Postnatal phenobarbital for the prevention of intraventricular hemorrhage in preterm infants

Whitelaw A, Odd D

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 20/08/2007
Date of last substantive update: 31/05/2007
Date of last minor update: 14/05/2007
Date next stage expected 16/05/2009
Protocol first published: Issue 3, 1999
Review first published: Issue 3, 1999

Contact reviewer

Prof Andrew Whitelaw
Professor of Pediatrics
Neonatal Intensive Care Unit
University of Bristol
Southmead Hospital
Bristol
UK
BS10 5NB
Telephone 1: +441 117 959 5325
Facsimile: +441 117 959 5324
E-mail: andrew.whitelaw@bristol.ac.uk

Contribution of reviewers

AW carried out a literature search and wrote the first draft of the protocol and the full review.
DO carried out the update literature search independently, and updated the review and analysis.

Internal sources of support

University of Bristol, UK

External sources of support

Wellcome Trust, UK

What's new

This review updates the existing review "Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants", published in The Cochrane Libarry, Issue 3, 1999 (Whitelaw 1999).

A repeat search 18th April 2007 identified one further eligible study.

Dates

Date review re-formatted: 02/11/2000
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 18/04/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

There is not enough evidence that phenobarbital is effective in preventing intraventricular hemorrhage (IVH) in premature babies.

Intraventricular hemorrhage (IVH) is a major problem of preterm birth. Large bleeds in the centre of the brain can cause disability or death in the preterm baby. Unstable blood pressure and blood flow to the brain are believed to cause IVH. The drug phenobarbital is believed to stabilise blood pressure and, therefore, potentially help prevent IVH. The review of trials found there was not enough evidence that postnatal phenobarbital is effective in preventing IVH. Furthermore, phenobarbitone suppresses breathing in infants who are breathing spontaneously, causing a need for mechanical ventilation.

Abstract

Background

Intraventricular hemorrhage (IVH) is a major complication of preterm birth. Large hemorrhages 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.

Objectives

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

Search strategy

See the Search Strategy of the Neonatal Collaborative Review Group. The reviewer has been a active trialist in this area and has personal contact with many groups in this field. Journals handsearched from 1976 (when cranial CT scanning started) to October 2000 include: Pediatrics, J Pediatrics, Archives of Disease in Childhood, Pediatric Research, Developmental Medicine and Child Neurology, Acta Paediatrica, European J of Pediatrics, Neuropediatrics, New England J of Medicine, Lancet and British Medical J. The National Library of Medicine (USA) database (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) were searched through to April 2007 using the MeSH terms intraventricular hemorrhage, newborn infants, premature infant, intracranial hemorrhage, phenobarbitone, phenobarbital. The searches were not limited to the English language, as long as the article included an English abstract. Promising articles were read in the original language or translated.

Selection criteria

Randomized or quasi-randomized 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 were included. Adequate determination of IVH by ultrasound or CT was also required.

Data collection & analysis

In addition to details of patient selection and control of bias, the details of the administration of phenobarbital were extracted. The end-points searched for included: IVH ( with grading), posthemorrhagic ventricular dilatation or hydrocephalus, neurodevelopmental impairment and death. In addition, possible adverse effects of phenobarbitone such as hypotension, mechanical ventilation, pneumothorax, hypercapnia, and acidosis were searched for.

Main results

Ten controlled trials were included with 740 infants recruited. There was heterogeneity between trials for the outcome IVH, with one trial finding a significant decrease in IVH and another 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 IVH (typical relative risk 1.04, 95% CI 0.87, 1.25), severe IVH (typical relative risk 0.91, 95% CI 0.66, 1.24), posthemorrhagic ventricular dilatation (typical relative risk 0.89, 95% CI 0.38, 2.08), severe neurodevelopmental impairment (typical relative risk 1.44, 95% CI 0.41, 5.04) or death before hospital discharge (typical relative risk 0.88, 95% CI 0.64, 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 relative risk 1.18, 95% CI 1.06, 1.32; typical risk difference 0.129, 95% CI 0.045, 0.213), but there was no significant difference in pneumothorax, acidosis or hypercapnia.

Reviewers' conclusions

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.

Background

Intraventricular hemorrhage (IVH) is a major complication of preterm birth and large hemorrhages or hemorrhages associated with parenchymal brain lesions have a high rate of disability (Vohr 1989). Massive intraventricular hemorrhage may result in death from hypovolemia and large hemorrhages may result in hydrocephalus in infants who survive (Volpe 1995). Intraventricular hemorrhage 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 1975; 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 hemorrhagic infarction (PHI) (Volpe1995). PHI lesions are typically unilateral and in continuity with the margin of the lateral ventricle. The etiology is thought to be obstruction of venous drainage by 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 intraventricular hemorrhage during life was first made by cerebral CT but the need for transport and the ionising radiation made this method unsuitable for studies of whole populations.

