Indian Journal of Pediatrics, Volume 74—November, 2007 1003

Original Article

Correspondence and Reprint requests : Dr. F. Eghbalian MD,Department of Pediatrics, Hamadan University of Medical SciencesBessat Hospital, Hamadan, Iran, Phone : +989181190121

[Received February 6, 2007; Accepted August 1, 2007]

Effect of Clofibrate in Non-hemolytic Indirect Hyperbiliru-binemia in Full Term Neonates

Fatemeh Eghbalian, Abolfazl Pourhossein and Hassan Zandevakili

Department of Pediatrics, Hamadan University of Medical Sciences Bessat Hospital, Hamadan, Iran

ABSTRACT

Objective. Jaundice is a common clinical problem in neonatal period which may result in brain damage even in healthy fullterm newborns, when it is severe. The aim of this study was to characterize the therapeutic effect of clofibrate in full termneonates who present with nonhemolytic jaundice.

Methods. A clinical controlled study was performed on 60 full term neonates who presented with non- hemolytic jaundice. 30neonates were treated with a single oral dose of clofibrate (100 mg/Kg) plus phototherapy (case group), while 30 neonatesreceived only phototherapy (control group). Both groups were compared in regard to post therapeutic mean total and indirectplasma bilirubin levels, admission duration and the rate of exchange transfusion.

Results. The reduction rate of total and indirect plasma bilirubin levels were significantly higher in the clofibrate- treated groupas compared with the control group (P<0.05). The mean duration of admission was found to be reduced from 2.9 +/- 0.9 daysin the control groupl to 2.2 +/- 0.6 days in clofibrate- treated group (P=0.002). The mean plasma total bilirubin level was lowerin the clofibrate- treated group. No cases required phototherapy after 48 hour in clofibrate- treated group, while 9 neonates (30%)and 2 neonates (6.7%) required phototherapy after 72 hour and 96 hour respectively in the control group. There was nodifference between both the groups for sex, the time of developing jaundice and the rate of exchange transfusion.

Conclusion. A single dose of clofibrate (100 mg/Kg) alongwith phototherapy is more effective than phototherapy alone intreating non-hemolytic hyperbilirubinemia in term healthy newborn infants. [Indian J Pediatr 2007; 74 (11) : 1003-1006]E-mail : eghbalian_fa@yahoo.com

Key words : Neonate; Clofibrate; Jaundice

Hyperbilirubinemia is a common problem of neonatalperiod ant it is usually benign, but it may result in lifelong neurologic sequel in infants who were not treated(Kernicterous).1 Thus treating indirect hyperbilirubinemiaat the appropriate time is of high importance in neonates.Increased bilirubin production, hepatic uptake reduction,impaired bilirubin conjugation and increased enterohep .bilirubin circulation are the pathologic etiologies ofhyperbilirubinemia in newborns. Despite recognitionenzymatic pathways of bilirubin production andelimination, phototherapy serves as the primarytreatment in neonates with unconjugatedhyperbilirubinemia.3 Exchange transfusion is the firstsuccessful therapeutic modality for severe neonataljaundice, where other therapeutic modalities, such as

phototherapy, have failed.4

Although, some pharmacologic agents, such as D-penicillamine Phenobarbital, agar, metalloporphyrins,and recently clofibrate are suggested for treating neonataljaundice, further investigations are needed to confirm theefficacy and safety of these agents, prior to their routineclinical usage.5 Clofibrate is an activator of peroxisomeproliferator- activated receptors (PPARS) which decreasesserum cholesterol and triglyceride levels.6 It is also aglucoronyl transferase inducer which may increasebilirubin conjugation and excretion.7 This agent has beensuggested for prevention and treatment of neonatalhyperbilirubinemia.8 The aim of the present study is toprove the effectiveness of oral clofibrate in the treatmentof non-hemolytic hyperbilirubinemia in the healthy fullterm neonates.

