We previously reported beneficial outcomes from treatment with hypothermia for neonatal hypox-ic–ischemic encephalopathy at 18 to 22 months of age, including significant reductions in the rate of combined outcome of death or moderate or severe disability.7
Other trials of whole-body or head-only cooling with whole-body hypothermia for neonatal encephalopathy have shown beneficial outcomes of hypothermia at 18 to 24 months of age in the entire study cohorts10-12
and in selected subgroups.6,9
In the present study assessing children at 6 to 7 years of age, the difference in rates of the composite outcome of death or an IQ score below 70 between hypothermia and usual care did not achieve statistical significance (P = 0.06); however, the previous finding of reduced mortality with hypothermia was maintained, with no appreciable increase in the risk of neurodevelopmental deficits among survivors. These results are reassuring since hypothermia is being used extensively around the world and currently is recommended by health care policy-makers.16,17
The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care16
and the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations17
state that during the postresuscitation period in neonates who are at 36 weeks’ gestational age or older with progressing moderate-to-severe encephalopathy, hypothermia should be offered in the context of clearly defined protocols similar to those used in published clinical trials.
The main limitation of our study is that it was not powered to evaluate secondary outcomes such as individual components of disability, cognitive and motor outcomes, and overall physical and psychosocial health. We cannot rule out the possibility of effects on the results of loss to follow-up, as there were some differences in the baseline characteristics of the group with and the group without primary outcome data. However, primary outcome data were available for most participants in both groups.
The majority of follow-up studies of children with birth asphyxia were published before intervention with hypothermia.1-5
Disability at 5 years of age was reported in 6 to 21% of children with moderate encephalopathy after acute perinatal asphyxia and in 42 to 100% of those with severe encephalopathy. Nondisabled children have delays in reading, spelling, arithmetic and language, memory, and sensorimotor perception scores,2,3
as well as increased rates of attention deficit–hyperactivity disorder.18
In the present study, we examined both gross and fine-motor outcomes to evaluate subtle benefits of hypothermia. We found a nonsignificant decrease (from 29% to 17%) in the rate of moderate or severe cerebral palsy in the hypothermia group as compared with the control group. We did not find a decrease in the risk of abnormalities in motor function among the non-disabled children in the hypothermia group as compared with those in the control group.
In a previous study assessing the relationship between early and later childhood neurologic assessments, the sensitivity of the 1-year evaluation in predicting the 5-year neurologic outcome was 96%, and the sensitivity of the Mental Developmental Index of the Bayley Scales of Infant Development to predict the IQ score was 87%.5
We likewise found a high concordance between assessment of moderate-to-severe disability at 18 to 22 months of age and similar assessment at 6 to 7 years of age.
Children with cerebral palsy have markedly poor health; however, the psychosocial health of children and the emotional impact of the child’s health on the parents tend to be similar regardless of the level of disability.19
We found only nonsignificant differences between the hypothermia group and the control group in the frequency of parental ratings of the child’s health as excellent or very good and of their ratings of concern about the child’s emotional well-being or behavior.
The significant difference in the rate of the primary outcome between the hypothermia group and the control group seen at 18 to 22 months of age in our previous report7
and the borderline significant difference in the rate of this outcome at 6 to 7 years of age in our current report were largely driven by deaths, with the majority occurring within the first 18 months of life. Two other trials10,11
have shown a reduction in mortality among infants 18 to 22 months of age undergoing hypothermia as compared with usual care. A concern with any therapy that reduces mortality among infants at high risk of death and disability is the possibility of an increase in the number of children who survive with disabilities. As reported here, there was no evidence of increased rates of an IQ score below 70, severe disability, or cerebral palsy at 6 to 7 years of age among surviving children treated with hypothermia; in our previous report, the frequency of ad-verse events was similar in the hypothermia and control groups both during the 72-hour study intervention period and during the neonatal-hospitalization period.7
In summary, whole-body hypothermia did not significantly reduce the rate of a composite end point of death or an IQ score below 70 at 6 to 7 years of age. However, whole-body hypothermia did reduce the rate of death and did not increase the rates of a low IQ score or severe disability among survivors. These data extend our previous support for the use of hypothermia in term and near-term infants with hypoxic–ischemic encephalopathy.