Recent Developments in the Management of Neonatal Hyperbilirubinemia Cathy Hammerman and Michael Kaplan Neoreviews 2000;1;e19 DOI: 10.

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3. when Sister Ward of Rochford General Hospital in Essex noted that a jaundiced baby’s skin had “faded” in natural sunlight. Phototherapy. MB. who seem to respond adequately.3% and 1. bilirubin is transformed into structural and configurational photoisomers that are water-soluble and easily excretable. which prompted investigators to propose that the currently available fiberoptic phototherapy alone is sufficient only for preterm infants. Describe the morbidity associated with exchange transfusion used to treat neonatal hyperbilirubinemia. which emit light from the sides and ends. potential morbidity related to exchange transfusion remains significant and includes anemia. Most efficient of the standard. A combination of the two types of phototherapy was more effective than either one alone.ARTICLE Recent Developments in the Management of Neonatal Hyperbilirubinemia Cathy Hammerman. MD* and Michael Kaplan. ChB* OBJECTIVES After completing this article. 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. 2. The most meaningful method of calculating the effective dose of phototherapy received is via spectral power.2% in healthy infants and as high as 10% to 25% in sicker preterm infants. 6. 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. In contrast. however. Describe the action of protoporphyrins on bilirubin. Jerusalem. 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. These lamps. enabling them to bypass the liver’s conjugation system. hypothermia. In the term infant who has hyperbilirubinemia. mortality associated with this therapy has been reported to be between 0. 5. The fibers are woven together and enclosed inside a pad. 2 February 2000 Downloaded from http://neoreviews. NeoReviews Vol. gentler approach” to the treatment of newborn hyperbilirubinemia have thrust concerns about bilirubin-related toxicity once again to the forefront of neonatologists’ consciousness. Faculty of Medicine of the Hebrew University. more relaxed.org/ at Indonesia:AAP Sponsored on May 4. fiberoptic phototherapy either must be combined with conventional phototherapy or with a second fiberoptic mat that encircles the infant’s other side. Describe potential toxicities of phototherapy. readers should be able to: 1. which has become the standard of care. Introduction Recent clinical trends toward early discharge coupled with a new.aappublications. Explain the role of carboxyhemoglobin in hemolysis. graft versus host disease. Accordingly. Israel. Shaare Zedek Medical Center. In recent years we even have witnessed a resurgence of kernicterus. physicians have been searching for artificial light sources that might be used safely to treat neonatal hyperbilirubinemia. necrotizing enterocolitis. “kinder. apnea. 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. Furthermore. Delineate the guidelines for administering intravenous immunoglobulin to healthy ABO-incompatible Coombs-positive neonates. Explain how phototherapy affects bilirubin. Tan found fiberoptic phototherapy to be significantly less effective than phototherapy with standard daylight bulbs in term healthy infants who had hyperbilirubinemia. 4. 2012 e19 . transient metabolic abnormalities. and thrombocytopenia. Although exchange transfusion is the oldest and most effective method of treating hyperbilirubinemia. which had been rendered almost nonexistent in the 1970s and 1980s. Newer options for phototherapy administration include tungstenhalogen lamps attached to fiberoptic cables. bradycardia. Phototherapy can be administered effectively either by fluorescent or nonfluorescent (halogen) lamps. 1 No. do make the babies appear blue and have been reported to cause discomfort among nursery personnel. 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. Shedding New Light on Photototherapy Ever since the 1950s. They concluded that the efficacy of fiberoptic phototherapy in preterm infants is comparable to that of conventional phototherapy. Under the effects of phototherapy light with maximal irradiance in the 425 to 475 nm wavelength band. sepsis. thromboembolic phenomena. currently available sources of phototherapy light are special blue lamps. it behooves us to re-evaluate other therapeutic modalities for hyperbilirubinemia that may be equally efficacious but less invasive.

