Recent Developments in the Management of Neonatal Hyperbilirubinemia Cathy Hammerman and Michael Kaplan Neoreviews 2000;1;e19 DOI: 10.1542/neo.

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ARTICLE

Recent Developments in the Management of Neonatal Hyperbilirubinemia

Cathy Hammerman, MD* and Michael Kaplan, MB, ChB*
OBJECTIVES After completing this article, readers should be able to: 1. 2. 3. 4. 5. 6. Describe the morbidity associated with exchange transfusion used to treat neonatal hyperbilirubinemia. Explain how phototherapy affects bilirubin. Describe potential toxicities of phototherapy. Explain the role of carboxyhemoglobin in hemolysis. Delineate the guidelines for administering intravenous immunoglobulin to healthy ABO-incompatible Coombs-positive neonates. Describe the action of protoporphyrins on bilirubin.

Introduction
Recent clinical trends toward early discharge coupled with a new, more relaxed, kinder, gentler approach to the treatment of newborn hyperbilirubinemia have thrust concerns about bilirubin-related toxicity once again to the forefront of neonatologists consciousness. In recent years we even have witnessed a resurgence of kernicterus, which had been rendered almost nonexistent in the 1970s and 1980s. Although exchange transfusion is the oldest and most effective method of treating hyperbilirubinemia, mortality associated with this therapy has been reported to be between 0.3% and 1.2% in healthy infants and as high as 10% to 25% in sicker preterm infants. Furthermore, potential morbidity related to exchange transfusion remains significant and includes anemia, apnea, bradycardia, hypothermia, sepsis, necrotizing enterocolitis, thromboembolic phenomena, graft versus host disease, transient metabolic abnormalities, and thrombocytopenia. Accordingly, it behooves us to re-evaluate other therapeutic modalities for hyperbilirubinemia that may be equally efficacious but less invasive.

Shedding New Light on Photototherapy

Ever since the 1950s, when Sister Ward of Rochford General Hospital in Essex noted that a jaundiced babys skin had faded in natural sunlight, physicians have been searching for artificial light sources that might be used safely to treat neonatal hyperbilirubinemia. Phototherapy, which has become the standard of care, has had such a dramatic impact that a recent editorial raised the concern that exchange transfusions are becoming extinct and lamented the fact that future generations of house officers may not receive adequate training in this procedure. Under the effects of phototherapy light with maximal irradiance in the 425 to 475 nm wavelength band, bilirubin is transformed into structural and configurational photoisomers that are water-soluble and easily excretable, enabling them to bypass the livers conjugation system. Phototherapy can be administered effectively either by fluorescent or nonfluorescent (halogen) lamps. The most meaningful method of calculating the effective dose of phototherapy received is via spectral power, which is the product of the spectral irradiance of the light used and the skin surface area of the infant that is exposed to the phototherapy. Most efficient of the standard, currently available sources of phototherapy light are special blue lamps. These lamps, however, do make the babies appear blue and

have been reported to cause discomfort among nursery personnel. Newer options for phototherapy administration include tungstenhalogen lamps attached to fiberoptic cables, which emit light from the sides and ends. The fibers are woven together and enclosed inside a pad. Despite the fact that the fiberoptic irradiance per unit area may be greater than that of conventional lights, these lights have less spectral power because of the small surface area exposed. van Kaam et al compared the efficacy of fiberoptic phototherapy with conventional phototherapy in 124 preterm infants and found no significant difference in the median duration of phototherapy required or the number of infants requiring exchange transfusions. They concluded that the efficacy of fiberoptic phototherapy in preterm infants is comparable to that of conventional phototherapy. In contrast, Tan found fiberoptic phototherapy to be significantly less effective than phototherapy with standard daylight bulbs in term healthy infants who had hyperbilirubinemia. A combination of the two types of phototherapy was more effective than either one alone, which prompted investigators to propose that the currently available fiberoptic phototherapy alone is sufficient only for preterm infants, who seem to respond adequately. In the term infant who has hyperbilirubinemia, fiberoptic phototherapy either must be combined with conventional phototherapy or with a second fiberoptic mat that encircles the infants other side,

ABBREVIATIONS
CBFV: CO: COHb: G6PD: cerebral blood flow velocity carbon monoxide carboxyhemoglobin glucose-6-phosphatase dehydrogenase IVIG: intravenous immunoglobulin tHb: total hemoglobin SnMP: Sn-mesoporphyrin

