University of Groningen. The management of hyperbilirubinemia in preterm infants Vader-van Imhoff, Deirdre Elisabeth

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1 University of Groningen The management of hyperbilirubinemia in preterm infants Vader-van Imhoff, Deirdre Elisabeth IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2013 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Vader-van Imhoff, D. E. (2013). The management of hyperbilirubinemia in preterm infants Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 3 Usefulness of the bilirubin/albumin ratio for predicting bilirubininduced neurotoxicity in premature infants Christian V. Hulzebos, Deirdre E. van Imhoff, Arend F. Bos, Charles E. Ahlfors, Henkjan J. Verkade, Peter H. Dijk Archives of Disease in Childhood Fetal & Neonatal Edition 2008,93:F384 F S D

3 Abstract Background: Unconjugated hyperbilirubinemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf), i.e. not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered as a surrogate parameter for Bf and as an interesting additional parameter in the management of hyperbilirubinemia. Objective: We reviewed the literature on the use of B/A ratios for predicting bilirubininduced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). Results: We performed a literature search and reviewed 6 publications regarding B/ A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials exist demonstrating that bilirubin-induced neurotoxicity is reduced or that unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomized controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Conclusion: Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants. 38

4 Background Neonatal jaundice due to unconjugated hyperbilirubinemia occurs in almost all premature infants. Unconjugated hyperbilirubinemia is potentially harmful for the central nervous system and may result in kernicterus, causing severe and permanent neurologic sequelae.(3,4) Alternatively, more subtle encephalopathy, i.e. bilirubininduced neurological dysfunction (BIND), including developmental delay may be due to hyperbilirubinemia.(5,6) Treatment of hyperbilirubinemia has been based on total serum bilirubin (TSB) concentration, but this has not been evidence based; explicit data on harmful TSB-thresholds are lacking.(7) The risk of kernicterus and BIND may be in part determined by TSB, but also by the level of non-albumin bound free bilirubin (Bf), which can easily pass the blood-brain barrier, and thus better reflects the bilirubin load distributed in the brain.(8) Data from in vitro and in vivo experiments have suggested that Bf, and not TSB, is the principal determinant of bilirubin neurotoxicity.(9 11) Yet, multiple other factors (i.e., cerebral blood flow, vascular permeability, intactness of blood brain barrier (BBB), cellular efflux pumps) may affect the development of neurotoxicity at any given Bf level.(12) Bilirubin-induced neurotoxicity may depend on the mutual relation between bilirubin and albumin as their levels and the intrinsic albumin-bilirubin binding constant (Ka) determine the Bf concentration, expressed in the equation: TotalSerumBilirubin FreeBilirubine K FreeBilirubine = Albumine 1 + (K FreeBilirubine) The equation is helpful in illustrating the potential value of the TSB/ albumin (B/A) ratio considering the notion that TSB levels (expressed in µmol/l) are far higher than levels of Bf (expressed in µmol/l) so that the left half of the equation essentially is equal to the B/A ratio, which can easily be calculated, because TSB and albumin are measured using routine laboratory techniques. Many authorities advocate that the B/A ratio provides an additional assessment, i.e. next to but not instead of TSB, on which to base the management of hyperbilirubinemia. Usefulness of the B/A ratio may be limited because many factors influence Ka; Ka may be decreased by drugs (e.g. ceftriaxon) or by plasma constituents (e.g. free fatty acids) that interfere with albumin-bilirubin binding.(13,14) Interindividual variations in Ka and in levels of albumin as well as binding of TSB to alternative binding sites render estimations of Bf predicted by Ka and B/A ratio at best a capricious exercise. In premature infants, especially in very low birth weight (VLBW) infants (birth weight < 1500 g), bilirubin neurotoxicity may occur at lower TSB concentrations as Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 39