1 No. Furthermore.org/ at Indonesia:AAP Sponsored on May 4. Some infants. CBFV returned to pretherapy values after discontinuation of phototherapy only in healthy. Although the clinical implications of these changes are not clear. as has been recommended traditionally. does not disturb swaddled infants as much as does conventional phototherapy. Feedings. In preliminary testing. clinical investigations should be pursued in antioxidant-depleted newborns.LIVER DISEASE Neonatal Hyperbilirubinemia thereby increasing the surface area exposed to light. but it is dangerous to be overly complacent in this regard. proteins. it is of concern that increased blood flow velocity in infants who already are at risk for intracranial hemorrhage may increase this susceptibility further. which does not require eye shielding. They found that phototherapy increased mean CBFV in all infants studied. and nucleic acids. while phototherapy. this study demonstrated no difference in phototherapy response rate between those fed solely formula and those fed a combination of formula and human milk. diene formation. 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. 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. and none was jaundiced within the first 24 hours of life. Although a positive Coombs test indicates erythrocyte sensitization. All of these infants had the same blood type as their mothers.aappublications. and allows for more effective motherinfant bonding. such as preterm and glucose-6-phosphatase dehydrogenase (G6PD)-deficient infants. and Fluids Breastfed infants are more likely to develop hyperbilirubinemia than are formula-fed infants. Thus. 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. lipids. Of note. Because infants are not ingesting any drug. which still are in the early testing phases. nonventilated infants. Furthermore. Gamma Globulin With the declining incidence of Rh hemolytic disease. but the concept that a well-hydrated infant’s serum can be diluted by overhydration to reduce total bilirubin level is not supported by any studies. nursing personnel and parents unanimously prefer the fiberoptic phototherapy. free cholesterol oxidation. and increased hemolysis in preterm infants. these units appear to be extremely effective in enhancing bilirubin degradation both in vitro and in vivo in jaundiced rats. it is not a good predictor of overt hemolytic disease. as currently administered. sicker infants. Previous attempts at developing predictive indices. because of their flexibility. and under the higher intensities that will be available in the next generation of light sources. Hyperbilirubinemia in both Rhand ABO-sensitized infants results from destruction of neonatal red blood cells that have been coated by NeoReviews Vol. We have noted an increasing trend to suggest hydration as an initial step in the treatment of neonatal hyperbilirubinemia. 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. may be mildly dehydrated. ABO incompatibility has become the single most common cause of neonatal hyperbilirubinemia requiring therapy. Newest on the phototherapy horizon are the gallium nitride light emitting diode units. The clinical course of any individual infant affected with ABO isoimmune disease remains difficult to anticipate. does not appear to cause photo-oxidative damage in vivo in healthy term infants. breastfeeding jaundice must be taken seriously. and their bilirubin levels continue to rise despite phototherapy. 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. It is also unclear whether the magnitude of CBFV changes is related to phototherapy irradiance. 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. but in 1995 Maisels and Newman documented the occurrence of classic kernicterus in six otherwise healthy breastfed infants. These are reported to be power-efficient. In the past it had been widely accepted that hyperbilirubinemia was benign in this population and that kernicterus did not occur in breastfeeding infants. necessitating additional intervention and sometimes even requiring exchange transfusion. Thus. Tan recently published interesting data demonstrating that term. have been of limited clinical usefulness at best. It did not return to baseline in ventilated. none was anemic. Additional areas of potential toxicity include possible photo-oxidative damage and toxic photodynamic reactions that have been observed in vitro with vitamins. There is no evidence that excess fluid administration affects serum bilirubin concentration. 2012 . but the clinical significance of this hyperbilirubinemia has been a source of controversy. otherwise healthy breastfed infants who had nonhemolytic hyperbilirubinemia responded more quickly to phototherapy if formula was added to their ingestion of human milk. it has become natural to consider light therapy to be innocuous. accounting for about 20% of clinically significant jaundice in the newborn. Formula. fiberoptic units are much more amenable to home phototherapy. especially some breastfed infants. including sociodemographic correlations and efforts to provide semiquantitative antibody levels. Benders et al recently reported on the effects of phototherapy on cerebral blood flow velocity (CBFV) in preterm infants (Ͻ32 wk gestational age). and these infants require supplemental fluid to correct the dehydration. a subgroup of ABO-incompatible infants do present with severe hemolysis. 2 February 2000 Downloaded from http://neoreviews.

