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Iranian Journal of Pediatrics
Tehran University of Medical Sciences Press
ISSN: 1018-4406 EISSN: 2008-2150
Vol. 18, Num. 1, 2008, pp. 20-24
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Iranian Journal of Pediatrics, Vol. 18, No. 1, March, 2008, pp. 20-24
The Effect of Clofibrate on Neonatal Hyperbilirubinemia
in Uncomplicated Jaundice
Hamid R. Badeli*1, MD, Pediatric Nephrologist; Reza Sharafi1, MD, Neonatologist; Seyed Aidin Sajedi1, MD
1Department of Pediatrics, Guilan University of Medical Sciences, Rasht, Iran
* Correspondence author; Address: 17 - Shahrivar Hospital, Majo St, Rasht, Iran. Email: badeli@gums.ac.ir
Received: 01/10/07; Revised: 23/11/07;
Accepted: 12/04/07
Code Number: pe08003
Abstract
Objective:Clofibrate has been used for several years as a
hypolipidemic drug. Our aim was to study the effect of Clofibrate on neonatal
hyperbilirubinemia in uncomplicated jaundice.
Material & Methods:This clinical trial study has been conducted on 90 normal term
neonates who were admitted for uncomplicated jaundice in 17th-Shahrivar
Children's Hospital of Guilan University of Medical Sciences from September
2005 to January 2006. The data included: age, sex, total and direct serum
bilirubin, weight and duration of hospitalization. All data were analyzed by
using statistical methods.
Findings: All 90 infants enrolled in our study had received phototherapy. The infants
were divided into Clofibrate group (G1) consisting of 26 boys (57.8%) and
19 girls (42.2%) and Control group with 24 boys (53.3%) and 21 girls (46.7%)
(G2). There were no statistically overt differences between the two groups regarding
sex distribution, age, weight and total serum bilirubin level at admission. Mean
values for total bilirubin of serum in Clofibrate group 12, 24, 36, and 48
hours after admission were significantly lower than those for Control group (P<0.00l).
The mean time needed for phototherapy in Clofibrate group (38.8) (20-48h) was
significantly shorter than that in control group (68.7) (36-96h) (P<0.00l).
Conclusion:Clofibrate is effective and probably a safe drug for
neonatal hyperbilirubinemia that can decrease the time needed for phototherapy
and hospitalization, although further studies with a more precise and longer
follow up is needed for proving its safety to be used routinely in the treatment
of neonatal hyperbilirubinemia.
Key Words: Clofibrate, Neonate, Hyperbilirubinemia,
Jaundice
Introduction
Bilirubin is one of the end products of Heme
catabolism. Its clinical significance in the neonate relates to its propensity
for deposition in the skin and mucous membranes and therefore producing
jaundice. It may also deposit in the brain where it has been implicated in
causing transient dysfunction and, occasionally, permanent neuronal damage.
''Kernicterus'' refers to neurological consequences of the deposition of
unconjugated bilirubin in brain tissue by damaging and scarring of the basal
ganglia and brain stem nuclei[1]. There are several
nonpharmacological and pharmacological modalities for treating hyperbilirubinemia.
Phototherapy has emerged as the most widely used non pharmacological therapy
for the treatment and prophylaxis of neonatal unconjugated hyperbilirubinemia[2]
but it has several untoward complications such as retinal damages,
hyperthermia, loose stool and bronze baby syndrome.
Pharmacological agents introduced for
treatment of unconjugated neonatal jaundice include Phenobarbital[3],
Metalloporphyrins[4], agar, oral charcoal and Dpenicillamine that
more researches are necessary to prove their safety in clinical use[5].
Clofibrate has been used for several years as
a hypolipidemic drug[6]. Clofibrate also increases bilirubin
conjugation and excretion via induction of glucuronosyl transferase activity[7],
Its potency is three times more than Phenobarbital in induction of bilirubin
conjugation[8]. The effect of Clofibrate on uncomplicated
hyperbilirubinemia was proposed in some studies[9,10]. Mohammadzadeh
and colleagues studied Clofibrate effect on reducing serum bilirubin level of
neonates beyond the first week of life[10]. The present study was
designed to assess Clofibrate effect on uncomplicated hyperbilirubinemia of
neonates during the first week of life.
Material & Methods
This clinical trial study was performed during
September 2005 to January 2006, in 17th-Shahrivar Children's Hospital
affiliated to Guilan University of Medical Sciences in the north of Iran.
Patients of the study were admitted during the
study period in this center for evaluation and treatment of jaundice. Infants
with dehydration, infection, ABO or Rh incompatibility, G6PD deficiency,
conjugated bilirubin above 2 mg/dl or exceeding 15% of total serum bilirubin (TSB)
and congenital anomalies were excluded, and from the remainder 90 neonates were
enrolled in this study. All selected neonates were born at term (with gestational
age of 38 to 41 weeks), breastfed, had serum bilirubin (TSB) levels between 15
to 29.9 mg/dl and body weight 2500g to 4000g.
These neonates were randomly allocated to
Clofibrate group (G1) and control group (G2) alternately; i.e. the first
patient to group G1, the second one to G2, and so on, with the permission of
their parents and the ethics committee of our university and the hospital. Both
groups (G1 and G2) received phototherapy under standard conditions with 4 special
white 420-480 nanometer lamps being used less than 240 hours and adjusted to
about 30 centimeters above neonate. Group G1 received a single dose of 100 mg/kg
Clofibrate. Immediately after admission and before starting any modalities,
blood samples were withdrawn from both groups for routine jaundice laboratory
tests such as complete blood count (CBC), total bilirubin (direct and
indirect), reticulocyte count, Coomb's test, G6PD activity, blood group and Rh
of neonates and their mothers. TSB and indirect bilirubin were measured every
12 hours till the end of phototherapy. All data were analyzed by using the
statistical package for social sciences (SPSS v.11) software and were summarized
and expressed as mean (and standard deviation). Statistical analysis of data
was performed by chi-square test, Fisher exact test and independent t-test.
