022-9

This article is cited by

Search

Quick links