290Ϯ459 NA 171Ϯ68** *** . forming carboxyhemoglobin (COHb). 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 39Ϯ2 3. it is not always successful. hemolysis can be quantitated by determining blood COHb levels. 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). and corrected COHb. Three groups of ABO-incompatible infants were defined for this investigation: IVIG nonresponders. Because endogenous CO production in the newborn occurs almost exclusively by this pathway. Uetani et al showed that hyperbilirubinemic. On the other hand. Elucidation of such parameters could serve as a basis for clinical guidelines for future use of IVIG in ABO isoimmunization. hemoglobin releases globin and heme. A given infant’s position along this continuum of severity can be defined by a combination of age at presentation with clinically significant jaundice.384Ϯ488 44Ϯ17 291Ϯ34 0 40Ϯ1 3. probably mediated by Fc receptor-bearing cells within the reticuloendothelial system. 2012 e21 . elevated COHbc values throughout the first 120 hours of life.org/ at Indonesia:AAP Sponsored on May 4. Using a standardized IVIG protocol. Hammerman et al. Hammerman et al demonstrated prospectively that COHb. there was no defined protocol for IVIG administration and no attempt to correlate COHb response with clinical efficacy. corrected for inhaled CO. 1 No. ABO-incompatible. However. Coombs-positive infants maintained stable.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 NeoReviews Vol. Within the reticuloendothelial system. extent of early jaundice.aappublications. At one extreme lay the infants who have the least clinical symptomatology and mildest hemolysis. in a second study. Endogenous production of carbon monoxide (CO) has been used to reflect bilirubin production.001 0. there is a clearly identifiable subgroup of ABO-incompatible infants whose bilirubin levels continue to rise despite phototherapy TABLE 1. IVIG responders. serum total hemoglobin (tHb). but it did not reduce hemolysis in the nonresponding Coombs-positive infants. 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. as defined by the previously noted factors.LIVER DISEASE Neonatal Hyperbilirubinemia transplacentally acquired maternal isoantibody that causes extravascular erythrocyte destruction. and those not meeting criteria for IVIG administration.059Ϯ463 12Ϯ10* 239Ϯ51 6* 39Ϯ5 3. This group of infants did not have severe enough hemolysis to meet even the initial IVIG administration criteria (Table 1). 2 February 2000 Downloaded from http://neoreviews. which in turn undergo further degradation to release equimolar amounts of bilirubin and CO. rate of bilirubin rise during the first day of life. This group of infants can be targeted safely for early discharge. Although IVIG clearly reduces hyperbilirubinemia in most cases of neonatal isoimmunization.001 0. Furthermore. Further. NS NS 0. thereby inhibiting hemolysis and reducing formation of bilirubin. it has been postulated that IVIG may accelerate the rate of immunoglobulin G (IgG) catabolism. These findings support the proposal that IVIG effect is mediated via decreased hemolysis. decreased proportionately with the decrease in bilirubin in infants who responded to IVIG. thereby reducing circulating pathogenic autoantibodies. Recent studies have demonstrated that intravenous immunoglobulin (IVIG) therapy is effective in modifying the hyperbilirubinemia in most cases of Coombs-positive hemolytic anemia. IVIG reduced hemolysis only in those infants who responded clinically to the therapy. in keeping with Uetani’s data. It has been proposed that IVIG blocks Fc receptors. Thus. 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%. 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. Although jaundice due to ABO incompatibility usually can be controlled by the use of phototherapy alone. These three groups appear to represent a spectrum of hemolysis ranging from severe to moderate to mild. The CO released then binds strongly to hemoglobin. infants who did not respond to IVIG maintained stable COHb levels throughout the study.

