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Indian Pediatr 2010;47: 401-407 |
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Phenobarbitone for Prevention and Treatment of
Unconjugated Hyperbilirubinemia in Preterm Neonates:
A Systematic Review and Meta-analysis |
Deepak Chawla and Veena Parmar
From the Department of Pediatrics, Government Medical
College Hospital, Chandigarh, India.
Correspondence to: Dr Deepak Chawla, Assistant Professor,
Department of Pediatrics, Government Medical College Hospital,
Chandigarh 160 030, India.
Email:
[email protected]
Received: August 4, 2008;
Initial review: September 5, 2008;
Accepted: May 8, 2009.
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Abstract
Objective: To evaluate the role of phenobarbitone
in the management of unconjugated hyperbilirubinemia during first two
weeks of life in preterm neonates.
Design: Meta-analysis.
Methods: A study was eligible for inclusion in
the meta-analysis if it randomized preterm neonates into control and
treatment groups. Standard search strategy of the Cochrane Neonatal
Review Group was used. For categorical and continuous data the odds
ratio (OR) and weighted mean difference (WMD) were calculated,
respectively. 95% confidence intervals were used and a fixed effects
model was assumed for the meta-analysis.
Main outcome measures: Peak serum bilirubin,
duration of phototherapy, need of phototherapy and exchange transfusion,
neurodevelopmental outcome and adverse effects.
Results: A total of 19 potentially relevant
studies were identified. Of these, 3 studies (497 neonates) were
included in the meta-analysis. Peak serum bilirubin was significantly
lower in phenobarbitone group (mean difference: –1.78 mg/dL, 95% CI:
–2.29 to –1.27). Duration of phototherapy was shorter (mean difference:
–14.75 h, 95% CI: –26.67 to –2.83). Need of phototherapy (OR: 0.33, 95%
CI: 0.13 to 0.81) and exchange transfusion (OR: 0.30, 95% CI: 0.14 to
0.64) were also reduced in phenobarbitone group.
Conclusion: Phenobarbitone reduces peak serum
bilirubin, duration and need of phototherapy and need of exchange
transfusion in preterm very low birthweight neonates. Further studies
are warranted to evaluate adverse effects and neurodevelopmental
outcome.
Keywords: Neonate, Jaundice, Phenobarbitone, Preterm,
Prevention.
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High incidence of neonatal jaundice
requiring therapeutic intervention in preterm neonates has been well
documented. Among seven hospitals of National Institute of Child Health
and Human Development (NICHD) Neonatal Intensive Care Network, 77% of very
low birthweight (VLBW) babies received phototherapy and 4% required
exchange transfusion for neonatal hyperbilirubinemia(1).
Hyperbilirubi-nemia was found to be the most common morbidity (65%) among
137 extremely low birthweight neonates born over a period of 7 years in a
tertiary care unit of India(2). In an analysis of 551 cases of neonatal
jaundice, 162 (65.6%) of 247 VLBW babies developed significant
jaundice(3). Other Indian studies have also found similar high rates of
jaundice in VLBW neonates(4). Preterm babies are also probably at higher
risk of bilirubin-induced brain damage because of lower serum albumin
concentration with weaker bilirubin binding sites and more permeable
blood-brain barrier(5).
Management of hyperbilirubinemia in preterm neonates
with phototherapy causes increased insensible water loss, increased
incidence of patent ductus arteriosus and temperature instability(6,7).
Exchange transfusion also has significant morbidity and mortality risk,
apart from risks associated with exposure to blood products. Therefore,
use of a preventive strategy which can decrease the incidence of
‘pathological’ hyperbilirubinemia in preterm neonates is desirable.
Phenobarbitone, by inducing the activity of
uridine-di-phosphate glucuronyl transferase enzyme, can blunt the
bilirubin rise seen in neonatal period. By decreasing the peak serum
bilirubin or duration of hyperbilirubinemia, phenobarbitone may decrease
the need of exchange transfusion and duration of phototherapy. We
conducted this meta-analysis to assess the effect of phenobarbitone on
unconjugated hyperbilirubinemia during first two weeks of life in preterm
neonates.
Methods
The systematic review was carried out as per
methodology recommended by Cochrane Neonatal Review Group(8) and is being
reported in accordance with the QUOROM statement(9). We planned to include
all randomized studies investigating efficacy of phenobarbitone
administration on clinical course of neonatal unconjugated
hyperbilirubinemia during first two weeks of life. A study was eligible
for inclusion if it enroled preterm neonates (born at less than 37 weeks
of gestation) and randomized the study subjects into control (placebo or
no treatment) and treatment groups (phenobarbitone by oral and/or
parenteral route with or without a loading dose; initiated before or after
appearance of jaundice). Trials were not excluded based on severity of
illness or clinical outcome of enroled subjects.
