allopurinol and Fetal-Hypoxia

Several experimental models on adult and newborn animals showed that in cerebral hypoxic-ischemic conditions similar to clinical states the main source of the excessive production of free oxygen radicals is the highly activated xanthine oxidase (XO) enzyme reaction. Long before this data were available, it became known that the main role of allopurinol (AP) is the inhibition of XO. On the basis of these results, many therapeutic trials with AP were performed both in experimental and clinical studies of ischemia and reperfusion. However, it has been shown that only preventive administration of AP has favorable effects. The explanation for the poor results of AP treatment in human fetal brain damage (FBD) cases is that the drug was applied postnatally. The clinical studies performed in healthy laboring mothers whose deliveries were complicated with FBD showed that placental transfer after prenatal administration of AP may be effective in protecting newborns at increased risk of hypoxic-ischemic cerebral damage. Further controlled trials are required to determine if the prophylactic use of the drug might prevent hypoxic-ischemic injuries when the drug is administered immediately prior to impending fetal hypoxia, or even in deliveries at risk of developing hypoxia.

Topics: Allopurinol; Animals; Animals, Newborn; Brain Injuries; Enzyme Inhibitors; Female; Fetal Hypoxia; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Pregnancy; Reperfusion Injury; Xanthine Oxidase

Objectives were to identify and to evaluate controlled trials of interventions for term infants developing hypoxic-ischaemic encephalopathy. Five randomized trials concerning prophylactic anticonvulsant therapy for neonatal HIE were identified. There were methodological problems with all of them, and meta-analysis of barbiturate prophylaxis showed no significant effect on death or disability. One randomized trial of allopurinol showed short-term benfits, but was too small to test death or disability. One small randomized trial of hypothermia found no adverse effects, but was too small to examine death or disability. No adequate trials of dexamethasone, calcium channel blockers, magnesium sulphate, or naloxone have yet been completed, but pilot studies in infants have shown the risks of magnesium sulphate and calcium channel blockers.

Topics: Allopurinol; Anti-Inflammatory Agents; Anticonvulsants; Asphyxia Neonatorum; Calcium Channel Blockers; Dexamethasone; Diuretics, Osmotic; Fetal Hypoxia; Free Radical Scavengers; Humans; Hypothermia, Induced; Infant, Newborn; Magnesium Sulfate; Mannitol; Naloxone; Perinatal Care; Research Design; Treatment Outcome

To evaluate the long-term neurodevelopmental and behavioral outcome of antenatal allopurinol treatment during suspected fetal hypoxia.. We studied children born from women who participated in a randomized double-blind placebo controlled multicenter study (ALLO-trial). Labouring women in whom the fetus was suspected to have fetal hypoxia were randomly allocated to receive allopurinol or placebo. At 5 years of age, the children were assessed with 2 parent reported questionnaires, the Ages and Stages Questionnaire (ASQ) and the Child Behavior Checklist (CBCL). A child was marked abnormal for ASQ if it scored below 2 standard deviation under the normative mean of a reference population in at least one domain. For CBCL, a score above the cut-off value (95th percentile for narrowband scale, 85th percentile for broadband scale) in at least one scale was marked as abnormal.. We obtained data from 138 out of the original 222 mildly asphyxiated children included in the ALLO-trial (response rate 62%, allopurinol n = 73, placebo n = 65). At 5 years of age, the number of children that scored abnormal on the ASQ were 11 (15.1%) in the allopurinol group versus 11 (9.2%) in the placebo group (relative risk (RR) 1.64, 95% confidence interval (CI): 0.64 to 4.17, p = 0.30). On CBCL 21 children (30.4%) scored abnormal in de allopurinol group versus 12 children (20.0%) in the placebo group (RR 1.52, 95% CI: 0.82 to 2.83, p = 0.18).. We found no proof that allopurinol administered to labouring women with suspected fetal hypoxia improved long-term developmental and behavioral outcome. These findings are limited due to the fact that the study was potentially underpowered.. NCT00189007 Dutch Trial Register NTR1383.