DIAGNOSIS OF IVH BY ULTRASOUND
Cranial ultrasound can be carried out at the cotside and exposes the infant to no ionizing radiation. This enables whole populations of infants to be safely and ethically examined. Papile's (1977) classification of IVH was originally developed for CT, but was quickly taken up by ultrasonographers. Grade I hemorrhage is confined to the subependymal germinal matrix with no blood clot in the lumen. Grade II hemorrhage is blood within the ventricular lumen without ventricular dilatation. Grade III hemorrhage is IVH with ventricular dilatation and grade IV hemorrhage is IVH plus parenchymal hemorrhagic infarction. Although ultrasound diagnosis of germinal matrix hemorrhage is not perfect with sensitivity of 61 % and specificity 78%, the diagnosis of intraventricular hemorrhage shows high sensitivity (91%) and specificity (81%) as does diagnosis of parenchymal hemorrhage (sensitivity 82 % and specificity 97%) (Hope 1988).

TIMING OF IVH
Approximately 80 % of IVH occurs by 72 hours after 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 certainly not be long delayed after birth.

POSTNATAL PHENOBARBITAL
The administration of postnatal phenobarbital to prevent intraventricular hemorrhage in low birthweight infants is based on
a) the observation that phenobarbital may dampen fluctuations in systemic blood pressure in premature infants (Wimberley 1982)
b) Goddard 1987 evidence that treatment with phenobarbital reduces the incidence of intracranial haemorrhage in newborn beagles made hypertensive with phenylephrine
c) experimental evidence that barbiturates can partially protect the brain against hypoxic-ischaemic damage (Steen 1979)
d) the suggestion that phenobarbital's free radical scavenging capacity may protect after hypoxia-ischemia (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.

A previous systematic review on this topic (Horbar 1992), including 8 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 hemorrhage' published in The Cochrane Library in Disk Issue 3, 1999 (Whitelaw 1999).

Objectives

To determine the effect of postnatal administration of phenobarbital on the risk of intraventricular hemorrhage (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 randomized or quasi-randomized, in which postnatal phenobarbital was compared to control treatment of preterm infants at risk of intraventricular hemorrhage (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. Preterm infants with gestational ages 33 - 36 weeks or birthweights up to 1750 g could also be included if they were mechanically ventilated. Infants with serious congenital malformations were excluded.

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

The main outcomes were
a) all grades of IVH
b) severe IVH i.e. grade III & IV IVH (Papile 1977)
c) ventricular dilatation or hydrocephalus
d) hypotension (mean arterial pressure < 30 mm Hg) during the first week
e) pneumothorax or interstitial emphysema during the first week
f) hypercapnia (> 8 kPa or 60 mm Hg) during the first week
g) acidosis (pH < 7.2) during the first week
h) mechanical ventilation (including infants who were ventilated at enrolment)
i) mild neurodevelopmental impairment (developmental quotient < 80 or motor abnormality on examination)
j) severe neurodevelopmental impairment (clinical cerebral palsy or DQ below the range that can be measured).
k) death before discharge from hospital
l) death at any time during the study.

Search strategy for identification of studies

See the Search Strategy of the Neonatal Collaborative Review Group. The reviewer has been an active trialist in this area and has personal contact with many groups in this field. Journals handsearched from 1976 (when cranial CT scanning started) to November 1998 include: Pediatrics, J Pediatrics, Archives of Disease in Childhood, Pediatric Research, Developmental Medicine and Child Neurology, Acta Paediatrica, European J of Pediatrics, Neuropediatrics, New England J of Medicine, Lancet and British Medical J. The National Library of Medicine (USA) database (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007) were searched through to April 2007 using the MeSH terms intraventricular hemorrhage, newborn infants, premature infant, preterm infant, intracranial hemorrhage, phenobarbitone, phenobarbital. The searches were not limited to the English language, as long as the article included an English abstract. Promising articles were read in the original language or translated.

Methods of the review

Each identified trial was assessed for methodological quality with respect to
a) allocation concealment
b) blinding of the intervention
c) completeness of follow-up
d) blinding of outcome ascertainment.
Trials without a simultaneous control group ( e.g. those with historical controls) were excluded. Inclusion criteria and therapeutic interventions for each trial were reviewed to see how they differed between trials. The outcomes in each trial were examined to see how compatible they were between studies. Statistics: 2 x 2 tables were made from each trial for each important outcome and the relative risk and risk difference with 95 % confidence intervals used in the meta-analysis. Heterogeneity was evaluated using the I² statistic.

Description of studies

Ten randomized or quasi-randomized trials having a simultaneous control group were identified, with data on 817 infants. These included Anwar 1986; Bedard 1984; Donn 1981; Kuban 1986; Mas-Munoz 1993; Morgan 1982; Porter 1985; Ruth 1988; Sluncheva 2006 and Whitelaw 1983. One study with historical controls (Hope 1982) was not included. Sluncheva 2006 compared four groups; control, indomethacin, phenobarbital and indomethacin and phenobarbital, indomethacin and surfactant. This review uses data comparing infants who received indomethacin and phenobarbital, versus indomethacin alone.

