Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy

Background Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and in human patients with other forms of organ reperfusion injury. Objectives To determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Search strategy The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), conference proceedings, and previous reviews. Selection criteria Randomised or quasi-randomised controlled trials that compared allopurinol administration vs. placebo or no drug in newborn infants with suspected hypoxic-ischaemic encephalopathy. Data collection and analysis The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference. Main results Three trials in which a total of 114 infants participated were identified. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately-severe encephalopathy. These studies were generally of good methodological quality, but were underpowered to detect clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death during infancy [typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11)], nor in the incidence of neonatal seizures [typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11)]. Only one trial assessed neurodevelopment in surviving children and did not find a statistically significant effect. Authors' conclusions The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.