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Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants

  1. Elisa Smit1,
  2. David Odd2,*,
  3. Andrew Whitelaw1

Editorial Group: Cochrane Neonatal Group

Published Online: 13 AUG 2013

Assessed as up-to-date: 17 DEC 2012

DOI: 10.1002/14651858.CD001691.pub3


How to Cite

Smit E, Odd D, Whitelaw A. Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD001691. DOI: 10.1002/14651858.CD001691.pub3.

Author Information

  1. 1

    University of Bristol, Neonatal Neuroscience, Bristol, UK

  2. 2

    University of Bristol Medical School, Neonatal Intensive Care Unit, Bristol, UK

*David Odd, Neonatal Intensive Care Unit, University of Bristol Medical School, Southmead Hospital, Bristol, BS10 5NB, UK. davidodd@doctors.org.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 13 AUG 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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

 

Postnatal phenobarbital

The administration of postnatal phenobarbital to prevent IVH in low birthweight infants is based on:

  1. the observation that phenobarbital may dampen fluctuations in systemic blood pressure in premature infants (Wimberley 1982);
  2. evidence that treatment with phenobarbital reduces the incidence of intracranial haemorrhage in newborn beagles made hypertensive with phenylephrine (Goddard 1987);
  3. experimental evidence that barbiturates can partially protect the brain against hypoxic-ischaemic damage (Steen 1979);
  4. 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).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

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.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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

 

Primary outcomes

  • All grades of IVH.
  • Severe IVH (i.e. grade III and IV IVH) (Papile 1978).

 

Secondary outcomes

  • 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).

 

Electronic searches

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 I2 statistic to measure heterogeneity among the trials in each analysis. If we identified substantial heterogeneity, we explored it by prespecified subgroup analysis and sensitivity analysis. We intended to grade the degree of heterogeneity as: 0% to 30% (might not be important), 31% to 50% (moderate heterogeneity), 51% to 75% (substantial heterogeneity) and 76% to 100% (considerable heterogeneity).

 

Data synthesis

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.

 

Sensitivity analysis

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.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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.

 

Included studies

 

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 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,

 

Excluded studies

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).

See Characteristics of excluded studies.

 

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 (Chi2 29.07, degrees of freedom (df) = 10). The first trial published reported a reduction in IVH among the babies receiving phenobarbital (RR 0.29; 95% CI 0.11 to 0.77; RD -0.33; 95% CI -0.55 to -0.12) (Donn 1981). Two of the remaining 10 trials also reported a significant reduction in IVH (Liang 2009; Zhang 2009), while Kuban's trial showed a significant increase in IVH among the phenobarbital-treated group (RR 1.83; 95% CI 1.21 to 2.75; RD 0.16; 95% CI 0.06 to 0.26), although in this trial the group receiving phenobarbital were significantly lighter and had a shorter gestation (Kuban 1986). The typical estimates from meta-analysis provide no evidence that prophylactic phenobarbital reduces IVH (typical RR 0.91; 95% CI 0.77 to 1.08). Because of the statistical heterogeneity, these typical estimates should be interpreted with caution ( Analysis 1.1).

 

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).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

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.

 

Methodological considerations

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).

 FigureFigure 1. Funnel plot of comparison: 1 Phenobarbital versus control, Outcome: 1.1 All intraventricular haemorrhage.
 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 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).

 

Other approaches

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).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

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.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

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

Thanks to Dr Xun Liu for help in translating the Liang 2009; Liu 2010; and Zhang 2009 manuscripts.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Phenobarbital versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All intraventricular haemorrhage11905Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.77, 1.08]

 2 Severe intraventricular haemorrhage12982Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.58, 1.04]

 3 Ventricular dilation or hydrocephalus3219Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.38, 2.08]

 4 Hypotension3382Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.97, 1.43]

 5 Pneumothorax/interstitial emphysema8682Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.92, 1.77]

 6 Hypercapnia5241Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.73, 1.37]

 7 Acidosis6521Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.90, 1.51]

 8 Use of mechanical ventilation5323Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.06, 1.32]

 9 Mild neurodevelopmental impairment1101Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.15, 2.17]

 10 Severe neurodevelopmental impairment1101Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.41, 5.04]

 11 Death before discharge9740Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.64, 1.21]

 12 All deaths during study11902Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.68, 1.20]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 17 December 2012.


DateEventDescription

17 December 2012New citation required but conclusions have not changedNew authorship.

A repeat search on October 31, 2012 identified four more studies, of which two were eligible for inclusion in this review update. One was excluded in view of lack of randomisation, one was excluded as it failed to meet the inclusion criteria.

31 October 2012New search has been performedThis review updates the original review "Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants", published in the Cochrane Library, Issue 4, 2007 (Whitelaw 2007).



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Protocol first published: Issue 3, 1999
Review first published: Issue 3, 1999


DateEventDescription

10 June 2008AmendedConverted to new review format

31 May 2007New citation required but conclusions have not changedSubstantive amendment

31 May 2007New search has been performedThis review updates the existing review "Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants", published in The Cochrane Library, Issue 3, 1999 (Whitelaw 1999).

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



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

None.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • University of Bristol, UK.