The standard search strategy of the Neonatal Review
Group, as outlined in the Cochrane Library, was used(8). The following
sources were searched for eligible reports: Cochrane Controlled Trials
Register (online search) and MEDLINE electronic searches using the terms:
"jaundice, jaundice/neonatal, preterm neonate, randomized controlled
trial, phenobarbitone", and the text words "pheno-barbitone, jaundice" (up
to May 2008). In addition, the following sources were hand-searched:
reference lists from the articles retrieved in electronic search and from
review articles and abstracts from proceedings of annual meetings of The
European Society for Paediatric Research and The Society for Pediatric
Research (up to 2008). Details of search strategy and its results are
depicted in Fig. 1.
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Fig. 1 Progress through stages of search
for eligible studies. |
Main outcomes sought in the studies were duration of
phototherapy (hours), need of exchange transfusion (proportion of study
subjects who underwent one or more exchange transfusion) and survival
without major disability at 18-24 months of life. Secondary out-comes were
peak serum bilirubin, need of photo-therapy, number of exchange
transfusions, apneic episodes needing methylxanthine therapy or
ventilatory support, duration of ventilation, duration of neonatal
intensive care unit stay, duration of hospital stay, incidence of
intraventricular hemorrhage, death before discharge from hospital and
major and minor disabilities during follow-up. Subgroup analysis was
planned for following categories: (i) Trials with and without
loading dose of phenobarbitone; (ii) Trials starting phenobarbitone
before and after appearance of clinical jaundice; and (iii) Trials
investigating phenobarbitone role in VLBW infants.
Potentially relevant studies were assessed for
inclusion independently by both the authors. The methodological quality of
each trial was assessed by both the authors, with second author blinded to
trial author and institution. Having decided which trials to include,
authors independently extracted the data and compared results.
Disagreements were resolved by consensus. For categorical and continuous
data the odds ratio (OR) and weighted mean difference (WMD) were
calculated, respectively. 95% confidence intervals were used and a fixed
effects model was assumed for the meta-analysis. Review Manager 5 (The
Cochrane Collaboration) was used for writing review and carrying out
statistical procedures.
Results
Search strategy resulted in retrieval of six studies;
five published in peer-review journals and one in a conference
proceeding(10-15). Three clinical trials were included in the
meta-analysis(10,11,15) and another three(12-14) were excluded as the
method of treatment allocation was not by randomization.
Characteristics of participants, intervention, outcomes
assessed and quality assessment of included studies are depicted in
Table I. Epstein, et al.(15) and Ruth, et al.(10)
reported secondary analysis of the trial conducted to evaluate efficacy of
phenobarbitone in preventing intraventricular hemorrhage. Kumar, et al.(11)
conducted a randomized controlled trial in neonates with birthweight
1000-1499 g. Subjects fulfilling the eligibility criteria were randomized
into 3 groups: Group I – babies were given 10 mg/kg loading dose of
phenobarbitone on day 1 followed by maintenance 5 mg/kg/day from day 2 to
day 5; Group II – neonates were given phenobarbitone in the maintenance
dose of 5 mg/kg/day from day 1 to day 5; and Group III babies acted as
controls (no placebo given). For the purpose of meta-analysis, Group I and
Group II in the study by Kumar, et al.(11) were combined and
compared with placebo or no treatment.
Table I
Characteristics and Potential of Bias of Included Studies
|
Epstein,
et al.(15) |
Ruth, et
al.(10) |
Kumar, et
al.(11) |
Methods |
Randomized controlled trial |
Randomized controlled trial |
Randomized controlled trial |
Participants |
Neonates with birth weight |
Neonates with gestation ³25 |
Neonates with birthweight |
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<1750 g needing intubation |
weeks, birthweight £1500 g, no |
1000-1499 g |
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and mechanical ventilation |
major congenital malformation, |
|
|
within 12 hr of birth |
no history of maternal barbitu- |
|
|
|
rate treatment and age <4 h |
|
Interventions |
Placebo or intravenous pheno- |
Intravenous glucose infusion |
10mg/kg loading dose of |
|
barbitone 10 mg/kg at 12 hr of |
(control group); or intravenous |
phenobarbitone on day 1 |
|
age and 2.5 mg/kg every 12 hr |
phenobarbitone (treatment group) |
followed by maintenance |
|
|
given as loading dose of 30 mg/kg |
5mg/kg/day from day |
|
|
(in two aliquots of 15 mg/kg each |
2 to day 5 OR pheno- |
|
|
4 hours apart) followed by mainte- |
barbitone in the main- |
|
|
nance dose of 5 mg/kg/d for 5 |
tenance dose of 5mg/kg/ |
|
|
days |
day from day 1 today 5 OR |
|
|
|
no treatment (no placebo) |
Outcomes |
Incidence of hyperbilirubinemia |
Peak serum bilirubin (PSB) |
PSB, Age at PSB, peak |
|
(STB> 10 mg/dL), duration of |
|
bilirubin-birth weight index, |
|
phototherapy, need of exchange |
|
duration of phototherapy, |
|
transfusion |
|
need of exchange |
|
|
|
transfusion |
Allocation concealment |
Yes |
Unclear |
Unclear |
Blinding |
Yes |
No |
No |
Incomplete outcome
data |
No |
No |
No |
Peak serum bilirubin (PSB) was reported in all three
trials. PSB was significantly lower in phenobarbitone group (n=497;
mean difference: –1.78 mg/dL, 95% confidence interval: –2.29 to –1.27)
(Fig. 2). Duration of phototherapy and need of exchange
transfusion were reported in two trials (n=396). Duration of
phototherapy was also shorter in the phenobarbitone group (mean
difference: –14.75 h, 95% confidence interval: –26.67 to –2.83). There was
70% reduction in need of exchange transfusion in the phenobarbitone group
(relative risk: 0.30, 95% CI: 0.14 – 0.64). Need of phototherapy was
reported in one study and it showed significant reduction in the
phenobarbitone group (relative risk: 0.33, 95% CI: 0.13 – 0.81). No
studied reported on other pre-specified outcomes and possible adverse
effects including survival without major disability at 18-24 months of
life, apneic episodes needing methylxanthine therapy or ventilatory
support, duration of ventilation, duration of NICU stay, duration of
hospital stay, death before discharge from hospital and major and minor
disabilities during follow-up.