*Department of Neonatology, Shaare Zedek Medical Center; Faculty of Medicine of the Hebrew University, Jerusalem, Israel. NeoReviews

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LIVER DISEASE Neonatal Hyperbilirubinemia thereby increasing the surface area exposed to light. Of note, nursing personnel and parents unanimously prefer the fiberoptic phototherapy, which does not require eye shielding, does not disturb swaddled infants as much as does conventional phototherapy, and allows for more effective motherinfant bonding. Furthermore, because of their flexibility, fiberoptic units are much more amenable to home phototherapy. Newest on the phototherapy horizon are the gallium nitride light emitting diode units, which still are in the early testing phases. These are reported to be power-efficient, low heat-producing light sources that have a narrow luminous spectra in the blue-green portion of the visible light spectrum and the potential to deliver high-intensity light of up to 200 mcw/cm2/nm. In preliminary testing, these units appear to be extremely effective in enhancing bilirubin degradation both in vitro and in vivo in jaundiced rats. Because infants are not ingesting any drug, it has become natural to consider light therapy to be innocuous, but it is dangerous to be overly complacent in this regard. Benders et al recently reported on the effects of phototherapy on cerebral blood flow velocity (CBFV) in preterm infants (32 wk gestational age). They found that phototherapy increased mean CBFV in all infants studied. CBFV returned to pretherapy values after discontinuation of phototherapy only in healthy, nonventilated infants. It did not return to baseline in ventilated, sicker infants. Although the clinical implications of these changes are not clear, it is of concern that increased blood flow velocity in infants who already are at risk for intracranial hemorrhage may increase this susceptibility further. It is also unclear whether the magnitude of CBFV changes is related to phototherapy irradiance. Additional areas of potential toxicity include possible photo-oxidative damage and toxic photodynamic reactions that have been observed in vitro with vitamins, proteins, lipids, and nucleic acids. In vitro studies have shown that bilirubin-sensitized photo-oxidation of plasma lipoproe20

tein and red blood cell membranes results in oxidative stress that is manifested by increased thiobarbituric acid reactivity, diene formation, free cholesterol oxidation, and increased hemolysis in preterm infants. Thus, while phototherapy, as currently administered, does not appear to cause photo-oxidative damage in vivo in healthy term infants, clinical investigations should be pursued in antioxidant-depleted newborns, such as preterm and glucose-6-phosphatase dehydrogenase (G6PD)-deficient infants, and under the higher intensities that will be available in the next generation of light sources.

Feedings, Formula, and Fluids

Breastfed infants are more likely to develop hyperbilirubinemia than are formula-fed infants, but the clinical significance of this hyperbilirubinemia has been a source of controversy. In the past it had been widely accepted that hyperbilirubinemia was benign in this population and that kernicterus did not occur in breastfeeding infants, but in 1995 Maisels and Newman documented the occurrence of classic kernicterus in six otherwise healthy breastfed infants. All of these infants had the same blood type as their mothers, none was anemic, and none was jaundiced within the first 24 hours of life. Thus, breastfeeding jaundice must be taken seriously, and treating physicians must navigate a fine line between encouraging and supporting mothers in breastfeeding and not risking long-term neurodevelopmental damage to their infants. Tan recently published interesting data demonstrating that term, otherwise healthy breastfed infants who had nonhemolytic hyperbilirubinemia responded more quickly to phototherapy if formula was added to their ingestion of human milk. Furthermore, this study demonstrated no difference in phototherapy response rate between those fed solely formula and those fed a combination of formula and human milk. Thus, it may be preferable to counsel the mother of an infant who has clinically significant breastfeeding jaundice to supplement her own

milk with formula rather than to suspend nursing completely, as has been recommended traditionally. As important as knowing what to do to address hyperbilirubinemia is knowing what not to do so as not to waste precious time within the therapeutic window with futile interventions. We have noted an increasing trend to suggest hydration as an initial step in the treatment of neonatal hyperbilirubinemia. There is no evidence that excess fluid administration affects serum bilirubin concentration. Some infants, especially some breastfed infants, may be mildly dehydrated, and these infants require supplemental fluid to correct the dehydration, but the concept that a well-hydrated infants serum can be diluted by overhydration to reduce total bilirubin level is not supported by any studies.

