Description of the condition
Intraventricular haemorrhage (IVH) is a major complication of preterm birth and large haemorrhages or haemorrhages associated with parenchymal brain lesions have a high rate of disability (Vohr 1989). Massive IVH may result in death from hypovolaemia and large haemorrhages may result in hydrocephalus in infants who survive (Volpe 1995). IVH in preterm infants originates, not from an artery, but from capillaries of the subependymal germinal matrix. The particular vulnerability of premature infants is thought to result from a) a subependymal germinal matrix that is rich in immature vessels poorly supported by connective tissue (Hambleton 1976; Gould 1987), b) marked fluctuations in cerebral blood flow (Perlman 1983), and c) severe respiratory problems that result in major swings in intrathoracic and venous pressure that are then transmitted to the fragile germinal matrix (Nakamura 1990). In addition, there is evidence that ischaemia followed by reperfusion plays a role in the pathogenesis and that cerebral ischaemia may result from IVH. This may take the form of periventricular haemorrhagic infarction (PHI) (Volpe 1995). PHI lesions are typically unilateral and in continuity with the margin of the lateral ventricle. The aetiology is thought to be obstruction of venous drainage by a blood clot in the germinal matrix. Interventions aimed at prevention of IVH or its consequences might be targeted at any one (or more) of the above mechanisms.
The non-invasive diagnosis of IVH during life was first made by cerebral computed tomography (CT) but the need for transport and the ionising radiation made this method unsuitable for studies of whole populations.
Diagnosis of intraventricular haemorrhage by ultrasound
Cranial ultrasound can be carried out at the cot side and exposes the infant to no ionising radiation. This enables whole populations of infants to be safely and ethically examined. Papile's classification of IVH was originally developed for CT (Papile 1978), but was quickly implemented by ultrasonographers. Grade I haemorrhage is confined to the subependymal germinal matrix with no blood clot in the lumen. Grade II haemorrhage is a small haemorrhage within the ventricular lumen without ventricular dilation. Grade III haemorrhage is a large haemorrhage sufficient to expand the ventricle from the amount of blood. Grade IV haemorrhage is IVH plus parenchymal haemorrhagic venous infarction (Volpe 1995). Although ultrasound diagnosis of germinal matrix haemorrhage is not perfect with sensitivity of 61% and specificity 78%, the diagnosis of IVH shows high sensitivity (91%) and specificity (81%), as does diagnosis of parenchymal haemorrhage (sensitivity 82% and specificity 97%) (Hope 1988).
Timing of intraventricular haemorrhage
Approximately 80% of IVH occurs within 72 hours of birth but a considerable proportion of IVH is visible on the first scan within a few hours of birth (Levene 1982). This means that interventions to prevent IVH should ideally start before delivery and should be commenced soon after birth.
Description of the intervention
Phenobarbital is a barbiturate that acts on the gamma aminobutyric acid (GABA)A receptors in the central nervous system. Phenobarbital prolongs and potentiates the action of GABA on GABAA receptors and at higher concentrations activates the receptors directly. It is frequently used in children as an anticonvulsant.
How the intervention might work
The administration of postnatal phenobarbital to prevent IVH in low birthweight infants is based on:
- the observation that phenobarbital may dampen fluctuations in systemic blood pressure in premature infants (Wimberley 1982);
- evidence that treatment with phenobarbital reduces the incidence of intracranial haemorrhage in newborn beagles made hypertensive with phenylephrine (Goddard 1987);
- experimental evidence that barbiturates can partially protect the brain against hypoxic-ischaemic damage (Steen 1979);
- the suggestion that the free radical scavenging capacity of phenobarbital may protect the brain after hypoxia-ischaemia (Ment 1985).
Drug side effects
Phenobarbital and other barbiturates have pharmacological effects in high doses that could be detrimental to preterm infants. These effects include respiratory depression with consequent respiratory acidosis and need for mechanical ventilation, cardiac depression and hypotension.