|
Fig. 2 Meta-analysis of phenobarbitone use
in jaundice in preterm neoataes. |
Discussion
We carried out this meta-analysis to evaluate the
efficacy of phenobarbitone in management of hyperbilirubinemia in preterm
neonates. Three studies qualified for inclusion in the meta-analysis. A
significant reduction was observed in peak serum bilirubin, duration of
phototherapy, need of phototherapy and exchange transfusion with
phenobarbitone use.
Several reports on use of phenobarbitone in decreasing
the incidence and/or severity of jaundice in low birthweight or other
‘at-risk’ neonates were published in late 1960s and 1970s, when use of
phototherapy was not common and incidence of kernicterus was high in small
babies(12,16-19). These trials suggested that phenobarbitone therapy may
reduce peak serum bilirubin if started early after birth. But with
improved intensive care and more aggressive use of phototherapy machines,
kernicterus almost disappeared in preterm VLBW neonates and interest in
use of phenobarbitone declined. Although, phenobarbitone was later
extensively evaluated for prophylaxis of intra-ventricular hemorrhage, its
effect on course of hyperbilirubinemia was rarely reported. Two of the
studies included in this review have reported hyperbilirubinemia-related
outcomes as secondary outcomes with intraventricular hemorrhage being the
major outcome(10,15).
Two of the three included studies have used loading
dose of phenobarbitone(10,15). Kumar, et al.(11) used two
intervention groups with one group receiving loading dose of 10 mg/kg.
They reported that beneficial effect of phenobarbitone was more pronounced
if loading dose was administered at start of phototherapy. Pharmacokinetic
evaluation of phenobarbitone given without loading dose has shown
increment in plasma drug level throughout the period of administration and
non-achievement of steady state even after 7 days of therapy(20).
Therefore, administration of loading dose and its amount may be important
in achieving the clinical benefit.
Due to non-availability of data or limited data, we
could not conduct analysis of adverse effects or pre-specified sub-group
analysis. Data on neurodevelop-mental outcome at 27 months of age was
reported by Ruth, et al.(10) and no significant difference was
observed in treatment and control groups. A major limitation of this
meta-analysis is clinical and statistical heterogeneity observed in
participants of the included studies. Although, subjects enrolled in the
studies were similar, use of different strategies and loading doses of
phenobarbitone resulted in clinical heterogeneity. Although significant
statistical heterogeneity was observed for one of the outcomes (peak serum
bilirubin), the observed benefit did not disappear with use of alternate
analysis strategies (fixed versus random effect analysis) and we
have reported only fixed-effect meta-analysis. There is also a possibility
of studies without clinically significant effect remaining unpublished. We
have not looked for the publication bias. We did not conduct sensitivity
analysis as number of eligible trials was small.
Beneficial effect of phenobarbitone in reducing
hyperbilirubinemia, need of treatment and treatment related morbidities
may be of special relevance to a resource-restricted setting where
availability of working phototherapy units and adequately trained manpower
to perform exchange transfusion is limited.
In summary, phenobarbitone used in preterm very low
birthweight neonates reduces peak serum bilirubin, duration of
phototherapy, need of photo-therapy and exchange transfusion. A loading
dose of 10 mg/kg at start of therapy may enhance the therapeutic benefit
without causing respiratory depression seen with higher doses. Due to
paucity of data, further studies are warranted to evaluate adverse effects
and neurodevelopmental outcome of this therapeutic strategy.
Contributors: DC conceptualized and designed the
study. Retrieval of relevant studies, quality assessment, pooling of
results and manuscript writing was done by DC and VP. DC will be guarantor
of the study.
Funding: None.
Competing interests: None stated.
What is Already Known?
• Hyperbilirubinemia and its treatment cause
significant morbidity in preterm neonates.
What This Study Adds?
• Phenobarbitone reduces peak serum bilirubin,
duration and need of phototherapy and need of exchange transfusion
in preterm very low birth weight neonates.
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