Clinical Significance of Early Pulmonary Hypertension in Preterm Infants.

OBJECTIVE: To characterize different phenotypes of early pulmonary hypertension (PH) in preterm infants and their respective associations with bronchopulmonary dysplasia (BPD) and survival. STUDY DESIGN: A prospective cohort study in a tertiary university medical center from June 2016 until March 2019. Infants with a gestational age <30 weeks and/or a birth weight <1000 g were included. Echocardiographic assessment for PH was performed at 3-10 days after birth. Subsequent development of BPD at 36 weeks postmenstrual age and mortality were assessed. RESULTS: Early PH was identified in 55% of 104 included infants, including 21% with persistent PH of the newborn (PPHN), 61% with flow-associated PH, and 18% PH without shunt. Only PPHN was associated with placental fetal vascular malperfusion, lower gestational age, and low Apgar score. Both PPHN and flow PH were associated with the development of BPD. Early PH was associated with poorer survival, driven by PPHN. CONCLUSIONS: Early PH is highly prevalent (55%) in preterm infants and associated with the development of BPD, independent of the phenotype of PH. Infants with PPHN had the poorest survival. Early PH presents in various phenotypes characterized by differences in etiology, pathophysiology, and associated long-term sequelae.

Thoracotomy Versus Sternotomy for Patent Ductus Arteriosus Closure in Preterm Neonates.

BACKGROUND: To date, a posterolateral thoracotomy approach is considered the gold standard for surgical closure of patent ductus arteriosus (PDA), also in preterm neonates. However, a posterolateral thoracotomy approach can induce post-thoracotomy lung injury of the immature and vulnerable lungs of preterm neonates. Therefore, this study aims to compare a posterolateral thoracotomy and median sternotomy for surgical closure of PDA in preterm neonates. METHODS: Between September 2010 and November 2014, both surgical approaches were used to treat a symptomatic PDA in very and extremely preterm neonates. The hospital records of all these neonates were retrospectively reviewed to assess all-cause mortality and postoperative morbidity in both groups. RESULTS: Despite comparable preoperative patient profiles, the postoperative pulmonary complication rate was significantly lower in the median sternotomy group (52.9% vs 94.7%; P = .006). Moreover, significantly lower mean airway pressures (MAPs) were seen in the median sternotomy group directly after surgery (ΔMAP median [interquartile range], 0.00 [2.13] vs 0.80 [1.67] cmH2O; P = .025). Postoperative blood transfusion (median [interquartile range], 20 [14] vs 17 [16] mL; P = .661) rates did not differ between both approaches. In addition, Kaplan-Meier survival analysis demonstrated no statistically significant differences between both groups. CONCLUSIONS: In our experience, a median sternotomy approach for surgical PDA closure is at least noninferior to a posterolateral thoracotomy approach. Given the lower postoperative pulmonary complication rate and lower postoperative MAPs directly after surgery, the median sternotomy approach may be considered superior for preterm neonates with immature and vulnerable lungs.

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.

Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B.

BACKGROUND: Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role. HYPOTHESIS: Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (primary outcome) and reduce S-100B and free radical formation (secondary outcome). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Development of postural control in typically developing children and children with cerebral palsy: possibilities for intervention?

The basic level of postural control is functionally active from early infancy onwards: young infants possess a repertoire of direction-specific postural adjustments. Whether or not direction-specific adjustments are used depends on the child's age and the nature of the postural task. The second level of control emerges after 3 months: children start to develop the capacity to adapt postural activity to environmental constraints. But the adult form of postural adaptation first emerges after adolescence. Children with cerebral palsy (CP) in general have the ability to generate direction-specific adjustments, but they show a delayed development in the capacity to recruit direction-specific adjustments in tasks with a mild postural challenge. Children with CP virtually always have difficulties in the adaptation of direction-specific activity. The limited data available on the effect of intervention on postural development suggest that intervention involving active trial and error experience may accelerate postural development in typically developing infants and may improve postural control in children with or at high risk for a developmental motor disorder.