Topics: Allopurinol; Child Behavior; Child Behavior Disorders; Child Development; Child, Preschool; Developmental Disabilities; Double-Blind Method; Female; Fetal Hypoxia; Follow-Up Studies; Free Radical Scavengers; Humans; Labor, Obstetric; Male; Pregnancy

To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage.. A randomised double-blind placebo controlled multicentre trial.. We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery.. Delivery rooms of 11 Dutch hospitals.. When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT).. Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage.. 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)).. 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.. NCT00189007, Dutch Trial Register NTR1383.

Topics: Adult; Aldehydes; Allopurinol; Dinoprost; Double-Blind Method; Enzyme Inhibitors; Female; Fetal Blood; Fetal Hypoxia; Humans; Ketones; Male; Maternal-Fetal Exchange; Oxypurinol; Pregnancy; S100 Calcium Binding Protein beta Subunit; Xanthine Oxidase

Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia.. We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007).. We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study.. Delivery rooms of 11 Dutch hospitals.. 500 mg allopurinol, intravenously to the mother, immediately prior to delivery.. Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events).. Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion.. A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects.. The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Topics: Adult; Allopurinol; Double-Blind Method; Female; Fetal Blood; Fetal Hypoxia; Fetus; Free Radical Scavengers; Free Radicals; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Labor, Obstetric; Maternal-Fetal Exchange; Neuroprotective Agents; Placenta; Pregnancy

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.. 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.. In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.. Clinical Trials, protocol registration system: NCT00189007.

Topics: Allopurinol; Asphyxia Neonatorum; Biomarkers; Double-Blind Method; Female; Fetal Hypoxia; Free Radical Scavengers; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Multivariate Analysis; Nerve Growth Factors; Netherlands; Phosphopyruvate Hydratase; Pilot Projects; Pregnancy; Prenatal Care; Prospective Studies; Regression Analysis; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Xanthine Oxidase

Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role.. Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (primary outcome) and reduce S-100B and free radical formation (secondary outcome).. In a randomized, double-blind feasibility study, 53 pregnant women in labor (54 fetuses) with a gestational age of >36 weeks and fetal hypoxia, as indicated by abnormal/nonreassuring fetal heart rate tracing or fetal scalp pH of <7.20, received 500 mg of allopurinol or placebo intravenously. Severity of fetal hypoxia, brain damage and free radical formation were assessed by arterial cord blood lactate, S-100B and non-protein-bound-iron concentrations, respectively. At birth, maternal and cord blood concentrations of allopurinol and its active metabolite oxypurinol were determined.. Allopurinol and oxypurinol concentrations were within the therapeutic range in the mother (allopurinol > 2 mg/L and/or oxypurinol > 4 mg/L) but not always in arterial cord blood. We therefore created 3 groups: a placebo (n = 27), therapeutic allopurinol (n = 15), and subtherapeutic allopurinol group (n = 12). Cord lactate concentration did not differ, but S-100B was significantly lower in the therapeutic allopurinol group compared with the placebo and subtherapeutic allopurinol groups (P < .01). Fewer therapeutic allopurinol cord samples had measurable non-protein-bound iron concentrations compared with placebo (P < .01).. Maternal allopurinol/oxypurinol crosses the placenta during fetal hypoxia. In fetuses/newborns with therapeutic allopurinol/oxypurinol concentrations in cord blood, lower plasma levels of the brain injury marker protein S-100B were detected. A larger allopurinol trial in compromised fetuses at term seems warranted. The allopurinol dosage must be adjusted to achieve therapeutic fetal allopurinol/oxypurinol concentrations.