5 compared with term infants. We reviewed the theoretical considerations and clinical evidence for the concept that additional use of the B/A ratio in jaundiced premature infants might improve the prediction of BIND including neurodevelopmental impairment. Objectives To determine the evidence supporting the use of B/A ratio in predicting BIND including neurodevelopmental impairment in premature infants (gestational age less than 32 weeks) with unconjugated hyperbilirubinemia. Search strategy Two authors independently searched the National Library of Medicine (Medline), Cochrane Library, including, Current Controlled Trials (CCT), ClinicalTrials.gov and NHS Centre for Reviews and Dissemination (CRD) from 1966 until July Search criteria included the following MESH and free text search terms: 1) infant, premature or low birth weight, 2) jaundice, neonatal, 3) hyperbilirubinemia or bilirubin, 4) albumin, 5) bilirubin/ albumin ratio or B/A ratio, 6) (neurodevelopmental) outcome, 7) kernicterus, 8) bilirubin-induced neurological dysfunction or BIND, and 9) neurotoxicity. Results We found maximal 293 references following the search containing one of the combinations from terms 1 3, 4 or 5, and 6 9 and screened the abstracts for relevance. The majority of the abstracts and papers that have been screened did not contain any outcome measure related to neurotoxicity or neurodevelopmental outcome; others did not contain albumin or B/A ratio measurements. All English-written papers with a combination of bilirubin or hyperbilirubinemia, albumin or B/A ratio, prematurity and an outcome related to neurotoxicity (including kernicterus) were included. Ultimately, 14 papers were eligible according to our selection criteria. Five (review) articles were found that provided opinion, but no data on the use of the B/A ratio in the management of hyperbilirubinemia in premature infants.(15 19) Three additional papers were excluded. One study concluded that the B/A ratio is a reliable surrogate for the Bf concentration and that the B/A ratio is a simple mode to incorporate the serum albumin concentration into exchange transfusion criteria, but provided no outcome data.(20) Another excluded study investigated the relation 40

6 between neonatal hyperbilirubinemia and several measures of psychoeducational outcome, including the Kaufman Mental Processing Composite (KMPC). Although albumin-determined binding capacity (calculated as 5(albumin)+2) was significantly and positively correlated with the KMPC, albumin and bilirubin levels were not explicitly provided. Thus, an inverse relationship between B/A ratio and outcome could only be speculated upon.(21) The third study was excluded, because part of the data were found to be similar to those of an already included publication.(22,23) Six articles were finally included. We found no prospective clinical trials evaluating the effic acy of B/A ratio, B/A ratio + TSB, or TSB in management or predicting outcome in premature infants with hyperbilirubinemia. One prospective cohort study evaluated short term effects of B/A ratios in predicting bilirubin encephalopathy,(24) and one study retrospectively examined the data of a prospective randomised controlled NICHD phototherapy trial to evaluate the association between neurodevelopmental outcome and the B/A ratio.(25 28) Two retrospective case-control post-mortem studies analyzed the relationship between the B/A ratio and kernicterus in premature infants.(29 31) Risk factors for kernicterus in VLBW infants were described in a prospective study.(32) One article reported MRI documented kernicterus and the relation with B/A ratios.(33) Amin et al. examined the usefulness of the B/A ratio and free bilirubin (Bf) as compared with TSB in predicting acute bilirubin encephalopathy in 143 infants of weeks of gestational age.(34) Bilirubin encephalopathy was assessed by maturation of the auditory brainstem responses (ABR) in this single centre prospective cohort study. The mean peak TSB concentration in infants with normal ABR maturation was not significantly different from the mean peak TSB in infants with abnormal ABR maturation and there was a trend suggesting the B/A ratio (p=0.19) was better than TSB (p=0.98) in predicting abnormal ABR maturation. In a subset of 45 infants in whom Bf was measured, higher Bf (10.6 vs. 6.8 µmol/l, abnormal vs. normal ABR, resp.; p < 0.01) and higher B/A ratios (0.39 vs molar ratios, abnormal vs. normal ABR, resp; p < 0.05) preceded abnormal ABR maturation, whereas TSB did not. Bf proved to be the most sensitive predictor of transient bilirubin encephalopathy in premature newborns with hyperbilirubinemia. A Bf level of > 8.55 µmol/l had a relative risk of abnormal ABR of 2.45 (95% CI: ). When Bf levels are not at hand, the authors suggest considering the B/A ratio along with the TSB in the management of hyperbilirubinemia in premature infants. The National Institute of Child Health and Human Development Cooperative Phototherapy Study was performed in the US between 1974 and 1976.(35 38) This randomized controlled trial (n=1339) aimed to compare the efficacy of (prophylactic) phototherapy and/or exchange transfusion. The controls did not receive phototherapy Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 41

