Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy: Current Evidence and Clinical Practice- A Literature Review
DOI:
https://doi.org/10.12775/QS.2026.54.70752Keywords
neonatal hypoxic ischemic encephalopathy, therapeutic hypothermia, neonatal asphyxia, hypothermia treatment, mild hypoxic ischemic encephalopathy, neonatal encephalopathy, therapeutic hypothermia neonatal complications, clinical efficacy of neonatal therapeutic hypothermiaAbstract
Background: Hypoxic-ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long term neurodevelopmental impairment worldwide. Therapeutic hypothermia (TH) is currently the standard of care for newborns with moderate-to-severe HIE; however, several aspects of its use remain controversial.
Aim: The aim of this paper is to present the current state of knowledge regarding the use of therapeutic hypothermia in newborns with HIE with particular emphasis on mechanisms of action, eligibility criteria, course of therapy, clinical efficacy and adverse effects, as well as to discuss current controversies and directions for further research.
Material and methods: A narrative literature review was conducted using the PubMed database to identify studies on therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy. Publications from the past 11 years were included with particular emphasis on studies published within the last 5 years. Relevant original articles and review papers focusing on clinical outcomes and effectiveness were analyzed.
Results: Therapeutic hypothermia reduces the risk of death and severe neurodevelopmental disability in newborns with moderate and severe HIE. Its neuroprotective effects are associated with reduced cerebral metabolism, decreased oxidative stress, modulation of inflammatory response, and inhibition of apoptosis. However, its efficacy in mild HIE and in preterm infants remains inconclusive. The most common adverse effects include cardiovascular, metabolic, and hematological disturbances requiring close monitoring.
Conclusions: Therapeutic hypothermia is an effective and relatively safe treatment for HIE; however, it does not completely eliminate the risk of neurodevelopmental impairment. Further research is needed to optimize treatment protocols, expand its use to other populations and evaluate combination therapies.
References
1. Chakkarapani E, de Vries LS, Ferriero DM, Gunn AJ. Neonatal encephalopathy and hypoxic-ischemic encephalopathy: the state of the art. Pediatric Research 2025;98(7):2444-2458. https://doi.org/10.1038/s41390-025-03986-2.
2. McDouall A, Wassink G, Bennet L, Gunn AJ, Davidson JO. Challenges in developing therapeutic strategies for mild neonatal encephalopathy. Neural Regeneration Research 2022;17(2):277-282. https://doi.org/10.4103/1673-5374.317963.
3. Weeke LC, Groenendaal F, Toet MC, Benders MJ, Nievelstein RA, van Rooij LG, de Vries LS. The aetiology of neonatal seizures and the diagnostic contribution of neonatal cerebral magnetic resonance imaging. Developmental Medicine and Child Neurology 2015;57(3):248-256. https://doi.org/10.1111/dmcn.12629.
4. Tsuda K, Shibasaki J, Isayama T, Takeuchi A, Mukai T, Sugiyama Y, Ioroi T, Takahashi A, Yutaka N, Iwata S, Nabetani M, Iwata O. Three-year outcome following neonatal encephalopathy in a high-survival cohort. Scientific reports 2022;12(1):7945. https://doi.org/10.1038/s41598-022-12091-x.
5. Greco P, Nencini G, Piva I, Scioscia M, Volta CA, Spadaro S, Neri M, Bonaccorsi G, Greco F, Cocco I, Sorrentino F, D'Antonio F, Nappi L. Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future. Acta Neurologica Belgica 2020;120(2):277-288. https://doi.org/10.1007/s13760-020-01308-3.
6. Namusoke H, Nannyonga MM, Ssebunya R, Nakibuuka VK, Mworozi E. Incidence and short term outcomes of neonates with hypoxic ischemic encephalopathy in a peri-urban teaching hospital, Uganda: a prospective cohort study. Maternal Health, Neonatology and Perinatology 2018;4:6. https://doi.org/10.1186/s40748-018-0074-4.
7. Ezenwa BN, Olorunfemi G, Fajolu I, Adeniyi T, Oleolo-Ayodeji K, Kene-Udemezue B, Olamijulo JA, Ezeaka C. Trends and predictors of in-hospital mortality among babies with hypoxic ischaemic encephalopathy at a tertiary hospital in Nigeria: a retrospective cohort study. Plos One 2021;16(4):e0250633. https://doi.org/10.1371/journal.pone.0250633.
8. Gunn AJ, Laptook AR, Robertson NJ, Barks JD, Thoresen M, Wassink G, Bennet L. Therapeutic hypothermia translates from ancient history into practice. Pediatric Research 2017;81(1-2):202-209. https://doi.org/10.1038/pr.2016.198.
9. Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatrics 2015;169(4):397-403.
https://doi.org/10.1001/jamapediatrics.2014.3269.
10. Chiang MC, Lien R, Chu SM, Yang PH, Lin JJ, Hsu JF, Fu RH, Lin KL. Serum lactate, brain magnetic resonance imaging and outcome of neonatal hypoxic ischemic encephalopathy after therapeutic hypothermia. Pediatrics and Neonatology 2016;57(1):35-40. https://doi.org/10.1016/j.pedneo.2015.04.008.
11. Mrelashvili A, Russ JB, Ferriero DM, Wusthoff CJ. The Sarnat score for neonatal encephalopathy: looking back and moving forward. Pediatric Research 2020;88(6):824-825. https://doi.org/10.1038/s41390-020-01143-5.
12. Widłak K, Wójtowicz A, Ściślak R, Drankowska J, Kos M, Szuster A, Tarkowska A, Szponar E, Furmaga-Jabłońska W. Ischemic Stroke As a Rare Cause of Seizures in a Newborn- Case Report. Journal Education Health Sport 2019,9, 76-84. http://dx.doi.org/10.5281/zenodo.3265753
13. Vesoulis ZA, Liao SM, Rao R, Trivedi SB, Cahill AG, Mathur AM. Re-examining the arterial cord blood gas pH screening criteria in neonatal encephalopathy. Archives of Disease in Childhood - Fetal and Neonatal Edition 2018;103(4):F377-F382. https://doi.org/10.1136/archdischild-2017-313078.
14. Branagan A, Hurley T, Quirke F, Devane D, Taneri PE, Badawi N, Sinha B, Bearer C, Bloomfield FH, Bonifacio SL, Boylan G, Campbell SK, Chalak L, D'Alton M, de Vries LS, El Dib M, Ferriero DM, Gale C, Gressens P, Gunn AJ, Kay S, Maeso B, Mulkey SB, Murray DM, Nelson KB, Nesterenko TH, Pilon B, Robertson NJ, Walker K, Wusthoff CJ, Molloy EJ; Steering Group for DEFiNE. Consensus definition and diagnostic criteria for neonatal encephalopathy: study protocol for a real-time modified Delphi study. Pediatric Research 2025;97(1):430 436. https://doi.org/10.1038/s41390-024-03303-3.
15. Sutin J, Vyas R, Feldman HA, Ferradal S, Hsiao CH, Zampolli L, Pierce LJ, Nelson CA, Morton SU, Hay S, El-Dib M, Soul JS, Lin PY, Grant PE. Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy. EBioMedicine 2023;94:104673. https://doi.org/10.1016/j.ebiom.2023.104673.
16. Koryszko K, Pokrywka N, Suwała D, Polak M, Hetnar P, Kiper S, Fortuna M, Toczek S, Tomala M, Jastrowicz-Chęć, K. Therapeutic Hypothermia As a Treatment Strategy for Neonates Born in Asphyxia - a Review of the Current State of Knowledge. Quality of Sport 2025, 43, 61418 https://doi.org/10.12775/QS.2025.43.61418
17. Vega-Del-Val C, Arnaez J, Caserío S, Gutiérrez EP, Castañón L, Benito M, Garcia-Alix A; Grupo ARAHIP. Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy. Anales de Pediatria (English Edition) 2022;97(1):30-39. https://doi.org/10.1016/j.anpede.2021.07.007.
18. Herrera TI, Edwards L, Malcolm WF, Smith PB, Fisher KA, Pizoli C, Gustafson KE, Goldstein RF, Cotten CM, Goldberg RN, Bidegain M. Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy. Early Human Development 2018;125:1-7. https://doi.org/10.1016/j.earlhumdev.2018.08.003.
19. Faix RG, Laptook AR, Shankaran S, Eggleston B, Chowdhury D, Heyne RJ, Das A, Pedroza C, Tyson JE, Wusthoff C, Bonifacio SL, Sánchez PJ, Yoder BA, Laughon MM, Vasil DM, Van Meurs KP, Crawford MM, Higgins RD, Poindexter BB, Colaizy TT, Hamrick SEG, Chalak LF, Ohls RK, Hartley-McAndrew ME, Dysart K, D'Angio CT, Guillet R, Kicklighter SD, Carlo WA, Sokol GM, DeMauro SB, Hibbs AM, Cotten CM, Merhar SL, Bapat RV, Harmon HM, Sewell E, Winter S, Natarajan G, Mosquera R, Hintz SR, Maitre NL, Benninger KL, Peralta-Carcelen M, Hines AC, Duncan AF, Wilson-Costello DE, Trembath A, Malcolm WF, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonatal encephalopathy in preterm infants 33 to 35 weeks' gestation: a randomized clinical trial. JAMA Pediatrics 2025;179(4):396-406. https://doi.org/10.1001/jamapediatrics.2024.6613.