Why it is important to do this review
One previous systematic review on this topic (Horbar 1992), including eight trials, concluded that postnatal phenobarbital did not reduce the frequency or severity of IVH in preterm infants. This Cochrane systematic review was undertaken in order to a) include studies after 1988 and b) include outcomes not included in the first review by Horbar 1992. This is an update of the existing review "Postnatal phenobarbital for the prevention of intraventricular haemorrhage" published in The Cochrane Library (Whitelaw 2007).
To determine the effect of postnatal administration of phenobarbital on the risk of IVH, neurodevelopmental impairment or death, and whether significant adverse effects are associated with postnatal phenobarbital administration in preterm infants.
Criteria for considering studies for this review
Types of studies
All controlled trials, whether randomised or quasi-randomised, in which postnatal phenobarbital was compared with control treatment of preterm infants at risk of IVH.
Types of participants
Newborn infants (less than 24-hours old) with a gestational age of less than 34 weeks or birthweight less than 1500 g. We included preterm infants with gestational ages 33 to 36 weeks or birthweights up to 1750 g if they were mechanically ventilated. We excluded infants with serious congenital malformations.
Types of interventions
Phenobarbitone (phenobarbital) by intravenous or intramuscular injection starting within 24 hours of birth, with or without maintenance therapy for up to seven days.
Types of outcome measures
- All grades of IVH.
- Severe IVH (i.e. grade III and IV IVH) (Papile 1978).
- Ventricular dilation or hydrocephalus.
- Hypotension (mean arterial pressure < 30 mm Hg) during the first week.
- Pneumothorax or interstitial emphysema during the first week.
- Hypercapnia (> 8 kPa or 60 mm Hg) during the first week.
- Acidosis (pH < 7.2) during the first week.
- Mechanical ventilation (including infants who were ventilated at enrolment).
- Mild neurodevelopmental impairment (developmental quotient (DQ) < 80 or motor abnormality on examination).
- Severe neurodevelopmental impairment (clinical cerebral palsy or DQ below the range that can be measured).
- Death before discharge from hospital.
- Death at any time during the study.
Search methods for identification of studies
See the Search Strategy of the Neonatal Collaborative Review Group (neonatal.cochrane.org).
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 using the MeSH terms of newborn infant, premature infant, intracranial haemorrhage, cerebral ventricles and phenobarbital. We did not limit the searches to the English language, as long as the article included an abstract written in English. We used the search engine Google using the search term 'phenobarbital for intraventricular haemorrhage (IVH)'. We read the identified articles in the original language or translated them.
Searching other resources
The original review author (A. Whitelaw) was an active trialist in this area and had personal contact with many groups in this field.
For the original review, he handsearched journals from 1976 (when cranial CT scanning started) to November 1998, which 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.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review Group (CNRG), as documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
Review authors independently assessed all the potential studies identified as a result of the search strategy for inclusion.
We excluded trials without a simultaneous control group (e.g. those with historical controls). We reviewed inclusion criteria and therapeutic interventions for each trial to see how they differed between trials. We examined the outcomes in each trial to see how compatible they were between studies. We resolved any disagreement through discussion.
Data extraction and management
Review authors independently performed trial searches, assessments of methodology and extraction of data with comparison and resolution of any differences found at each stage. We entered data into Review Manager 5 software (RevMan 2011) and checked for accuracy. If information regarding any of the above was missing or unclear, we intended to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
We used the standardised review methods of the CNRG to assess the methodological quality of included studies. We assessed each identified trial for methodological quality: a) allocation concealment, b) blinding of the intervention, c) completeness of follow-up and d) blinding of outcome ascertainment.
In addition, review authors independently assessed study quality and risk of bias using the following criteria documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
- Sequence generation: was the allocation sequence adequately generated?
- Allocation concealment: was allocation adequately concealed?
- Blinding of participants, personnel and outcome assessors for each main outcome or class of outcomes: was knowledge of the allocated intervention adequately prevented during the study?
- Incomplete outcome data for each main outcome or class of outcomes: were incomplete data adequately addressed?
- Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
- Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias? We will give particular attention to baseline imbalance in factors and to the length of follow-up studies to identify whether any benefits claimed were robust.
We intended to request additional information and clarification of published data from the authors of individual trials. We assessed each trial for risk of bias based on the criteria listed above and marked as: 'low' risk of bias, 'unclear' risk of bias and 'high' risk of bias.
