Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

Abstract

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.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (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.

Figures

Fig 1 Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on death or disability (“events”). All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals. Test for heterogeneity: χ2=0.82, degrees of freedom=2 (P=0.66); I2=0%. Test for overall effect: Z=3.03 (P=0.002). Studies shown are the Total Body Hypothermia (TOBY) trial, the National Institute of Child Health and Human Development (NICHD) trial, and the CoolCap trial

Fig 2 Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on survival with normal neurological function (“events”). All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals. Test for heterogeneity: χ2=0.05, degrees of freedom=2 (P=0.66); I2=0%. Test for overall effect: Z=3.66 (P=0.0003). Studies shown are the Total Body Hypothermia (TOBY) trial, the National Institute of Child Health and Human Development (NICHD) trial, and the CoolCap trial

Fig 3 Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on neurological outcomes (“events”). All infants surviving to 18 months randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals. Studies shown are the Total Body Hypothermia (TOBY) trial, the National Institute of Child Health and Human Development (NICHD) trial, and the CoolCap trial. Abbreviations: MDI, mental developmental index score; PDI, psychomotor developmental index score

Fig 4 Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on mortality (“events”) in all 10 trials identified. Studies shown are Akisu et al (2003), the CoolCap trial, Eicher et al (2005), the Infant Cooling Evaluation (ICE) trial, Lin et al (2006) the neo.nEURO.network trial, the National Institute of Child Health and Human Development (NICHD) study, Robertson et al (2008), Shankaran et al (2002), and the Total Body Hypothermia (TOBY) trial. All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals. Test for heterogeneity: χ2=7.73, degrees of freedom=9 (P=0.56); I2=0%. Test for overall effect: Z=2.89 (P=0.005)

Fig 5 Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on death or disability stratified by severity of encephalopathy (“events”). Assessment of grade of encephalopathy was by amplitude integrated electroencephalogram and clinical examination in the CoolCap and National Institute of Child Health and Human Development (NICHD) studies and by amplitude integrated electroencephalogram only in the Total Body Hypothermia (TOBY) study. All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals