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ORIGINAL ARTICLE
Year : 2015  |  Volume : 4  |  Issue : 2  |  Page : 82-86

Effect of fenofibrate on indirect neonatal hyperbilirubinemia


1 Department of Pediatrics, Tanta Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Analytical Chemistry of Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt

Date of Web Publication6-Apr-2015

Correspondence Address:
Prof. Hassan Mohamed Al-Asy
Department of Pediatrics faculty of Medicine, Tanta University, Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2249-4847.154111

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  Abstract 

Background: Neonatal jaundice is a cause for anxiety in parents as well as physicians due to its complications and prolonged hospital stay with increased cost. With early discharge practice, neonatal hyperbilirubinemia has become an important cause for readmission. Aim: The aim of this study is to evaluate the efficacy of oral fenofibrate in the treatment of neonatal hyperbilirubinemia in full term (FT) neonates due to ABO or Rh incompatibility. Design: The type of the study is prospective case control study. Patients and Methods: This study was carried out on 60 FT newborns suffering from neonatal hyperbilirubinemia due to ABO or Rh incompatibility and exaggerated physiological jaundice divided into two groups. Group A (control group): This group included 30 FT neonates with neonatal hyperbilirubinemia 19 males and 11 females. Their duration of stay ranged from 4 to 7 days. All the neonates in this group received phototherapy only. Group B (fenofibrate group): This group included 30 FT neonates with neonatal hyperbilirubinemia 20 males and 10 females. Their postnatal age ranged from day 1 to day 6. Their duration of stay ranged from 4 to 7 days. All the neonates in this group received one single oral dose of fenofibrate suspension with a dose 10 mg/kg beside phototherapy. Results: In our study, there was a statistically significant difference between the two groups (fenofibrate group vs. control group) as regard the response of babies to decrease the level of total serum bilirubin (TSB) and the duration of stay on phototherapy in hospital "lower in fenofibrate group". We found that babies in fenofibrate group showed lower values in successive TSB levels and lower duration of stay in comparison to the control group. We studied the highest level of TSB reached during treatment and found that mean TSB of fenofibrate group was 15.797 mg/dl while mean TSB of the control group was 16.593 mg/dl. In our study, we found that the mean duration of stay at the hospital of fenofibrate group was 4.366 days, while mean duration of stay at the hospital of the control group was 5.633 days (P = 0.0058*). Conclusion: The use of a single oral dose of fenofibrate (with a dose 10 mg/kg) with phototherapy accelerates bilirubin conjugation and excretion via induction of glucuronyl transferase activity hence reduces the duration of stay in hospital.

Keywords: Fenofibrate, hyperbilirubinemia, neonatal jaundice


How to cite this article:
Al-Asy HM, El-Sharkawy HM, Mabrouk MM, Hamad MR. Effect of fenofibrate on indirect neonatal hyperbilirubinemia. J Clin Neonatol 2015;4:82-6

How to cite this URL:
Al-Asy HM, El-Sharkawy HM, Mabrouk MM, Hamad MR. Effect of fenofibrate on indirect neonatal hyperbilirubinemia. J Clin Neonatol [serial online] 2015 [cited 2020 Apr 7];4:82-6. Available from: http://www.jcnonweb.com/text.asp?2015/4/2/82/154111


  Introduction Top


Destruction of red blood cell and its hemoglobin component produces bilirubin which is then conjugated to a soluble form and excreted. In neonates, this becomes more significant because of high red cell mass and relative immaturity for bilirubin conjugation. [1] Free bilirubin deposits in the skin and mucous membranes and produces jaundice. It may also deposit in the brain where it has been implicated in causing transient dysfunction and, occasionally, permanent neuronal damage. [2] "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. [3] Clinicians usually suffer from "Vigintiphobia" that is, a bilirubin level of more than 20 mg/dl where there may be a high probability of development of Kernicterus. [4] There are several nonpharmacological and pharmacological modalities for treating hyperbilirubinemia. Phototherapy has emerged as the most widely used nonpharmacological therapy for the treatment and prophylaxis of neonatal unconjugated hyperbilirubinemia, but it has several untoward complications such as deleterious effect to eyes, high temperature, loose stool and bronze baby syndrome. [5] Pharmacological agents introduced for treatment of unconjugated neonatal jaundice include phenobarbitone, metalloporphyrins and D-penicillamine. [6] However, so far they have not been proved very effective and safe in clinical use. [6] Fibrates have been used for several years as a hypolipidemic drug. [7] Fibrates also increase bilirubin conjugation and excretion via induction of glucuronyl transferase activity. [8] Its potency to induce bilirubin conjugation is many times more than phenobarbitone. [9] The effect of clofibrate on uncomplicated hyperbilirubinemia was proposed in some studies. [10] Mohammadzadeh et al. (2005) studied clofibrate effect on reducing serum bilirubin level of neonates beyond the 1 st week of life. [11] Clofibrate, however, is no longer routinely used for hyperlipidemia in adults due to its adverse effect profile. Fenofibrate is now the most widely used fibrate in treating hyperlipidemia and has a comparatively much better safety profile than clofibrate. [12] This study is designed to assess the effect of fenofibrate on indirect hyperbilirubinemia of neonates during the 1 st weeks of life.


  Patients and Methods Top


This study included 60 full term (FT) neonates admitted to the "NICU" of Tanta University Hospital suffering from neonatal indirect hyperbilirubinemia in the period between January 2013 and August 2013 (39 males and 21 females), (42 ABO incompatibility and 6 Rh incompatibility and 12 exaggerated physiological jaundice). These neonates were randomly allocated into two groups with the permission of their parents and the ethical committee of hospital. Group A: This group included 30 FT neonates with neonatal indirect hyperbilirubinemia. All the neonates in this group received phototherapy only. Group B (fenofibrate group): This group included 30 FT neonates with neonatal indirect hyperbilirubinemia. All the neonates in this group received one single oral dose of fenofibrate suspension with a dose 10 mg/kg beside phototherapy. All the patients were subjected to the detailed medical history including gestational age, sex, body weight, postnatal age, mode of delivery, family history, onset of jaundice and if there are other problems associated with jaundice and detailed clinical examination.

Samples collection

About a volume of blood 2 ml were withdrawn immediately after admission and before starting any treatment from both groups for laboratory tests. 0.5 ml of the sample is added to ethylenediaminetetraacetic acid for complete blood count and blood grouping (ABO) and Rh while the rest of the sample is centrifugated and the serum is used to investigate Total bilirubin (direct and indirect), Coomb's test (direct), C-reactive protein, TSB and indirect bilirubin were measured every 24 h until the end of phototherapy.

Management

Both groups received phototherapy under standard conditions with four special white 420-480 nm lamps, adjusted to about 30 cm above the neonate. Group A received phototherapy only, while Group B received phototherapy plus a single oral dose of 10 mg/kg of non-micronized fenofibrate. [5]

Preparation of fenofibrate suspension

Because of fenofibrate present in tablet and capsule forms, we dissolved the content of the capsule in water to get a well-known concentration of fenofibrate suspension (e.g. 300 mg tablets. Dissolved in 10 ml distilled water to get concentration 30 mg fenofibrate in 1 ml). Outcome of patients regarding the duration of admission, the level of serum bilirubin at the time of discharge and any possible complications could happen because of the drug was estimated.

Inclusion criteria

All selected neonates were born at term (with gestational age of 37-41 weeks) with signs of neonatal hyperbilirubinemia. All selected neonates were of TSB levels between 15 and 20 mg/dl. All selected neonates were weight between 2500 g and 3500 g.

Exclusion criteria included

Preterms (<37 weeks gestational age). Neonates with conjugated bilirubin above 2 mg/dl or exceeding 15% of TSB. Neonates with congenital anomalies. Neonates with sepsis or exchange transfusion. Neonates with respiratory distress. Neonates with cephalohematoma or subgaleal bleeding.

