Effect of clofibrate in jaundiced term newborns
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《美国医学杂志》
Department of Neonatology, Emam-Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Abstract
OBJECTIVE: Clofibrate is a glucuronosyl transferase inducer that has been proposed to increase the elimination of bilirubin in neonates with hyperbilirubinemia. The aim of this study was to characterize the therapeutic effect of clofibrate in neonates born at full term and present with non-hemolytic jaundice. METHODS: A clinical controlled study was performed in two groups of healthy full term neonates. Thirty neonates were treated with a single oral dose of clofibrate (100 mg/kg) plus phototherapy (clofibrate-treated group) while another 30 neonates (control group) received only phototherapy. RESULT: The mean plasma total bilirubin levels of 12th, 24th and 48th hours were significantly lower in the clofibrate-treated group as compared with the control group (P < 0.0001, P < 0.0001 and P = 0.004, respectively). Treatment with clofibrate also resulted in a shorter duration of jaundice and a decreased use of phototherapy (P < 0.0001). No side effects were observed. CONCLUSION: Although other pharmacological agents such as metalloporphyrins and Sn-mesoporphyrin also seem to be effective in decreasing bilirubin production, these products are not available for routine use and cannot be used because the safety of these drugs has to be confirmed prior to their widespread use. Therefore, clofibrate is now the only available pharmacological treatment of neonatal jaundice.
Keywords: Clofibrate; Neonate; Jaundice; Hyperbilirubinemia
Jaundice is the most common clinical problem in neonatal period and in severe circumstances may cause brain damage even in healthy term newborns.[1] Between 30 and 60% of full term newborns and a high percentage of premature infants develop clinical jaundice during the first 7 postnatal days.[2] Increased production of bilirubin, deficiency of hepatic uptake, impaired conjugation of bilirubin and increased enterohepatic circulation of bilirubin account for pathologic causes of hyperbilirubinemia in newborn infants.[3] Phototherapy has remained the standard treatment in neonatal hyperbilirubinemia and exchange transfusion is indicated for severe jaundice when other therapeutic modalities have failed.[4] Although some pharmacological agents such as D-penicillamine, Phenobarbital, agar, oral charcoal, metalloporphyrins and clofibrate are suggested to treat neonatal jaundice, further studies are needed to confirm the safety and efficacy of these drugs prior to their routine clinical use.[5] Clofibrate is an activator of peroxisome proliferator-activated receptors (PPARs), hence decreases serum cholesterol and triglyceride levels and has been used for many years as an effective hypolipidemic agent in adult.[6] Clofibrate is also a glucuronosyl transferase inducer and can increase bilirubin conjugation and excretion.[7] This drug has been proposed for prevention and treatment of neonatal hyperbilirubinemia.[8],[9] Clofibrate treatment also decreased the intensity of jaundice and decreased the need for phototherapy and hospitalization.[10] The aim of the present study was to prove the effectiveness of oral clofibrate in the treatment of non hemolytic hyperbilirubinemia in term healthy neonates.
Materials and methods
During the period from November 2002 until July 2003, sixty neonates with jaundice who were admitted to the neonatal ward of Emam-Reza Hospital, a University hospital affiliated to Mashhad University of Medical Science, Iran, were selected. These neonates were healthy, breastfed, delivered between 38th and 41st weeks gestational age after an uncomplicated pregnancy and had a total serum bilirubin (TSB) between 17 and 29.9 mg/dl. We excluded infants with any congenital anomaly, hemolytic disease (Rh or ABO incompatibility and a positive coombs' test), infection (congenital or acquired), dehydration, G6PD deficiency and conjugated bilirubin > 2.0 mg/dl or exceeding 15% of total serum bilirubin. After parental permission was obtained, infants were randomly allocated to the treatment group (clofibrate) or to the control group by a simple randomization method using a table of random numbers. All neonates in both the groups received phototherapy. Each phototherapy unit contained six special white lamps and adjusted to 20 cm above the infant's cots. The lamps were changed regularly after 250 hours of usage.
