Longer-term outcomes of cooling for term neonatal encephalopathy.

Abstract

Some large-scale cooling studies in term infants with encephalopathy of presumed asphyxial origin are now publishing longer-term results with interesting, if at times contradictory, results. In 2012 Shankaran et al.1 reported that out of 208 child participants in the US National Institute of Child Health and Human Development (NICHD) study, 190 were assessed at the ages of 6 to 7 years. The main outcome of death and/or an IQ below 70, while lower in the cooled group, was not significantly different from the control group. The difference had been significant at 18 to 22 months of age, but just lost statistical significance at the later age. However, at the older age there was still a significant reduction in the risk of death, death or severe disability (defined as an IQ score below 55, Gross Motor Function Classification System [GMFCS] level of IV or V, and/or bilateral blindness) and death or cerebral palsy (CP). There was no significant difference in survivors for CP rates or levels of disability. In those who were followed up, survival without disability (i.e. an IQ above 85 and no neurological problems) was 29% in the cooled versus 23% in the control group. In 2014 Azzopardi et al.2 reported data from 280 of 325 newborn infants originally enrolled in the European Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial, followed to the same age. Their prime outcome, survival with an IQ score of 85 or more, was significantly better in the cooled group, as were the chances of avoiding neurological abnormalities, including CP and moderate or severe disability. Yet there was no difference in deaths in the two groups. In those who were followed up, survival without disability (i.e. an IQ above 85 and no neurological problems) was 45% in the cooled versus 27% in the control group. Apart from different primary outcome measures, both studies were very similar in design. As well as showing increasingly convincing benefits from cooling in terms of reducing motor and intellectual disability, they also allay fears that survivors of cooling might have increased rates of disability. This information builds on a larger number of shorter-term outcome studies which were the subject of a 2013 Cochrane Review.3 This concluded that there are benefits from cooling in terms of death, cognitive development, and CP. When comparing outcomes in neonates with moderate or severe encephalopathy, there was a clear reduction in mortality in both groups but survival without severe disability was only significantly improved in those with moderate encephalopathy. In both groups seven (range 4–17) and six (range 4–11) children respectively needed to be cooled to prevent one from dying or surviving with severe disability. Finally, it remained unclear whether whole body cooling differs in effectiveness from selective head cooling with milder body cooling. Other useful results from the longer-term studies are the comparisons of outcomes at 18 to 22 months and 6 to 7 years, which corroborates previously published data.4 A survivor's IQ classification could change but not the severity of their CP if they already had a GMFCS level of III to V, indicating that the diagnosis of more severe CP can be reasonably confident by 18 months of age. However, they did not give information on changes between these levels. Another important finding was that while the 10-minute Apgar score correlated closely with outcome, three out of 24 infants with a score of zero (i.e. who were technically dead even at that stage) could still survive without disability.5 As always there are now further questions to answer. The first is whether the results from these trials can be replicated in real life and, even more importantly, in countries with less well-resourced health services. Other questions include dosage (e.g. 48 vs 72h of cooling); timing (e.g. could infants still benefit if cooling is introduced after 6h of age?); whether preterm infants could benefit; and whether adjunctive therapy makes a difference. However, it is very heartening that in this group of infants one intervention is now proved to reduce the risk of the rightly feared outcomes of death and disability.