000039 Research Article Antioxidative Vitamine und Hyperbilirubinämie bei Neugeborenen Abdul-Razzak Abdul-Razzak Khalid K. KK

Department of Clinical Pharmacy, Jordan University of Science and Technology, Faculty of Pharmacy, P.O Box 3030. Irbid 22110, Jordan, Tel.: 962-2-7201000 Ext. 23536, Fax: 962-2-7201075Department of Clinical Pharmacy, Jordan University of Science and Technology, Faculty of Pharmacy, Irbid, Jordan

kkalani@just.edu.jo author Nusier Nusier Mohamad K. MK

Department of Biochemistry and Molecular Biology, Jordan University of Science and Technology, Faculty of Medicine, Irbid, Jordan

mick@just.edu.jo author Obediat Obediat Ahmad D. AD

Department of Pediatrics, Princess Rahma Hospital, Irbid, Jordan

dr_ahmadobeidat@yahoo.com author Salim Salim Ahmad M. AM

College of Applied Medical Science, Jordan University of Science and Technology, Irbid, Jordan

biolabstudy@yahoo.com author German Medical Science GMS Publishing House

Düsseldorf

HYPERBILIRUBINEMIA, NEONATAL etiology chemically induced JAUNDICE, NEONATAL etiology ASCORBIC ACID blood VITAMIN E blood VITAMIN E DEFICIENCY pathology physiopathology ASCORBIC ACID DEFICIENCY pathology physiopathology BILIRUBIN blood INFANT, NEWBORN HUMANS 610 hyperbilirubinemia vitamin C vitamin E newborn Hyperbilirubinämie Vitamin C Vitamin E Neugeborene 20061105 20070625 engl 1612-3174 5 GMS German Medical Science GMS Ger Med Sci 03 Zielsetzung: Ein vermindertes antioxidatives System kann zur Verstärkung der neonatalen Bilirubinämie führen. Das Ziel dieses Projektes war die Beziehung zwischen den Konzentrationen der Vitamine E und C im Plasma und die Höhe der Hyperbilirubinämie bei Neugeborenen mit normaler Glucose-6-phosphat-Dehydrogenase-Aktivität zu erforschen.Methoden: 130 am regelrechten Termin geborene gesunde Neugeborene mit normaler Glucose-6-phosphat-Dehydrogenase-Aktivität von gesunden Müttern wurden in diese Studie einbezogen. Neben den Routineanalysen im Blut wurde Gesamtbilirubin, Vitamin E und C im Plasma sowie die Glucose-6-phosphat-Dehydrogenase-Aktivität am 1. Lebenstag bestimmt. Keines der Neugeborenen hatte eine AB0–Inkompatibilität oder eine Anämie. Ergebnisse: Neugeborene, die keine Hyperbilirubinämie entwickelt hatten (n=119), hatten am 1. Lebenstag einen mittleren Plasma-Bilirubinspiegel von 65±24 µmol/l (Median 58,1 µmol/l), während Neugeborene mit einer signifikant erhöhten Hyperbilirubinämie (n=11) mittlere Plasma-Bilirubinkonzentrationen von 238±56 µmol/l (Median 246,2 µmol/l ) aufwiesen.Der mittlere Vitamin C-Spiegel im Plasma von Neugeborenen, die eine Hyperbilirubinämie entwickelt hatten, war mit 87±22 µmol/l (Median 89,4 µmol/l) signifikant niedriger als der von Neugeborenen, die keine Hyperbilirubinämie aufwiesen (132±36 µmol/l, Median=127,7 µmol/l). Diese Unterschiede waren statistisch signifikant (P=0,001).Ähnliche Ergebnisse wurden bei den Vitamin E-Spiegeln bei Neugeborenen beobachtet, die eine Hyperbilirubinämie entwickelt bzw. nicht entwickelt hatten: Die Vitamin E-Spiegel lagen bei 7,5±2 µmol/l (Median 6,3 µmol/l) bzw. bei 10,4±5 µmol/l (Median 9,1 µmol/l). Hämoglobinkonzentrationen und Hämatokritwerte waren bei den Neugeborenen, die eine Hyperbilirubinämie entwickelt hatten, signifikant niedriger, obgleich die Schwangerschaftsdauer und die Geburtsgewichte der beiden Gruppen keine Unterschiede zeigten.Schlussfolgerung: Die Ergebnisse der vorliegenden Studie zeigen, dass bei ausgereiften Neugeborenen niedrige Konzentrationen von Vitamin C und Vitamin E im Plasma mit einer signifikant erhöhten Hyperbilirubinämie korreliert sind. Objective: Low antioxidant system may contribute to the severity of neonatal hyperbilirubinemia. The aim of this research was to explore the relationship between plasma vitamin E and C levels and the severity of hyperbilirubinemia in full-term neonates with normal glucose 6-phosphate dehydrogenase (G6PD) activities. Methods: A total of 130 full-term healthy live birth neonates of healthy mothers with normal G6PD activity were included in this study. In addition to routine blood analysis, plasma total bilirubin, vitamin E and C levels and G6PD activity were measured on the first day of life. None of the neonates was ABO incompatible or anemic. Results: Neonates who did not develop hyperbilirubinemia (n=119) had a mean plasma bilirubin level of 65±24 µmol/l (median 58.1), while neonates who developed significant hyperbilirubinemia (n=11) had a mean plasma bilirubin level of 238±56 µmol/l (median 246.2) on the first day of life. Mean plasma vitamin C levels of neonates who developed hyperbilirubinemia were significantly lower than those who did not develop hyperbilirubinemia (87±22 µmol/l (median 89.4) vs. 132±36 µmol/l (median 127.7), respectively, P=0.0001). Similar results were observed for plasma vitamin E levels in neonates who did or did not develop hyperbilirubinemia (7.5±2 µmol/l (median 6.3) vs. 10.4±5 µmol/l (median 9.1), respectively, P=0.001). Hemoglobin and hematocrit were significantly lower in neonates who developed hyperbilirubinemia (P=0.0002 and P=0.0003, respectively), although gestational age and birth weight for the two groups showed no significant difference. Conclusion: The results of the present work indicate that low level of plasma vitamins C and E are associated with significant hyperbilirubinemia in full-term neonates. IntroductionHyperbilirubinemia is a common problem in neonatal period worldwide and is a main cause of readmission to hospitals . Increased production of bilirubin, immature hepatic uptake and conjugation processes, and increased enterohepatic circulation of bilirubin are the most common factors that contribute to the development of hyberbilirubinemia in neonates , . The combination of glucose-6-phosphate dehydrogenase deficiency, the most common enzyme deficiency known and Gilbert's syndrome, which is characterized by decreased activity of bilirubin-conjugating enzymes, increase the possibility of severe neonatal hyperbilirubinemia . Higher bilirubin load due to erythrocyte hemolysis play an important role in neonatal hyperbilirubinemia due to higher erythrocyte turnover and shorter life span (80 days compared with the adult 120 days) , , . Normal newborn erythrocytes are relatively sensitive to oxidative damage in comparison with those of adults . This is due to diminished capacity of neonatal erythrocytes to deal with oxidative stress as a result of decreased antioxidant defense system particularly in the preterm infants . The body possesses an efficient antioxidant defense system against oxidative damage. A series of enzymes, including catalase, superoxide dismutase, and glutathion peroxidase and nonenzymatic antioxidants such as glutathione, vitamins E and C . Bilirubin, in particular unconjugated bilirubin which is regarded as a toxic metabolic waste, also was shown to have antioxidant role . Also bilirubin has been shown to display some toxicity towards erythrocytes .The relationship between preterm neonatal hyperbilirubinemia and reduced antioxidants vitamins and enzymes has been reported , . However, there are contradictory reports regarding plasma vitamin C level and the development of hyperbilirubinemia in preterm neonates. Ballin et al. described Heinz body hemolytic anemia in premature infants as a result of high vitamin C supplementation. Such finding had not been supported by the work of Doyle et al. . Also Bass et al. found the administration of vitamin C to preterm neonates to be