20. Rao R, Trivedi S, Vesoulis Z, Liao SM, Smyser CD, Mathur AM. Safety and short-term outcomes of therapeutic hypothermia in preterm neonates 34-35 weeks gestational age with hypoxic-ischemic encephalopathy. The Journal Pediatrics 2017;183:37-42. https://doi.org/10.1016/j.jpeds.2016.11.019.
21. Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen KA, Mir I, Pappas A, Montaldo P, Thayyil S, Sánchez PJ, Shankaran S, Laptook AR, Sant'Anna G. Prospective research on infants with mild encephalopathy: the PRIME study. Journal of Perinatology 2018;38(1):80-85. https://doi.org/10.1038/jp.2017.164.
22. Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatrics 2020;174(1):48-55. https://doi.org/10.1001/jamapediatrics.2019.4011.
23. Garegrat R, Montaldo P, Burgod C, Pant S, Mazlan M, Palanisami B, Chakkarapani E, Woolfall K, Johnson S, Grant PE, Land S, Mahmoud M, Brady T, Cornelius V, Adams E, Dorling J, Aladangadi N, Fleming P, Pressler R, Shennan A, Petrou S, Soe A, Basset P, Shankaran S, Thayyil S. Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomized controlled trial. BMC Pediatrics 2024;24(1):460. https://doi.org/10.1186/s12887-024-04935-4.
24. Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, Parikh NA, Ambalavanan N, Pedroza C, Pappas A, Das A, Chaudhary AS, Ehrenkranz RA, Hensman AM, Van Meurs KP, Chalak LF, Khan AM, Hamrick SEG, Sokol GM, Walsh MC, Poindexter BB, Faix RG, Watterberg KL, Frantz ID 3rd, Guillet R, Devaskar U, Truog WE, Chock VY, Wyckoff MH, McGowan EC, Carlton DP, Harmon HM, Brumbaugh JE, Cotten CM, Sánchez PJ, Hibbs AM, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA 2017;318(16):1550-1560. https://doi.org/10.1001/jama.2017.14972.
25. Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Huitema CMP, Grisby C, Devaskar U, Ehrenkranz RA, Harmon HM, Chalak LF, DeMauro SB, Garg M, Hartley-McAndrew ME, Khan AM, Walsh MC, Ambalavanan N, Brumbaugh JE, Watterberg KL, Shepherd EG, Hamrick SEG, Barks J, Cotten CM, Kilbride HW, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA. 2017;318(1):57-67. https://doi.org/10.1001/jama.2017.7218.
26. Ouwehand S, Smidt LCA, Dudink J, Benders MJNL, de Vries LS, Groenendaal F, van der Aa NE. Predictors of outcomes in hypoxic-ischemic encephalopathy following hypothermia: a meta-analysis. Neonatology 2020;117(4):411-427. https://doi.org/10.1159/000505519.
27. Chakkarapani E, Poskitt KJ, Miller SP, Zwicker JG, Xu Q, Wong DS, Roland EH, Hill A, Chau V. Reliability of early magnetic resonance imaging and necessity of repeating MRI in noncooled and cooled infants with neonatal encephalopathy. Journal of Child Neurology 2016;31(5):553-559. https://doi.org/10.1177/0883073815600865.
28. Mitra S, Kendall GS, Bainbridge A, Sokolska M, Dinan M, Uria-Avellanal C, Price D, McKinnon K, Gunny R, Huertas-Ceballos A, Golay X, Robertson NJ. Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year outcomes in neonatal encephalopathy after therapeutic hypothermia. Archives of Disease in Childhood - Fetal and Neonatal Edition 2019;104(4):F424-F432. https://doi.org/10.1136/archdischild-2018-315478.
29. Spencer APC, Lee-Kelland R, Brooks JCW, Jary S, Tonks J, Cowan FM, Thoresen M, Chakkarapani E. Brain volumes and functional outcomes in children without cerebral palsy after therapeutic hypothermia. Developmental Medicine and Child Neurology 2023;65(3):367-375. https://doi.org/10.1111/dmcn.15369.
30. Spencer APC, Lequin MH, de Vries LS, Brooks JCW, Jary S, Tonks J, Cowan FM, Thoresen M, Chakkarapani E. Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy. Developmental Medicine and Child Neurology 2023;65(6):792-802. https://doi.org/10.1111/dmcn.15453.
31. Geisinger R, Rios DR, McNamara PJ, Levy PT. Asphyxia, therapeutic hypothermia, and pulmonary hypertension. Clinics in Perinatology 2024;51(1):127-149. https://doi.org/10.1016/j.clp.2023.11.007.