PARTICIPANTS
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 by Anwar 1986; Donn 1981; Mas-Munoz 1993; Sluncheva 2006 and Ruth 1988 already had IVH before randomization. Despite randomization, three trials had unbalanced treatment groups at randomization. Kuban's trial (1986) had lower gestational age and birthweight in the phenobarbital group, Sluncheva's trial had greater gestational age and birthweight in the treatment group, and Porter's trial had lower Apgar score in the control group.

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 nine trials started treatment by injection of a loading dose, the dose varying between 20 mg/kg (seven trials) and 30 mg/kg (two trials). Five of the trials divided the loading dose into two separate injections with 30 minutes, four hours or 12 hours interval. In eight trials, maintenance therapy with phenobarbital was given for three to seven days. Except for Sluncheva 2006, blood levels of phenobarbital were measured in all the trials, but were not revealed to the clinicians in the two double blind trials (Kuban and Whitelaw).

OUTCOMES IN INCLUDED STUDIES
The main outcome, IVH, was ascertained by ultrasonography. 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, 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).

All ten original reports gave some data on mortality. Mortality data from Kuban's trial (1986) were not given in the original publication but were subsequently supplied as a personal communication from Dr Kuban to Dr Horbar (Horbar 1992). The age-limit for ascertainment of mortality is not stated by Morgan 1982. 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, e.g. 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 < 7.2 in three trials, < 7.15 in two trials and need for sodium bicarbonate therapy in one trial.

Methodological quality of included studies

BLINDING OF RANDOMIZATION AND ALLOCATION CONCEALMENT
In only two of the trials (Kuban 1986; Whitelaw 1983) was it evident that allocation concealment was achieved; these two trials used numbered identical vials and were double blind. Among seven other trials stated to be randomized, the method of randomization was described only by Bedard 1984 (deck of cards), Donn 1981(lottery) and Ruth 1988 (lottery). In none of these seven randomized trials was it clear how allocation concealment was achieved. 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 Anwar 1986; Bedard 1984; Donn 1981; Mas-Munoz 1993; Morgan 1982; Porter 1985; Sluncheva 2006 and Ruth 1988 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's trial (1986), 11 out of 291 (3.8%) infants enrolled were withdrawn after randomization.
In Ruth's trial (1988), 10 out of 111 infants enrolled were excluded because of gestation < 25 weeks or congenital anomaly.
In Whitelaw's trial (1983), two of 32 ( 7%) infants were excluded because of congenital anomalies and these two infants were replaced in the randomization.
None of the other trials reported any infants excluded after enrolment.
Only Ruth's trial (1988) reported 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; Sluncheva 2006 and Mas-Munoz 1993 described the main endpoint, ultrasound diagnosis of IVH, as being determined by ultrasonographers and radiologists who had no knowledge of treatment allocation. In Ruth's trial (1988) the neurologist and psychologist assessing neurodevelopment at 27 months were blind to treatment allocation.

Results

PROPHYLACTIC ADMINISTRATION OF PHENOBARBITAL IN PRETERM INFANTS AT RISK OF DEVELOPING IVH (COMPARISON 01):
All Grades of IVH (Outcome 01.01):
There is statistical heterogeneity between the nine trials reporting all grades of IVH (Chi square 23.22 df=8). The first trial published (Donn 1991) reported a reduction in IVH among the babies receiving phenobarbital (relative risk 0.29, 95% CI 0.11, 0.77; risk difference -0.33, 95% CI -0.55, -0.12). None of the subsequent eight trials reported a significant reduction in IVH and Kuban's trial (1986) showed a significant increase in IVH among the phenobarbital treated group (relative risk 1.83, 95% CI 1.21, 2.75; risk difference 0.16, 95% CI 0.06, 0.26), although in this trial the group receiving phenobarbital were significantly lighter and had shorter gestation. The typical estimates from meta-analysis provide no evidence that prophylactic phenobarbital reduces IVH (typical relative risk 1.04, 95% CI 0.87, 1.25; typical risk difference -0.02, 95% CI -0.05, 0.08). Because of the statistical heterogeneity, these typical estimates should be interpreted with caution.

Severe IVH (Outcome 01.02):
Data were available from all ten trials on severe IVH. No individual trial showed a statistically significant decrease in severe IVH in the phenobarbital treated group and the meta-analysis provides no evidence of a significant reduction in severe IVH (typical relative risk 0.91, 95% CI 0.66, 1.24; typical risk difference -0.01, 95% CI -0.06, 0.03).

Posthemorrhagic ventricular dilatation or hydrocephalus (Outcome 01.03):
Ventricular dilatation or posthemorrhagic hydrocephalus was reported in three trials and none of these trials reported a significant difference between the two treatment group. The typical estimates from the meta-analysis provide no evidence of a reduction in the risk of posthemorrhagic ventricular dilatation (typical relative risk 0.89, 95% CI 0.38, 2.08, typical risk difference -0.01, 95% CI -0.08, 0.06).