7 and had TSB levels maintained below specified levels using exchange transfusions. The study included a cohort of low birth weight (LBW) infants (< 2000 g; n=922). Phototherapy was considered safe and at least as effective as exchange transfusions only; neurodevelopmental outcome at 6 years of age was similar in both treatment groups.(39) Scheidt et al. evaluated neurodevelopmental outcome and TSB levels in a subgroup of 224 premature / LBW infants who were randomized to the control group (no phototherapy, TSB below specified levels using exchange transfusions).(40) Neither cerebral palsy, nor IQ was significantly associated with TSB levels, time, or duration of exposure to bilirubin. IQ decreased at higher B/A ratios (r=-0.12; p=0.06) but the relationship disappeared after correction for neonatal risk factors. Kim et al. reviewed 398 neonatal autopsies in infants.(41) Kernicterus, defined as yellowish staining of cerebral gray matter, was reported in 27 of 398 (7%) autopsied infants. Clinical and pathologic factors in these 27 kernicteric infants (32 weeks and 1417 g, mean GA and BW, respectively.) were retrospectively compared to a control group of 103 autopsied infants with similar birth weight and gestational age, but without kernicterus. Kernicteric infants had rather low mean TSB peak concentrations, which were similar to those in the infants without kernicterus (197 ± 55 vs. 205 ± 96 µmol/l). Serum albumin values and the reserve albumin binding capacity were significantly lower in kernicteric infants compared to controls. B/A ratios could be calculated in 6 of the 27 kernicteric infants and in 15 of the 103 non-kernicteric infants, and appeared similar (0.44 ± 0.21 vs ± 0.36, kernicteric vs. non-kernicteric infants, respectively). Cashore et al. determined TSB, Bf, B/A ratio and bilirubin binding affinity in 13 premature infants (< 1500 gram) with hyperbilirubinemia before exchange transfusions were performed and who died in the neonatal period.(42) Five of these 13 infants had kernicterus, defined as yellowish staining of the basal ganglia or brainstem at autopsy. Compared to non-kernicteric infants, Bf levels were increased in infants with kernicterus (27 ± 9 vs. 13 ± 10 µmol/l, kernicteric vs. non-kernicteric infants respectively; p< 0.05). Moreover, bilirubin binding capacities expressed as moles of bilirubin per mole of albumin, i.e. molar B/A ratios, were lower in infants with kernicterus (0.42 ± 0.07 vs ± 0.08, kernicteric vs. non-kernicteric infants, respectively; p< 0.05). Ritter et al. prospectively assessed risk factors in the development of kernicterus in 91 VLBW infants.(43) Peak TSB, and Bf or albumin did not significantly differ between infants with and without kernicterus. Although not explicitly provided in their paper, B/A ratios appeared higher in VLBW infants with kernicterus (calculated group mean values 2.6 vs. 2.2 mg/g, kernicteric vs. non-kernicteric VLBW infants, respectively). Methodological shortcomings, e.g. measuring Bf in 40-fold diluted 42