Measures of treatment effect
We analysed the results of the studies using Review Manager 5 software (RevMan 2011). We summarised data in a meta-analysis if they were sufficiently homogeneous, both clinically and statistically.
Dichotomous data: for dichotomous data, we present results as risk ratios (RRs) with 95% confidence intervals (CIs). If there was a statistically significant reduction, we intended to report risk differences (RDs) and calculate the number needed to treat for additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH), and associated 95% CIs.
Continuous data: for continuous data, we used the mean difference (MD) if outcomes were measured in the same way between trials. We used the standardised mean difference (SMD) to combine trials that measured the same outcome, but use different methods.
Unit of analysis issues
The unit of randomisation and the unit of analysis was the individual infant.
Dealing with missing data
We intended to contact the authors of all published studies if clarifications were required, or to provide additional information. In the case of missing data, we intended to describe the number of participants with missing data in the 'Results' section and the 'Characteristics of included studies' table. We only presented results for the available participants. We intended to discuss the implications of missing data in the discussion of the review.
Assessment of heterogeneity
We used the I
We conducted our statistical analysis using Review Manager 5 software (RevMan 2011). We used a fixed-effect Mantel-Haenszel method meta-analysis for combining data where trials were examining the same intervention, and the trials population and methods were judged to be similar.
Subgroup analysis and investigation of heterogeneity
If sufficient data were available, we explored potential sources of clinical heterogeneity through the following a priori subgroup analyses.
Potential subgroups for analysis included: gestational age less than 30 weeks; infants on mechanical ventilation.
If sufficient data were available, we explored methodological heterogeneity through the use of sensitivity analyses. We planned to perform these through including trials of higher quality, based on the presence of any of the following: adequate sequence generation, allocation concealment and less than 10% loss to follow-up.
Description of studies
Results of the search
We identified 12 randomised or quasi-randomised trials having a simultaneous control group, with data on 982 infants (Donn 1981; Morgan 1982; Whitelaw 1983; Bedard 1984; Porter 1985; Anwar 1986; Kuban 1986; Ruth 1988; Mas-Munoz 1993; Sluncheva 2006; Liang 2009; Zhang 2009). One study with historical controls was not included (Hope 1982). We excluded two further studies as one was not randomised or quasi-randomised (Chen 2008), and one did not meet the inclusion criteria for birthweight and lacked information on mechanical ventilation (Liu 2010). Sluncheva 2006 compared four groups; control, indomethacin, phenobarbital plus indomethacin, and phenobarbital plus indomethacin plus surfactant. This review used the data comparing infants who received indomethacin plus phenobarbital versus indomethacin alone.
The infants participating were relatively similar, being preterm infants who were at risk of IVH either because of gestational age below 34 weeks, birthweight below 1500 g, respiratory distress syndrome requiring mechanical ventilation or a combination of these factors. Cranial ultrasound was carried out before trial entry in only five trials and infants who already had IVH were thereby excluded. It is very likely that some infants in the trials already had IVH before randomisation (Donn 1981; Anwar 1986; Ruth 1988; Mas-Munoz 1993; Sluncheva 2006). Despite randomisation, three trials had unbalanced treatment groups at randomisation. Kuban's trial (Kuban 1986) had lower gestational age and birthweight in the phenobarbital group, Sluncheva's trial had greater gestational age and birthweight in the treatment group (Sluncheva 2006), and Porter's trial had lower Apgar score in the control group (Porter 1985). One trial had unequal group sizes (Liang 2009).
Variation in the intervention in included studies
Sluncheva 2006 used no loading dose of phenobarbital (infants were treated with 5 mg/kg for five days). The other 11 trials started treatment by injection of a loading dose, the dose varying between 20 mg/kg (nine trials) and 30 mg/kg (two trials). Seven of the trials divided the loading dose into two separate injections with 30-minute, four-hour or 12-hour intervals. In 10 trials, maintenance therapy with phenobarbital was given for three to seven days. With the exception of Sluncheva 2006, Liang 2009 and Zhang 2009, blood levels of phenobarbital were measured in all the trials, but were not revealed to the clinicians in the two double-blind trials (Whitelaw 1983; Kuban 1986).