Statistics all data were expressed in mean standard deviation. Student's t-test were used to compare both studied groups. P < 0.05 was considered as significant.


  Results Top


There was no significant statistical difference between the two groups regarding the demographic data as age, sex, gestational age [Table 1] and [Figure 1], [Figure 2], [Figure 3], [Figure 4] and [Figure 5]. We found that babies in fenofibrate group showed lower values in successive TSB levels and lower duration of stay [Table 2] in comparison to the control group. We studied the highest level of TSB reached during treatment and found that mean TSB of fenofibrate group was 15.797 mg/dl, while mean TSB of control group was 16.593 mg/dl [Figure 6] and [Figure 7]. Mean TSB of fenofibrate group after 24 h. was 13.88 mg/dl, while mean TSB after 24 h. of control group was 15.513 mg/dl. Mean TSB of fenofibrate group after 48 h. was 12.287 mg/dl, while mean TSB after 48 h. of control group was 13.58 mg/dl. Mean TSB of fenofibrate group after 72 h. was 9.743 mg/dl, while mean TSB after 72 h. of control group was 11.46 mg/dl as shown in [Table 3].
Figure 1: The sex distribution of both the studied groups

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Figure 2: Postnatal age (in days) in fenofibrate group

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Figure 3: Postnatal age (in days) in control group

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Figure 4: Gestational age (in weeks) in fenofibrate group

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Figure 5: Gestational age (in weeks) in control group

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Figure 6: The highest level of total serum bilirubin reached during the course of treatment of the studied groups

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Figure 7: The highest level of total serum bilirubin reached during the course of treatment of the studied groups

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Table 1: The sex distribution of the studied groups

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Table 2: The mean duration of stay of the studied groups

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Table 3: The demographic data of the studied groups

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  Discussion Top


In our study, the effect of oral fenofibrate with phototherapy was compared with phototherapy alone on TSB level. There was no a statistically significant difference between the two groups (fenofibrate group vs. control group) regarding the sex of babies, but we found that neonatal jaundice are more common in males than females. In our study, there was a statistically significant difference between the two groups (fenofibrate group vs. control group) as regard the response of babies to decrease the level of TSB and the duration of stay on phototherapy in hospital "lower in fenofibrate group". We found that babies in fenofibrate group showed lower values in successive TSB levels and lower duration of stay in comparison to the control group. We studied the highest level of TSB reached during treatment and found that mean TSB of fenofibrate group was 15.797 mg/dl, while mean TSB of control group was 16.593 mg/dl. Mean TSB of fenofibrate group after 24 h. was 13.88 mg/dl, while mean TSB after 24 h. of control group was 15.513 mg/dl. Mean TSB of fenofibrate group after 48 h. was 12.287 mg/dl, while mean TSB after 48 h. of control group was 13.58 mg/dl. Mean TSB of fenofibrate group after 72 h. was 9.743 mg/dl, while mean TSB after 72 h. of control group was 11.46 mg/dl. In our study, we found that mean duration of stay at hospital of fenofibrate group was 5.366 days, while mean duration of stay at hospital of control group was 5.633 days (P = 0.0058).There was no need for exchange transfusion in both studied groups as this study was done on exagerated physiological jaundice. Although unconjugated hyperbilirubinemia is very common neonatal problem, but few drugs have been found to be used and to be very effective in treatment of neonatal jaundice. Some of these drugs such as phenobarbital acts by induction of conjugation of bilirubin which make bilirubin soluble and thus fit for renal excretion, but phenobarbital need time to affect the enzyme and produces sleepness, and causes feeding difficulty and may cause respiratory depression. [13] Fibrates induce bilirubin conjugation more effectively, and converts unconjugated bilirubin to conjugated bilirubin, and increases its clearance. Some studies showed the effectiveness of clofibrate in treatment and prophylaxis of infantile hyperbilirubinemia if given in a dose of 100 mg/kg. Finofibrate is very similar to clofibrate in its mechanism of action, and easily available, and has much better safety than clofibrate. Fenofibrate produces some side effects in adults as gastrointestinal upset and muscle cramps with prolonged use but in neonatal period in a single dose it causes no side effects in our study and up to one month after therapy. Furthermore, our results is coincident with the findings of Kumar et al. [14]