Infants in the clofibrate-treated group received a single oral dose of clofibrate (100 mg/kg birth weight). Placebo was not administered to control infants. Serum total and direct bilirubin levels were measured at the beginning, every 12-hour in first the 24 hours and then every 24 hours. Phototherapy and measurement of bilirubin were continued until the TSB declined to less than 14 mg/dl. Blood exchange transfusions were performed with TSB above 30 mg/dl or above 25 mg/dl when the phototherapy failed. All infants in this study were examined 2 days after discharge in the outpatient clinic for evaluation of their icterus and any side effects of the drug. Laboratory investigations included, complete blood count, blood group typing of neonates and their mothers, direct and indirect coombs' tests, reticulocyte count, serum bilirubin level (total and direct) and erythrocyte G6PD level. In cases with prolonged indirect hyperbilirubinemia further investigation such as thyroid function tests, liver function tests and metabolic screening tests were done. The clinical examination, gestational age, birth weight, sex, age at admission, weight at enrollment, serial TSB and direct bilirubin and duration of phototherapy were recorded. Total serum bilirubin (TSB) was estimated by using a UnistatBilirubinometer (Reichert-Jung, Germany). The determination of direct bilirubin was made by the colorimetric method of Lathe and Ruthven.
The obtained data was analyzed with Statistical Package for Social Science (SPSS version 10.05). Numerical variables were compared between the control and clofibrate treated groups using the Independent student's t test. The chi-square test was used to compare sex between the two groups. P values of less than 0.05 were considered statistically significant.
Results
Of the total of 60 infants, 30 neonates (20 boys 66.7%, 10 girls 33.3%) were put to the clofibrate-treated group and 30 neonates (14 boys 46.7%, 16 girls 53.3%) to the control group. There was no statistically significant difference between the groups in sex distribution (P = 0.11). In addition, there were no significant differences between the two groups regarding age at the time of enrollment, gestational age, birth weight, weight at enrollment, reticulocyte count, hematocrit, hemoglobin and TSB levels at enrollment table1. Thus, the clofibrate-treated and the control group were comparable. The ages at enrollment of two neonates in clofibrate-treated group were 18 and 19 days, in whom thyroid stimulating hormone concentration was below 5 μu/ml, liver function tests were normal and metabolic screening tests were negative. Thus, except for jaundice, the infants were healthy and did not show any evidence of hemolytic disease, liver dysfunction and hypothyroidism.
The mean TSB in clofibrate-treated group is statistically less than control group after 12 hour, 24 hour and 48 hour table2. All neonates in treated groups did not require phototherapy after 48 hours (TSB < 14 mg/dl) but 8 neonates (26.7%)and 2 neonates (6.7%) in the control group received phototherapy till 72 hours and 96 hours, respectively. The mean duration ± SD (range) of phototherapy was significantly reduced with clofibrate administration from 54 ±18.83 (24-96) hours in the control group to 30 ±12.89 (12- 48) hours in the clofibrate-treated group (P < 0.0001). On serial examination during hospitalization and 2 days after discharge in the outpatient clinic no side effects were observed. None of the neonates in both groups needed exchange transfusion and hyperbilirubinemia was simply controlled with phototherapy.
Discussion
The present study demonstrated that a single dose of clofibrate (100 mg/kg) in healthy full-term breastfed newborn with marked hyperbilirubinemia (TSB>17mg/dl) can significantly reduce indirect bilirubin levels after 12 hours of treatment compared to control group and also decreases phototherapy requirement. These finding are consistent with the result of other studies that have demonstrated the efficacy of clofibrate in decreasing of indirect hyperbilirubinemia. In a double blind controlled study on the therapeutic effect of clofibrate in full term infants with non-hemolytic hyperbilirubinemia, 47 infants were treated with a single oral dose of clofibrate which significantly lowered bilirubin levels after 16 hours of treatment compared to 46 control infants given corn oil alone and also the duration of jaundice and phototherapy requirements decreased in clofibrate-treated group.[12]
In the present study the mean age of enrollment for both the groups was beyond the first week of life table1. This pattern of jaundice is relatively common in our country and is likely due to cultural and socioeconomic issues of families that take their icteric neonates to our referral center very late. Genetic factors and breast-feeding may also play a role in this regard.