8 Table 1. Publications regarding the use of B/A ratios and outcome in premature infants with unconjugated hyperbilirubinemia. Author/ year Study design Study population Method Relation B/A ratio* and outcome Amin, 2001(89) Scheidt, 1991(90) Prospective cohort study Retrospective analysis of a RCT Kim, 1980(91) Case-control postmortem study Cashore, 1982(92) Ritter, 1982(93) Govaert, 2003(94) Case-control postmortem study Prospective cohort study Retrospective case study 143 infants (GA: weeks) 224 premature / LBW infants (<2000g) 27 kernicteric infants (GA: weeks) and 103 matched controls 13 premature infants (< 1500 gram); 5 with kernicterus 91 premature VLBW infants (<1500g) 5 premature (GA: 25 to 29 weeks) and 3 term infants with clinical signs of kernicterus Maturation of the auditory brainstem responses (ABR) Neurological examination, Wechsler Intelligence Scale for Children-Revised at 6 years Comparison of clinical, laboratory and histopathological data Comparison of laboratory data Assessment of risk factors in the development of kernicterus ABR, magnetic resonance imaging (MRI) and/or ultrasound Higher B/A ratios preceded abnormal ABR maturation IQ decreased at higher B/A ratios, no relationship after correction for neonatal risk factors Lower albumin levels in kernicteric infants, but available B/A ratios (6 of 27 and 15 of 103) appeared similar Binding capacities expressed as molar B/A ratios were lower in infants with kernicterus B/A ratios appeared higher in infants with kernicterus # Abnormal ABR, MRI and/or ultrasound in all premature infants with elevated B/A ratios *: B/A ratios were calculated from serum bilirubin and albumin concentrations, which were measured by routine laboratory techniques. In the study of Cashore, bilirubin binding capacities were estimated from bilirubin titration curves and expressed as moles of bilirubin per mole of albumin, i.e. molar B/A ratios at apparent saturation of first binding site of albumin. Accordingly, low B/A ratios reflect low bilirubin binding capacities in the latter study. # : data not provided, but calculated by presenting authors Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 43

9 samples according to the original peroxidase method of Jacobsen and not correcting for rate limiting dissociation of bilirubin from albumin, may have prevented the differences in Bf levels (but not the TSB) from reaching statistically significance.(44,45) Govaert et al. reported five premature infants (25 to 29 weeks gestational age) with clinical signs of kernicterus and long term changes in globus pallidus on magnetic resonance imaging (MRI) and/or sonography.(46) Although TSB levels remained below exchange transfusion thresholds, B/A ratios were high in these infants. ABR were severely impaired in all premature infants with elevated B/A ratios and all developed hearing loss. In three infants, a combined respiratory and metabolic acidosis had been present around the peak TSB level. The authors conclude that the pathophysiological role of low serum albumin levels must be considered in BIND, especially when acidosis and jaundice are present in premature infants. Discussion Premature infants are more prone to neurological impairment as well as bilirubin neurotoxicity than their term counterparts.(47 50) Recently, the role of albumin and bilirubin-albumin binding in the pathophysiology of bilirubin-induced neurotoxicity in premature infants has been discussed.(51 54) Several advisory committees and experts in the field of bilirubin research advocate the additional use of B/A ratios in jaundiced premature (or term infants), especially when the TSB level is close to that at which exchange transfusion is recommended.(55 62) We found no published prospective clinical trials documenting that the use of B/A ratios (or TSB for that matter) in the management of hyperbilirubinemia reduces long term bilirubin-induced neurotoxicity. The relationship between TSB and neurodevelopmental outcome is unclear and has resulted in guidelines with arbitrary TSB thresholds for intervention in premature as well as in term infants with unconjugated hyperbilirubinemia. (63 66) Compared with TSB, Bf has been found a more reliable predictor of bilirubin neurotoxicity as assessed by ABR maturation and electroencephalography and to correlate better with long term outcome (kernicterus).(67 70) Unfortunately, routine clinical laboratory measurements of Bf are not generally available. B/A ratios can be calculated based on standard laboratory assays and the B/A ratio has been more useful than TSB alone to indicate the Bf concentration.(71,72) However, due to the presence of drugs that interfere with bilirubin binding to albumin, Bf may be much higher than suggested by the calculated B/A ratio and the intrinsic affinity of the albumin for bilirubin. Furthermore, other plasma constituents such as apolipoproteins bind unconjugated bilirubin. Consequently, the B/A ratio seems an imperfect surrogate to estimate Bf, but even Bf is likely to 44