  Conclusion Top


From this study, we can conclude that, phototherapy is still the corner stone in treatment of neonatal jaundice. The use of a single oral dose of fenofibrate (with a dose 10 mg/kg) with phototherapy accelerates bilirubin conjugation and excretion via induction of glucuronyl transferase activity hence reduces the duration of stay in hospital. Furthermore, fenofibrate decreases the cost of stay and lowers the cost/benefit ratio, and at the same time fenofibrate is safe and economic. We can't confirm if fenofibrate can decrease the need for exchange transfusion, and this can be a matter for further studies. Although, no side-effects of fenofibrates were observed after a single dose, 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 Top


For the best of our knowledge, we are the first to do this study on fenofibrate in neonatal hyperbilirubinemia in Egypt, and we thank pediatric Department and neonatology unit for helping us to achieve this research.

 
  References Top

1.
Maisels MJ, Kring E. The contribution of hemolysis to early jaundice in normal newborns. Pediatrics 2006;118:276-9.  Back to cited text no. 1
    
2.
Newman TB, Liljestrand P, Jeremy RJ, Ferriero DM, Wu YW, Hudes ES, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med 2006;354:1889-900.  Back to cited text no. 2
    
3.
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316.  Back to cited text no. 3
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4.
Harris MC, Roth P. Neonatology. In: Richard A, Polin RA, Ditmer MF, editors. Pediatrics Secret. 1 st ed. Philadelphia: Hanley and Belfus; 1989. p. 261.4.  Back to cited text no. 4
    
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Piazza AJ, Stoll BJ. The fetus and the neonatal infant-digestive system disorders (Kernicterus). In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, editors. Nelson Text Book of Pediatrics. 18 th ed., Vol. I. Philadelphia: Saunders, An Imprint of Elsevier; 2008. p. 761-5.  Back to cited text no. 5
    
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Dennery PA. Pharmacological interventions for the treatment of neonatal jaundice. Semin Neonatol 2002;7:111-9.  Back to cited text no. 6
    
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Bennet PN, Brown MJ. Clinical Pharmacology. Sect. 5. 10 th ed. New Delhi: Churchill Livingstone, an Imprint of Elsevier; 2008. p. 474-5.  Back to cited text no. 7
    
8.
Kutz K, Kandler H, Gugler R, Fevery J. Effect of clofibrate on the metabolism of bilirubin, bromosulphophthalein and indocyanine green and on the biliary lipid composition in Gilbert's syndrome. Clin Sci (Lond) 1984;66:389-97.  Back to cited text no. 8
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9.
Bourget P, Broise I, Quinquis-Desmaris V, Gabilan JC. Pharmacokinetics of clofibrate in jaundiced newborn infants at term. Arch Pediatr 1995;2:722-8.  Back to cited text no. 9
    
10.
Gabilan JC, Benattar C, Lindenbaum A. Clofibrate treatment of neonatal jaundice. Pediatrics 1990;86:647-8.  Back to cited text no. 10
    
11.
Mohammadzadeh A, Farhat ASh, Iranpour R. Effect of clofibrate in jaundiced term newborns. Indian J Pediatr 2005;72:123-6.  Back to cited text no. 11
    
12.
Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493-8.  Back to cited text no. 12
    
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Sterm L, Khanna NN, Levy G. Effect of phenobarbitone on hyperbilirubinemia and glucuronide formation in newborn. Am J Dis Child 1970:120:26-31.  Back to cited text no. 13
    
14.
Kumar B, Agarwal PK, Ashutosh C, Dhaneria M. Fenofibrate: A novel approach in treating uncomplicated neonatal hyperbilirubinemia? Peoples J Sci Res 2012;5:5-8.4.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


This article has been cited by
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Journal of Comprehensive Pediatrics. 2019; In Press(In Press)
[Pubmed] | [DOI]



 

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