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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 doi: (Published 09 February 2010) Cite this as: BMJ 2010;340:c363
  1. A David Edwards, professor of neonatal medicine12,
  2. Peter Brocklehurst, director 3,
  3. Alistair J Gunn, professor of physiology4,
  4. Henry Halliday, professor of perinatal medicine56,
  5. Edmund Juszczak, head of trials 3,
  6. Malcolm Levene, professor of paediatrics and child health78,
  7. Brenda Strohm, trial coordinator3,
  8. Marianne Thoresen, professor of neonatal neuroscience9,
  9. Andrew Whitelaw, professor of neonatal medicine9,
  10. Denis Azzopardi, clinical reader in neonatal medicine12
  1. 1Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ
  2. 2Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, London W12 0NN
  3. 3National Perinatal Epidemiology Unit, Department of Public Health, University of Oxford, Oxford OX3 7LF
  4. 4Department of Physiology, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand
  5. 5Royal Jubilee Maternity Service, Royal Maternity Hospital, Belfast BT12 6BA
  6. 6Department of Child Health, Queen’s University of Belfast, Belfast BT12 6BL
  7. 7University of Leeds, Leeds LS1 3BR
  8. 8Leeds General Infirmary, Leeds LS1 3EX
  9. 9Department of Clinical Science at South Bristol, Faculty of Medicine and Dentistry, University of Bristol, St Michael’s Hospital, Bristol BS2 8EG
  1. Correspondence to: D Azzopardi d.azzopardi{at}
  • Accepted 9 December 2009


Objective To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age.

Design A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured.

Data sources Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts.

Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected.

Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months’ follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference −0.11, 95% CI −0.18 to −0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference −0.07, 95% CI −0.12 to −0.02), with a number needed to treat of 14 (95% CI 8 to 47).

Conclusions In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.


  • Contributors: All the authors contributed to the study design, analysis of the data, and preparation of the manuscript. DA is the study guarantor.

  • Funding: AJG was supported by the Health Research Council of New Zealand. Imperial College London (ADE and DA) and University of Oxford (PB, EJ, and BS) are Comprehensive Biomedical Research Centres.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare that (1) Olympic Medical Corp (Seattle, WA) loaned equipment to AJG, MT, and DA for pilot studies preceding the CoolCap trial. The University of Auckland has applied for a related patent that names AJG; however, AJG has no financial interest. DA, ADE, AJG, MT, and AW were members of the CoolCap trial scientific group. DA, PB, ADE, EJ, BS, HH, ML, MT, and AW were members of the TOBY trial scientific group and are members of the TOBY Children study scientific group. (2) The authors have no relationships with companies that might have an interest in the submitted work in the previous 3 years; (3) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) none of the authors have non-financial interests that may be relevant to the submitted work.

  • Ethical approval: Approval from an ethics committee was not required for this study.

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