Similar to Phenobarbital, clofibrate increases bilirubin conjugation and excretion whereas this drug is a better enhancer of glucuronosyl transferase induction than phenobarbital and causes 100% increase of hepatic bilirubin clearance within 6 hours so that it significantly reduces bilirubinemia in 16 hours.[10] Phenobarbital has a long half-life and its immediate effects in severe jaundice is questionable.[5] In addition, phenobarbital causes drowsiness in infants and also worsens bilirubin toxicity by alteration of bilirubin oxidation in the brain.[11]Therefore, although phenobarbital like clofibrate is a hepatic bilirubin metabolism inducer, it is not suggested for the treatment of neonatal hyperbilirubinemia while clofibrate is quite preferable. In the present study administration of a single dose of clofibrate was well tolerated and no side effects were observed, however we followed up the patients only till 2 days after discharge. Clofibrate in adults when used as an antilipidemic agent has some side effects such as nausea, gastrointestinal disturbances, vomiting and loose stool. Other possible complications are muscle cramping, fatigue, pruritus, and alopecia.[13] In the neonatal study with a single dose of clofibrate none of these side effects were reported.[9],[10],[12]
Other newer pharmacological agents are utilized in the treatment of neonatal hyperbilirubinemia. Although recent clinical trials have shown that a single dose of the tin-mesoporphyrin (SnMP), a hemoxygenase inhibitor, has the best efficacy with minimal side effects when used prophylactically in premature infants and also curatively in full-term neonates it is not yet manufactured outside research protocols.[10], [14] Indeed, clofibrate only is actually available pharmacologic agent that could be used effectively in neonatal hyperbilirubinemia without any side effects. However, the widespread use of this drug in high-risk infants such as premature infants and hemolytic jaundice needs to be confirmed with further studies.
Acknowledgments
We thank all nurses of the neonatal ward of Emam-Reza Hospital and especially Ms.Amiri for collection of blood samples and follow-up of study subjects.
References
1. Newman TB, Maisels MS. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995; 96: 730-733
2. American Academy of Pediatrics. Practice parameter: management of Hyperbilirubinemia in the healthy term newborn. Provisional Committee for Quality Improvement and Subcommittee on hyperbilirubinemia. Pediatrics 1994; 94: 558-565.
3. Maisels MJ. Neonatal Hyperbilirubinemia. In Klaus MH, Fanaroff AA, eds. Care of the High-Risk Neonate. Pennsylvania: Saunders, 2001: 324-362.
4. Jahnson LH, Brown AK, Bhutani VK. System-based approach to management of neonatal jaundice and prevention of Kernicterus. J Pediatr 2002; 140: 397-386.
5. Dennery PA. Pharmacological interventions for the treatment of neonatal jaundice. Semin Neonatol 2002; 7(2): 111-119.
6. Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, et al. Activators of peroxisome proliferator-activated receptor- alpha induce the expression of the uncoupling pritein-3 gene expression at birth. Diabetes 1999; 48(6): 1217-2122.
7. 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 1984; 66(4): 389-397.
8. Lindenbaum A, Delaporte B, Benattar C, Dehan M, Magny JF, Gerbet D et al. Preventive treatment of jaundice in Preterm newborn infants with clofibrate. Double blind controlled therapeutic trial. Arch Fr Pediatr 1985; 42(9): 759-63. French
9. Bourget P, Broise I, Quinquis-Desmaris V, Gabilan JC. Pharmacokinetics of clofibrate in jaundiced newborn infants at term. Arch Perdiatr 1995; 2(8): 722-728.
10. Gabilan JC. Pharmacologic treatment of neonatal jaundice. A new approach. Arch Pediatr 1998; 5(11): 1274-1278.
11. Hansen TW, Tommarello S. Effect of phenobarbital on bilirubin metabolism in rat brain. Biol Neonate 1998; 73(2): 106-111.
12. Lindenbaum A, Hernandorena X, Vial M, Benattar C, Janaud JC, Dehan M et al. Clofibrate for the treatment of hyperbilirubinemia in neonates born at term: a double blind controlled study. Arch Fr Pediatr 1981; 38 Suppl 1: 867-73.
13. Steiner A, Weisser B, Vetter N. A comparative review of the advers effects of treatments for huperbilirubinemia. Drug Saf 1991; 6(2): 118-130.
