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.

  • Article
  • Published:

Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia

Journal of Perinatology volume 40, pages 275–283 (2020)Cite this article

Subjects

Abstract

Objective

To compare the characteristics and outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) who received hypothermia versus standard care.

Study design

We conducted a retrospective cohort study of neonates ≥35 weeks’ gestation and ≥1800 g admitted with a diagnosis of Sarnat stage 1 encephalopathy. We evaluated length of hospital stay, duration of ventilation, evidence of brain injury on MRI, and neonatal morbidities.

Results

Of 1089 eligible neonates, 393 (36%) received hypothermia and 595 (55%) had neuroimaging. The hypothermia group was more likely to be outborn, born via C-section, had lower Apgar scores, and required extensive resuscitation. They had longer durations of stay (9 vs. 6 days, P < 0.001), respiratory support (3 vs. 2 days, P < 0.001), but lower odds of brain injury on MRI (adjusted odds ratio 0.33, 95% CI: 0.22–0.52) compared with standard care group.

Conclusion

Despite prolongation of hospital stay, hypothermia may be potentially beneficial in neonates with mild HIE; however, selection bias cannot be ruled out.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2

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.

    Article  Google Scholar 

  2. Wassink G, Gunn ER, Drury PP, Bennet L, Gunn AJ. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci. 2014;8:40.

    Article  Google Scholar 

  3. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37 Suppl 7:S186–202.

    Article  Google Scholar 

  4. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res. 1999;46:274–80.

    Article  CAS  Google Scholar 

  5. Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. 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;318:57–67.

    Article  Google Scholar 

  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.

  7. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010;340:c363.

    Article  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. Zhang W, Ma J, Danzeng Q, Tang Y, Lu M, Kang Y. Safety of moderate hypothermia for perinatal hypoxic-ischemic encephalopathy: a meta-analysis. Pediatr Neurol. 2017;74:51–61.

    Article  Google Scholar 

  10. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr. 1989;114:753–60.

    Article  CAS  Google Scholar 

  11. Murray DM, O’Connor CM, Ryan CA, Korotchikova I, Boylan GB. Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. Pediatrics. 2016;138:e20160659.

    Article  Google Scholar 

  12. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Behavioral outcome in children with a history of neonatal encephalopathy following perinatal asphyxia. J Pediatr Psychol. 2010;35:286–95.

    Article  Google Scholar 

  13. El-Dib M, Inder TE, Chalak LF, Massaro AN, Thoresen M, Gunn AJ. Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth? Pediatr Res. 2019;85:442–8.

    Article  Google Scholar 

  14. Canadian Neonatal Network. The Canadian Neonatal Network Abstractor’s Manual v.3.4.1. Toronto:CNN; 2019.

  15. Shah PS, Seidlitz W, Chan P, Yeh S, Musrap N, Lee SK. Internal audit of the Canadian Neonatal Network Data Collection System. Am J Perinatol. 2017;34:1241–9.

    Article  Google Scholar 

  16. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33:696–705.

    Article  CAS  Google Scholar 

  17. Kracer B, Hintz SR, Van Meurs KP, Lee HC. Hypothermia therapy for neonatal hypoxic ischemic encephalopathy in the state of California. J Pediatr. 2014;165:267–73.

    Article  Google Scholar 

  18. Massaro AN, Murthy K, Zaniletti I, Cook N, DiGeronimo R, Dizon M, et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group. J Perinatol. 2015;35:290–6.

    Article  CAS  Google Scholar 

  19. Gagne-Loranger M, Sheppard M, Ali N, Saint-Martin C, Wintermark P. Newborns referred for therapeutic hypothermia: association between initial degree of encephalopathy and severity of brain injury (what about the newborns with mild encephalopathy on admission?). Am J Perinatol. 2016;33:195–202.

    Article  Google Scholar 

  20. Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, et al. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed. 2018;103:F388–90.

    Article  Google Scholar 

  21. Wusthoff CJ, Clark CL, Glass HC, Shimotake TK, Schulman J, Bonifacio SL. Cooling in neonatal hypoxic-ischemic encephalopathy: practices and opinions on minimum standards in the state of California. J Perinatol. 2018;38:54–8.

    Article  CAS  Google Scholar 

  22. Soll RF. Cooling for newborns with hypoxic ischemic encephalopathy. Neonatology. 2013;104:260–2.

    Article  Google Scholar 

  23. Saw CL, Rakshasbhuvankar A, Rao S, Bulsara M, Patole S. Current practice of therapeutic hypothermia for mild hypoxic ischemic encephalopathy. J Child Neurol. 2019;34:402–9.

    Article  Google Scholar 

  24. DuPont TL, Chalak LF, Morriss MC, Burchfield PJ, Christie L, Sanchez PJ. Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy. J Pediatr. 2013;162:35–41.