Outcomes in included studies
The main outcome, IVH, was ascertained by ultrasonography in 10 trials and by CT in two trials (Liang 2009; Zhang 2009). IVH was classified in a way that made it possible to grade them as mild (grade I or II according to Papile) or severe (grade III or IV according to Papile). In Whitelaw's original paper (Whitelaw 1983), this type of grading was not used, but the scan reports by ultrasonographers blinded to treatment have been reclassified by Dr Whitelaw (who did have knowledge of treatment by this time).
Ten reports gave some data on mortality. Mortality data from Kuban's trial were not given in the original publication (Kuban 1986), but were subsequently supplied as a personal communication from Dr Kuban to Dr Horbar (Horbar 1992). The age-limit for ascertainment of mortality was not stated by Morgan 1982 and Liang 2009. Sluncheva 2006 recorded mortality up to 10 days of age. Ruth 1988 provided mortality data up to 27 months of age.
Data on potential adverse effects were provided in many of the reports, for example hypotension in three, hypercapnia in five, acidosis in six and mechanical ventilation in all cases where ventilation was not a mandatory inclusion criterion. The numbers of days during which data were recorded for hypotension, hypercapnia and acidosis varied between the trials from one to seven days. The definition of acidosis varied, being less than 7.2 in three trials, less than 7.15 in two trials and need for sodium bicarbonate therapy in one trial.
See Characteristics of included studies table,
We excluded one study with historical controls (Hope 1982). We excluded two further studies as one was not randomised or quasi-randomised (Chen 2008), and one did not meet the inclusion criteria for birthweight and lacking information on mechanical ventilation (Liu 2010).
Risk of bias in included studies
Blinding of randomisation and allocation concealment
It was evident in only two of the trials that allocation concealment was achieved (Whitelaw 1983; Kuban 1986). These two trials used numbered identical vials and were double blind. Among nine other trials stated to be randomised, the method of randomisation was described only by Bedard 1984 (deck of cards), Donn 1981 (lottery) and Ruth 1988 (lottery). It was not clear how allocation concealment was achieved in any of these nine randomised trials. Morgan 1982 used alternate rather than random allocation with no attempt at allocation concealment.
Blinding of the intervention and performance bias
In the open trials by Donn 1981; Morgan 1982; Bedard 1984; Porter 1985; Anwar 1986; Ruth 1988; Mas-Munoz 1993; Sluncheva 2006; Liang 2009 and Zhang 2009, it is likely that the medical and nursing staff knew the treatment allocation. Thus, there is the possibility that the clinical care given to the two groups could have been biased by the knowledge and beliefs of the clinical staff.
Completeness of follow-up
In Kuban 1986, 11 out of 291 (3.8%) infants enrolled were withdrawn after randomisation.
In Ruth 1988, 10 out of 111 infants enrolled were excluded because of gestation less than 25 weeks or congenital anomaly.
In Whitelaw 1983, two of 32 (7%) infants were excluded because of congenital anomalies and these two infants were replaced in the randomisation.
None of the other trials reported any infants excluded after enrolment.
Only Ruth 1988reported long-term follow-up and achieved 100% ascertainment of survivors at 27 months of age.
Blinding of outcome ascertainment and detection bias
All the trials except those by Anwar 1986; Mas-Munoz 1993; Sluncheva 2006; Liang 2009; and Zhang 2009, described the main endpoint, ultrasound or CT diagnosis of IVH, as being determined by ultrasonographers and radiologists who had no knowledge of treatment allocation. In Ruth 1988, the neurologist and psychologist assessing neurodevelopment at 27 months were blind to treatment allocation.
Effects of interventions
Prophylactic administration of phenobarbital in preterm infants at risk of developing intraventricular haemorrhage (Comparison 1)
All grades of intraventricular haemorrhage (Outcome 1.1)
There was statistical heterogeneity between the 11 trials reporting all grades of IVH (Chi
Severe intraventricular haemorrhage (Outcome 1.2)
Data were available from all 12 trials on severe IVH. One trial showed a statistically significant decrease in severe IVH in the phenobarbital treated group (Zhang 2009), but the meta-analysis provided no evidence of a significant reduction in severe IVH (typical RR 0.77; 95% CI 0.58 to 1.04) ( Analysis 1.2).