Topics: Adult; Allopurinol; Chromatography, High Pressure Liquid; Double-Blind Method; Feasibility Studies; Female; Fetal Blood; Fetal Hypoxia; Fetus; Free Radical Scavengers; Humans; Maternal-Fetal Exchange; Nerve Growth Factors; Pilot Projects; Pregnancy; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Young Adult

Hypoxia is a common challenge to the fetus, promoting a physiological defence to redistribute blood flow towards the brain and away from peripheral circulations. During acute hypoxia, reactive oxygen species (ROS) interact with nitric oxide (NO) to provide an oxidant tone. This contributes to the mechanisms redistributing the fetal cardiac output, although the source of ROS is unknown. Here, we investigated whether ROS derived from xanthine oxidase (XO) contribute to the fetal peripheral vasoconstrictor response to hypoxia via interaction with NO-dependent mechanisms. Pregnant ewes and their fetuses were surgically prepared for long-term recording at 118 days of gestation (term approximately 145 days). After 5 days of recovery, mothers were infused i.v. for 30 min with either vehicle (n = 11), low dose (30 mg kg(-1), n = 5) or high dose (150 mg kg(-1), n = 9) allopurinol, or high dose allopurinol with fetal NO blockade (n = 6). Following allopurinol treatment, fetal hypoxia was induced by reducing maternal inspired O2 such that fetal basal P aO 2 decreased approximately by 50% for 30 min. Allopurinol inhibited the increase in fetal plasma uric acid and suppressed the fetal femoral vasoconstrictor, glycaemic and lactate acidaemic responses during hypoxia (all P < 0.05), effects that were restored to control levels with fetal NO blockade. The data provide evidence for the activation of fetal XO in vivo during hypoxia and for XO-derived ROS in contributing to the fetal peripheral vasoconstriction, part of the fetal defence to hypoxia. The data are of significance to the understanding of the physiological control of the fetal cardiovascular system during hypoxic stress. The findings are also of clinical relevance in the context of obstetric trials in which allopurinol is being administered to pregnant women when the fetus shows signs of hypoxic distress.

Topics: Allopurinol; Animals; Blood Glucose; Blood Pressure; Enzyme Inhibitors; Female; Fetal Heart; Fetal Hypoxia; Gestational Age; Heart Rate; Lactic Acid; Nitric Oxide; Oxygen; Oxygen Consumption; Pregnancy; Reactive Oxygen Species; Regional Blood Flow; Sheep; Uric Acid; Vasoconstriction; Xanthine Oxidase

Topics: Animals; Blood Pressure; Female; Fetal Heart; Fetal Hypoxia; Heart Rate; Pregnancy; Xanthine Oxidase

To evaluate the transplacental effect of allopurinol, which acts as a xanthine oxidase inhibitor and free radical scavenger, on inhibiting the production of superoxides during intermittent partial umbilical cord occlusion.. Using four chronically instrumented fetal lambs, ewes received 400 mg allopurinol over a period of two hours. Concentrations of allopurinol and oxypurinol in blood samples from mothers and fetuses and fetal brain microdialysis perfusate were measured by HPLC. In another three cases the production of superoxide during intermittent umbilical cord occlusion was studied by measurement of chemiluminescence in perfusate before and after administration of Allopurinol.. (i) Allopurinol concentration in mothers had reached equilibrium by 30 min after starting administration and maintained a concentration about 6 mug/ml. Allopurinol concentration in fetuses increased gradually and reached 2.25 +/- 0.54 microg/ml at 120 min; (ii) Oxypurinol concentration in both mothers and fetuses increased during administration of allopurinol; (iii) Concentrations of allopurinol and oxypurinol in the perfusates reached 0.32 +/- 0.12 microg/ml, 0.53 +/- 0.22 microg/ml at 120 min respectively; and (iv) Administration of allopurinol significantly suppressed superoxide production during intermittent partial umbilical cord occlusion.. These results demonstrated a good transfer of allopurinol from mother to fetus and suggested the possibility of intrauterine treatment to inhibit fetal brain damage resulting from increased oxygen free radicals.

Topics: Allopurinol; Animals; Brain; Enzyme Inhibitors; Female; Fetal Hypoxia; Fetus; Free Radical Scavengers; Oxidative Stress; Oxypurinol; Placenta; Pregnancy; Reactive Oxygen Species; Sheep; Superoxides; Umbilical Cord; Xanthine Oxidase