    Article  Google Scholar 

  25. Mehta S, Joshi A, Bajuk B, Badawi N, McIntyre S, Lui K. Eligibility criteria for therapeutic hypothermia: from trials to clinical practice. J Paediatr Child Health. 2017;53:295–300.

    Article  Google Scholar 

  26. Takenouchi T, Cuaycong M, Ross G, Engel M, Perlman JM. Chain of brain preservation–a concept to facilitate early identification and initiation of hypothermia to infants at high risk for brain injury. Resuscitation. 2010;81:1637–41.

    Article  Google Scholar 

  27. Walsh BH, Neil J, Morey J, Yang E, Silvera MV, Inder TE, et al. The frequency and severity of magnetic resonance imaging abnormalities in infants with mild neonatal encephalopathy. J Pediatr. 2017;187:26–33.e21.

    Article  Google Scholar 

  28. 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  Google Scholar 

  29. Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019;18:35–45.

    Article  Google Scholar 

  30. Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997;86:757–61.

    Article  CAS  Google Scholar 

  31. 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. https://doi.org/10.1016/j.jpeds.2019.06.026.

    Article  Google Scholar 

  32. Graham EM, Everett AD, Delpech JC, Northington FJ. Blood biomarkers for evaluation of perinatal encephalopathy: state of the art. Curr Opin Pediatr. 2018;30:199–203.

    Article  Google Scholar 

  33. Lorch SA. Determining the optimal neonatal care for preterm infants in the era of personalized medicine. Pediatrics. 2017.https://doi.org/10.1542/peds.2016-2442.

    Article  Google Scholar 

  34. Yue JK, Vassar MJ, Lingsma HF, Cooper SR, Okonkwo DO, Valadka AB, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma. 2013;30:1831–44.

    Article  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge all site investigators and data abstractors of the Canadian Neonatal Network (CNN). We thank the staff at the Maternal-infant Care (MiCare) Research Centre at Mount Sinai Hospital, Toronto, Ontario, for organizational support of CNN. We also thank EWY, of MiCare, for assistance with the statistical analyses; Heather McDonald-Kinkaid, PhD, of MiCare, for editorial support in preparing this manuscript; and Ms Rosanna Yankanah, MSc, CCRP Manager, Clinical Research for assistance with the ethics submission.

Canadian Neonatal Network Investigators

Prakesh S. Shah8, Jaideep Kanungo9, Joseph Ting10, Zenon Cieslak11, Rebecca Sherlock12, Ayman Abou Mehrem13, Jennifer Toye14, Carlos Fajardo15, Zarin Kalapesi16, Jaya Bodani16, Koravangattu Sankaran17, Sibasis Daspal17, Mary Seshia18, Deepak Louis18, Ruben Alvaro19, Amit Mukerji20, Orlando Da Silva21, Mohammad Adie22, Kyong-Soon Lee23, Michael Dunn24, Brigitte Lemyre25, Faiza Khurshid26, Ermelinda Pelausa27, Keith Barrington28, Anie Lapoint28, Guillaume Ethier28, Christine Drolet29, Bruno Piedboeuf29, Martine Claveau30, Marc Beltempo30, Valerie Bertelle31, Edith Masse31, Roderick Canning32, Hala Makary33, Cecil Ojah34, Luis Monterrosa34, Julie Emberley35, Jehier Afifi36, Andrzej Kajetanowicz37, Shoo K. Lee38

Funding

Organizational support for the Canadian Neonatal Network was provided by the Maternal-infant Care (MiCare) Research Centre at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by a team grant from the Canadian Institutes of Health Research (CIHR) (CTP 87518), by the Ontario Ministry of Health and Long-Term Care, and by the participating hospitals. PSS holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research from the CIHR (APR-126340).

Author information

Authors and Affiliations

  1. Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ipsita R. Goswami & Hilary Whyte