MATERIALS AND METHODS

A randomized clinical trial was performed in newbornservices at Ekbatan hospital, with the consent of

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1004 Indian Journal of Pediatrics, Volume 74—November, 2007

appropriate ethics committee on research affair and theinfants ‘parents. During a 6 months period (June 2005-December 2005), 60 neonates with jaundice, admitted atEkbatan neonatal department, were selected. All caseswere healthy, breast fed, full term neonates with birthweight more than 2500g, and total serum bilirubin levelof 15-25mg/dl. Infants with any congenital anomalies,hemolytic diseases (Rh or ABO incompatibility), sepsissigns or dehydration, and infants who required exchangetransfusion were excluded. Infants were randoml.vdivided into two groups: clofibrate- treated group andcontrol group, by a simple randomization method usinga table of random numbers. All neonates receivedphototherapy in both the groups. Each phototherapy unit(Tosan Co Ltd) contained 8 blue lamps (with a wavelength of approximately 420-450 nm) which adjusted at a25cm distance above the infants cots. Phototherapcuticlamps were changed regularly after 1500 hours of usage.A single 100mg/Kg dose of clofibrate was administeredorally in the cIofibrate- treated group. Total and directserum bilirubin levels were determined at admission, 12hours later, and then every 24 hours. Phototherapy andbilirubin measurement were continued until the totalserum bilirubin concentration declined to less than12mg/dl. Exchange transfusion was indicated at serumtotal bilirubin concentration of > 30 mg/dl or 25 mg/dland above, and also when phototherapy had failed.Laboratory investigations included; complete bloodcount, maternal and neonatal blood groups, direct comb’stest, reticulocyte count, total and direct serum bilirubinlevels, glucose 6 phosphate dehydrogenase level, and aperipheral blood smear. All infants were examined at thesecond day after discharge for evaluation of icter and anyprobable pharmacologic side effects. Bilirubin wasmeasured using Techinca RA 1000 instrument. Data wereanalyzed using SPSS 13. Chi-square was used to comparesex and the time of developing icter. Total and indirectbilirubin level changes were analyzed by ANOVA test Pvalue < 0.05 was considered to be significant.

RESULTS

Of the sixty neonates studied, 36 (60%) were boys and 24(40%) were girls. The mean admission duration was 2.6 ±0.8 days (1-5 days). There were no differences betweenboth groups for sex and the time of developing icterus(P>0.05) Table 1.

The present study results showed that total andindirect serum bilirubin levels at 12, and 24 hours posttherapeutically were significantly lower in clofibratetreated group as compared to control group.

Fifteen patients (50%) in treatment group and 23(76.7%) patients in control group required phototherapyfor 48 h; No cases in treatment group requiredphototherapy after 9h; while 9 (30%) neonates required

phototherapy after 72 h and 2 (6.7%) requiredphototherapy after 96 h in the control group (Table 2).None of the cases in the present study required exchangetransfusion. The reduction rate of plasma total andindirect bilirubin levels, were higher in clofibrate treatedgroup as compared to phototherapy group (P<0.05)(Table 2,3) (Fig. 1,2). The mean hospitalization durationreduced from 2.9±0.9 days (68.8 ± 21.6 hours) in controlgroup to 2.2 ± 0.6 (53.6 ± 15 hours) days in the treatmentgroup (P=0.002).

TABLE 1. Comparison of the Sex and the time of DevelopingJaundice in Clofibrate-treated and Control Groups

Treatment GroupsPhototherapy Phototherapy+ P. Value

(N=30) (Clofibrate (N=30)

Sexboy 21 (70%) 15 (50%) P = 0.11girl 9 (30%) 15 (50%) df=1 Chi2=2.5

Time of developingjaundice

days 2 and 3 23 (76.7%) 24 (80%) P=0.60days 4-7 6 (20%) 6 (20%) df = 2 Chi2 = 1.02after 1st week 1 (3.3%) -

treatmentphotophoto+Clofibrate

Fig. 1. Total bilirubin changes in clofibrate-treated and controlgroups.(Mean ± SD in treatment group: at admission: 20.8±2.9, 12h post therapeutic: 14.2±2.8, 24h post therapeutic: 10.8±2.5),(Mean ± SD in control group: at admission: 20.9±4.3, 12hpost therapeutic: 16.6±3.8, 24h post therapeutic: 12.9±2.8)

DISCUSSION

The present study showed that administration of a singleoral dose of clofibrate (100mg/Kg) in a healthy- full termneonate, with non-hemolytic hyperbilirubinemia, willsignificantly reduce plasma total and indirect bilirubin

Effect of Clofibrate in Non-hemolytic Indirect Hyperbilirubinemia in Full Term Neonates

Indian Journal of Pediatrics, Volume 74—November, 2007 1005

levels after 12h; and therefore admission duration. Thesefindings are consistent with the results of other studies,which have shown the efficacy of clofibrate in treatingneonatal hyperbilirubinemia. The therapeutic effect ofclofibrate in non hemolytic neonatal hyperbilirubinemiawas studied in a double blind controlled trial in France,where 47 neonates were treated with a single oral dose ofclofibrate (50 mg/Kg) plus phototherapy and 46 nconatesreceived corn oil plus phototherapy; and they showedthat serum total bilirubin level was significanlly lower inthe former group (clofibrate plus phototherapy).9 In

another study in Iran, it was shown that clofibratereduces total plasma bilirubin level, admission duration,and the need for phototherapy in neonatal non-hemolytichyperbilirubinemia.10 Clofibrate increases bilirubinconjugation and excretion and may cause a 100% increasein hepatic bilirubin clearance within 6h; so it maysignificantly reduce plasma bilirubin level.11 It is simplyabsorbable in the gastrointestinal (Gl) system. Although ithas side effects in long term consumption such as:diarrhea, vomiting, drowsiness, hepatomegaly, increasingthe cholestasis rate, increasing gallstone prevalence,pancreatitis, renal failure, and peripheral neuropathy; butthere are no reports of side effects with a single oraldose.12 Administration of a single dose of clofibrate (100mg/Kg) was simply tolerated in the present study,without any side effects at hospitalization period andeven at follow up visits (second and seventh days postdischarge). Phenobarbital, like clofibrate, is a glucoronyltransferase inducer, but its efficacy in bilirubin reductionis lower than clofibrate. In addition, it has a long half-lifeand may cause drowsiness in infants. Thu althoughphenooarbital is a hepatic bilirubin metabolism inducer,it is not suggested for the treatment of neonatalhyperbilirubinemia.13,14

Recent clinical trials have shown that a single dose ofmesoporphyrin has the best efficacy with minimal sideeffects, when is used prophylactically in prematureinfants and also curatively in full term neonates.14

Actually, clofibrate is an available pharmacologic agentthat could be used effectively in non-hemolytic neonatalhyperbilirubinemia.

CONCLUSION

It seems that a single dose of clofibrate (100 mg/Kg)alongwith phototherapy is more effective than

TABLE 2. Total and Indirect Bilirubin Changes in Clofibrate-treated and Control Groups

Total and indirect Treatment groupsbilirubin Phototherapy Clofibrate + Phototherapy *P. Value

(N=30) (N=30)Mean ± SD Mean ± SD

Total bilirubin at admission 20.9 ± 4.3 20.8 ± 2.9Total bilirubin at 12 h post therapeutic 16.6 ± 3.8 14.2 ± 2.8 P=0.002Total bilirubin at 24 h post therapeutic 12.9 ± 2.8 10.8 ± 2.5 df = 2 F=6.7

Indirect bilirubin at admission 20.4 ± 4.2 20.3 ± 2.8Indirect bilirubin at 12 h post therapeutic 16.1 ± 3.7 13.7 ± 3 P = 0.002Indirect bilirubin at 24 h post therapeutic 12.4 ± 2.7 10.3 ± 2.5 df = 2 F=6.7

Total bilirubin at 48 h post therapeutic 10.4 ± 2.0 (N=23) 9.3 ± 1.5 (N=15)Indirect bilirubin at 48 h post therapeutic 10.0 ± 2.0 (N=23) 8.9 ± 1.7 (N=15)Total bilirubin at 72h post therapeutic 9.9 ± 1.4 (N=9) -Indirect bilirubin at 72h post therapeutic 9.1 ± 1.2 (N=9) -Total bilirubin at 96h post therapeutic 8.9 ± 0.2 (N=2) -Indirect bilirubin at 96h post therapeutic 8.0 ± 0.2 (N=2) -

*Repeated measurement (ANOVA)

treatmentphotophoto+Clofibrate

Fig. 2. Indirect bilirubin changes in clofibrate-treated and controlgroups(Mean ± SD in treatment group: at admission: 20.3±2.8, 12hpost therapeutic: 13.7±3.0, 24h post therapeutic: 10.3±2.5),(Mean ± SD in control group: at admission: 20.4±4.2, 12hpost therapeutic: 16.1±3.7, 24h post therapeutic: 12.4±2.7)

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1006 Indian Journal of Pediatrics, Volume 74—November, 2007

phototherapy alone in treating non-hemolytichyperbilirubinemia in term healthy newborn infants.

Acknowledgements

The authors have the honor to thank Ekbatan neonataldepartment and laboratory staff.

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