Gamma Globulin
With the declining incidence of Rh hemolytic disease, ABO incompatibility has become the single most common cause of neonatal hyperbilirubinemia requiring therapy, accounting for about 20% of clinically significant jaundice in the newborn. Although it generally is believed that ABO immune hemolytic disease is not as critical as Rh isoimmunization and that it usually can be controlled by the use of phototherapy alone, a subgroup of ABO-incompatible infants do present with severe hemolysis, and their bilirubin levels continue to rise despite phototherapy, necessitating additional intervention and sometimes even requiring exchange transfusion. Although a positive Coombs test indicates erythrocyte sensitization, it is not a good predictor of overt hemolytic disease. Previous attempts at developing predictive indices, including sociodemographic correlations and efforts to provide semiquantitative antibody levels, have been of limited clinical usefulness at best. The clinical course of any individual infant affected with ABO isoimmune disease remains difficult to anticipate. Hyperbilirubinemia in both Rhand ABO-sensitized infants results from destruction of neonatal red blood cells that have been coated by

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LIVER DISEASE Neonatal Hyperbilirubinemia transplacentally acquired maternal isoantibody that causes extravascular erythrocyte destruction, probably mediated by Fc receptor-bearing cells within the reticuloendothelial system. Recent studies have demonstrated that intravenous immunoglobulin (IVIG) therapy is effective in modifying the hyperbilirubinemia in most cases of Coombs-positive hemolytic anemia. It has been proposed that IVIG blocks Fc receptors, thereby inhibiting hemolysis and reducing formation of bilirubin. Further, it has been postulated that IVIG may accelerate the rate of immunoglobulin G (IgG) catabolism, thereby reducing circulating pathogenic autoantibodies. Endogenous production of carbon monoxide (CO) has been used to reflect bilirubin production. Within the reticuloendothelial system, hemoglobin releases globin and heme, which in turn undergo further degradation to release equimolar amounts of bilirubin and CO. The CO released then binds strongly to hemoglobin, forming carboxyhemoglobin (COHb). Because endogenous CO production in the newborn occurs almost exclusively by this pathway, hemolysis can be quantitated by determining blood COHb levels. Elevated COHb levels have been correlated with increased hemolysis in fetuses and neonates suffering from immune hemolytic disease and even with kernicterus and death in G6PD-deficient infants. Uetani et al showed that hyperbilirubinemic, ABO-incompatible, Coombs-positive infants maintained stable, elevated COHbc values throughout the first 120 hours of life. Preliminary data relating to COHb reduction in response to IVIG was presented in the form of a collection of case reports in which four of five treated infants showed a reduction in COHb (uncorrected for inhaled CO). However, there was no defined protocol for IVIG administration and no attempt to correlate COHb response with clinical efficacy. Furthermore, the co-oximeter method used to quantitate COHb has been shown to be less accurate in neonates who have levels of COHb of less than 5%. Using a standardized IVIG protocol, Hammerman et al demonstrated prospectively that COHb, corrected for inhaled CO, decreased proportionately with the decrease in bilirubin in infants who responded to IVIG. On the other hand, infants who did not respond to IVIG maintained stable COHb levels throughout the study, in keeping with Uetanis data. Thus, IVIG reduced hemolysis only in those infants who responded clinically to the therapy, but it did not reduce hemolysis in the nonresponding Coombs-positive infants. These findings support the proposal that IVIG effect is mediated via decreased hemolysis. Although IVIG clearly reduces hyperbilirubinemia in most cases of neonatal isoimmunization, it is not always successful. Hammerman et al, in a second study, sought to define pretreatment factors associated both with a more severe clinical course and with therapeutic responsiveness to IVIG in an effort to predict the type of infant most likely to benefit from IVIG administration. Elucidation of such parameters could serve as a basis for clinical guidelines for future use of IVIG in ABO isoimmunization. Three groups of ABO-incompatible infants were defined for this investigation: IVIG nonresponders, IVIG responders, and those not meeting criteria for IVIG administration. These three groups appear to represent a spectrum of hemolysis ranging from severe to moderate to mild. A given infants position along this continuum of severity can be defined by a combination of age at presentation with clinically significant jaundice, rate of bilirubin rise during the first day of life, extent of early jaundice, serum total hemoglobin (tHb), and corrected COHb. At one extreme lay the infants who have the least clinical symptomatology and mildest hemolysis, as defined by the previously noted factors. This group of infants did not have severe enough hemolysis to meet even the initial IVIG administration criteria (Table 1). This group of infants can be targeted safely for early discharge. Although jaundice due to ABO incompatibility usually can be controlled by the use of phototherapy alone, there is a clearly identifiable subgroup of ABO-incompatible infants whose bilirubin levels continue to rise despite phototherapy