14. Bhutani VK, Johnson LH. Newborn Jaundice and Kernicterus- Health and Societal Perspectives. Indian J Pediatr 2003; 70(5): 407-416.(Mohammadzadeh Ashraf, Far)
Abstract
OBJECTIVE: Clofibrate is a glucuronosyl transferase inducer that has been proposed to increase the elimination of bilirubin in neonates with hyperbilirubinemia. The aim of this study was to characterize the therapeutic effect of clofibrate in neonates born at full term and present with non-hemolytic jaundice. METHODS: A clinical controlled study was performed in two groups of healthy full term neonates. Thirty neonates were treated with a single oral dose of clofibrate (100 mg/kg) plus phototherapy (clofibrate-treated group) while another 30 neonates (control group) received only phototherapy. RESULT: The mean plasma total bilirubin levels of 12th, 24th and 48th hours were significantly lower in the clofibrate-treated group as compared with the control group (P < 0.0001, P < 0.0001 and P = 0.004, respectively). Treatment with clofibrate also resulted in a shorter duration of jaundice and a decreased use of phototherapy (P < 0.0001). No side effects were observed. CONCLUSION: Although other pharmacological agents such as metalloporphyrins and Sn-mesoporphyrin also seem to be effective in decreasing bilirubin production, these products are not available for routine use and cannot be used because the safety of these drugs has to be confirmed prior to their widespread use. Therefore, clofibrate is now the only available pharmacological treatment of neonatal jaundice.
Keywords: Clofibrate; Neonate; Jaundice; Hyperbilirubinemia
Jaundice is the most common clinical problem in neonatal period and in severe circumstances may cause brain damage even in healthy term newborns.[1] Between 30 and 60% of full term newborns and a high percentage of premature infants develop clinical jaundice during the first 7 postnatal days.[2] Increased production of bilirubin, deficiency of hepatic uptake, impaired conjugation of bilirubin and increased enterohepatic circulation of bilirubin account for pathologic causes of hyperbilirubinemia in newborn infants.[3] Phototherapy has remained the standard treatment in neonatal hyperbilirubinemia and exchange transfusion is indicated for severe jaundice when other therapeutic modalities have failed.[4] Although some pharmacological agents such as D-penicillamine, Phenobarbital, agar, oral charcoal, metalloporphyrins and clofibrate are suggested to treat neonatal jaundice, further studies are needed to confirm the safety and efficacy of these drugs prior to their routine clinical use.[5] Clofibrate is an activator of peroxisome proliferator-activated receptors (PPARs), hence decreases serum cholesterol and triglyceride levels and has been used for many years as an effective hypolipidemic agent in adult.[6] Clofibrate is also a glucuronosyl transferase inducer and can increase bilirubin conjugation and excretion.[7] This drug has been proposed for prevention and treatment of neonatal hyperbilirubinemia.[8],[9] Clofibrate treatment also decreased the intensity of jaundice and decreased the need for phototherapy and hospitalization.[10] The aim of the present study was to prove the effectiveness of oral clofibrate in the treatment of non hemolytic hyperbilirubinemia in term healthy neonates.
Materials and methods
During the period from November 2002 until July 2003, sixty neonates with jaundice who were admitted to the neonatal ward of Emam-Reza Hospital, a University hospital affiliated to Mashhad University of Medical Science, Iran, were selected. These neonates were healthy, breastfed, delivered between 38th and 41st weeks gestational age after an uncomplicated pregnancy and had a total serum bilirubin (TSB) between 17 and 29.9 mg/dl. We excluded infants with any congenital anomaly, hemolytic disease (Rh or ABO incompatibility and a positive coombs' test), infection (congenital or acquired), dehydration, G6PD deficiency and conjugated bilirubin > 2.0 mg/dl or exceeding 15% of total serum bilirubin. After parental permission was obtained, infants were randomly allocated to the treatment group (clofibrate) or to the control group by a simple randomization method using a table of random numbers. All neonates in both the groups received phototherapy. Each phototherapy unit contained six special white lamps and adjusted to 20 cm above the infant's cots. The lamps were changed regularly after 250 hours of usage.
