Kim Annink

160 Chapter 7 normal values within 90 minutes. Based on these results, antenatal allopurinol might reduce superoxide production in sheep with HIE (55). Again, no follow-up has been performed to assess long-term outcome in these animals. Human antenatal studies in HIE To investigate the neuroprotective effect of antenatal allopurinol therapy in neonates with suspected fetal hypoxia, a double blinded randomized pilot study was performed including 54 infants based on an abnormal cardiotocography or abnormal fetal scalp sampling, indicating that fetal hypoxia was imminent. The time between allopurinol administration and delivery of the baby varied between 18 and 190 minutes, which is relatively short. Allopurinol rapidly crossed the placenta in these pregnant women, but only in 15 out of 27 allopurinol treated infants therapeutic allopurinol or oxypurinol levels were reached. Apparently, the time between administration of allopurinol and actual delivery was too short for allopurinol to cross the placenta and to reach therapeutic plasma levels in some fetuses. Therefore, the allopurinol treated group was split into two subgroups: infants with therapeutic allopurinol or oxypurinol levels (n=15) and infants with sub-therapeutic allopurinol or oxypurinol levels (n=12). The sum of the allopurinol and oxypurinol concentrations in the umbilical cord were negatively correlated with S100ß concentrations, a biomarker for brain tissue damage (r=0.59, p<0.01). Furthermore, the S100ß levels were significantly reduced in the therapeutic allopurinol group compared to the other groups. Limitations of this study were the small sample size and the relatively high rate of sub-therapeutic allopurinol or oxypurinol levels (58). Therefore, a Dutch multicenter, double-blinded, randomized controlled trial was performed in 222 pregnant women with suspected fetal hypoxia during labor, half of which received 500mg allopurinol intravenously and half a placebo. Primary outcomes were the concentrations of S100ß in umbilical cord blood and the concentrations of oxidative stress markers, e.g. neuroketal and 8-isoprostane. In the total group, there was no significant difference in S100ß or oxidative stress marker levels between allopurinol treated infants and controls. In a post-hoc analysis, S100ß and neuroketal levels were significantly reduced in girls in the allopurinol group compared to the controls, but the oxidative stress markers were similar for boys (59). This gender difference is possibly explained by different pathways for programmed cell death and is also seen in other neuroprotective strategies and other neurological