These compounds act by competitively inhibiting the activity of the enzyme heme oxygenase. Although ABO disease is generally less problematic than Rh disease. Tin. NeoReviews Vol. Based on our preliminary data. Tin porphyrins are more potent than zinc or cobalt porphyrins. IVIG treatment of neonatal jaundice associated with both ABO and Rh hemolytic disease is effective. A single small dose of SnMP administered preventively shortly after birth can moderate the severity of subsequent hyperbilirubinemia significantly. Clinical trials have demonstrated that Sn-mesoporphyrin (SnMP) suppresses bilirubin production. zinc. In two recent studies of otherwise healthy infants.5 g IVIG should be infused over 2 hours. possibly because the hemolysis already was so severe that it could not be reversed. although that probably would have required several extra days of hospitalization. They demonstrated a reduced need for phototherapy. With side chains comprised of ethyl groups. is presented in Table 2. with the only side effect observed being a transient. a subset of the population does develop more severe symptomatology. 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. severe hemolysis in whom IVIG was less effective in preventing either further bilirubin rise or exchange transfusion.06 mmol/L (13 g/dL) are at high risk for not responding to the current regimen of IVIG administration. Although we cannot predict the subsequent course of this group had they not been treated with IVIG. 2012 . heme oxygenase actually favors some of these metalloporphyrins over heme as a substrate.org/ at Indonesia:AAP Sponsored on May 4. therapeutic administration of SnMP TABLE. 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. Guidelines for Total Serum Bilirubin (TSB) for IVIG Administration in Term Healthy ABO-incompatible Coombs-positive Neonates First 12 hours of age TSB Ն204 mcmol/L (Ն12 mg/dL) despite trial of phototherapy (4 hr minimum) TSB Ն272 mcmol/L (Ն16 mg/dL) despite trial of phototherapy (4 hr minimum) TSB Ն306 mcmol/L (Ն18 mg/dL) despite trial of phototherapy (4 hr minimum) tHb Ͻ8. 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. Rh hemolytic disease. therefore. The dose can be repeated at 12-hour intervals until bilirubin stabilizes. IVIG use seems to be less routine in North America. rather treating all infants with 1 g/kg IVIG. appear most likely to benefit from IVIG administration. At the other extreme lay infants presenting with early.aappublications. Nevertheless. It is possible that these infants will respond to a higher IVIG dose. nondose-dependent erythema that disappears without sequelae. and a tHb of less than 8. The potency of metalloporphyrins and their side effects are influenced by the central metal cation and the nature of the side chains. and shorter hospitalizations in the treated infants. 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.06 mmol/L (Ͻ13 mg/dL) 12 to 24 hours of age 24 to 72 hours of age Additional Criteria: When an infant meets above criteria. Alpay et al employed a higher dose of IVIG to treat 116 infants who had either ABO hemolytic disease. they did not attempt to identify those who had more severe hemolysis.0 mg/ dL) per hour with a minimum of 4 hours between measurements. tHb ‫ ؍‬total hemoglobin. 1 No. or both with no e22 adverse effects. or cobalt protoporphyrin can be effective. mesoporphyrins are far more potent and stable than other forms. 2 February 2000 Downloaded from http://neoreviews. This group of infants. despite having received phototherapy. a dose of 0. The hemolysis is severe enough to meet IVIG administration criteria. metalloporporphyrins can help to prevent bilirubin accumulation. In fact.LIVER DISEASE Neonatal Hyperbilirubinemia and who sometimes even require exchange transfusion. the rate-limiting enzyme in heme catabolism. the catalytic binding site of the heme oxygenase recognizes metalloporphyrins that have metallic ions other than iron. they clearly displayed a pattern of increasing hyperbilirubinemia that was not responding to phototherapy at the time of intervention. In summary. and is not associated with any known toxicity. We suspect that most eventually would have stabilized. In cases of hyperbilirubinemia due to increased production. fewer exchange transfusions. who have a moderate degree of hemolysis and present after the first 24 hours of life with tHb greater than 8. an increase in bilirubin of greater than 17 mcmol/L (1. we would predict that infants who have clinically significant jaundice within first 24 hours of life. This group. which can be modified by individual institutions. and identifying this subset and defining precise clinical guidelines for which infants are most likely to benefit from such treatment is critical. but not so severe as to preclude benefit from the drug. is no longer experimental. and this approach deserves further study. Possibly others may have proceeded to meet the criteria for exchange transfusion.06 mmol/L (13 mg/ dL). Although it is used routinely in Europe and the Middle East. A sample protocol summarizing our current approach to IVIG administration. 2.

