Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants

Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. Phenobarbital has been suggested as a safe treatment that stabilises blood pressure and may protect against free radicals.

To determine the effect of postnatal administration of phenobarbital on the risk of IVH, neurodevelopmental impairment or death in preterm infants.

We used the search strategy of the Neonatal Collaborative Review Group. The original review author (A Whitelaw) was an active trialist in this area and had personal contact with many groups in this field. He handsearched journals from 1976 (when cranial computed tomography (CT) scanning started) to October 2000; these included: Pediatrics, Journal of Pediatrics, Archives of Disease in Childhood, Pediatric Research, Developmental Medicine and Child Neurology, Acta Paediatrica, European Journal of Pediatrics, Neuropediatrics, New England Journal of Medicine, Lancet and British Medical Journal. We searched the National Library of Medicine (USA) database (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL, 2012, Issue 10) through to 31 October 2012. We did not limit the searches to the English language, as long as the article included an English abstract. We read identified articles in the original language or translated.

We included randomised or quasi-randomised controlled trials in which phenobarbital was given to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birthweight below 1500 g or respiratory failure. Adequate determination of IVH by ultrasound or CT was also required.

In addition to details of patient selection and control of bias, we extracted the details of the administration of phenobarbital. We searched for the following endpoints: IVH (with grading), posthaemorrhagic ventricular dilation or hydrocephalus, neurodevelopmental impairment and death. In addition, we searched for possible adverse effects of phenobarbitone, for example hypotension, mechanical ventilation, pneumothorax, hypercapnia and acidosis.

We included 12 controlled trials that recruited 982 infants. There was heterogeneity between trials for the outcome IVH, with three trials finding a significant decrease in IVH and one trial finding an increase in IVH in the group receiving phenobarbital. Meta-analysis showed no difference between the phenobarbital-treated group and the control group in either all IVH (typical risk ratio (RR) 0.91; 95% CI 0.77 to 1.08), severe IVH (typical RR 0.77; 95% CI 0.58 to 1.04), posthaemorrhagic ventricular dilation (typical RR 0.89; 95% CI 0.38 to 2.08), severe neurodevelopmental impairment (typical RR 1.44; 95% CI 0.41 to 5.04) or death before hospital discharge (typical RR 0.88; 95% CI 0.64 to 1.21). There was a consistent trend in the trials towards increased use of mechanical ventilation in the phenobarbital-treated group, which was supported by the meta-analysis (typical RR 1.18; 95% CI 1.06 to 1.32; typical risk difference 0.129; 95% CI 0.04 to 0.21), but there was no significant difference in pneumothorax, acidosis or hypercapnia.

Postnatal administration of phenobarbital cannot be recommended as prophylaxis to prevent IVH in preterm infants and is associated with an increased need for mechanical ventilation.