10 be an imperfect predictor of neurotoxicity; many (downstream) factors affect the development of neurotoxicity at any given Bf level. Bf in plasma is always available for diffusion across the blood-brain barriers, at rates that depend on the gradient compared to the unmeasured Bf levels in the brain and cerebrospinal fluid (CSF). The B/A ratio need not be very high for Bf in plasma to exceed Bf in the brain or CSF. Bf in cerebral tissue ultimately determines the development of UCB neurotoxicity. Protective mechanisms moderating neurotoxicity include: 1) limited binding to GSH (reduced glutathione)-transferases in the brain or albumin in the CSF which impairs ongoing movement of bilirubin to the brain, 2) membrane-bound transporters (e.g., the multi-drug resistance protein 1 (MDR1), multi-drug resistance related protein 1 (MRP1)) which are involved in bilirubin efflux from the central nervous system, and 3) intracellular metabolism of UCB, i.e. conjugation and/or oxidation of UCB.(73 75) Development of toxicity may depend also on protective anti-oxidant and anti-apoptotic mechanisms, which may differ among cell types. In vitro and in vivo studies demonstrating the neurotoxic potential of Bf are often confounded by solubility issues and poor delineation of the Bf present.(76 78) Contrary to earlier reports,(6,30) in vitro toxicity to neurons and astrocytes may occur well below aqueous saturation of Bf (70 nm) if protective mechanisms, e.g. activity of MRP1, are impaired.(79,80) Self-aggregation of UCB is, therefore, not a necessary condition for UCB toxicity. These studies have recently been reviewed;(81 83) although Bf is the measurable principal determinant of bilirubin neurotoxicity, more information is needed on the approximate levels of Bf associated with neurotoxicity. Experts in neonatal jaundice have suggested that in the absence of commercial assays for Bf the B/A ratio can be used in conjunction with TSB in the evaluation and treatment of premature infants with hyperbilirubinemia.(84 88) It is currently mainly theoretical considerations that favor the use of the B/A ratio in addition to TSB levels, considering the rather small number of publications regarding B/A ratio and outcome and the lack of prospective clinical trials supporting the clinical benefit, i.e. prevention or reduction of BIND in premature infants. The use of B/A ratios (and/or Bf) in addition to TSB measurements needs to be evaluated in premature newborns in randomized clinical trials which include assessment of neurodevelopmental outcome and/ or ABR and MRI for detecting and documenting bilirubin toxicity. In line with this, a prospective randomized controlled trial has started in April 2007 in the Netherlands to evaluate the additional use of the B/A ratio in jaundiced premature infants. Primary outcome of this so-called Bilirubin Albumin Ratio Trial (BARTrial) is neurodevelopmental outcome at months corrected age ( Treatment thresholds of TSB and Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 45

11 B/A ratio in standard and high risk infants for intervention with phototherapy and exchange transfusion in this continuing RCT are shown in Table 2. Table 2. Treatment thresholds* of TSB (µmol/l) and B/A ratio (µmol/g) for intervention with phototherapy and exchange transfusion in standard and high risk premature infants included in the Bilirubin Albumin Ratio Trial (BARTrial). Birthweight (g) Phototherapy Exchange transfusion Standard risk High risk Standard risk High risk TSB B/A TSB B/A TSB B/A TSB B/A < *: adapted from Ahlfors (95) and Maisels (96) Inclusion criteria: gestational age < 32 weeks without chromosomal or syndromal abnormalities. Intervention: Hyperbilirubinemia is evaluated daily and treatment is based on B/A ratio and TSB (whichever comes first) in the study group versus TSB only in the control group. Risk factors: asphyxia, hypoxemia, acidosis, haemolysis, extreme low birth weight, sepsis/ meningitis and intracranial haemorrhage. Conclusion The need for additional parameters for the use of phototherapy and exchange transfusion in jaundiced premature infants is generally agreed upon; the wide range of currently used TSB-thresholds are arbitrary and poorly evidenced based as is reflected by the poor relationship between TSB levels and neurodevelopmental outcome. Awaiting prospective data of a recently started RCT, available data suggests that the concurrent use of B/A ratio and TSB in the management of hyperbilirubinemia may provide a tool for the development of more robust criteria for managing newborn jaundice and is likely to be better than TSB alone. 46

