Special Feature

Journal of Perinatology (2012) 32, 660–664; doi:10.1038/jp.2012.71; published online 7 June 2012

An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation

M J Maisels1, J F Watchko2, V K Bhutani3 and D K Stevenson3

  1. 1Division of Newborn Medicine, Department of Pediatrics, Oakland University William Beaumont School of Medicine, Beaumont Children's Hospital, Royal Oak, MI, USA
  2. 2Divison of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  3. 3Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, Stanford, CA, USA

Correspondence: Dr MJ Maisels, Division of Newborn Medicine, Department of Pediatrics, Oakland University William Beaumont School of Medicine, Beaumont Children's Hospital, 3601 W. 13 Mile Road, Royal Oak, MI 48073, USA. E-mail: jmaisels@beaumont.edu

Received 19 March 2012; Revised 26 April 2012; Accepted 27 April 2012
Advance online publication 7 June 2012

Top

Abstract

We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.

Keywords:

hyperbilirubinemia; jaundice; phototherapy; exchange transfusion

Top

Introduction

The American Academy of Pediatrics (AAP) has published a guideline for the management of hyperbilirubinemia in the newborn infant greater than or equal to35 weeks gestation,1 and similar consensus-based guidelines have been published recently in Canada, Israel, Norway, South Africa, the Netherlands, and the United Kingdom (UK).2, 3, 4, 5, 6, 7 The AAP guideline1 has been widely adopted in the United States and elsewhere but there is no similar guideline in the United States for the treatment of infants <35 weeks gestation. In lieu of such direction, neonatal intensive care units (NICUs) have established their own criteria for the use of phototherapy and exchange transfusion in these infants, most often based on birth weight or gestational age.

It is generally believed that infants <35 weeks gestation are at greater risk for the development of bilirubin-associated brain damage than term infants, although a paucity of data has made quantification of the magnitude of this risk difficult,8 and the reported range of bilirubin thresholds used to initiate treatment at different birth weights and gestations is remarkably wide.5, 9, 10 The recent, consensus-based national guidelines published in the UK, South Africa and Norway, include recommendations for the management of preterm infants.5, 11 Recognizing the need, the AAP Committee on Fetus and Newborn in 2007 asked a group of experts to develop a guideline for the management of jaundiced infants <35 weeks of gestation and a recent survey of neonatologist members of the Section on Perinatal Pediatrics of the AAP,12 confirmed this need. But the current AAP policy requires that guidelines be evidence-based and, as the evidence for such a guideline is limited, it was not possible to comply with this requirement. Thus the recommendations that follow are, of necessity, consensus-based.

Top

Hyperbilirubinemia and the preterm infant

Chronic bilirubin encephalopathy, including kernicterus at postmortem, is currently a rare event in premature neonates but has not disappeared completely and, whether modest elevations in total serum bilirubin (TSB) contribute to subtle forms of central nervous system dysfunction in premature infants, remains controversial.13, 14, 15 In past decades, autopsy proven kernicterus was reported in sick, very low birth weight infants who were exposed to low TSB levels (the so-called ‘low bilirubin kernicterus’)16, 17 and recent case series document that this remains a clinical risk.18, 19, 20, 21 In a recent study from the Netherlands,18 5 sick, preterm infants (25 to 29 weeks gestation) with peak TSB levels ranging from 8.7 to 11.9mgdl−1 (148 to 204μmoll−1) developed the classical MRI findings of kernicterus. Serum albumin levels in these infants were strikingly low, ranging from 1.4 to 2.1gdl−1. Two extremely low birth weight (ELBW) neonates with complicated neonatal courses and comorbid CNS injury, had peak TSB levels of 7.5mgdl−1 (128μmoll−1) and 9.9mgdl−1 (168μmoll−1) and developed clinical sequelae and MRI findings consistent with chronic bilirubin encephalopathy.19 Choreoathetosis, and the classical MRI findings of kernicterus at follow-up, were documented in two preterm infants of 31 and 34 weeks gestation.20 Neither of these infants was acutely ill in the newborn period and their peak TSB levels were 13.1mgdl−1 (224μmoll−1) and 14.7mgdl−1 (251μmoll−1) respectively.