Posthaemorrhagic ventricular dilation or hydrocephalus (Outcome 1.3)
Ventricular dilation or posthaemorrhagic hydrocephalus was reported in three trials and none of these trials reported a significant difference between the two treatment groups. The typical estimates from the meta-analysis provided no evidence of a reduction in the risk of posthaemorrhagic ventricular dilation (typical RR 0.89; 95% CI 0.38 to 2.08, typical RD -0.01; 95% CI -0.08 to 0.06) ( Analysis 1.3).
Hypotension (Outcome 1.4)
Three trials reported hypotension (Donn 1981; Bedard 1984; Kuban 1986). The trial by Kuban 1986 reported a significant increase in hypotension in the infants receiving phenobarbital (RR 1.24; 95% CI 1.00 to 1.53; RD 0.12; 95% CI 0.00 to 0.23). The other two trials found no significant difference and the meta-analysis found no significant difference in the risk of hypotension (typical RR 1.18; 95% CI 0.97 to 1.43; typical RD 0.09; 95% CI -0.01 to 0.19) ( Analysis 1.4). Kuban's finding could have been influenced by the lower gestational age and birthweight in the group receiving phenobarbital. This would be expected to give a greater number of infants with blood pressures below 30 mm Hg as neonatal blood pressure has a positive correlation with birthweight.
Pneumothorax/interstitial emphysema (Outcome 1.5)
Eight trials reported the number of infants with pneumothorax or interstitial emphysema. Only the trial by Kuban 1986 reported a significant increase in pneumothorax in the infants receiving phenobarbital (RR 2.11; 95% CI 1.20 to 3.70; RD 0.123; 95% CI 0.04 to 0.21). Four trials found non-significant trends towards a reduction in pneumothorax among the infants receiving phenobarbital. The trial by Kuban 1986 had lower gestational age and birthweight in the phenobarbital-treated group. This could have increased the risk of respiratory distress syndrome and the need for higher pressure ventilation. The meta-analysis found no evidence of a difference in the risk of pneumothorax (typical RR 1.28; 95% CI 0.92 to 1.77; typical RD -0.04; 95% CI -0.01 to 0.10) ( Analysis 1.5). There was no statistical heterogeneity.
Hypercapnia (Outcome 1.6)
Five trials reported the number of infants with hypercapnia. None of the trials found a significant difference and the meta-analysis provided no evidence of a difference in the risk of hypercapnia (typical RR 1.00; 95% CI 0.73 to 1.37; typical RD 0.00; 95% CI -0.12 to 0.12) ( Analysis 1.6).
Acidosis (Outcome 1.7)
Six trials reported the number of infants with acidosis. None of the trials reported a significant difference and the meta-analysis provided no evidence of a difference in the risk of acidosis (typical RR 1.16; 95% CI 0.90 to 1.51; typical RD 0.04; 95% CI -0.03 to 0.17) ( Analysis 1.7). Because of the different definitions used for acidosis, this meta-analysis should be treated with caution.
Mechanical ventilation (Outcome 1.8)
Five trials that did not require respiratory support as an obligatory entry criterion reported the number of babies who required ventilation. The trial by Ruth 1988 found a significant increase in use of mechanical ventilation in the group receiving phenobarbital (RR 1.20; 95% CI 1.01 to 1.43). Three trials found a trend towards increased use of mechanical ventilation (RR ranging from 1.09 to 1.54) with the fifth trial finding an RR of 1.00. Meta-analysis showed a significant increase in use of mechanical ventilation in the infants receiving phenobarbital (typical RR 1.18; 95% CI 1.06 to 1.32; typical RD 0.129; 95% CI 0.05 to 0.21) ( Analysis 1.8). This suggests that prophylactic phenobarbital treatment would, on average, result in one extra infant receiving mechanical ventilation for every eight preterm infants treated.