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13 18. Kaplan M, Hammerman C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta 2005 Jun;356(1 2): Bhutani VK, Johnson LH, Shapiro SM. Kernicterus in sick and preterm infants ( ): a need for an effective preventive approach. Semin Perinatol 2004 Oct;28(5): Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994 Mar;93(3): Hansen RL, Hughes GG, Ahlfors CE. Neonatal bilirubin exposure and psychoeducational outcome. J Dev Behav Pediatr 1991 Oct;12(5): Cashore WJ. Free bilirubin concentrations and bilirubin-binding affinity in term and preterm infants. J Pediatr 1980 Mar;96(3 Pt 2): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4): Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics 2001 Apr;107(4): Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985 Feb;75(2 Pt 2): Bryla DA. Randomized, controlled trial of phototherapy for neonatal hyperbilirubinemia. Development, design, and sample composition. Pediatrics 1985 Feb;75(2 Pt 2): Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 1990 Apr;85(4): Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM, et al. Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics 1991 Jun;87(6): Kim MH, Yoon JJ, Sher J, Brown AK. Lack of predictive indices in kernicterus: a comparison of clinical and pathologic factors in infants with or without kernicterus. Pediatrics 1980 Dec;66(6): Cashore WJ. Free bilirubin concentrations and bilirubin-binding affinity in term and preterm infants. J Pediatr 1980 Mar;96(3 Pt 2): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4): Ritter DA, Kenny JD, Norton HJ, Rudolph AJ. A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics 1982 Mar;69(3): Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics 2003 Dec;112(6 Pt 1): Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics 2001 Apr;107(4):

14 35. Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985 Feb;75(2 Pt 2): Bryla DA. Randomized, controlled trial of phototherapy for neonatal hyperbilirubinemia. Development, design, and sample composition. Pediatrics 1985 Feb;75(2 Pt 2): Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 1990 Apr;85(4): Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM, et al. Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics 1991 Jun;87(6): Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 1990 Apr;85(4): Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM, et al. Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics 1991 Jun;87(6): Kim MH, Yoon JJ, Sher J, Brown AK. Lack of predictive indices in kernicterus: a comparison of clinical and pathologic factors in infants with or without kernicterus. Pediatrics 1980 Dec;66(6): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4): Ritter DA, Kenny JD, Norton HJ, Rudolph AJ. A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics 1982 Mar;69(3): Jacobsen J, Wennberg RP. Determination of unbound bilirubin in the serum of newborns. Clin Chem 1974 Jul;20(7): Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr 2001 Aug;139(2): Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics 2003 Dec;112(6 Pt 1): Gartner LM, Snyder RN, Chabon RS, Bernstein J. Kernicterus: high incidence in premature infants with low serum bilirubin concentrations. Pediatrics 1970 Jun;45(6): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4): Watchko JF, Oski FA. Kernicterus in preterm newborns: past, present, and future. Pediatrics 1992 Nov;90(5): Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F455-F458. Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 49

15 51. Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F459-F Ahlfors CE, Parker AE. Evaluation of a model for brain bilirubin uptake in jaundiced newborns. Pediatr Res 2005 Dec;58(6): Kaplan M, Hammerman C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta 2005 Jun;356(1 2): Wennberg R, Ahlfors C, Bhutani V, Johnson L, Shapiro S. Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns. Pediatrics 2006 Feb 1,117(2): Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994 Mar;93(3): Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F455-F Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F459-F Blackmon LR, Fanaroff AA, Raju TN. Research on prevention of bilirubin-induced brain injury and kernicterus: National Institute of Child Health and Human Development conference executive summary Pediatrics 2004 Jul;114(1): Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin measurements in the United States to prevent kernicterus. Clin Chem 2004 Mar;50(3): Bhutani VK, Johnson LH, Shapiro SM. Kernicterus in sick and preterm infants ( ): a need for an effective preventive approach. Semin Perinatol 2004 Oct;28(5): Kaplan M, Hammerman C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta 2005 Jun;356(1 2): Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004 Jul;114(1): Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ, et al. Association Between Peak Serum Bilirubin and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants. Pediatrics 2003 Oct 1,112(4): Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F455-F Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F459-F Wennberg R, Ahlfors C, Bhutani V, Johnson L, Shapiro S. Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns. Pediatrics 2006 Feb 1,117(2): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4):