TABLE 1. Characteristics of IVIG Candidates

COOMBS-POSITIVE NOT MEETING IVIG CRITERIA

NONRESPONDERS

RESPONDERS

P VALUE

Gestational Age (wk) Birthweight (g) Age at IVIG Administration (hr) Baseline Bilirubin (mcmol/L) Exchange Transfusion

392 3,059463 1210* 23951 6*

395 3,384488 4417 29134 0

401 3,290459 NA 17168** ***

,

NS NS 0.001 0.001 0.001

0***

NS: Not significant NA: Not applicable *Significant difference: Nonresponder versus responders **Significant difference: Responders versus those not meeting IVIG criteria ***Significant difference: Nonresponders versus those not meeting IVIG criteria

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LIVER DISEASE Neonatal Hyperbilirubinemia and who sometimes even require exchange transfusion. This group of infants, who have a moderate degree of hemolysis and present after the first 24 hours of life with tHb greater than 8.06 mmol/L (13 mg/ dL), appear most likely to benefit from IVIG administration. The hemolysis is severe enough to meet IVIG administration criteria, but not so severe as to preclude benefit from the drug. Although we cannot predict the subsequent course of this group had they not been treated with IVIG, they clearly displayed a pattern of increasing hyperbilirubinemia that was not responding to phototherapy at the time of intervention. We suspect that most eventually would have stabilized, although that probably would have required several extra days of hospitalization. Possibly others may have proceeded to meet the criteria for exchange transfusion. Brouwers et al found in a prospective study of the severity of ABO hemolytic disease that 6 of 80 ABO-incompatible infants required one or more exchange transfusions, despite having received phototherapy. This group, therefore, should be targeted for IVIG treatment in an attempt to minimize the duration of phototherapy and hospitalization and possibly to obviate the need for exchange transfusion. At the other extreme lay infants presenting with early, severe hemolysis in whom IVIG was less effective in preventing either further bilirubin rise or exchange transfusion, possibly because the hemolysis already was so severe that it could not be reversed. Based on our preliminary data, we would predict that infants who have clinically significant jaundice within first 24 hours of life, an increase in bilirubin of greater than 17 mcmol/L (1.0 mg/ dL) per hour with a minimum of 4 hours between measurements, and a tHb of less than 8.06 mmol/L (13 g/dL) are at high risk for not responding to the current regimen of IVIG administration. It is possible that these infants will respond to a higher IVIG dose, and this approach deserves further study. Alpay et al employed a higher dose of IVIG to treat 116 infants who had either ABO hemolytic disease, Rh hemolytic disease, or both with no
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adverse effects. Nevertheless, they did not attempt to identify those who had more severe hemolysis, rather treating all infants with 1 g/kg IVIG. They demonstrated a reduced need for phototherapy, fewer exchange transfusions, and shorter hospitalizations in the treated infants. In summary, IVIG treatment of neonatal jaundice associated with both ABO and Rh hemolytic disease is effective, is no longer experimental, and is not associated with any known toxicity. Although it is used routinely in Europe and the Middle East, IVIG use seems to be less routine in North America. Many informal discussions with American neonatologists suggest that this reflects a feeling that ABO disease is not a clinically significant problem rather than a lack of belief in the efficacy of IVIG. Although ABO disease is generally less problematic than Rh disease, a subset of the population does develop more severe symptomatology, and identifying this subset and defining precise clinical guidelines for which infants are most likely to benefit from such treatment is critical. A sample protocol summarizing our current approach to IVIG administration, which can be modified by individual institutions, is presented in Table 2.

