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Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage
C A Crowther1, D J Henderson-Smart
1Department of Obstetrics and Gynaecology, University of Adelaide, Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, Australia.
Insights
Maternal phenobarbital administration does not prevent periventricular haemorrhage in preterm infants, despite initial findings. This treatment also increases maternal sedation and lacks long-term neurodevelopmental benefits.
Area of Science:
- Neonatal Medicine
- Obstetrics
- Clinical Pharmacology
Background:
- Preterm infants face risks of periventricular haemorrhage (PVH).
- Phenobarbital is investigated for its potential to prevent brain injury by stabilizing blood pressure and flow.
Purpose of the Study:
- To evaluate the efficacy and safety of prenatal phenobarbital for preventing PVH in infants born very preterm.
- To assess neonatal mortality, neurological morbidity, long-term neurodevelopment, and maternal morbidity.
Main Methods:
- Systematic review and meta-analysis of randomized controlled trials.
- Searched Cochrane databases and bibliographies for relevant trials.
- Assessed trial eligibility, quality, and extracted data on infant and maternal outcomes.
Main Results:
- Initial analyses suggested phenobarbital reduced rates of all and severe PVH.
- However, these benefits were attributed to low-quality trials; higher-quality trials showed no significant effect.
- No difference in neurodevelopmental abnormalities was observed; maternal sedation increased with phenobarbital use.
Conclusions:
- Current evidence does not support prophylactic maternal phenobarbital for preventing PVH or neurological disability in preterm infants.
- Maternal sedation is a significant adverse effect.
- Future research should prioritize robust neurodevelopmental assessments.
Background:
Preterm infants are at risk of periventricular haemorrhage. Phenobarbital might prevent ischaemic injury or reduce fluctuations in blood pressure and blood flow in the brain.
Objectives:
To assess the benefits and harms of giving phenobarbital to women at risk of imminent very preterm birth with the primary aim of preventing periventricular haemorrhage in the infant.
Search Strategy:
We searched the Cochrane Pregnancy and Childbirth Group trials register (18 October 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2003) and bibliographies.
Selection Criteria:
Randomised trials with reported data that compare outcomes, such as neonatal mortality, neonatal neurological and other morbidity, long-term neurodevelopment and maternal morbidity, following prenatal exposure to phenobarbital, with outcomes in controls with or without placebo.
Data Collection And Analysis:
We independently assessed trial eligibility and quality and extracted data. We included eligible trials in the initial analysis and prespecified sensitivity analyses to evaluate the effect of trial quality. Results are expressed as relative risk (RR) and 95% confidence intervals (CI).
Main Results:
Over 1750 women were entered into the nine trials included. Analyses of all included trials showed a significant reduction in the rates of all grades of periventricular haemorrhage (PVH) (RR 0.65, 95% CI 0.50 to 0.83, 9 trials, 1591 women) and severe grades PVH (3 and 4) (RR 0.41, 95% CI 0.20 to 0.85, 8 trials, 1527 women) in infants whose mothers had been given prenatal phenobarbital. These results were influenced by trials of poor quality which contributed excessive weight in the analysis due to their higher rates of severe PVH. When only the two higher quality trials were included, these beneficial effects disappeared for all grades of PVH (RR 0.90, 95% CI 0.75 to 1.08, 2 trials, 945 women), and severe grades of PVH (RR 1.05, 95% CI 0.60 to 1.83, 2 trials, 945 women). No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow up assessed between 18 to 36 months of age. Maternal sedation was more likely in women receiving phenobarbital (RR 2.06, 95% CI 1.79 to 2.37, 1 trial, 576 women).
Reviewer'S Conclusions:
The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent periventricular haemorrhage or to protect from neurological disability in preterm infants. Phenobarbital administration leads to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.