Hypotension (Outcome 01.04):
Three trials reported hypotension. The trial by Kuban 1986 reported a significant increase in hypotension in the infants receiving phenobarbital (relative risk 1.24, 95% CI 1.00, 1.53; risk difference 0.12, 95% CI 0.00, 0.23). The other two trials found no significant difference and the meta-analysis found no significant difference in the risk of hypotension (typical relative risk 1.18, 95% CI 0.97, 1.43; typical risk difference 0.09, 95% CI -0.01, 0.19). 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 01.05):
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 (relative risk 2.11, 95% CI 1.20, 3.70; risk difference 0.123, 95% CI 0.04, 0.21). Four trials found non-significant trends towards a reduction in pneumothorax among the infants receiving phenobarbital. The trial by Kuban 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 relative risk 1.28, 95% CI 0.92, 1.77; typical risk difference -0.04, 95% CI -0.01, 0.10). There was no statistical heterogeneity.

Hypercapnia (Outcome 01.06):
Five trials reported the number of infants with hypercapnia. None of the trials found a significant difference and the meta-analysis provides no evidence of a difference in the risk of hypercapnia (typical relative risk 1.00, 95% CI .73, 1.37; typical risk difference 0.00, 95% CI -0 .12, 0.12).

Acidosis (Outcome 01.07):
Six trials reported the number of infants with acidosis. None of the trials reported a significant difference and the meta-analysis provides no evidence of a difference in the risk of acidosis (typical relative risk 1.16, 95% CI 0.90, 1.51; typical risk difference 0.04, 95% CI -0.03, 0.17). Because of the different definitions used for acidosis, this meta-analysis should be treated with caution.

Mechanical ventilation (Outcome 01.08:
Five trials which 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 (relative risk 1.20, 95% CI 1.01, 1.43). Three trials found a trend towards increased use of mechanical ventilation ( relative risk ranging from 1.09 to 1.54) with the fifth trial finding a relative risk of 1.00. Meta-analysis showed a significant increase in use of mechanical ventilation in the infants receiving phenobarbitone (typical relative risk 1.18, 95% CI 1.06, 1.32; typical risk difference 0.129, 95% CI 0.05, 0.21). This suggests that prophylactic phenobarbital treatment would, on average, result in one extra infant receiving mechanical ventilation for every 8 preterm infants treated.

Neurodevelopmental impairment (Outcome 01.09, 01.10):
Mild neurodevelopmental impairment was reported only in Ruth's trial (1988) and this showed no significant difference (relative risk 0.57, 95% CI 0.15, 2.17; risk difference -0.05, 95% CI -0.16, 0.06). Severe neurodevelopmental impairment was also reported only in Ruth's trial (1988) and showed no significant difference (relative risk 1.44, 95% CI 0.41, -5.04; risk difference -0.03, 95% CI -0.08, 0.15).

Mortality prior to hospital discharge (Outcome 01.11):
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 relative risk 1.17, 95% CI 1.06, 1.30; typical risk difference -0.02, 95% CI -0.07, 0.03).

Mortality during study period (Outcome 01.12):
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. If these additional deaths are added in to give mortality during study period, no trial 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 relative risk 0.91, 95% CI 0.67, 1.25; typical risk difference -0.02, 95% CI -0.07, 0.03).

Discussion

Horbar's systematic review (Horbar 1992) of postnatal phenobarbital for preterm infants included eight trials and noted the heterogeneity between trials concerning any IVH and severe IVH. 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 dilatation, neuromotor impairment, mechanical ventilation, hypotension, pneumothorax or acidosis.

In the current review, it has been possible to include two more trials than in Horbar's systematic review (Horbar 1992) and to include more data from Whitelaw's trial (Whitelaw 1983). The current review also covers ventricular dilatation 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 applies 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.

METHODOLOGICAL CONSIDERATIONS
There is some clinical heterogeneity between the ten 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 were capable of giving plasma phenobarbitone concentrations in the recommended anticonvulsant range for 72 hours, the period during which IVH usually occurs.

A cause for concern was that five of the trials did not have a normal cranial ultrasound scan as an entry criterion. The only trial which found that postnatal phenobarbital reduced IVH (Donn 1981) was an open trial which lacked a pre-randomisation cerebral ultrasound scan. 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 but, unfortunately, the randomization failed to give two groups with similar risk factors for IVH. Kuban's group receiving phenobarbital had a significantly greater risk for IVH than did the control group at the time of randomization. These factors in the trials by Donn 1981and Kuban 1986 could contribute to the heterogeneity found for the outcome, all grades of IVH. It is important to point out that none of the trials showed a significant difference for severe IVH nor did the meta-analysis.