Protoporphyrins
An alternative therapeutic approach to the control of neonatal hyperbili-

rubinemia involves attempts to reduce bilirubin production rather than to increase bilirubin elimination after production. In cases of hyperbilirubinemia due to increased production, metalloporporphyrins can help to prevent bilirubin accumulation. These compounds act by competitively inhibiting the activity of the enzyme heme oxygenase, the rate-limiting enzyme in heme catabolism. Tin, zinc, or cobalt protoporphyrin can be effective; the catalytic binding site of the heme oxygenase recognizes metalloporphyrins that have metallic ions other than iron. In fact, heme oxygenase actually favors some of these metalloporphyrins over heme as a substrate. The potency of metalloporphyrins and their side effects are influenced by the central metal cation and the nature of the side chains. Tin porphyrins are more potent than zinc or cobalt porphyrins. With side chains comprised of ethyl groups, mesoporphyrins are far more potent and stable than other forms. Clinical trials have demonstrated that Sn-mesoporphyrin (SnMP) suppresses bilirubin production, with the only side effect observed being a transient, nondose-dependent erythema that disappears without sequelae. A single small dose of SnMP administered preventively shortly after birth can moderate the severity of subsequent hyperbilirubinemia significantly. In two recent studies of otherwise healthy infants, therapeutic administration of SnMP

TABLE. 2. Guidelines for Total Serum Bilirubin (TSB) for IVIG Administration in Term Healthy ABO-incompatible Coombs-positive Neonates
First 12 hours of age TSB 204 mcmol/L (12 mg/dL) despite trial of phototherapy (4 hr minimum) TSB 272 mcmol/L (16 mg/dL) despite trial of phototherapy (4 hr minimum) TSB 306 mcmol/L (18 mg/dL) despite trial of phototherapy (4 hr minimum) tHb 8.06 mmol/L (13 mg/dL)

12 to 24 hours of age

24 to 72 hours of age

Additional Criteria:

When an infant meets above criteria, a dose of 0.5 g IVIG should be infused over 2 hours. The dose can be repeated at 12-hour intervals until bilirubin stabilizes. tHb total hemoglobin.

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LIVER DISEASE Neonatal Hyperbilirubinemia (administered when serum bilirubin levels approached 255 mcmol/L [15 mg/dL]) as opposed to prophylactic administration at birth entirely supplanted the need for supplemental phototherapy. Control infants required significantly more phototherapy treatment. Other studies have found these compounds to be effective in preventing or minimizing neonatal jaundice due to G6PD deficiency and Coombs-positive ABO incompatibility in both term and preterm newborns. Concern does arise, however, if phototherapy must be used in conjunction with metalloporphyrinsa situation that is likely to be unpredictable. More severe photosensitization and risks ensuing from the effects of photodegradation of the metalloporphyrins could become substantial. For example, naturally elevated levels of a related substance, copper porphyrins, in children who have cholestasis make them vulnerable to photo-induced chemical alterations that result in the formation of the brown pigments made famous in the bronze baby syndrome. Today, therapy with metalloporphyrins remains experimental, but it appears to hold great potential for the future. animal studies. Although these concerns have not been substantiated in human studies, clinicians have remained reluctant to adopt this therapy. As a result, clofibrate currently is being used therapeutically only in France.
nous immunoglobulin therapy in neonatal immune haemolytic jaundice. Acta Paediatr. 1999;88:216 219 Aouthmany M. Phototherapy increases hemoglobin degradation and bilirubin production in preterm infants. J Perinatol. 1999; 19:271274 Benders MJ, van Bel F, van de Bor M. The effect of phototherapy on cerebral blood flow velocity in preterm infants. Acta Paediatr. 1998;87:786 791 Brouwers HA, Overbeeke MA, van Ertbruggen I, et al. What is the best predictor of the severity of ABO-haemolytic disease of the newborn? Lancet. 1988;2:641 644 Chan ML, Vreman HJ, Wong RJ, Young BW, Stevenson DK. In vivo efficacy of light emitting diodes (LEDs) as a light source for phototherapy in neonatal jaundiced rats. Pediatr Res. 1999;45:189A Cohen AN, Ostrow JD. New concepts in phototherapy: photoisomerization of bilirubin IX alpha and potential toxic effects of light. Pediatrics. 1980;65:740 750 Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, Stevenson DK. Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med. 1995;19: 395 404 Dobbs RH, Cremer RJ. Looking back: phototherapy. Arch Dis Child. 1975;50:833- 836 Ergaz Z Arad I. Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. J Perinat Med. 1993;21:183187 Ergaz Z, Gross D, Bar-Oz B, Peleg O, Arad I. Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin. Vox Sang. 1995;69:9599 Gabilan JC. Pharmacologic treatment of neonatal jaundice: a new approach. Arch Pediatr. 1998;11:1274 1278 Gopinathan V, Miller NJ, Milner AD, RiceEvans CA. Bilirubin and ascorbate antioxidant activity in neonatal plasma. FEBS Lett. 1994;349:197200 Hammerman C, Goldstein R, Kaplan M. Bilirubin in the premature: toxic waste or natural defense? Clin Chem. 1998;44: 25512553 Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal isoimmunization: factors associated with clinical efficacy. Biol Neonate. 1996;70:69 74 Hammerman C, Vreman HJ, Kaplan M, Stevenson DK. Intravenous immune globulin in neonatal isoimmunization: does it reduce hemolysis? Acta Paediatr. 1996;85: 13511353 Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics. 1997;99:e7 e13. http://www.pediatrics.org/cgi/content/full/ 99/5/e7 Kaplan E, Herz F, Scheye E. ABO hemolytic disease of the newborn without hyperbilirubinemia. Am J Hematol. 1976;1: 279 282 Kappas A, Drummond GS, Manola T, Petmezaki S, Valaes T. Sn-protoporphyrin use in the management of hyperbilirue23