Cremer RJ. significantly reduced hyperbilirubinemia in 16 hours. however. McDonagh AF. Erdem G.85: 1351–1353 Jackson JC. 2012 . In one study. these data cannot be extrapolated directly to the human neonatal in vivo condition and require further study. Rodgers PA. RiceEvans CA. Mireles et al have attempted to resolve this apparent discrepancy in vitro. 1998.2:641– 644 Chan ML.65:740 –750 Dennery PA. 1995. it was suggested that bilirubin might possess certain physiologically protective antioxidant functions. What is the best predictor of the severity of ABO-haemolytic disease of the newborn? Lancet. Arad I.87:786 –791 Brouwers HA. Milner AD. Sarici SU. Pediatr Res.50:833. Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. and tolerance to the treatment is reported to be excellent. Pharmacologic treatment of neonatal jaundice: a new approach. If this proves true. 1976. However. SUGGESTED READING Alpay F. decisions about when and how to intervene therapeutically become even more delicate and complex. Overbeeke MA. and decreased phototherapy requirements. 1998. However. Miller NJ. Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. van Ertbruggen I. bilirubin levels are physiologically elevated. Today. ABO hemolytic disease of the newborn without hyperbilirubinemia. 1999. 1996.88:216 –219 Aouthmany M. Gokcay E. Adverse events associated with exchange transfusion in healthy and ill newborns. nous immunoglobulin therapy in neonatal immune haemolytic jaundice. For example. High dose intrave- Clofibrate Increasing the ability of the body to excrete bilirubin via stimulation of the liver’s conjugation ability long has been recognized as an effective approach to controlling hyperbilirubinemia. 1988. 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. The effect of phototherapy on cerebral blood flow velocity in preterm infants. naturally elevated levels of a related substance. its efficacy requires several days of treatment. Stevenson DK.70:69 –74 Hammerman C. Although these concerns have not been substantiated in human studies. Manola T. Yet. Sn-protoporphyrin use in the management of hyperbilirue23 Protective Properties of Bilirubin There are some fascinating potential beneficial properties of the compound bilirubin. but it appears to hold great potential for the future. Scheye E. J Perinatol. Wong RJ. when oxidative stresses are common and severe and levels of most other antioxidant enzymes are naturally depressed. In their system. During early neonatal life. bilirubin toxicity is real and potentially dangerous. Intravenous immune globulin in neonatal isoimmunization: does it reduce hemolysis? Acta Paediatr.836 Ergaz Z Arad I. 1996. Stevenson DK. Spitz DR.org/cgi/content/full/ 99/5/e7 Kaplan E. Biol Neonate. Ozcan O.45:189A Cohen AN. New concepts in phototherapy: photoisomerization of bilirubin IX alpha and potential toxic effects of light. Pediatrics.aappublications. animal studies. 1975. Herz F. Kaplan M. a direct and significant correlation between serum bilirubin concentration and total antioxidant potential has been observed. Vox Sang. Free Radic Biol Med. More severe photosensitization and risks ensuing from the effects of photodegradation of the metalloporphyrins could become substantial. 1 No. 1997. Am J Hematol. FEBS Lett. 1999. Vreman HJ.11:1274 –1278 Gopinathan V. Kaplan M.349:197–200 Hammerman C. Arch Dis Child.44: 2551–2553 Hammerman C. Valaes T. which limits its clinical feasibility in most cases of neonatal hyperbilirubinemia. Stevenson DK. Young BW. Ostrow JD. rather than merely being a toxic waste. 1994.org/ at Indonesia:AAP Sponsored on May 4. van de Bor M. Pediatrics. actually may be a component of the natural defense system. Looking back: phototherapy.99:e7– e13. Bilirubin in the premature: toxic waste or natural defense? Clin Chem. Kaplan M. 1998. clinicians have remained reluctant to adopt this therapy.1: 279 –282 Kappas A. Arch Pediatr. Bilirubin and ascorbate antioxidant activity in neonatal plasma. However. Dennery et al exposed Gunn rats to hyperoxia and demonstrated that jaundiced rats were more resistant to oxidative damage than were nonjaundiced rats. if phototherapy must be used in conjunction with metalloporphyrins—a situation that is likely to be unpredictable. Stevenson DK.pediatrics. 1999. 1995. A single oral dose of 50 mg/kg seems to be suitable. van Bel F. Drummond GS. bilirubin at physiologic concentrations protected neonatal red blood cells against oxidative stress. toxicity concerns have been raised based on NeoReviews Vol. it caused a 100% increase of hepatic bilirubin clearance within 6 hours. Gross D. Goldstein R. As a result. 19:271–274 Benders MJ. Phenobarbital was the first such agent demonstrated as effective. Vreman HJ. which has been confirmed subsequently both in vitro and in vivo. clofibrate currently is being used therapeutically only in France. http://www. 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.19: 395– 404 Dobbs RH. This raises the question: Is there possibly some teleologic reason that bilirubin is naturally elevated in newborns? It is enticing to speculate that bilirubin. Some 35 years ago. copper porphyrins. 2 February 2000 Downloaded from http://neoreviews. Acta Paediatr. 1993. Phototherapy increases hemoglobin degradation and bilirubin production in preterm infants. Intravenous immune globulin in neonatal isoimmunization: factors associated with clinical efficacy. decreased the intensity and duration of jaundice. J Perinat Med. therapy with metalloporphyrins remains experimental. et al.21:183–187 Ergaz Z. Petmezaki S. Concern does arise. but cytotoxic effects prevailed at pathologic concentrations. Clofibrate is a better enhancer of glucuronosyl transferase induction than phenobarbital. Bar-Oz B. Acta Paediatr. In human infants. Okutan V. Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin. In vivo efficacy of light emitting diodes (LEDs) as a light source for phototherapy in neonatal jaundiced rats. Control infants required significantly more phototherapy treatment. 1980. Peleg O. Vreman HJ.LIVER DISEASE Neonatal Hyperbilirubinemia (administered when serum bilirubin levels approached Ͼ255 mcmol/L [15 mg/dL]) as opposed to prophylactic administration at birth entirely supplanted the need for supplemental phototherapy.69:95–99 Gabilan JC.