  2. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Pia Wintermark

  3. Department of Pediatrics, University of Calgary, Calgary, AB, Canada

    Khorshid Mohammad

  4. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    Sandesh Shivananda

  5. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada

    Deepak Louis

  6. Maternal-infant Care Research Centre, Mount Sinai Hospital, Toronto, ON, Canada

    Eugene W. Yoon & Prakesh S. Shah

  7. Department of Pediatrics, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada

    Prakesh S. Shah

  8. Mount Sinai Hospital, Toronto, ON, Canada

    Prakesh S Shah

  9. Victoria General Hospital, Victoria, BC, Canada

    Jaideep Kanungo

  10. B.C. Women’s Hospital and Health Centre, Vancouver, BC, Canada

    Joseph Ting

  11. Royal Columbian Hospital, New Westminster, BC, Canada

    Zenon Cieslak

  12. Surrey Memorial Hospital, Surrey, BC, Canada

    Rebecca Sherlock

  13. Foothills Medical Centre, Calgary, AB, Canada

    Ayman Abou Mehrem

  14. Royal Alexandra Hospital, Edmonton, AB, Canada

    Jennifer Toye

  15. Alberta Children’s Hospital, Calgary, AB, Canada

    Carlos Fajardo

  16. Regina General Hospital, Regina, SK, Canada

    Zarin Kalapesi & Jaya Bodani

  17. Royal University Hospital, Saskatoon, SK, Canada

    Koravangattu Sankaran & Sibasis Daspal

  18. Winnipeg Health Sciences Centre, Winnipeg, MB, Canada

    Mary Seshia & Deepak Louis

  19. St. Boniface General Hospital, Winnipeg, MB, Canada

    Ruben Alvaro

  20. Hamilton Health Sciences Centre, Hamilton, ON, Canada

    Amit Mukerji

  21. London Health Sciences Centre, London, ON, Canada

    Orlando Da Silva

  22. Windsor Regional Hospital, Windsor, ON, Canada

    Mohammad Adie

  23. Hospital for Sick Children, Toronto, ON, Canada

    Kyong-Soon Lee

  24. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Michael Dunn

  25. Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, ON, Canada

    Brigitte Lemyre

  26. Kingston General Hospital, Kingston, ON, Canada

    Faiza Khurshid

  27. Jewish General Hospital, Montréal, QC, Canada

    Ermelinda Pelausa

  28. Hôpital Sainte-Justine, Montréal, QC, Canada

    Keith Barrington, Anie Lapoint & Guillaume Ethier

  29. Centre Hospitalier Universitaire de Québec, Sainte Foy, QC, Canada

    Christine Drolet & Bruno Piedboeuf

  30. Montreal Children’s Hospital at McGill University Health Centre, Montréal, QC, Canada

    Martine Claveau & Marc Beltempo

  31. Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada

    Valerie Bertelle & Edith Masse

  32. Moncton Hospital, Moncton, NB, Canada

    Roderick Canning

  33. Dr. Everett Chalmers Hospital, Fredericton, NB, Canada

    Hala Makary

  34. Saint John Regional Hospital, Saint John, NB, Canada

    Cecil Ojah & Luis Monterrosa

  35. Janeway Children’s Health and Rehabilitation Centre, St. John’s, NL, Canada

    Julie Emberley

  36. IWK Health Centre, Halifax, NS, Canada

    Jehier Afifi

  37. Cape Breton Regional Hospital, Sydney, NS, Canada

    Andrzej Kajetanowicz

  38. Mount Sinai Hospital, Toronto, ON, Canada

    Shoo K Lee

Authors
  1. Ipsita R. Goswami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hilary Whyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pia Wintermark
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Khorshid Mohammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandesh Shivananda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Deepak Louis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eugene W. Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Prakesh S. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the Canadian Neonatal Network Investigators

  • Prakesh S Shah
  • , Jaideep Kanungo
  • , Joseph Ting
  • , Zenon Cieslak
  • , Rebecca Sherlock
  • , Ayman Abou Mehrem
  • , Jennifer Toye
  • , Carlos Fajardo
  • , Zarin Kalapesi
  • , Jaya Bodani
  • , Koravangattu Sankaran
  • , Sibasis Daspal
  • , Mary Seshia
  • , Deepak Louis
  • , Ruben Alvaro
  • , Amit Mukerji
  • , Orlando Da Silva
  • , Mohammad Adie
  • , Kyong-Soon Lee
  • , Michael Dunn
  • , Brigitte Lemyre
  • , Faiza Khurshid
  • , Ermelinda Pelausa
  • , Keith Barrington
  • , Anie Lapoint
  • , Guillaume Ethier
  • , Christine Drolet
  • , Bruno Piedboeuf
  • , Martine Claveau
  • , Marc Beltempo
  • , Valerie Bertelle
  • , Edith Masse
  • , Roderick Canning
  • , Hala Makary
  • , Cecil Ojah
  • , Luis Monterrosa
  • , Julie Emberley
  • , Jehier Afifi
  • , Andrzej Kajetanowicz
  •  & Shoo K Lee

Contributions

IRG conceptualized and designed the study, designed the data collection instruments, collected data, carried out the initial analyses, and drafted, reviewed, and revised the paper. HW reviewed the initial study proposal and research ethics application, contributed to the acquisition and interpretation of data, and reviewed and revised the paper. PW, KM, SS, and DL contributed to the interpretation of data and critically reviewed and revised the paper. EWY contributed to the analysis and interpretation of data and revised the paper. PSS conceptualized and designed the study, coordinated and supervised the data collection, and critically reviewed and revised the paper for important intellectual content. As corresponding author, PSS confirms that he has had full access to the data in the study and final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Prakesh S. Shah.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

The members of the Canadian Neonatal Network Investigators are listed below the Acknowledgements.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goswami, I.R., Whyte, H., Wintermark, P. et al. Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia. J Perinatol 40, 275–283 (2020). https://doi.org/10.1038/s41372-019-0551-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-019-0551-2

This article is cited by

Search

Advanced search

Quick links