safe and not associated with hemolysis.Low level of vitamin E, the potent antioxidant that effectively protects biological membranes against oxidative injury , was also attributed to a significant hyperbilirubinemia in full-term neonates , while the role of vitamin C in the development of hyperbilirubinemia in full-term neonates has not been reported.The aim of the present study was to investigate the relationship between vitamin E and C levels and the severity of hyperbilirubinemia in full-term neonates with normal glucose 6-phosphate dehydrogenase (G6PD) activity. Material and methodsPatientsThe study group consisted of full-term healthy live birth neonates of healthy mothers that occurred at Princes Rahma Hospital, Irbid-Jordan for the period from March to July 2004. The University Review Committee for Research on Human approved this study. Healthy neonates and mothers were discharged within 24 hours for vaginal births and within 48-72 hours for cesarean births, as the hospital follows an early discharge protocol. In all cases gender, birth weight, gestation period, and delivery route were recorded. A total of 130 full-term neonates with normal G6PD activity and gestational period >37 week were included in this study. One hundred nineteen of them had serum bilirubin levels <102 µmol/l with a mean of 65±24 µmol/l (median 58.1) on the first day of life. None of these were readmitted to the hospital for significant hyperbilirubinemia. Yet 11 full-term neonates had serum bilirubin levels ≥102 µmol/l with a mean of 238±56 µmol/l (median 246.2) on the first day of life and all of them received either phototherapy treatment or blood exchange. None of the neonates included in this study was ABO incompatible or anemic. Therefore, the significant hyperbilirubinemia was not related to hemolytic disease.Blood samplesVenous blood was obtained into two heparnized glass tubes from all infants included in this study on the day of birth. One tube was used for routine blood analysis. The other tube was placed immediately on ice and used for vitamin E, C and G6PD activity measurements. For vitamin C determination, samples were stored at 4°C for no more than 30 minutes before the plasma was separated and vitamin C was stabilized by metaphosphoric acid. Plasma vitamin C level and G6PD activity were measured within 3 hours after blood collection. For vitamin E measurements, 100 µl of plasma was stored at –20°C until analysis.Laboratory technique:Plasma total bilirubin levels were measured using bilirubin analyzer BA III (Tokyo, Japan), while hemoglobin and hematocrit were measured using automated blood counter (Micros 60 OT, France). Methaemglobin reduction test was used for detection of G6PD deficiency . Plasma vitamin C levels were measured by calorimetric method , while vitamin E levels were measured by HPLC as described by George et al. .Statistical analysisData was evaluated by Minitab release 14 statistical software. Mann-Whitney test was used to compare the significance of median difference between the two groups. P values <0.05 were considered statistically significant. ResultsThe result of this study revealed that mean plasma vitamin C level of the first day of life of full-term neonates who did develop hyperbilirubinemia was significantly lower than that of full-term neonates who did not develop hyperbilirubinemia (Table 1 ).Similar significant difference has been noticed for plasma vitamin E levels in neonates who did or did not develop hyperbilirubinemia. The clinical characteristics of the neonates are shown in Table 2 . Hemoglobin and hematocrit were significantly lower in neonates who developed hyperbilirubinemia, while gestational age and birth weight of the two groups showed no