Recent studies of large populations of ELBW infants suggest an association between neurodevelopmental impairment (NDI) and modest elevations in TSB.21, 22 In a retrospective analysis of ELBW infants born between 1994 and 1997, peak TSB levels, generally in the 5 to 12mgdl−1 (85 to 204μmoll−1) range were directly correlated with the risk of (i) death or NDI (odds ratio (OR): 1.068; 95% confidence interval (CI): 1.03 to 1.11), (ii) hearing impairment (OR: 1.138; CI 1.00 to 1.30) and (iii) a psychomotor development index <70 (OR: 1.057; CI 1.00 to 1.12)22 although the effect size of each association was very small and barely significant. Nevertheless, other studies suggest that moderate hyperbilirubinemia in these infants poses no risk of neurotoxicity.23, 24 These conflicting data prompted the Neonatal Research Network to perform a prospective randomized controlled trial in ELBW infants of aggressive phototherapy (used prophylactically and started at 23±9h after birth) vs conservative phototherapy (started when the TSB level was greater than or equal to8mg/dl (137μmoll−1) for infants 500 to 750g, or 10mgdl−1 (171μmol−1) for infants 751 to 1000g).25 There was no difference in the primary outcome of death or NDI at 18 to 20 months of corrected age but, among survivors, when compared with conservative phototherapy, aggressive phototherapy produced a significant decrease in NDI, hearing loss, profound impairment and athetosis.25 The mean TSB level in infants with hearing loss was 6.5±1.7mgdl−1 vs 5.4±1.5mgdl−1 (111±29.1 vs 94±25.7μmoll−1) in those with no hearing loss (P<0.001). Peak TSB levels in infants with NDI were 8.6±2.3 vs 8.3±2.3 (147±39.3 vs 142±39.3μmoll−1, P=0.02) in unimpaired survivors. Whether these small differences in TSB levels, the use of aggressive phototherapy, or other factors were responsible for the outcomes is difficult to say.

An unexpected finding in this study was an increase in mortality in infants with birth weights 501 to 750g who received aggressive phototherapy (discussed in more detail below), and this must be balanced against the apparent benefit of this therapy.

Unbound or free bilirubin

Bilirubin–albumin binding is a function of the concentrations of bilirubin and albumin, and the binding affinity for bilirubin (strength of bilirubin binding to albumin). The fraction of unbound (UB) bilirubin (nonalbumin-bound or free bilirubin) increases significantly as the bilirubin approaches the binding capacity of albumin or when the apparent albumin affinity decreases.26 The binding affinity may be decreased in the presence of sepsis, acidosis, hypoxia, free fatty acids and various albumin-binding drugs.26 Because the peak TSB level, by itself, is a rather poor predictor of the likelihood of NDI or kernicterus, it has been suggested that measurement of UB or free bilirubin might be a better index of neurodevelopmental risk.27, 28

Most bilirubin in the circulation is albumin bound, but a relatively small fraction remains UB. The concentration of UB is believed to dictate the biological effects of bilirubin in jaundiced newborns, including its neurotoxicity, and elevations of UB have been associated with kernicterus or NDI in sick, preterm infants.29, 30, 31 Routine, clinical laboratory measurement of UB is not commercially available in the United States, so that even if there was agreement regarding UB levels that require intervention, such recommendations, currently, could not be implemented. Some experts have recommended using the ratio of bilirubin (mgdl−1) to albumin (gdl−1) as an approximate surrogate for the measurement of UB.1, 32

It is also important to understand that the risk of bilirubin encephalopathy may not be a function of the UB concentration alone or the TSB level, but a combination of both, that is, the total amount of bilirubin available (the miscible pool of bilirubin), as well as the tendency for UB to enter the tissue.32 The susceptibility of the cells of the central nervous system is also an important factor in determining the likelihood of damage by bilirubin.33, 34 Currently, no recommendations can be made with regard to the use of UB in the management of infants <35 weeks gestation. As noted in the table legend, it is probably appropriate to treat those with low albumin levels at lower TSB levels.