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 intraventricular hemorrhages have started was one reason for testing antenatal maternal administration of phenobarbital. Sluncheva 2006 did not use a loading dose at all. Prophylactic antenatal phenobarbital is the subject of a separate Cochrane systematic review by Crowther 2003, which concluded that the trials with most reliable methodology showed no evidence that the intervention was effective in reducing intraventricular hemorrhage.

ABSENCE OF THERAPEUTIC ADVANTAGE
The results from individual trials and 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, posthemorrhagic ventricular dilatation 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.

OTHER APPROACHES
Postnatal phenobarbital has not been brought into general use in preterm infants as prophylaxis against IVH but a general decrease in IVH has been noted in developed countries over the last 10 years 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 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, posthemorrhagic 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 CSF tapping (Whitelaw 2001) and intraventricular streptokinase (Whitelaw 2001a).

Reviewers' conclusions

Implications for practice

With no evidence of a reduction in 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.

Acknowledgements

Thanks to Dr Yana S Kovacheva for help in translating the Sluncheva 2006 manuscript.

Potential conflict of interest

None.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Anwar 1986	Open randomised controlled trial. Blinding of randomisation: can't tell. No blinding of intervention. Complete follow-up: yes. Blinding of main outcome measurement: can't tell.	Preterm infants with a birthweight below 1500g with no congenital malformations and no maternal phenobarbitone administration. N = 58	Two loading doses of phenobarbital 10 mg/kg intravenously starting before 6 hours of age and the second loading dose 12 hours later, followed by a maintenance dose of 2.5 mg/kg every 12 hours for 7 days. Maintenance doses were adjusted to achieve trough phenobarbitone concentrations of 20 - 30 mg/l	Papile grade of intraventricular hemorrhage by ultrasound on days 1,3,7, posthemorrhagic hydrocephalus, death. It is not clear that the ultrasonographers were blind to treatment allocation.	Cerebral ultrasound was not carried out prior to trial entry so it was not possible to exclude babies who already had IVH before the first dose of phenobarbitone.	B
Bedard 1984	Open randomised controlled trial. Randomisation was by using a deck of cards but it is not clear how blinding to treatment allocation was achieved. Blinding of intervention: no. Blinding of main outcome measurement:yes. Complete follow-up: yes.	Infants less than 24 hours old with birthweights < 1500g or gestation < 33 weeks were all eligible. Infants with gestational ages between 33 and 36 weeks or birthweight > 1500g, were eligible if they required mechanical ventilation for RDS. Another requirement was a cranial ultrasound scan showing no haemorrhage. N = 42.	Two intravenous loading doses of phenobarbital 10 mg/kg 12 hours apart, followed by maintenance doses of 2.5 mg/kg i.v.or orally every 12 hours for 6 days.	Ultrasound diagnosis of grade of intraventricular hemorrhage as mild (grade I or II on Papile scale) or medium/severe (grade III or IV on Papile scale). Death. Mechanical ventilation, pneumothorax, hypotension (< 2 SD below mean), pH < 7.2, pCO2 > 60 mm Hg, pCO2 < 25 mm HG, Bicarbonate administration (for metabolic acidosis).	Of 95 potential trial participants, 42 were excluded because of IVH on the initial ultrasound scan. The control group were, on average, 1.1 weeks less mature and 220g lighter than the phenobarbitone group. No infants excluded after enrolment.	B
Donn 1981	Open randomised controlled trial. Randomisation is described as by lottery but there is no description of how allocation concealment was achieved. Blinding of intervention: no. Complete follow-up: yes. Blinding of main outcome measurement: yes.	Infants with birthweights below 1500g, admitted to the NICU within 6 hours, without congenital malformations and where the mother had not received barbiturates during pregnancy. N = 60. No information on infants excluded or lost after enrolment.	Two loading doses of 10 mg/kg phenobarbital each administered intravenously 12 hours apart. Maintenance does of 2.5 mg/hr every 12 hours were begun 12 hours after. Doses were adjusted to maintain serum concentrations in the 20-30 micrograms/ml range for 7 days.	Papile grade of intraventricular hemorrhage on ultrasound, ventriculomegaly, mechanical ventilation, pneumothorax requiring drainage, hypercapnia (pCO2 > 60 mm Hg), hypotension ( systolic blood pressure 10 mm Hg below expected value or impaired perfusion), bicarbonate therapy, death.	Cerebral ultrasound was not carried out prior to trial entry so it was not possible to exclude babies who already had IVH before the first dose of phenobarbitone.	B
Kuban 1986	Randomised, double-blind, controlled trial. Identical numbered ampoules were prepared by the pharmacy. Blinding of randomisation:yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of main outcome measurement: yes.	Inclusion criteria were a) birthweight <1751g b) endotracheal intubation before 12 hours c) absence of congenital anomaly d) no evidence of intracranial hemorrhage on ultrasound scan e) neonatal phenobarbital level < 5 micrograms/ml. N = 280. Of 291 enrolled, 11 had to be withdrawn and were excluded from analysis. 48 infants were excluded from enrolment because IVH was already present.	Two loading doses of phenobarbital 10 mg/kg or placebo intravenously with a half hour interval. Twelve hours later, the baby received the first of nine maintenance doses of 2.5 mg/kg or placebo at 12 hour intervals.	Papile grade of intraventricular hemorrhage on ultrasound scan (any hemorrhage or severe grade III or IV) hemorrhage, acidosis (pH< 7.2 on day 1), pneumothorax/pulmonary interstitial emphysema, hypotension (< 30 mm Hg on day 1. Mortality data were by personal communication between Dr Kuban and Dr Horbar although age at death is not clear.	The randomisation failed to give a similar gestational age in the two treatment groups. Thus 52.4 % of the phenobarbitone group had gestational age < 30 weeks but this was true of only 41.5 % of the control group. The authors attempted to allow for this imbalance by analysis within weight groups.	A