significant differences. DiscussionErythrocyte hemolysis plays an important role in the development of hyperbilirubinemia in neonates . Erythrocytes from neonates are susceptible to peroxide hemolysis due to continuous exposure to high concentration of oxygen and high polyunsaturated rich plasma membrane , . Higher levels of lipid peroxidation markers were found in plasma and in the erythrocytes at birth, especially in preterm neonates , . This finding was a reflex of low levels of antioxidant vitamins and/or low activities of antioxidant enzymes and the reduction in plasma bilirubin was associated with an increase in plasma antioxidant capacity. Decrease in oxidative stress in preterm neonates was also reported .Vitamin E and C are potent antioxidants at the cellular level, thus play an important role in the protection of cells against oxidative damage and hemolysis. Therefore, the level of vitamins E and C may be associated with the development of hyperbilirubinemia in neonates. In this study, plasma vitamin E and C concentrations were measured during the first day of life in 119 neonates who did not develop hyperbilirubinemia and 11 neonates who did develop significant hyperbilirubinemia. Alpay et al. used a serum bilirubin level of 120 µmol/l in predicting the development of significant hyperbilirubinemia in all healthy full-term neonates. Nearly all full-term neonates with serum bilirubin level of <120 µmol/l in the first day of life did not develop hyperbilirubinemia. Such observation has been supported by the prospective cohort study of Stevenson et al. .Our study clearly demonstrates the association between low levels of vitamin E and C and neonatal hyperbilirubinemia. These results were in agreement to those obtained by Ojo et al. who observed significant low plasma vitamin E level in full-term neonates associated with significant increase in bilirubin level and red blood cell hemolysis.Our finding is also similar to what has been previously reported for the association between antioxidant plasma vitamins A, E, and C as well as erythrocyte antioxidant enzymes and hyperbilirubinemia in preterm neonates . Lower level of antioxidant defense system was found in preterm infants with hyperbilirubinemia (bilirubin 256 µmol/l) than in those of the preterm infants with no jaundice (bilirubin 68-102 µmol/l). Also the administration of vitamin E to premature infants who are known to have low vitamin E concentration , reduces red cell hemolysis and significantly decreases bilirubin level on the first week of life .On the other hand, Bracci et al. showed that erythrocyte antioxidant enzymes activities were significantly lower in neonates with peak bilirubin (>214 µmol/l) than in less jaundiced neonates on the 4th day of life. Although they did not measure the level of antioxidant vitamins, indirectly it can be concluded that antioxidant vitamins are low since they are dietary micronutrients .Vitamin C is a water soluble antioxidant, also found to suppress erythrocyte hemolysis induced by water-soluble radical initiator, but vitamin E which functions as antioxidant within membrane was found to be more effective in suppressing the hemolysis .The synergistic effect between vitamin E and C in inhibition of lipid peroxidation has been reported . Vitamin C helps in regeneration of vitamin E as vitamin E is oxidized by free radicals in the lipid bilayer , . In conclusion, the results of the present work indicate that low levels of plasma vitamins E and C are associated with significant hyperbilirubinemia in full-term neonates due to increased oxidative stress and intern red blood hemolysis. NotesConflicts of interestNone declared.AcknowledgementsThe research project was supported by grant No.14/2003 from the Dean of Research Council, Jordan University of Science and Technology. Porter ML Dennis BL Hyperbilirubinemia in the term newborn 2002 Am Fam Physician 599-606 Porter ML, Dennis BL. Hyperbilirubinemia in the term newborn. Am Fam Physician. 