Top

Phototherapy

The remarkable decrease in the incidence of kernicterus at autopsy in infants who have died in the NICU in the last 2 to 3 decades is likely the result of overall improvements in the care of preterm neonates and the liberal use of phototherapy. Certainly, effective phototherapy has dramatically decreased the need for exchange transfusion in preterm infants, so that this procedure has become increasingly rare in the NICU.23, 25, 35, 36 In the Neonatal Research Network Study,25 only 5 of 1974 (0.25%) ELBW infants received an exchange transfusion.

Although, as noted above, survivors in the Neonatal Research Network study who received aggressive phototherapy were less likely to have NDI, there was a 5% increase in mortality in infants with birth weights 501 to 750g who received aggressive phototherapy25 (relative risk 1.05 (CI 0.90 to 1.22)). The difference was not statistically significant but a post hoc, Bayesian analysis, estimated an 89% probability that aggressive phototherapy increased the rate of deaths in this subgroup. In an earlier NICHD study,17, 37 infants with birth weights less than or equal to1000g, who received phototherapy, had a 19% increase in mortality compared with control infants (no phototherapy) (P=0.14). The reasons for these findings are not clear, but these tiny, immature infants have gelatinous, thin skin, through which light will penetrate readily reaching more deeply into the subcutaneous tissue. There is some evidence that phototherapy can produce oxidative injury to cell membranes and DNA,38, 39, 40, 41 and such injury could have a negative effect on these immature infants. In the Neonatal Research Network study, the average irradiance level was reported as 22 to 23μWcm−2nm−1 and the ‘target irradiance level’ was 15 to 40μWcm−2nm−1.25

Top

Effective use of phototherapy

Phototherapy in most infants less than or equal to35 weeks of gestation is generally used in a prophylactic mode—the goal being to prevent further elevation of the TSB. The most effective irradiance is delivered by a light source (such as special blue fluorescent lamps or LED systems) that will deliver irradiance predominately in the 430 to 490nm band.42, 43 Detailed information on phototherapy use can be found in a recent technical report.43 If, in spite of phototherapy, the TSB continues to rise, either the irradiance can be increased by bringing the phototherapy lamp closer to the baby (except when halogen or tungsten lights are used) or by increasing the body surface area of the infant exposed to phototherapy (by placing a light source beneath the infant and reflecting material around the incubator or radiant warmer bed). Because there is significant variation in the irradiance measurements provided by commercial radiometers,39, 43 it is difficult to recommend a specific irradiance level. Nevertheless, when possible, clinicians should use the radiometer recommended by the manufacturer of the phototherapy system and provide sufficient irradiance to prevent an increase in the TSB.

Because of the reported increase in mortality in infants with birth weights 501 to 750g,25 it seems prudent, at least in infants with birth weights <750g, to initiate phototherapy at lower irradiance levels and only to increase these levels, or to increase the surface area of the infant exposed to phototherapy, if the TSB continues to rise (see Table 1).


Top

Exchange transfusion

Most reports suggest that sick, preterm infants, are more likely than term infants to experience a wide range of serious complications as well as mortality from exchange transfusion.44, 45, 46 The complications include cardio-respiratory arrest, arrhythmias, thrombosis, thrombocytopenia, hypothermia, necrotizing enterocolitis and infection, among others.45, 46 Of the total of 25 sick infants who received exchange transfusions at the Children's Hospital and University of Washington Medical Center in Seattle between 1980 to 1995, 3 (12%) had serious complications and 2 (8%) died, whereas in 81 healthy infants there were no deaths and there was one case of necrotizing enterocolitis.45 Between 1992 and 2002, at two perinatal centers in Cleveland, OH, 15 infants less than or equal to32 weeks gestation, received exchange transfusions and there was one death (7%).46 This infant was a 731-g, 25-week gestation infant with hydrops fetalis, respiratory distress syndrome and pulmonary hemorrhage before the exchange. On the other hand, less serious complications such as thrombocytopenia (38 to 67%) and hypocalcemia (13 to 38%) in very low birth weight infants are quite common.35, 46 In a recent study, there were no significant differences in the frequency of exchange transfusion-related complications in neonates <1500g birth weight compared with those >1500g.35 The sample sizes for infants <1500g birth weight in all of these studies were small.