Mas-Munoz 1993	Open controlled trial. The method of randomisation is not described nor is any means of allocation concealment. Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome measurement: can't tell.	Newborn infants with gestational ages between 27 and 34 weeks and who were ventilator dependent. N = 60. No information on infants excluded or lost after enrolment.	Phenobarbital 20 mg/kg i.v. as a loading dose within 12 hours of birth followed by phenobarbitone 2.5 mg/kg every 12 hours for the next 5 days.	Cerebral ultrasound every 48 hours for 14 days. Intraventricular hemorrhage graded as I/II or III/IV on the Papile scale. Death. It is not clear whether the ultrasonographers were blind to treatment allocation.	Cerebral ultrasound was not carried out prior to trial entry so it was not possible to exclude babies who already had IVH before the first dose of phenobarbitone.	B
Morgan 1982	An open controlled trial using alternate allocation to phenobarbitone or no injection. Blinding of randomisation: no. Blinding of intervention: no. Complete follow-up: no. Blinding of main outcome measurement: yes.	Infants with birthweights below 1250g and infants with birthweights 1250-1500g who required mechanical ventilation in the first 24 hours. An ultrasound scan showing absence of intraventricular haemorrhage was also a requirement. N = 60. No information on infants excluded or lost after enrolment.	A loading dose of 20 mg/kg phenobarbital intramuscularly at a median time of 2 hours after birth (range 1 - 22 hours).	Papile grade of intraventricular hemorrhage on ultrasound, death, pneumothorax, hypercapnia (pCO2 >8 kPa), acidosis (pH< 7.15). The age limit for death is not specified but "one cot death". occurred at home at 4 months.		D
Porter 1985	Open randomised controlled trial. The method of randomisation is not described. Blinding of randomisation: can't tell. Blinding of intervention: no. Complete follow-up: yes. Blinding of main outcome measurement.	Newborn infants with birthweight below 1500g with a normal cerebral ultrasound scan before 6 hours of birth and receiving respiratory supportt. N = 19. No information on infants excluded after enrolment.	A loading dose of phenobarbital 30 mg/kg i.v. within 6 hours of birth, followed by a maintenance dose of 5 mg/kg per day for 72 hours.	Cerebral ultrasound scans were carried out daily by sonographers who were blind to the initial treatment allocation. Intraventricular hemorrhage was graded according to the Papile scale. Mechanical ventilation, pneumothorax, hypercapnia (> 60 mm Hg), acidosis (pH < 7.15). Death.		B
Ruth 1988	Open randomised controlled trial. Randomisation was by "lottery". Blinding of randomization: can't tell. Complete follow-up: yes. Blinding of outcome measurement: yes.	Infants with birthweights below 1501g and gestational age 25 weeks or more, less than 4 hours old. Infants with malformations or maternal barbiturate treatment were excluded. N = 101. 111 infants were originally enrolled but 10 were excluded (7 in the phenobarbitone group and 3 in the control group) either because the gestational age was < 25 weeks or because of congenital anomaly.	2 loading doses of phenobarbital 15 mg/kg i.v. were given 4 hours apart. Maintenance treatment with phenobarbitone 5 mg/kg per day was started 24 hours after the first dose and continued for 5 days.	Cerebral ultrasound scans were carried out on days 1,3,5 and 7 and then weekly. Intraventricular hemorrhage was graded according to the Papile scale. Neurodevelopmental assessment at 27 months of age. Neonatal death, postnatal death, mechanical ventilation (total and > 7days), pneumothorax.	Cerebral ultrasound was not carried out prior to trial entry so it was not possible to exclude babies who already had IVH before the first dose of phenobarbitone.	B
Sluncheva 2006	Randomised controlled trial	Infants with birthweights below 1500g and under 32 weeks gestation.	5mg/kg/day dose of phenobarbital i.v. for the first 5 days	Cerebral ultrasound scans were carried out on days 1, 3, 5 and 10. Intraventricular hemorrhage was graded according to the Papile scale. Neonatal death, pulmonary haemorrage, oxygen requirement, respiratory rate, and patent ductus arterious up to 10 days of age.		B
Whitelaw 1983	Randomised double-blind controlled trial. The infants received numered, identical ampoules for injection. Blinding of randomization: yes. Blinding of intervention: yes. Complete follow-up:yes. Blinding of outcome measurement: yes.	Infants under 1500g with a normal cerebral ultrasound scan in the first 4 hours. N = 60. Two infants were excluded after randomisation because of congenital malformations and they were replaced.	Phenobarbital 20 mg/kg or isotonic saline given i.v. or i.m. within 4 hours of birth. No maintenance doses given.	Intraventricular hemorrhage on cerebral ultrasound scans carried out daily for the two weeks and then weekly. Grading 1,2,3 according to Levene initially, subsequently reclassified to be compatible with Papile grading. Mechanical ventilation after injection, pneumothorax, hypercapnia (pCO2 > 8 kPa), acidosis (pH < 7.2), Death before discharge from hospital.		A