2002;65(4):599-606. Maisels MJ Kring E Length of stay, jaundice, and hospital readmission 1998 Pediatrics 995-8 Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics. 1998;101(6):995-8. Dennery PA Seidman DS Stevenson DK Neonatal hyperbilirubinemia 2001 N Engl J Med 581-90 Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344(8):581-90. Watchko JF Neonatal hyperbilirubinemia--what are the risks? 2006 N Engl J Med. 1947-9 Watchko JF. Neonatal hyperbilirubinemia--what are the risks? N Engl J Med. 2006;354(18):1947-9. Kaplan M Renbaum P Levy-Lahad E Hammerman C Lahad A Beutler E Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia 1997 Proc Natl Acad Sci U S A 12128-32 Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997;94(22):12128-32. Pearson HA Life-span of the fetal red blood cell 1967 J Pediatr 166-71 Pearson HA. Life-span of the fetal red blood cell. J Pediatr. 1967;70(2):166-71. Brouillard RP Measurement of red blood cell life-span 1974 JAMA 1304-5 Brouillard RP. Measurement of red blood cell life-span. JAMA. 1974;230(9):1304-5. Connolly AM Volpe JJ Clinical features of bilirubin encephalopathy 1990 Clin Perinatol 371-9 Connolly AM, Volpe JJ. Clinical features of bilirubin encephalopathy. Clin Perinatol. 1990;17(2):371-9. Gross RT Bracci R Rudolph N Schroeder E Kochen JA Hydrogen peroxide toxicity and detoxification in the erythrocytes of newborn infants 1967 Blood 481-93 Gross RT, Bracci R, Rudolph N, Schroeder E, Kochen JA. Hydrogen peroxide toxicity and detoxification in the erythrocytes of newborn infants. Blood. 1967;29(4):481-93. Kilic M Turgut M Taskin E Cekmen M Aygun AD Nitric oxide levels and antioxidant enzyme activities in jaundices of premature infants 2004 Cell Biochem Funct 339-42 Kilic M, Turgut M, Taskin E, Cekmen M, Aygun AD. Nitric oxide levels and antioxidant enzyme activities in jaundices of premature infants. Cell Biochem Funct. 2004;22(5):339-42. Dani C Cecchi A Bertini G Role of oxidative stress as physiopathologic factor in the preterm infant 2004 Minerva Pediatr 381-94 Dani C, Cecchi A, Bertini G. Role of oxidative stress as physiopathologic factor in the preterm infant. Minerva Pediatr. 2004;56(4):381-94. Hammerman C Goldstein R Kaplan M Eran M Goldschmidt D Eidelman AI Gartner LM Bilirubin in the premature: toxic waste or natural defense? 1998 Clin Chem. 2551-3 Hammerman C, Goldstein R, Kaplan M, Eran M, Goldschmidt D, Eidelman AI, Gartner LM. Bilirubin in the premature: toxic waste or natural defense? Clin Chem. 1998;44(12):2551-3. Mireles LC Lum MA Dennery PA Antioxidant and cytotoxic effects of bilirubin on neonatal erythrocytes 1999 Pediatr Res 355-62 Mireles LC, Lum MA, Dennery PA. Antioxidant and cytotoxic effects of bilirubin on neonatal erythrocytes. Pediatr Res. 1999;45(3):355-62. Turgut M Basaran O Ēekmen M Karatas F Kurt A Aygun AD Oxidant and antioxidant levels in preterm newborns with idiopathic hyperbilirubinaemia 2004 J Paediatr Child Health 633-7 Turgut M, Basaran O, Ēekmen M, Karatas F, Kurt A, Aygun AD. Oxidant and antioxidant levels in preterm newborns with idiopathic hyperbilirubinaemia. J Paediatr Child Health. 2004;40(11):633-7. Bracci R Buonocore G Talluri B Berni S Neonatal hyperbilirubinemia. Evidence for a role of the erythrocyte enzyme activities involved in the detoxification of oxygen radicals 1988 Acta Paediatr Scand 349-56 Bracci R, Buonocore G, Talluri B, Berni S. Neonatal hyperbilirubinemia. Evidence for a role of the erythrocyte enzyme activities involved in the detoxification of oxygen radicals. Acta Paediatr Scand. 