16 68. Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatr Jpn 1992 Dec;34(6): Funato M, Tamai H, Shimada S, Nakamura H. Vigintiphobia, unbound bilirubin, and auditory brainstem responses. Pediatrics 1994 Jan;93(1): Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics 2001 Apr;107(4): Ahlfors CE, Wennberg RP. Bilirubin-albumin binding and neonatal jaundice. Semin Perinatol 2004 Oct;28(5): Ahlfors CE, Parker AE. Evaluation of a model for brain bilirubin uptake in jaundiced newborns. Pediatr Res 2005 Dec;58(6): Hansen TW. Bilirubin oxidation in brain. Mol Genet Metab 2000 Sep;71(1 2): Tiribelli C, Ostrow JD. The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1 2 October, Journal of Hepatology 2005 Jul;43(1): Wennberg R, Ahlfors C, Bhutani V, Johnson L, Shapiro S. Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns. Pediatrics 2006 Feb 1,117(2): Ostrow JD, Pascolo L, Tiribelli C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res 2003 Jul;54(1): Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts in bilirubin encephalopathy. Eur J Clin Invest 2003 Nov;33(11): Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med 2004 Feb;10(2): Gennuso F, Fernetti C, Tirolo C, Testa N, L Episcopo F, Caniglia S, et al. Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1). Proc Natl Acad Sci U S A 2004 Feb 24,101(8): Falcao AS, Bellarosa C, Fernandes A, Brito MA, Silva RFM, Tiribelli C, et al. Role of multidrug resistance-associated protein 1 expression in the in vitro susceptibility of rat nerve cell to unconjugated bilirubin. Neuroscience 2007 Feb 9,144(3): Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts in bilirubin encephalopathy. Eur J Clin Invest 2003 Nov;33(11): Ostrow JD, Pascolo L, Tiribelli C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res 2003 Jul;54(1): Tiribelli C, Ostrow JD. The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1 2 October, Journal of Hepatology 2005 Jul;43(1): Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F459-F463. Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity 51

17 85. Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F455-F Bhutani VK, Johnson LH, Shapiro SM. Kernicterus in sick and preterm infants ( ): a need for an effective preventive approach. Semin Perinatol 2004 Oct;28(5): Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin measurements in the United States to prevent kernicterus. Clin Chem 2004 Mar;50(3): Kaplan M, Hammerman C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta 2005 Jun;356(1 2): Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics 2001 Apr;107(4): Scheidt PC, Graubard BI, Nelson KB, Hirtz DG, Hoffman HJ, Gartner LM, et al. Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy. Pediatrics 1991 Jun;87(6): Kim MH, Yoon JJ, Sher J, Brown AK. Lack of predictive indices in kernicterus: a comparison of clinical and pathologic factors in infants with or without kernicterus. Pediatrics 1980 Dec;66(6): Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics 1982 Apr;69(4): Ritter DA, Kenny JD, Norton HJ, Rudolph AJ. A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics 1982 Mar;69(3): Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics 2003 Dec;112(6 Pt 1): Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994 Mar;93(3): Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003 Nov;88(6):F459-F Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O Shea TM, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008 Oct 30,359(18): Jangaard KA, Vincer MJ, Allen AC. A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: Short- and longterm outcomes. Paediatr Child Health 2007 Dec;12(10): Curtis-Cohen M, Stahl GE, Costarino AT, Polin RA. Randomized trial of prophylactic phototherapy in the infant with very low birth weight. J Pediatr 1985 Jul;107(1):