Characteristics of excluded studies

Study	Reason for exclusion
Hope 1982	Not a randomized or quasi-randomised trial.

References to studies

References to included studies

Anwar 1986 {published data only}

Anwar M, Kadam S, Hiatt IM, Hegyi T. Phenobarbitone prophylaxis of intraventricular haemorrhage. Archives of Diseases in Childhood 1986;61:196-7.

Bedard 1984 {published data only}

Bedard MP, Shankaran S, Slovis TL, Pantoja A, Dayal B. Poland RL. Effect of prophylactic phenobarbital on intraventricular hemorrhage in high-risk infants. Pediatrics 1984;73:435-9.

Donn 1981 {published data only}

Donn SM, Roloff DW, Goldstein GW. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone. Lancet 1981;ii:215-7.

Kuban 1986 {published and unpublished data}

Kuban K, Leviton A, Brown ER. Krishnamoorthy K, Baglivo J, Sullivan KF, Allred E. Respiratory complications in low-birth-weight infants who received phenobarbital. American Journal of Diseases in Children 1987;141:996-9.

* Kuban KCB, Leviton A, Krishnamoorthy KS, Brown ER, Teele RL, Baglivo JA, et al. Neonatal intracranial hemorrhage and phenobarbital. Pediatrics 1986;77:443-50.

Mas-Munoz 1993 {published data only}

Mas-Munoz RL, Udaeta-Mora E, Barrera-Reyes RH, Rivera-Rueda MA, Morales-Suarez M. Efecto del fenobarbital sobre la gravedad de la hemorragia intraventricular. Bol Med Hosp Infant Mex. Boletín Médico del Hospital Infantil de México 1993;50:376-82.

Morgan 1982 {published data only}

Morgan MEI, Massey RF, Cooke RWI. Does phenobarbitone prevent periventricular hemorrhage in very low birth weight babies: a controlled trial. Pediatrics 1982;70:186-9.

Porter 1985 {published data only}

Porter FL, Marshall RE, Moore JA, Miller H. Effect of phenobarbital on motor activity and intraventricular hemorrhage in preterm infants with respiratory disease weighing less than 1500g. American Journal of Perinatology 1985;2:63-6.

Ruth 1988 {published data only}

Ruth V, Virkola K, Paetau R, Raivio KO. Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants. Journal of Pediatrics 1988;112:81-6.

Sluncheva 2006 {published data only}

Sluncheva B, Vakrilova L, Emilova Z, Garnizov T. Prevention of brain hemorrhage in infants with low and extremely low birth weight and infants treated with surfactants. Late observation. Akusherstvo i Ginekologii (Sofiia) 2006;45(3):34-8.

Whitelaw 1983 {published data only}

Whitelaw A, Placzek M, Dubowitz L, Lary S, Levene M. Phenobarbitone for prevention of periventricular haemorrhage in very low birth-weight infants. A randomised double-blind trial. Lancet 1983;ii:1168-70.

References to excluded studies

Hope 1982 {published data only}

Hope PL, Stewart AL, Thorburn RJ, Reynolds O. Failure of phenobarbitone to prevent intraventricular haemorrhage in small preterm infants. Lancet 1982;1:444-5.

* indicates the primary reference for the study

Other references

Additional references

Crowther 2003

Crowther CA, Henderson-Smart DJ. Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage haemorrhage. Cochrane Database of Systematic Reviews 2003, Issue 3.

Goddard 1987

Goddard-Finegold J, Armstrong DL. Reduction in incidence of periventricular intraventricular hemorrhages in hypertensive newborn beagles pretreated with phenobarbital. Pediatrics 1987;79:901-6.

Gould 1987

Gould SJ, Howard S. An immunohistochemical study of the germinal matrix in the late gestation human fetal brain. Neuropathology and Applied Neurobiology 1987;13:421-37.

Guzzetta 1986

Vohr BR, Garcia-Coll C, Mayfield S et al. Neurologic and developmental status related to the evolution pf visuo-motor abnormalities from birth to 2 years of age in preterm infants with intraventricular hemorrhage. Journal of Pediatrics 1989;115:296-302.