Protective Properties of Bilirubin

There are some fascinating potential beneficial properties of the compound bilirubin. Some 35 years ago, it was suggested that bilirubin might possess certain physiologically protective antioxidant functions, which has been confirmed subsequently both in vitro and in vivo. Dennery et al exposed Gunn rats to hyperoxia and demonstrated that jaundiced rats were more resistant to oxidative damage than were nonjaundiced rats. In human infants, a direct and significant correlation between serum bilirubin concentration and total antioxidant potential has been observed. Yet, bilirubin toxicity is real and potentially dangerous. Mireles et al have attempted to resolve this apparent discrepancy in vitro. In their system, bilirubin at physiologic concentrations protected neonatal red blood cells against oxidative stress, but cytotoxic effects prevailed at pathologic concentrations. However, these data cannot be extrapolated directly to the human neonatal in vivo condition and require further study. During early neonatal life, when oxidative stresses are common and severe and levels of most other antioxidant enzymes are naturally depressed, bilirubin levels are physiologically elevated. This raises the question: Is there possibly some teleologic reason that bilirubin is naturally elevated in newborns? It is enticing to speculate that bilirubin, rather than merely being a toxic waste, actually may be a component of the natural defense system. If this proves true, decisions about when and how to intervene therapeutically become even more delicate and complex.
SUGGESTED READING
Alpay F, Sarici SU, Okutan V, Erdem G, Ozcan O, Gokcay E. High dose intrave-

Clofibrate
Increasing the ability of the body to excrete bilirubin via stimulation of the livers conjugation ability long has been recognized as an effective approach to controlling hyperbilirubinemia. Phenobarbital was the first such agent demonstrated as effective. However, its efficacy requires several days of treatment, which limits its clinical feasibility in most cases of neonatal hyperbilirubinemia. Clofibrate is a better enhancer of glucuronosyl transferase induction than phenobarbital. In one study, it caused a 100% increase of hepatic bilirubin clearance within 6 hours, significantly reduced hyperbilirubinemia in 16 hours, decreased the intensity and duration of jaundice, and decreased phototherapy requirements. A single oral dose of 50 mg/kg seems to be suitable, and tolerance to the treatment is reported to be excellent. However, toxicity concerns have been raised based on
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LIVER DISEASE Neonatal Hyperbilirubinemia