1988;77(3):349-56. Ballin A Brown EJ Koren G Zipursky A Vitamin C-induced erythrocyte damage in premature infants 1988 J Pediatr 114-20 Ballin A, Brown EJ, Koren G, Zipursky A. Vitamin C-induced erythrocyte damage in premature infants. J Pediatr. 1988;113(1 Pt 1):114-20. Doyle J Vreman HJ Stevenson DK Brown EJ Schmidt B Paes B Ohlsson A Boulton J Kelly E Gillie P Lewis N Merko S Shaw D Zipursky A Does vitamin C cause hemolysis in premature newborn infants? Results of a multicenter double-blind, randomized, controlled trial 1997 J Pediatr 103-9 Doyle J, Vreman HJ, Stevenson DK, Brown EJ, Schmidt B, Paes B, Ohlsson A, Boulton J, Kelly E, Gillie P, Lewis N, Merko S, Shaw D, Zipursky A. Does vitamin C cause hemolysis in premature newborn infants? Results of a multicenter double-blind, randomized, controlled trial. J Pediatr. 1997;130(1):103-9. Bass WT Malati N Castle MC White LE Evidence for the safety of ascorbic acid administration to the premature infant 1998 Am J Perinatol 133-40 Bass WT, Malati N, Castle MC, White LE. Evidence for the safety of ascorbic acid administration to the premature infant. Am J Perinatol. 1998;15(2):133-40. Vanderpas J Vertongen F Erythrocyte vitamin E is oxidized at a lower peroxide concentration in neonates than in adults 1985 Blood 1272-7 Vanderpas J, Vertongen F. Erythrocyte vitamin E is oxidized at a lower peroxide concentration in neonates than in adults. Blood. 1985;66(6):1272-7. Ojo CO Dawodu AH Osifo BO Vitamin E deficiency in the pathogenesis of haemolysis and hyperbilirubinaemia of neonatal jaundice 1986 J Trop Pediatr 251-4 Ojo CO, Dawodu AH, Osifo BO. Vitamin E deficiency in the pathogenesis of haemolysis and hyperbilirubinaemia of neonatal jaundice. J Trop Pediatr. 1986;32(5):251-4. Gordon-Smith EC Investigation of the hereditary haemolytic anemia 1984 Practical haematology 152-78 Gordon-Smith EC. Investigation of the hereditary haemolytic anemia. In: Dacie JV and Lewis SM, editors. Practical haematology. Edinburgh: Churchill Livingstone, 1984. p. 152-78. McCormick DB Green HL The vitamins 1999 Tietz text book of clinical chemistry 999-1028 McCormick DB, Green HL. The vitamins. In: Burtis CA and Ashwood ER, editors. Tietz text book of clinical chemistry. Philadelphia: Saunders; 1999. p. 999-1028 Catignani GL Bieri JG Simultaneous determination of retinol and alpha-tocopherol in serum or plasma by liquid chromatography 1983 Clin Chem 708-12 Catignani GL, Bieri JG. Simultaneous determination of retinol and alpha-tocopherol in serum or plasma by liquid chromatography. Clin Chem. 1983;29(4):708-12. Necheles TF Rai US Valaes T The role of haemolysis in neonatal hyperbilirubinaemia as reflected in carboxyhaemoglobin levels 1976 Acta Paediatr Scand 361-7 Necheles TF, Rai US, Valaes T. The role of haemolysis in neonatal hyperbilirubinaemia as reflected in carboxyhaemoglobin levels. Acta Paediatr Scand. 1976;65(3):361-7. Cross CE Halliwell B Borish ET Pryor WA Ames BN Saul RL McCord JM Harman D Oxygen radicals and human disease 1987 Ann Intern Med 526-45 Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D. Oxygen radicals and human disease. Ann Intern Med. 1987;107(4):526-45. Robles R Palomino N Robles A Oxidative stress in the neonate 2001 Early Hum Dev S75-81 Robles R, Palomino N, Robles A. Oxidative stress in the neonate. Early Hum Dev. 2001;65 Suppl:S75-81. Yigit S Yurdakok M Kilin K Oran O Erdem G Tekinalp G Serum malondialdehyde concentration in babies with hyperbilirubinaemia 1999 Arch Dis Child Fetal Neonatal Ed F235-7 Yigit S, Yurdakok M, Kilin K, Oran O, Erdem G, Tekinalp G. Serum malondialdehyde concentration in babies with hyperbilirubinaemia. Arch Dis Child Fetal Neonatal Ed. 1999;80(3):F235-7. Huertas JR Palomino N Ochoa JJ Quiles JL Ramirez-Tortosa MC Battino M Robles R Mataix J Lipid peroxidation and antioxidants in erythrocyte membranes of full-term and preterm newborns 1998 Biofactors 133-7 Huertas JR, Palomino N, Ochoa JJ, Quiles JL, Ramirez-Tortosa MC, Battino M, Robles R, Mataix J. Lipid peroxidation and antioxidants in erythrocyte membranes of full-term and preterm newborns. Biofactors. 