Effective phototherapy and the prevention of Rh hemolytic disease with Rh (D) immunoglobulin47 have produced a dramatic decrease in the number of exchange transfusions performed in the NICU and, in particular, in infants with birth weights <1500g.23, 25, 36 Before the introduction of phototherapy, as many as one in three infants with birth weights <1500g received an exchange transfusion during their stay in the NICU48 compared with between 0 to 0.25% of these infants admitted to NICU's in the last three decades.23, 25, 36

Top

Elevated direct-reacting or conjugated bilirubin levels

There are no good data to guide the clinician in dealing with the occasional infant who has a significant elevation of direct-reacting or conjugated bilirubin. Kernicterus has been described in term infants with TSB levels >20mgdl−1 (314μmoll−1) but in whom, because of significant elevations in direct bilirubin levels, the indirect bilirubin levels were well below 20mgdl−1.49, 50 There is some evidence that elevated direct bilirubin levels can decrease the infant's albumin-binding capacity51 and it has been suggested, but not confirmed, that infants with the bronze baby syndrome might be at an increased risk of developing bilirubin encephalopathy.51, 52 As a general rule, when considering the use of phototherapy or exchange transfusion, the direct-reacting (or conjugated) bilirubin level should not be subtracted from the total. Infants with conjugated bilirubin levels >50% of the TSB require individual expert evaluation.

Top

Hemolytic disease

Infants with hemolytic disease are generally considered to be at a greater risk for the development of bilirubin encephalopathy than are nonhemolyzing infants with similar bilirubin levels.1 Thus, exchange transfusion is recommended at lower levels for infants who have hemolytic disease (see Table 1). Although the use of intravenous gamma-globulin has been shown, in several randomized controlled trials, to reduce the need for exchange transfusions in both Rh and ABO hemolytic disease,53, 54, 55 a recent study of intravenous gamma-globulin administration to infants with severe Rh hemolytic disease did not confirm these findings.56 It is possible that the severity of hemolysis has a role in determining the response to intravenous gamma-globulin.57

Top

New recommendations

The table provides an approach to the use of phototherapy and exchange transfusion based on gestation. As there are limited data for evidence-based recommendations, this table is, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds or therapeutic normal levels (a level beyond which specific therapy will likely do more good than harm).58 Other guidelines have suggested lower intervention levels in the first 72–96h,5, 11 but we have opted to keep the table as simple as possible.

Based on a recent survey,12 the levels are close to those currently in use in many NICUs in the United States. They do represent a fairly aggressive approach to the use of phototherapy, perhaps influenced by the results in the recent NICHD Neonatal Network Study.25 Compared with both the NICE11 and Norwegian5 guidelines, we recommend phototherapy at lower bilirubin levels although our thresholds are similar to the Dutch recommendations.2 A long-term follow-up of a large population of such infants might identify which of these suggested approaches is preferred.

Top

Conflict of interest

The authors declare no conflict of interest.