binemia in term newborns with direct Coombs positive ABO incompatibility. Pediatrics. 1988;81:485 497 Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbidity and mortality associated with exchange transfusion. Pediatrics. 1985;75(suppl 2):417 421 Maisels MJ. Is exchange transfusion for hyperbilirubinemia in danger of becoming extinct? Pediatr Res. 1999;45:210A Maisels MJ, Newman TB. Kernicterus in otherwise healthy breast-fed term newborns. Pediatrics. 1995;96:730 733 Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics. 1999;103: 15 McDonagh A. Is bilirubin good for you? Clin Perinatol. 1990;17:359 369 Mireles LC, Lum MA, Dennery PA. Antioxidant and cytotoxic effects of bilirubin on neonatal erythrocytes. Pediatr Res. 1999; 45:355362 Rubaltelli FF, Jori G, Reddi E. Bronze baby syndrome: a new porphyrin related disorder. Pediatr Res 1983;17:327330 Rubo J, Albrecht K, Lasch P, et al. High dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr. 1992;121:9397 Sato K, Hara T, Kondo T, Iwao H, Honda S, Ueda K. High dose intravenous gamma globulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand. 1991;80:163166 Stocker R, Yamamoto Y, Mcdonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:10431046 Tan KL. Comparison of the efficacy of fiberoptic and conventional phototherapy for neonatal hyperbilirubinemia. J Pediatr. 1994;125:607 612 Tan KL. Decreased response to phototherapy for neonatal jaundice in breast fed infants. Arch Pediatr Adolesc Med. 1998;152: 11871190 Tan KL. Efficacy of bidirectional fiberoptic phototherapy for neonatal hyperbilirubinemia. Pediatrics. 1997;99:e13 Uetani Y, Nakamura H, Okamoto O, Yamazaki T, Vreman HJ, Stevenson DK. Carboxyhemoglobin measurements in the diagnosis of ABO hemolytic disease. Acta Paediatr Jpn. 1989;31:171176 Valaes T, Drummond GS, Kappas A. Control of hyperbilirubinemia in glucose-6-phosphate dehydrogenase deficient newborns using an inhibitor of bilirubin production, Sn-mesoporphyrin. Pediatrics. 1998;101: e1 e7. http://www.pediatrics.org/cgi/content/full/101/5/e1 van Kaam AH, van Beek RH, Vergunst-van Keulen JG, et al. Fiberoptic versus conventional phototherapy for hyperbilirubinaemia in preterm infants. Eur J Pediatr. 1998;157:132137 Vreman HJ, Ekstrand BC, Stevenson DK. Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. Pediatr Res. 1993;33: 195200 Vreman HJ, Mahoney JJ, Stevenson DK. Carbon monoxide and carboxyhemoglobin. Adv Pediatr. 1995;42:303334 Vreman HJ, Wong RJ, Stevenson DK, et al. Light emitting diodes: a novel light source for phototherapy. Pediatr Res. 1998;44: 809 809 Warshaw JB, Gagliardi J, Patel A. A comparison of fluorescent and nonfluorescent light sources for phototherapy. Pediatrics. 1980;65:795798 Widness JA, Lowe LS, Stevenson DK, et al. Direct relationship of fetal carboxyhemoglobin with hemolysis in alloimmunized pregnancies. Pediatr Res. 1994;35: 713719 Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody mediated autoimmune diseases. N Engl J Med. 1999;340:227228

NEOREVIEWS QUIZ
Quiz also available online at www.neoreviews.org. 1. Your institution is experimenting with newer methods of delivering phototherapy to newborns who have hyperbilirubinemia. A true statement about such therapy is that: A. A special fiberoptic pad used alone is considered first-line therapy. B. A special fiberoptic pad used in conjunction with conventional phototherapies is the most efficacious, leading-edge treatment. C. Halogen lamps do not provide adequate spectral power for effective phototherapy. D. Gallium nitride lamps produce substantial heat and are preferred for treatment of preterm infants. E. Special blue lamps are not efficient in lowering bilirubin levels, and their use still is considered experimental. 2. Which statement about protoporphyrins is most accurate? A. No studies of their use have yet been performed on human infants. B. There are no potential problems with using protoporphyrin therapy in conjunction with phototherapy. C. They are competitive inhibitors of glucuronosyl transferase. D. They are competitive inhibitors of heme oxygenase. E. They work by improving elimination of bilirubin that already has been formed. 3. Hyperbilirubinemia is a serious problem among infants who have Rh and ABO sensitivity. Affected infants who may benefit the most from the administration of intravenous immunoglobulin are those who: A. Exhibit an increase in bilirubin of 17 mcmol/L (1 mg/dL) per hour during the first day of life. B. Exhibit clinically significant jaundice within the first 24 hours of life. C. Exhibit minimal jaundice within the first 24 hours of life. D. Present after 24 hours of life with a total hemoglobin level 8.06 mmol/L (13 g/dL). E. Present after 24 hours of life with a total hemoglobin 8.06 mmol/L (13 g/dL).

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Recent Developments in the Management of Neonatal Hyperbilirubinemia Cathy Hammerman and Michael Kaplan Neoreviews 2000;1;e19 DOI: 10.1542/neo.1-2-e19

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