Hambleton 1975

Hambleton G, Wigglesworth JS. Origin of intraventricular haemorrhage in the preterm infant. Archieves of Disease in Childhood 1975;51:651-9.

Hope 1988

Hope PL, Gould SJ, Howard S, Hamilton PA, Costello AM, Reynolds EO. Precision of ultrasound diagnosis of pathologically verified lesions in the brains of very preterm infants. Developmental Medicine and Child Neurology 1988;30:457-71.

Horbar 1992

Horbar J. Prevention of periventricular-intraventricular hemorrhage. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press:562-89.

Levene 1982

Levene MI, Fawer CL, Lamont RF. Risk factors in the developmental of intraventricular haemorrhage in the preterm neonate. Archieves of Disease in Childhood 1982;57:410-7.

Ment 1985

Ment LR, Stewart WB, Duncan CC. Beagle puppy model of intraventricular hemorrhage. Effect of superoxide dismutase on cerebral blood flow and prostaglandins. Journal of Neurosurgery 1985;62:563-9.

Nakamura 1990

Nakamura Y, Okudera T, Fukuda S et al. Germinal matrix hemorrhage of venous origin in preterm neonates. Human Pathology 1990;21:1059-62.

Papile 1978

Papile L-A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhages; a study of infants with birth weights less than 1500 grams. Journal of Pediatrics 1978;92:529-34.

Perlman 1983

Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood flow velocity in respiratory distress syndrome. Relation to the development of intraventricular hemorrhage. New England Journal of Medicine 1983;309:204-9.

Roberts 2006

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3.

Schmidt 2001

Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants infants. New England Journal of Medicine 2001;344:1966-72.

Steen 1979

Steen PA, Mitchelfelder JD. Barbiturate protection in tolerant and nontolerant hypoxic mice: comparison with hypothermic protection. Anesthesiology 1979;50:404-8.

Volpe 1995

Volpe JJ. Neurology of the Newborn. 3rd edition. Philadelphia: Saunders, 1995.

Whitelaw 2001

Whitelaw A. Repeated lumbar or ventricular punctures in newborns with intraventricular hemorrhage. Cochrane Database of Systematic Reviews 2001, Issue 1.

Whitelaw 2001a

Whitelaw A. Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 2.

Whitelaw 2001b

Whitelaw A, Kennedy CR, Brion LP. Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database of Systematic Reviews 2001, Issue 2.

Wimberley 1982

Wimberley PD, Lou HC, Pedersen H, Hejl M, Lassen NA, Friis-Hansen B. Hypertensive peaks in the pathogenesis of intraventricular hemorrhage in the newborn. Abolition by phenobarbitone sedation. Acta Paediatrica Scandinavica 1982;71:537-42.

Other published versions of this review

Whitelaw 1999

Whitelaw A. Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 3.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Phenobarbital v control
01 All intraventricular hemorrhage	9	740	RR (fixed), 95% CI	1.04 [0.87, 1.25]
02 Severe intraventricular hemorrhage	10	817	RR (fixed), 95% CI	0.91 [0.66, 1.24]
03 Ventricular dilatation or hydrocephalus	3	219	RR (fixed), 95% CI	0.89 [0.38, 2.08]
04 Hypotension	3	382	RR (fixed), 95% CI	1.18 [0.97, 1.43]
05 Pneumothorax/interstitial emphysema	8	682	RR (fixed), 95% CI	1.28 [0.92, 1.77]
06 Hypercapnia	5	241	RR (fixed), 95% CI	1.00 [0.73, 1.37]
07 Acidosis	6	521	RR (fixed), 95% CI	1.16 [0.90, 1.51]
08 Use of mechanical ventilation	5	323	RR (fixed), 95% CI	1.18 [1.06, 1.32]
09 Mild neurodevelopmental impairment	1	101	RR (fixed), 95% CI	0.57 [0.15, 2.17]
10 Severe neurodevelopmental impairment	1	101	RR (fixed), 95% CI	1.44 [0.41, 5.04]
11 Death before discharge	9	740	RR (fixed), 95% CI	0.88 [0.64, 1.21]
12 All deaths during study	10	817	RR (fixed), 95% CI	0.89 [0.66, 1.21]

01 Phenobarbital v control

01.01 All intraventricular hemorrhage

01.02 Severe intraventricular hemorrhage

01.03 Ventricular dilatation or hydrocephalus

01.04 Hypotension

01.05 Pneumothorax/interstitial emphysema

01.06 Hypercapnia

01.07 Acidosis

01.08 Use of mechanical ventilation

01.09 Mild neurodevelopmental impairment

01.10 Severe neurodevelopmental impairment

01.11 Death before discharge

01.12 All deaths during study

Contact details for co-reviewers

Dr David Odd
Neonatal Medicine
University of Bristol Medical School
Southmead Hospital
Bristol
UK
BS10 5NB
Telephone 1: 44 117 959 5699
E-mail: davidodd@doctors.org.uk

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.