Statistical significance was considered at a P value less than 0.05.
Findings
All 90 infants enrolled in our study received
phototherapy. 45 infants include 26 boys (57.8%), and 19 girls (42.2%) belonged
to Clofibrate (G1) and the rest 24 boys (53.3%),
Table 1- Mean (and standard deviation) of
age, weight and total serum bilirubin in two groups neonatal hyperbilirubinemia
Parameter |
Clofibrate
group
G1
|
Control
group
G2
|
Age (day) |
5.0 (1.5) |
5.6 (2.1) |
Weight (g) |
3190 (268) |
3151 (289) |
TSB (mg/dl) |
18.4 (1.4) |
18.4 (1.8) |
and 21 girls (46.7%) to control group (G2). There
were no statistically overt differences between the two groups regarding sex, age, weight
and TSB at the time of admission (Table 1).
No problems were detected in daily routine
examinations during the hospitalization by neonatal ward physicians. There was
no persistent hyperbilirubinemia. The mean values for TSB at 12th,
24th, 36th and 48th hours after admission in
group G1 were statistically less than G2 group (Table 2).
All neonates in group G1 after 48 hours of starting
the treatment did not need phototherapy, but in G2 38 of 45 neonates needed it
for 72 hours and remainder for 96 hours. The mean (SD) and range duration of
phototherapy in Clofibrate group (G1) was 38.8 (7.5) and 20-48 hours
respectively, while in control group (G2) was 68.75 (15.40) and 36-96 hours,
respectively (P<0.001). During hospitalization and 48 hours after
discharge none of neonates demonstrated any complication. All neonates were
followed for a period of a month and there was fortunately no
complications found. Limitation of this tudy was inability to follow our
patients with laboratory data on proceeding months.
Discussion
In the present study we compared the effect of
combination therapy of single oral 100 mg/kg/dose of Clofibrate and
phototherapy (group G1) with phototherapy alone (group G2) on TSB level of two
groups of 45 neonates with marked hyperbilirubinemia.
TSB levels in group G1 at 12th, 24th,
36th and 48th hours after starting the treatment were
significantly lower than those in group G2. Also, the mean time of phototherapy
needed in group G1 was significantly lower than that in group G2.
Although unconjugated hyperbilirubinemia is a
common neonatal disease, to date there are few drugs introduced to its treatment.
Table 2. Mean plasma
bilirubin values during treatment in Clofibrate and Control group
Time(hour)
|
Control
group(G2)
Plasma
bilirubin (mg/dl)
(n
= 45)
|
Clofibrate
group (G1)
Plasma
bilirubin (mg/dl)
( n
= 45 )
|
P
value |
12th |
17. 63
± 1.06 |
15. 82
± 1.03 |
<0.001 |
24th |
16.61
± 1.59 |
13.62
± 1.57 |
<0.001 |
36th |
15.24
± 1.65 |
11.95
± 1.57 |
<0.001 |
48th |
13.97 ±
1.40 |
10.93 ±
0.87 |
<0.001 |
Some of these drugs such as Phenobarbital[2]
and Chinese herbal remedies[12] act via similar way as induction of the conjugation of bilirubin, but
they have some complications such as somnolence, stupor and respiratory
insufficiency with Phenobarbital[5] and induced neurotoxicity in
Chinese remedies such as Artemisia by displacement of bilirubin from albumin.
Although Clofibrate has several side effects
in adults in longtime use such as nausea, loose stool, gastrointestinal upset,
vomiting, muscle cramp, and pruritus[18], in the neonatal period
with single high dose of Clofibrate such side effects have not been reported by
researchers[9,18,11].
During our study and follow up of the patients
no side effects could be detected too. In comparison to the recent similar
study by Mohammadzadeh et al on the effect of Clofibrate in neonatal hyperbilirubinemia[10]
we found similar significant decreasing effect of Clofibrate on TSB levels with
proceeding times and shorter duration of phototherapy, but in Mohammadzadeh
study the mean age of enrolled neonates was between 8-9 days (5.04 in their
Clofibrate group)[10]. This is the time when in most term babies
with hyperbilirubinemia the bilirubin level will be on receding trend[19];
in our study neonates were selected near to maximum level of bilirubin
elevation in usual trend (5 days) for this treatment. In conformity with
Mohammadzadeh et al[10], we did not find any side effects after a
month of clinical follow up.
Conclusion
Clofibrate, a hypolipidemic drug, is an effective
and probably safe drug also for neonatal hyperbilirubinemia and decreases the
time needed for phototherapy. Although we didn't find any side effects of
Clofibrate after a course of one month of clinical evaluation, further studies
with a more precise and longer follow up is needed for proving its safety to be
used in the treatment of neonatal hyperbilirubinemia.
Acknowledgment
We would like to thank Dr Azita Tangestaninejad,
Dr Zhaleh Mortazavi and Mrs Zahra Atrkar Roushan for their invaluable and generous
support for providing
this article. In addition, we are extremely grateful to the staff of the
neonatal ward and laboratory department of 17th-Shahrivar Children's
Hospital for the support of the study.
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