Background Hypoxic-ischemic encephalopathy due to perinatal hypoxia-induced free radical formation is an important cause of long-term neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced reperfusion damage. With this trial we aimed to assess whether maternal allopurinol treatment during fetal hypoxia would reduce the release of brain-tissue-specific biomarkers associated with neonatal brain damage.

Methods We performed a randomized double blind placebo controlled multicenter trial (NCT00189007) studying laboring women at term with imminent fetal hypoxia. Fetal distress was suspected in case of an abnormal fetal heart rate trace, ST-wave abnormalities on fetal ECG or fetal scalp pH<7.20. Women were allocated to receive allopurinol 500 mg IV or placebo immediately prior to delivery. Endpoints were S100B and neuroketal in cord blood, which are brain-tissue-specific biomarkers for brain damage. Because S100B followed a non-normal distribution, we used a poisson regression model with associated RR (95%CI). For neuroketal we report geometric mean differences.

Results We randomized 222 women to allopurinol (n=111) or placebo (n=111). S100B was significantly lower in the allopurinol-group (median 43.4; IQR 20.2–71.5) compared to the placebo-group (median 54.9; IQR 26.8–94.7), RR 0.91 (95%CI 0.88–0.94). Neuroketal did not significantly differ between groups, geometric mean difference –7.57 (95%CI –15.6; 3.57).

Post-hoc analysis showed a marked gender difference in treatment effect in favor of girls for S100B (RR 0.63 (95%CI 0.59–0.68)) and neuroketal (geometric mean difference –16.5 (95%CI –24.6; -1.83)).

Conclusion Maternal treatment with allopurinol during fetal hypoxia reduces damage to neuronal cells as indicated by brain-tissue-specific chemical biomarkers.