Neurodevelopmental impairment (Outcomes 1.9 and 1.10)
Mild neurodevelopmental impairment was reported only in Ruth 1988, and this showed no significant difference (RR 0.57; 95% CI 0.15 to 2.17; RD -0.05; 95% CI -0.16 to 0.06). Severe neurodevelopmental impairment was also reported only in Ruth 1988 and showed no significant difference (RR 1.44; 95% CI 0.41 to 5.04; RD -0.03; 95% CI -0.08 to 0.15) ( Analysis 1.9; Analysis 1.10).
Mortality prior to hospital discharge (Outcome 1.11)
Nine of the trials reported deaths before discharge from hospital and none reported a significant difference. The typical estimates from the meta-analysis found no evidence of an effect on death prior to hospital discharge (typical RR 0.88; 95% CI 0.64 to 1.21; typical RD -0.02; 95% CI -0.07 to 0.03) ( Analysis 1.11).
Mortality during study period (Outcome 1.12)
Morgan 1982 and Ruth 1988 reported mortality documented after discharge from hospital while the infants were still being followed. Sluncheva 2006 reported deaths within the first 10 days of life only and Liang 2009 reported mortality without information on age at time of death. If these additional deaths are added in to give mortality during study period, none of the trials shows a significant difference and the typical estimates from the meta-analysis provide no evidence of a difference in the risk of death during the study (typical RR 0.90; 95% CI 0.68 to 1.20) ( Analysis 1.12).
Horbar's systematic review of postnatal phenobarbital for preterm infants included eight trials and noted the heterogeneity between trials concerning any IVH and severe IVH (Horbar 1992). The author concluded that postnatal phenobarbital could not be recommended but the question was raised that, in specific settings, phenobarbital might be beneficial. Horbar's review did not present data on ventricular dilation, neuromotor impairment, mechanical ventilation, hypotension, pneumothorax or acidosis.
In the original review, it was possible to include one more trial than in Horbar's systematic review (Horbar 1992), and to include more data from Whitelaw's trial (Whitelaw 1983). The updated reviews in 2007 and 2012 included additional studies (one in 2007 and two in 2012). The original and subsequent updated reviews also covered ventricular dilation and neuromotor impairment, as well as possible cardiorespiratory and acid-base side effects of the intervention. The statistical heterogeneity concerning all grades of IVH persists but no longer applied to severe IVH. This review supports Horbar's conclusion that phenobarbital does not reduce the frequency of IVH, severe IVH or death and provides new evidence that phenobarbital increases the need for mechanical ventilation. The data now available do not identify any specific setting where prophylactic phenobarbital might reduce the risk of IVH.
There is some clinical heterogeneity between the 12 trials but the infants recruited were all similar in that they were preterm, and at risk of IVH because of their immaturity or respiratory failure or both. Although the dosages of phenobarbital varied, they all gave plasma phenobarbital concentrations in the recommended anticonvulsant range for 72 hours, the period during which IVH usually occurs. There does not appear to be a publication bias as illustrated by the funnel plot (Figure 1). The risk of bias in the included studies is summarised graphically (Figure 2; Figure 3).
|Figure 1. Funnel plot of comparison: 1 Phenobarbital versus control, Outcome: 1.1 All intraventricular haemorrhage.|
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
|Figure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
A cause for concern was that seven of the trials did not have a normal cranial ultrasound scan as an entry criterion. The three trials that found that postnatal phenobarbital reduced IVH were open trials that lacked a pre-randomisation cerebral ultrasound scan (Donn 1981; Liang 2009; Zhang 2009). Some of the IVH reported could have arisen before the administration of phenobarbital. The double-blind trial by Kuban 1986 was planned with adequate sample size; however, randomisation did not result in the two groups having similar risk factors for IVH since the group receiving phenobarbital had a significantly greater risk for IVH than did the control group at the time of randomisation. These factors in the trials by Donn 1981; Kuban 1986; Liang 2009 and Zhang 2009 could contribute to the heterogeneity found for the outcome, all grades of IVH. It is important to point out that only one of the trials showed a significant difference for severe IVH (Zhang 2009), but the meta-analysis did not show a significant difference.