32. Acun C, Ali M, Liu W, Karnati S, Fink K, Aly H. Effectiveness and safety of dexmedetomidine in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. The Journal of Pediatric Pharmacology and Therapeutics 2024;29(3):232-240. https://doi.org/10.5863/1551-6776-29.3.232.
33. Odd D, Sabir H, Jones SA, Gale C, Chakkarapani E. Risk factors for infection and outcomes in infants with neonatal encephalopathy: a cohort study. Pediatric Research 2024;96(3):785-791. https://doi.org/10.1038/s41390-024-03157-9.
34. Lakatos A, Kolossváry M, Szabó M, Jermendy Á, Barta H, Gyebnár G, Rudas G, Kozák LR. Neurodevelopmental effect of intracranial hemorrhage in hypoxic ischemic brain injury in hypothermia-treated neonates. BMC Pediatrics 2019;19(1):430. https://doi.org/10.1186/s12887-019-1777-z.
35. Puzone S, Diplomatico M, Caredda E, Maietta A, Miraglia Del Giudice E, Montaldo P. Hypoglycaemia and hyperglycaemia in neonatal encephalopathy: a systematic review and meta-analysis. Archives of Disease in Childhood - Fetal and Neonatal Edition 2023;109(1):18-25. https://doi.org/10.1136/archdischild-2023-325592.
36. Mietzsch U, Wood TR, Wu TW, Natarajan N, Glass HC, Gonzalez FF, Mayock DE, Comstock BA, Heagerty PJ, Juul SE, Wu YW; HEAL Study Group. Early glycemic state and outcomes of neonates with hypoxic-ischemic encephalopathy. Pediatrics. 2023;152(4):e2022060965. https://doi.org/10.1542/peds.2022-060965.
37. Ali MAM, Farghaly MAA, El-Dib I, Karnati S, Aly H, Acun C. Glucose instability and outcomes of neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. Brain and Development 2024;46(8):262-267. https://doi.org/10.1016/j.braindev.2024.05.003.
38. Mess E.A., Rybakiewicz A., Pawelak A., Lisowska A., Ornat M. Assessment of the Level of Anxiety of Caring for Disabled. Pedagogy and Psychology of Sport 2019, 5, 165-182. http://dx.doi.org/10.5281/zenodo.2561188
39. Pappas A, Shankaran S, McDonald SA, Vohr BR, Hintz SR, Ehrenkranz RA, Tyson JE, Yolton K, Das A, Bara R, Hammond J, Higgins RD; Hypothermia Extended Follow-up Subcommittee of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Cognitive outcomes after neonatal encephalopathy. Pediatrics. 2015;135(3):e624-e634. https://doi.org/10.1542/peds.2014-1566.
40. Lee-Kelland R, Jary S, Tonks J, Cowan FM, Thoresen M, Chakkarapani E. School-age outcomes of children without cerebral palsy cooled for neonatal hypoxic-ischaemic encephalopathy. Archives of Disease in Childhood - Fetal and Neonatal Edition 2020;105(1):8-13. https://doi.org/10.1136/archdischild-2018-316509.
41. Robb TJ, Tonks J, Spencer APC, Jary S, Whitfield CK, Thoresen M, Cowan FM, Chakkarapani E. Communication skills in children aged 6-8 years without cerebral palsy cooled for neonatal hypoxic-ischemic encephalopathy. Scientific Report 2022;12(1):17757. https://doi.org/10.1038/s41598-022-21723-1.
42. Wisnowski JL, Monsell SE, Bluml S, Goodman AM, Li Y, Comstock BA, Heagerty PJ, Juul SE, Wu YW, McKinstry RC, Mathur AM; HEAL Consortium. Brain injury outcomes after adjuvant erythropoietin neuroprotection for moderate or severe neonatal hypoxic-ischemic encephalopathy. Developmental Neuroscience 2024;46(5):285-296. https://doi.org/10.1159/000534618.
43. Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, Juul SE; HEAL Consortium. Trial of erythropoietin for hypoxic-ischemic encephalopathy in newborns. The New England Journal of Medicine 2022;387(2):148-159. https://doi.org/10.1056/nejmoa2119660.
44. Ivain P, Montaldo P, Khan A, Elagovan R, Burgod C, Morales MM, Pant S, Thayyil S. Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis. Journal of Perinatology 2021;41(9):2134-2140. https://doi.org/10.1038/s41372-021-01132-4.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Alicja Trzepizur, Monika Spaczyńska-Kwiatkowska , Zuzanna Socha, Izabela Ochońska , Dawid Studziński, Sandra Michałek, Julia Pakulska

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 5
Number of citations: 0