Top

References

  1. American Academy of Pediatrics. Subcommittee on hyperbilirubinemia. Clinical practice guideline: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297–316. | Article | PubMed | ISI |
  2. van Imhoff DE, Dijk PH, Hulzebos CV, BARTrial Study Group, Netherlands Neonatal Research Network. Uniform treatment thresholds for hyperbilirubinemia in preterm infants: background and synopsis of a national guideline. Early Hum Dev 2011; 87: 521–525. | Article | PubMed |
  3. Kaplan M, Merlob P, Regev R. Israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus. J Perinatol 2008; 28: 389–397. | Article | PubMed |
  4. Rennie J, Burman-Roy S, Murphy MS. Neonatal jaundice: summary of NICE guidance. BMJ 2010; 340: 1190–1192. | Article |
  5. Bratlid D, Nakstad B, Hansen TWR. National guidelines for treatment of jaundice in the newborn. Acta Paediatr 2011; 100(4): 499–505. | Article | PubMed |
  6. Canadian Paediatric Society. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ gestation) - summary. Paediatr Child Health 2007; 12: 401–418. | ISI |
  7. Horn AR, Kirsten GF, Kroon SM, Henning PA, Moller G, Pieper C et al. Phototherapy and exchange transfusion for neonatal hyperbilirubinaemia. S Afr Med J 2006; 96: 819–824. | PubMed |
  8. Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003; 88: F459–F463. | Article | PubMed |
  9. Rennie JM, Sehgal A, De A, Kendall GS, Cole TJ. Range of UK practice regarding thresholds for phototherapy and exchange transfusion in neonatal hyperbilirubinaemia. Arch Dis Child Fetal Neonatol Ed 2009; 94: F323–F327. | Article |
  10. Hansen TWR. Therapeutic approaches to neonatal jaundice: an international survey. Clin Pediatr 1996; 35: 309–316. | Article |
  11. National Institute for Health and Clinical Excellence. Neonatal Jaundice. National Institute for Health and Clinical Excellence, 2010, www.nice.org.uk/CG98.
  12. Bhutani VK. Survey of neonatologists in the Perinatal Section of the AAP (personal communication). 2011.
  13. Watchko JF, Maisels MJ. Jaundice in low birth weight infants - pathobiology and outcome. Arch Dis Child Fetal Neonatol Ed 2003; 88: F455–F459. | Article |
  14. Watchko JF, Oski FA. Kernicterus in preterm newborns: past, present and future. Pediatrics 1992; 90: 707–715. | PubMed |
  15. Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonat Med 2010; 15: 157–163. | Article |
  16. Keenan WJ, Perlstein PH, Light IJ, Sutherland JM. kernicterus in small, sick, premature infants receiving phototherapy. Pediatrics 1972; 49: 652–655. | PubMed |
  17. Lipsitz PJ, Gartner LM, Bryla DA. Neonatal and infant mortality in relation to phototherapy. Pediatrics 1985; 75: 422–426. | PubMed |
  18. 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; 112: 1256–1263. | Article | PubMed | ISI |
  19. Moll M, Goelz R, Naegele T, Wilke M, Poets CF. Are recommended phototherapy thresholds safe enough for extremely low birth weight (ELBW) infants? A report on 2 ELBW infants with kernicterus despite only moderate hyperbilirubinemia. Neonatology 2011; 99: 90–94. | Article | PubMed |
  20. Sugama S, Soeda A, Eto Y. Magnetic resonance imaging in three children with kernicterus. Pediatr Neurol 2001; 25: 328–331. | Article | PubMed |
  21. Mazeiras G, Roze J-C, Ancel P-Y, Caillaux G, Frondas-Chauty A, Denizot S et al. Hyperbilirubinemia and neurodevelopmental outcome of very low birthweight infants: results from the LIFT cohort. PLoS ONE 2012; 7(1): 1–8. | Article |
  22. 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; 112: 773–779. | Article | PubMed |
  23. O’Shea TM, Dillard RG, Klinepeter KL, Goldstein DJ. Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight infants. Pediatrics 1992; 90: 888–892. | PubMed |
  24. Yeo KL, Perlman M, Hao Y, Mullaney P. Outcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy. Pediatrics 1998; 102(6): 1426–1431. | Article | PubMed |
  25. Morris BH, Oh W, Tyson JE, Stevenson D, Phelps DL, O’Shea TM et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. New Engl J Med 2008; 359: 1885–1896. | Article | PubMed |
  26. Brodersen R. Binding of bilirubin to albumin. CRC Crit Rev Clin Lab Sci 1980; 11: 305–399. | Article | PubMed |
  27. McDonagh AF, Maisels MJ. Bilirubin unbound: deja vu all over again? Pediatrics 2006; 117: 523–525. | Article | PubMed |
  28. Wennberg RP, Ahlfors CE, Bhutani V, Johnson LH, Shapiro SM. Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 2006; 117: 474–485. | Article | PubMed |