 

External sources

  • 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We have updated the methodology for judging risk of bias.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
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(2):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(4):435-9.
Donn 1981 {published data only}
  • Donn SM, Roloff DW, Goldstein GW. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone. Lancet 1981;2(8240):215-7.
Kuban 1986 {published and unpublished data}
  • Kuban K, Leviton A, Brown ER, Krishnamoorthy K, Baglivo J, Sullivan KF, et al. Respiratory complications in low-birth-weight infants who received phenobarbital. American Journal of Diseases in Children 1987;141(9):996-9.
  • Kuban KC, Leviton A, Krishnamoorthy KS, Brown ER, Teele RL, Baglivo JA, et al. Neonatal intracranial hemorrhage and phenobarbital. Pediatrics 1986;77(4):443-50.
Liang 2009 {published data only}
  • Liang GL, He YZ, Luo L. Phenobarbitone to prevent intraventricular hemorrhage in preterm infants - an observational study (38 cases). Journal of Medical Theory and Practice 2009;22(4):449-50. [: 1001-7585(2009)04-0449-02]
Mas-Munoz 1993 {published data only}
  • Mas-Munoz RL, Udaeta-Mora E, Barrera-Reyes RH, Rivera-Rueda MA, Morales-Suarez M. The effect of phenobarbital on the severity of intraventricular hemorrhage [Efecto del fenobarbital sobre la gravedad de la hemorragia intraventricular]. Boletín Médico del Hospital Infantil de México 1993;50(6):376-82.
Morgan 1982 {published data only}
  • Morgan ME, Massey RF, Cooke RW. Does phenobarbitone prevent periventricular hemorrhage in very low birth weight babies: a controlled trial. Pediatrics 1982;70(2):186-9.
Porter 1985 {published data only}
  • Porter FL, Marshall RE, Moore JA, Miller RH. Effect of phenobarbital on motor activity and intraventricular hemorrhage in preterm infants with respiratory disease weighing less than 1500 grams. American Journal of Perinatology 1985;2(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(1):81-6.
Sluncheva 2006 {published data only}
  • Sluncheva B, Vakrilova L, Emilova Z, Kalaĭdzhieva M, Garnizov T. Prevention of brain hemorrhage in infants with low and extremely low birth weight and infants treated with surfactants. Late observation. Akusherstvo i Ginekologiia (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;2(8360):1168-70.
Zhang 2009 {published data only}
  • Zhang ZJ, Yuan J, Meng YQ, Guo JX. An observational study of phenobarbitone in preventing intraventricular hemorrhage in preterm infants. Inner Mongolian Medical Journal 2009;41(5):617-8. [: 1004-0951(2009)05-0617-02]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Chen 2008 {published data only}
  • Chen H, Wei K, Yao Y, Yang Y, Zhou C, Fang X, et al. Multicenter investigative report for the effect of prophylactic phenobarbital on intraventricular hemorrhage in premature infants in China. Journal of Clinical Pediatrics 2008;26(11):986-93.
Hope 1982 {published data only}
  • Hope PL, Stewart AL, Thorburn RJ, Whitehead MD, Reynolds EO, Lowe D. Failure of phenobarbitone to prevent intraventricular haemorrhage in small preterm infants. Lancet 1982;1(8269):444-5.
Liu 2010 {published data only}
  • Liu Z, Zhao Y, Chen W, Wang H. Efficacy and safety of phenobarbital in preventing intraventricular hemorrhage in premature newborns. Journal of Bengbu Medical College 2010;35(10):1030-2. [: 1000-2200(2010)10-1030-03]

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Bittigau 2002
  • Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proceedings of the National Academy of Sciences USA 2002;99(23):15089-94.
Crowther 2010
  • Crowther CA, Crosby DD, Henderson-Smart DJ. Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD000164.pub2]
Forcelli 2012
Goddard 1987
  • Goddard-Finegold J, Armstrong DL. Reduction in incidence of periventricular intraventricular hemorrhages in hypertensive newborn beagles pretreated with phenobarbital. Pediatrics 1987;79(6):901-6.
Gould 1987
Hambleton 1976
  • Hambleton G, Wigglesworth JS. Origin of intraventricular haemorrhage in the preterm infant. Archives of Disease in Childhood 1976;51(9):651-9.
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
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(4):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, 1992:562-89.
Levene 1982
  • Levene MI, Fawer CL, Lamont RF. Risk factors in the developmental of intraventricular haemorrhage in the preterm neonate. Archives of Disease in Childhood 1982;57(6):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(4):563-9.
Nakamura 1990
Papile 1978
  • Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):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(4):204-9.
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Roberts 2006
Schmidt 2001
  • Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344(26):1966-72.
Steen 1979
Vohr 1989
  • Vohr BR, Garcia-Coll C, Mayfield S, Brann B, Shaul P, Oh W. Neurologic and developmental status related to the evolution of visual-motor abnormalities from birth to 2 years of age in preterm infants with intraventricular hemorrhage. Journal of Pediatrics 1989;115(2):296-302.
Volpe 1995
  • Volpe JJ. Neurology of the Newborn. 3rd Edition. Philadelphia: Saunders, 1995:403-463.
Whitelaw 2001
  • Whitelaw A. Repeated lumbar or ventricular punctures in newborns with intraventricular hemorrhage. Cochrane Database of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/14651858.CD000216]
Whitelaw 2001a
  • Whitelaw A. Intraventricular streptokinase after intraventricular hemorrhage in newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/14651858.CD000498.pub2]
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. [DOI: 10.1002/14651858.CD002270]
Wimberley 1982

References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to 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. [DOI: 10.1002/14651858.CD001691]
Whitelaw 2007