[show abstract][hide abstract] ABSTRACT: Free radical-induced reperfusion injury is a recognized cause of brain damage in the newborn after birth asphyxia. The xanthine oxidase inhibitor allopurinol reduces free radical synthesis and crosses the placenta easily. Therefore, allopurinol is a promising therapeutic candidate. This study tested the hypothesis that maternal treatment with allopurinol during fetal asphyxia limits ischemia-reperfusion (I/R) damage to the fetal brain in ovine pregnancy. The I/R challenge was induced by 5 repeated measured compressions of the umbilical cord, each lasting 10 minutes, in chronically instrumented fetal sheep at 0.8 of gestation. Relative to control fetal brains, the I/R challenge induced significant neuronal damage in the fetal hippocampal cornu ammonis zones 3 and 4. Maternal treatment with allopurinol during the I/R challenge restored the fetal neuronal damage toward control scores. Maternal treatment with allopurinol offers potential neuroprotection to the fetal brain in the clinical management of perinatal asphyxia.
[show abstract][hide abstract] ABSTRACT: Abstract Measurement of amniotic fluid (AF) lactate concentration in complicated pregnancies may provide information on the extent of fetal acidemia. However, normalisation for AF volume may be necessary by calculating the lactate:creatinine (L:C) ratio. We measured these AF parameters and compared them to arterial cord blood lactate in 28 term and 10 preterm pregnancies. Cord blood lactate was not correlated to AF lactate, but was correlated to the L:C ratio in the complete study population (R=0.54,p=0.001) and the subgroups. Correlation was strongest in a preterm IUGR subgroup (n=7,R=0.83,p=0.02). The L:C ratio is more accurate in estimating fetal lacticaemia than AF lactate.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 01/2013; · 1.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical cord. This study tested the hypothesis that maternal treatment with clinical doses of the antioxidant allopurinol in the setting of fetal asphyxia would reduce oxidative stress in the fetal cardiovascular system. The hypothesis was tested in chronically instrumented fetal sheep in late gestation by investigating the effects of maternal treatment with therapeutic doses of allopurinol or vehicle on the fetal cardiovascular system during and after episodes of I/R. The latter were produced by repeated, measured compressions of the umbilical cord. The data show that maternal treatment with allopurinol helped maintain umbilical blood flow and it reduced fetal cardiac oxidative stress after I/R of the type associated with clinically relevant acidemia and repetitive fetal heart rate decelerations. The data support the hypothesis tested and suggest that maternal treatment with allopurinol may offer plausible clinical intervention in the management of perinatal asphyxia in complicated labor.
Pediatric Research 11/2010; 68(5):374-80. · 2.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
BMC Pregnancy and Childbirth 02/2010; 10:8. · 2.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are no randomized studies on the effect of antenatal corticosteroids in preterm intrauterine growth restricted (IUGR) fetuses. Fetal lung maturation has been postulated to be enhanced in these fetuses, which may result in little benefit of steroid treatment. Furthermore, corticosteroid treatment may be detrimental, as has been shown in IUGR animal models. The objective of this study was to review the available literature on antenatal steroid treatment of the IUGR fetus. All available reports on antenatal steroid treatment of IUGR and small for gestational age (SGA) fetuses published prior to October 2007 were included in this review. IUGR fetuses are a subgroup of SGA fetuses that are small due to placental insufficiency, which is reflected in abnormal Doppler examination of the umbilical artery. The main outcome measures were respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and neonatal mortality. No difference in neonatal mortality was seen in any of the reviewed studies and RDS, IVH, and NEC incidence did not differ between treated and untreated IUGR fetuses. In SGA fetuses, results on RDS incidence and intracranial outcome were inconclusive. Antenatal steroid treatment does not seem to have an effect on neonatal mortality or morbidity in IUGR fetuses. In SGA fetuses, it remains unclear if antenatal steroid treatment is beneficial due to heterogeneous populations and treatment regimes. A randomized controlled trial should be performed to confirm prior results and answer further questions regarding antenatal steroid treatment of these fetuses.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Respiratory distress syndrome (RDS) incidence is increased in infants of preeclamptic mothers with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. RDS and HELLP syndrome have been associated with oxidative stress and inflammatory processes.
We hypothesize that end-tidal carbon monoxide corrected for inhaled CO (ETCOc), malondialdehyde (MDA) (markers of oxidative stress) and proinflammatory cytokine (IL-6, IL-8) production are higher in infants of preeclamptic mothers with HELLP syndrome than in those of preeclamptic mothers without HELLP syndrome.
Prospective study of 36 infants of preeclamptic mothers (GA <32 weeks) admitted to the Neonatal Intensive Care Unit. ETCOc was measured at 0-12, 48-72 and 168 h postnatally using the CO-Stattrade mark End-Tidal Breath Analyzer. Simultaneously, blood was sampled for MDA, IL-8 and IL-6.
At 0-12 h, ETCOc, MDA and IL-8 values (median[range]) were significantly higher in HELLP infants than in infants from preeclamptic mothers without HELLP (ETCOc 2.2 [1.5-3.9] vs. 1.8 [0.5-2.9] ppm; MDA 2.3 [1.3-4.1] vs. 1.5 [0.4-3.1] mumol/l; IL-8 145 [24-606] vs. 62 [26-397] pg/ml; all p <0.05). MDA remained significantly higher during the first 168 h of life (2.3 [0.8-5.8] vs. 1.1 [0.8-3.7] mumol/l, p = 0.02).
Oxidative stress and proinflammatory cytokine levels are increased in infants of preeclamptic mothers with HELLP syndrome. These processes may cause inactivation of surfactant explaining the increased RDS incidence in these infants.
[show abstract][hide abstract] ABSTRACT: To study respiratory outcome in preterm small for gestational age (SGA) fetuses with or without signs of intrauterine growth restriction due to placental insufficiency, and with or without maternal hypertension.
This was a retrospective study of 187 neonates with birth weight <10(th) percentile and gestational age <34 weeks. Results from umbilical artery Doppler velocimetry were used to identify the abnormal Doppler subgroup.
No significant difference in respiratory outcome between SGA fetuses with normal (SGA-N) or abnormal (SGA-A) umbilical artery Doppler examination was found. Within the SGA-A group, the respiratory distress syndrome (RDS) incidence (OR 5.6, 95% CI 1.7-18.3), RDS grade (OR 6.7, 95% CI 1.2-38.5), and need for surfactant (OR 5.3, 95% CI 1.1-24.4) were higher in infants of women with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome as compared to those of normotensive mothers.
Lung maturation is not accelerated with placental insufficiency. SGA-A fetuses of mothers with HELLP syndrome have a significantly poorer respiratory outcome than those with healthy mothers. Possibly, fetuses of mothers with HELLP syndrome are subjected to 'oxidative stress' causing lung damage rather than lung maturation.
Journal of Maternal-Fetal and Neonatal Medicine 08/2007; 20(8):613-21. · 1.52 Impact Factor