Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.

BACKGROUND: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. METHODS/DESIGN: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. DISCUSSION: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. TRIAL REGISTRATION NUMBER: Clinical Trials, protocol registration system: NCT00189007.

Comparing brain white matter on sequential cranial ultrasound and MRI in very preterm infants.

INTRODUCTION: Periventricular white matter (WM) echodensities, frequently seen in preterm infants, can be associated with suboptimal neurodevelopment. Major WM injury is well detected on cranial ultrasound (cUS). cUS seems less sensitive for diffuse or more subtle WM injury. Our aim was to assess the value of cUS and magnetic resonance imaging (MRI) for evaluating WM changes and the predictive value of cUS and/or MRI findings for neurodevelopmental outcome in very preterm infants with normal to severely abnormal WM on sequential high-quality cUS. MATERIALS AND METHODS: Very preterm infants (<32 weeks) who had sequential cUS and one MRI within the first three postnatal months were included. Periventricular WM on cUS and MRI was compared and correlated with neurodevelopmental outcome at 2 years corrected age. RESULTS: Forty preterm infants were studied; outcome data were available in 32. WM changes on sequential cUS were predictive of WM changes on MRI. Severely abnormal WM on cUS/MRI was predictive of adverse outcome, and normal-mildly abnormal WM of favorable outcome. Moderately abnormal WM on cUS/MRI was associated with variable outcome. Additional MRI slightly increased the predictive value of cUS in severe WM changes. CONCLUSION: Sequential cUS in preterm infants is reliable for detecting WM changes and predicting favorable and severely abnormal outcome. Conventional and diffusion-weighted MRI sequences before term equivalent age in very preterm infants, suggested on cUS to have mild to moderately abnormal WM, do not seem to be warranted.

Pediatric outcome in Rhesus hemolytic disease treated with and without intrauterine transfusion.

OBJECTIVE: To study the short-term morbidity in Rhesus hemolytic disease of infants treated either with or without intrauterine transfusions (IUT). STUDY DESIGN: All term and near term infants (gestational age > or = 36 weeks) with neonatal Rhesus hemolytic disease admitted to our center between January 2000-March 2005 were retrospectively included in the study. We recorded the duration of phototherapy, the need of exchange transfusions, and the need of top-up red blood cell transfusions until 6 months of age. RESULTS: A total of 89 infants were included, of whom 52 received at least one IUT. Duration of phototherapy in the IUT and no-IUT group was 3.8 and 5.1 days, respectively (P = .01). The percentage of infants requiring an exchange transfusion in the IUT group was 71% compared to 65% in the no-IUT group (P = .64). The percentage of infants requiring a top-up transfusion in the IUT and no-IUT group was 77% and 26.5%, respectively (P < .01). CONCLUSION: Infants with Rhesus hemolytic disease treated with IUT required less days of phototherapy and more top-up red blood cell transfusions than neonates without IUT. However, the need for exchange transfusion was similar in both groups.