Infants in the clofibrate-treated group received a single oral dose of clofibrate (100 mg/kg birth weight). Placebo was not administered to control infants. Serum total and direct bilirubin levels were measured at the beginning, every 12-hour in first the 24 hours and then every 24 hours. Phototherapy and measurement of bilirubin were continued until the TSB declined to less than 14 mg/dl. Blood exchange transfusions were performed with TSB above 30 mg/dl or above 25 mg/dl when the phototherapy failed. All infants in this study were examined 2 days after discharge in the outpatient clinic for evaluation of their icterus and any side effects of the drug. Laboratory investigations included, complete blood count, blood group typing of neonates and their mothers, direct and indirect coombs' tests, reticulocyte count, serum bilirubin level (total and direct) and erythrocyte G6PD level. In cases with prolonged indirect hyperbilirubinemia further investigation such as thyroid function tests, liver function tests and metabolic screening tests were done. The clinical examination, gestational age, birth weight, sex, age at admission, weight at enrollment, serial TSB and direct bilirubin and duration of phototherapy were recorded. Total serum bilirubin (TSB) was estimated by using a UnistatBilirubinometer (Reichert-Jung, Germany). The determination of direct bilirubin was made by the colorimetric method of Lathe and Ruthven.
The obtained data was analyzed with Statistical Package for Social Science (SPSS version 10.05). Numerical variables were compared between the control and clofibrate treated groups using the Independent student's t test. The chi-square test was used to compare sex between the two groups. P values of less than 0.05 were considered statistically significant.
Results
Of the total of 60 infants, 30 neonates (20 boys 66.7%, 10 girls 33.3%) were put to the clofibrate-treated group and 30 neonates (14 boys 46.7%, 16 girls 53.3%) to the control group. There was no statistically significant difference between the groups in sex distribution (P = 0.11). In addition, there were no significant differences between the two groups regarding age at the time of enrollment, gestational age, birth weight, weight at enrollment, reticulocyte count, hematocrit, hemoglobin and TSB levels at enrollment table1. Thus, the clofibrate-treated and the control group were comparable. The ages at enrollment of two neonates in clofibrate-treated group were 18 and 19 days, in whom thyroid stimulating hormone concentration was below 5 μu/ml, liver function tests were normal and metabolic screening tests were negative. Thus, except for jaundice, the infants were healthy and did not show any evidence of hemolytic disease, liver dysfunction and hypothyroidism.
The mean TSB in clofibrate-treated group is statistically less than control group after 12 hour, 24 hour and 48 hour table2. All neonates in treated groups did not require phototherapy after 48 hours (TSB < 14 mg/dl) but 8 neonates (26.7%)and 2 neonates (6.7%) in the control group received phototherapy till 72 hours and 96 hours, respectively. The mean duration ± SD (range) of phototherapy was significantly reduced with clofibrate administration from 54 ±18.83 (24-96) hours in the control group to 30 ±12.89 (12- 48) hours in the clofibrate-treated group (P < 0.0001). On serial examination during hospitalization and 2 days after discharge in the outpatient clinic no side effects were observed. None of the neonates in both groups needed exchange transfusion and hyperbilirubinemia was simply controlled with phototherapy.
Discussion
The present study demonstrated that a single dose of clofibrate (100 mg/kg) in healthy full-term breastfed newborn with marked hyperbilirubinemia (TSB>17mg/dl) can significantly reduce indirect bilirubin levels after 12 hours of treatment compared to control group and also decreases phototherapy requirement. These finding are consistent with the result of other studies that have demonstrated the efficacy of clofibrate in decreasing of indirect hyperbilirubinemia. In a double blind controlled study on the therapeutic effect of clofibrate in full term infants with non-hemolytic hyperbilirubinemia, 47 infants were treated with a single oral dose of clofibrate which significantly lowered bilirubin levels after 16 hours of treatment compared to 46 control infants given corn oil alone and also the duration of jaundice and phototherapy requirements decreased in clofibrate-treated group.[12]
In the present study the mean age of enrollment for both the groups was beyond the first week of life table1. This pattern of jaundice is relatively common in our country and is likely due to cultural and socioeconomic issues of families that take their icteric neonates to our referral center very late. Genetic factors and breast-feeding may also play a role in this regard.