It is worth noting the relatively late timing of the initial injection of phenobarbital and the splitting of the loading dose so that it would have been well after 12 hours, in some cases, before anticonvulsant plasma concentrations of phenobarbital could have been achieved. Many IVHs have started by 12 hours of age. The difficulty in achieving therapeutic blood levels of phenobarbital before many IVHs have started was one reason for testing antenatal maternal administration of phenobarbital. Sluncheva 2006 did not use a loading dose. Prophylactic antenatal phenobarbital is the subject of a separate Cochrane systematic review by Crowther 2010, which concluded that the trials with most reliable methodology showed no evidence that the intervention was effective in reducing IVH.
Absence of therapeutic advantage
The results from the meta-analyses of postnatal phenobarbital for preterm infants showed no significant difference between the phenobarbital-treated group and the control group with respect to all grades of IVH, severe IVH, death, posthaemorrhagic ventricular dilation or neurodevelopmental impairment.
Potential side effects
In the current review, the only adverse effect associated with phenobarbital that reached statistical significance was mechanical ventilation, with no significant difference with respect to hypotension, acidosis, hypercapnia or pneumothorax. Increased need for mechanical ventilation is a clinically relevant adverse effect because of the associated iatrogenic risks such as tube blockage, infection, trauma to the larynx and the increased level of equipment and nursing required. Clearly, respiratory depression in spontaneously breathing infants with inadequate monitoring is potentially dangerous.
Since the original publication of this review, it has become apparent that administration of antiepileptic drugs in the newborn period may have a harmful effect on the developing brain. Phenobarbital has a proapoptotic effect in newborn rat brains (Bittigau 2002). More recently, it has been shown that neonatal rat exposure to a single dose of phenobarbital results in reduced synaptic connectivity in the striatum (Forcelli 2012).
Postnatal phenobarbital is not generally used in preterm infants as prophylaxis against IVH but a general decrease in IVH has been noted in developed countries since the 1980s despite an increase in survival of very immature infants. Maternal corticosteroid administration before preterm delivery has been mainly responsible for this decrease in IVH as demonstrated in a separate Cochrane review (Roberts 2006). Of the other pharmacological interventions assessed, indomethacin appeared promising, but results of a multicentre trial of indomethacin recruiting 1200 infants with birthweights below 1100 g showed that the reduction in IVH was not accompanied by an improvement in survival without disability (Schmidt 2001). Although IVH has been reduced in many centres, posthaemorrhagic hydrocephalus remains a problem without an effective treatment and requires further research into mechanisms and treatment. See Cochrane reviews on diuretic therapy (Whitelaw 2001b), repeated cerebrospinal fluid (CSF) tapping (Whitelaw 2001) and intraventricular streptokinase (Whitelaw 2001a).
Implications for practice
With no evidence of a reduction in intraventricular haemorrhage (IVH), neurodevelopmental impairment or death and with consistent evidence of an increase in need for mechanical ventilation, postnatal phenobarbital cannot be recommended for prophylaxis against IVH in preterm infants.
Implications for research
There would seem to be no justification for further studies of postnatal barbiturates as prophylaxis against IVH.
Thanks to Dr Yana S Kovacheva for help in translating the Sluncheva 2006 manuscript.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Last assessed as up-to-date: 17 December 2012.
Protocol first published: Issue 3, 1999
Review first published: Issue 3, 1999
Contributions of authors
AW carried out a literature search and wrote the first draft of the protocol and the full review.
DO carried out a literature search in 2007 and updated the review and analysis.
ES carried out a literature search in 2012 and updated the review and analysis.
Declarations of interest
Sources of support
- University of Bristol, UK.
- Wellcome Trust, UK.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C
Differences between protocol and review
We have updated the methodology for judging risk of bias.
Medical Subject Headings (MeSH)
Cerebral Hemorrhage [*prevention & control]; Cerebral Ventricles; Excitatory Amino Acid Antagonists [*therapeutic use]; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases [*prevention & control]; Phenobarbital [*therapeutic use]; Randomized Controlled Trials as Topic
MeSH check words
* Indicates the major publication for the study