  29. Cashore WJ, Oh W. Unbound bilirubin and kernicterus in low birthweight infants. Pediatrics 1982; 69: 481–485. | PubMed | CAS |
  30. Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birth weight infants. Acta Paediatr Jpn 1992; 54: 642–647. | Article |
  31. Oh W, Stevenson DK, Tyson JE, Morris BH, Ahlfors CE, Bender GJ et al. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr 2010; 99: 673–678. | PubMed |
  32. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics 1994; 93: 488–494. | PubMed | CAS |
  33. Watchko JF. Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. NeuroMolecular Med 2006; 8: 513–529. | Article | PubMed | CAS |
  34. Wennberg RP. Cellular basis of bilirubin toxicity. NY State J Med 1991; 91: 493–496.
  35. Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG. A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality. Pediatrcs 2007; 120: 27–32. | Article |
  36. Maisels MJ. Phototherapy - traditional and nontraditional. J Perinatol 2001; 21: S93–S97. | Article | PubMed |
  37. Bryla DA, Brown A, Gartner L, Lipsitz P. Phototherapy for neonatal hyperbilirubinemia. Pediatrics 1986; 78(1): 180–181.
  38. Tozzi E, Tozzi-Ciancarelli MG, Di Giulio A, D’Alfonso A, Farello G, Spennati GF et al. In vitro and in vivo effects of erythrocyte phototherapy in newborns. Biol Neonate 1989; 56(4): 204–209. | Article | PubMed |
  39. Vreman HJ, Wong RJ, Stevenson DK. Phototherapy: current methods and future directions. Semin Perinatol 2004; 28: 326–333. | Article | PubMed |
  40. Vreman HJ, Knauer Y, Wong RJ, Chan M-L, Stevenson DK. Dermal carbon monoxide excretion in neonatal rats during light exposure. Pediatr Res 2009; 66: 66–69. | Article | PubMed |
  41. Zuniga-Gonzalez G, Gomez-Meda BC, Lemus-Varela M, Zamora-Perez AL, Armendariz-Borunda J, Barros-Hernandez A et al. Micronucleated erythrocytes in preterm newborns exposed to phototherapy and/or oxygentherapy. Photochem Photobiol 2012; 107: 79–83. | Article |
  42. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008; 358: 920–928. | Article | PubMed | CAS |
  43. Bhutani VK, Committee on Fetus and Newborn. Technical Report: phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128: e1046–e1052. | Article | PubMed |
  44. Watchko JF. Exchange transfusion in the management of neonatal hyperbilirubinemia In: Maisels MJ, Watchko JF (eds). Neonatal Jaundice 2000, pp 169–176.
  45. Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997; 99: e7. | Article | PubMed | CAS |
  46. Patra K, Storfer-Isser A, Siner B, Moore J, Hack M. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr 2004; 144: 626–631. | Article | PubMed |
  47. Bowman JM. RhD hemolytic disease of the newborn. New Engl J Med 1998; 339: 1775–1777. | Article | PubMed |
  48. Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbidity and mortality associated with exchange transfusion. Pediatrics (Suppl) 1985; 75: 417–421.
  49. Grobler JM, Mercer MJ. Kernicterus associated with elevated predominantly direct-reacting bilirubin. S Afr Med J 1997; 87: 146. | PubMed |
  50. Clark CF, Torii S, Hamamoto Y, Kaito H. The ‘bronze baby’ syndrome: postmortem data. J Pediatr 1976; 88: 461–464. | Article | PubMed |
  51. Ebbesen F. Low reserve albumin for binding of bilirubin in neonates with deficiency of bilirubin excretion and bronze baby syndrome. Acta Paediatr Scand 1982; 71: 415–420. | Article | PubMed |
  52. Bertini G, Dani C, Fonda C, Zorzi C, Rubaltelli F. Bronze baby syndrome and the risk of kernicterus. Acta Paediatr 2005; 94: 968–971. | Article | PubMed |
  53. Rübo J, Albrecht K, Lasch P, Laufkötter E, Leititis J, Marsan D et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992; 121: 93–97. | Article | PubMed | CAS |
  54. Sato K, Hara T, Kondo T, Iwao H, Honda S, Ueda K. High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand 1991; 80: 163–166. | Article | PubMed |
  55. Alpay F, Sarici SÜ, Okutan V, Erdem G, Özcan O, Gökçay E. High-dose intravenous immunoglobin therapy in neonatal immune haemolytic jaundice. Acta Paediatr 1999; 88: 216–219. | Article | PubMed |
  56. Smits-Wintjens VEHJ, Walther FJ, Rath MEA, Lindenburg ITM, te Pas AB, Kramer CM et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics 2011; 127: 680–686. | Article | PubMed |
  57. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy. Biol Neonate 1996; 70: 69–74. | Article | PubMed |
  58. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. 2nd edn. Little, Brown and Co: Boston, 1991.