Similar to Phenobarbital, clofibrate increases bilirubin conjugation and excretion whereas this drug is a better enhancer of glucuronosyl transferase induction than phenobarbital and causes 100% increase of hepatic bilirubin clearance within 6 hours so that it significantly reduces bilirubinemia in 16 hours.[10] Phenobarbital has a long half-life and its immediate effects in severe jaundice is questionable.[5] In addition, phenobarbital causes drowsiness in infants and also worsens bilirubin toxicity by alteration of bilirubin oxidation in the brain.[11]Therefore, although phenobarbital like clofibrate is a hepatic bilirubin metabolism inducer, it is not suggested for the treatment of neonatal hyperbilirubinemia while clofibrate is quite preferable. In the present study administration of a single dose of clofibrate was well tolerated and no side effects were observed, however we followed up the patients only till 2 days after discharge. Clofibrate in adults when used as an antilipidemic agent has some side effects such as nausea, gastrointestinal disturbances, vomiting and loose stool. Other possible complications are muscle cramping, fatigue, pruritus, and alopecia.[13] In the neonatal study with a single dose of clofibrate none of these side effects were reported.[9],[10],[12]
Other newer pharmacological agents are utilized in the treatment of neonatal hyperbilirubinemia. Although recent clinical trials have shown that a single dose of the tin-mesoporphyrin (SnMP), a hemoxygenase inhibitor, has the best efficacy with minimal side effects when used prophylactically in premature infants and also curatively in full-term neonates it is not yet manufactured outside research protocols.[10], [14] Indeed, clofibrate only is actually available pharmacologic agent that could be used effectively in neonatal hyperbilirubinemia without any side effects. However, the widespread use of this drug in high-risk infants such as premature infants and hemolytic jaundice needs to be confirmed with further studies.
Acknowledgments
We thank all nurses of the neonatal ward of Emam-Reza Hospital and especially Ms.Amiri for collection of blood samples and follow-up of study subjects.
References
1. Newman TB, Maisels MS. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995; 96: 730-733
2. American Academy of Pediatrics. Practice parameter: management of Hyperbilirubinemia in the healthy term newborn. Provisional Committee for Quality Improvement and Subcommittee on hyperbilirubinemia. Pediatrics 1994; 94: 558-565.
3. Maisels MJ. Neonatal Hyperbilirubinemia. In Klaus MH, Fanaroff AA, eds. Care of the High-Risk Neonate. Pennsylvania: Saunders, 2001: 324-362.
4. Jahnson LH, Brown AK, Bhutani VK. System-based approach to management of neonatal jaundice and prevention of Kernicterus. J Pediatr 2002; 140: 397-386.
5. Dennery PA. Pharmacological interventions for the treatment of neonatal jaundice. Semin Neonatol 2002; 7(2): 111-119.
6. Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, et al. Activators of peroxisome proliferator-activated receptor- alpha induce the expression of the uncoupling pritein-3 gene expression at birth. Diabetes 1999; 48(6): 1217-2122.
7. 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 1984; 66(4): 389-397.
8. Lindenbaum A, Delaporte B, Benattar C, Dehan M, Magny JF, Gerbet D et al. Preventive treatment of jaundice in Preterm newborn infants with clofibrate. Double blind controlled therapeutic trial. Arch Fr Pediatr 1985; 42(9): 759-63. French
9. Bourget P, Broise I, Quinquis-Desmaris V, Gabilan JC. Pharmacokinetics of clofibrate in jaundiced newborn infants at term. Arch Perdiatr 1995; 2(8): 722-728.
10. Gabilan JC. Pharmacologic treatment of neonatal jaundice. A new approach. Arch Pediatr 1998; 5(11): 1274-1278.
11. Hansen TW, Tommarello S. Effect of phenobarbital on bilirubin metabolism in rat brain. Biol Neonate 1998; 73(2): 106-111.
12. Lindenbaum A, Hernandorena X, Vial M, Benattar C, Janaud JC, Dehan M et al. Clofibrate for the treatment of hyperbilirubinemia in neonates born at term: a double blind controlled study. Arch Fr Pediatr 1981; 38 Suppl 1: 867-73.
13. Steiner A, Weisser B, Vetter N. A comparative review of the advers effects of treatments for huperbilirubinemia. Drug Saf 1991; 6(2): 118-130.
14. Bhutani VK, Johnson LH. Newborn Jaundice and Kernicterus- Health and Societal Perspectives. Indian J Pediatr 2003; 70(5): 407-416.(Mohammadzadeh Ashraf, Far)