1998;8(1-2):133-7. Dani C Martelli E Bertini G Pezzati M Filippi L Rossetti M Rizzuti G Rubaltelli FF Plasma bilirubin level and oxidative stress in preterm infants 2003 Arch Dis Child Fetal Neonatal Ed F119-23 Dani C, Martelli E, Bertini G, Pezzati M, Filippi L, Rossetti M, Rizzuti G, Rubaltelli FF. Plasma bilirubin level and oxidative stress in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F119-23. Alpay F Sarici SU Tosuncuk HD Serdar MA Inanc N Gokēay E The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns 2000 Pediatrics E16 Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokēay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics. 2000;106(2):E16. Stevenson DK Fanaroff AA Maisels MJ Young BW Wong RJ Vreman HJ MacMahon JR Yeung CY Seidman DS Gale R Oh W Bhutani VK Johnson LH Kaplan M Hammerman C Nakamura H Prediction of hyperbilirubinemia in near-term and term infants 2001 Pediatrics 31-9 Stevenson DK, Fanaroff AA, Maisels MJ, Young BW, Wong RJ, Vreman HJ, MacMahon JR, Yeung CY, Seidman DS, Gale R, Oh W, Bhutani VK, Johnson LH, Kaplan M, Hammerman C, Nakamura H. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics. 2001;108(1):31-9. Lee YS Chou YH Antioxidant profiles in full term and preterm neonates 2005 Chang Gung Med J 846-51 Lee YS, Chou YH. Antioxidant profiles in full term and preterm neonates. Chang Gung Med J. 2005;28(12):846-51. Gross SJ Vitamin E and neonatal bilirubinemia 1979 Pediatrics 321-3 Gross SJ. Vitamin E and neonatal bilirubinemia. Pediatrics. 1979;64(3):321-3. Gupta P Narang M Banerjee BD Basu S Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study 2004 BMC Pediatr 14 Gupta P, Narang M, Banerjee BD, Basu S. Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study. BMC Pediatr. 2004;4:14. Niki E Yamamoto Y Komuro E Sato K Membrane damage due to lipid oxidation 1991 Am J Clin Nutr 201S-205S Niki E, Yamamoto Y, Komuro E, Sato K. Membrane damage due to lipid oxidation. Am J Clin Nutr. 1991;53(1 Suppl):201S-205S. Strain JJ Mulholland CW Vitamin C and vitamin E--synergistic interactions in vivo? 1992 EXS 419-22 Strain JJ, Mulholland CW. Vitamin C and vitamin E--synergistic interactions in vivo? EXS. 1992;62:419-22. Nakagawa Y Cotgreave IA Moldeus P Relationships between ascorbic acid and alpha-tocopherol during diquat-induced redox cycling in isolated rat hepatocytes 1991 Biochem Pharmacol 883-8 Nakagawa Y, Cotgreave IA, Moldeus P. Relationships between ascorbic acid and alpha-tocopherol during diquat-induced redox cycling in isolated rat hepatocytes. Biochem Pharmacol. 1991;42(4):883-8. May JM Qu ZC Morrow JD Interaction of ascorbate and alpha-tocopherol in resealed human erythrocyte ghosts. Transmembrane electron transfer and protection from lipid peroxidation 1996 J Biol Chem 10577-82 May JM, Qu ZC, Morrow JD. Interaction of ascorbate and alpha-tocopherol in resealed human erythrocyte ghosts. Transmembrane electron transfer and protection from lipid peroxidation. J Biol Chem. 1996;271(18):10577-82. 11

Table 1: Plasma vitamin E, C and bilirubin levels in full-term neonates with or without hyperbilirubinemia

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Table 2: Some clinical data of full-term neonates with or without hyperbilirubinemia

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