1998. Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. C. Stevenson DK. Pediatr Res 1983. Hyperbilirubinemia is a serious problem among infants who have Rh and ABO sensitivity. e24 NeoReviews Vol. Iwao H. Ekstrand BC. Carboxyhemoglobin measurements in the diagnosis of ABO hemolytic disease. Mahoney JJ.06 mmol/L (13 g/dL). Ames BN. Yamazaki T. Patel A. Drummond GS. Comparison of the efficacy of fiberoptic and conventional phototherapy for neonatal hyperbilirubinemia. Stevenson DK. Jori G. Wong RJ. Pediatrics. Glazer AN. Lennon VA. B. Affected infants who may benefit the most from the administration of intravenous immunoglobulin are those who: A. et al. No studies of their use have yet been performed on human infants. Pediatrics.101: e1– e7.235:1043–1046 Tan KL.neoreviews. Acta Paediatr Jpn.152: 1187–1190 Tan KL.LIVER DISEASE Neonatal Hyperbilirubinemia binemia in term newborns with direct Coombs positive ABO incompatibility. A special fiberoptic pad used in conjunction with conventional phototherapies is the most efficacious. 1994. J Pediatr. High dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. Bilirubin is an antioxidant of possible physiological importance.aappublications. D. Stevenson DK. 1991. Science. leading-edge treatment. and their use still is considered experimental.42:303–334 Vreman HJ. E. 1993. Sutherland JM. Pediatrics. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. et al. There are no potential problems with using protoporphyrin therapy in conjunction with phototherapy. 1994.80:163–166 Stocker R. Light emitting diodes: a novel light source for phototherapy. B. van Beek RH. Lum MA. Halogen lamps do not provide adequate spectral power for effective phototherapy. 1987. E.pediatrics. Otheguy LE. Special blue lamps are not efficient in lowering bilirubin levels. Garcia HO. Stevenson DK. 1990. Gagliardi J. Kappas A. Sn-mesoporphyrin. A comparison of fluorescent and nonfluorescent light sources for phototherapy. Pediatrics. D.340:227–228 NEOREVIEWS QUIZ Quiz also available online at www. Hara T.65:795–798 Widness JA.org/cgi/content/full/101/5/e1 van Kaam AH. Kappas A.121:93–97 Sato K. Honda S. 1998. Newman TB. A true statement about such therapy is that: A. Pediatrics.103: 1–5 McDonagh A.157:132–137 Vreman HJ. Your institution is experimenting with newer methods of delivering phototherapy to newborns who have hyperbilirubinemia.33: 195–200 Vreman HJ. Carbon monoxide and carboxyhemoglobin.75(suppl 2):417– 421 Maisels MJ.org/ at Indonesia:AAP Sponsored on May 4. et al. Pediatrics. Vergunst-van Keulen JG. 1998. Kondo T. Gallium nitride lamps produce substantial heat and are preferred for treatment of preterm infants. 1999. Direct relationship of fetal carboxyhemoglobin with hemolysis in alloimmunized pregnancies. Fiberoptic versus conventional phototherapy for hyperbilirubinaemia in preterm infants. 3.org. Efficacy of bidirectional fiberoptic phototherapy for neonatal hyperbilirubinemia. 1992. Vreman HJ.45:210A Maisels MJ. C. 1999.96:730 –733 Martinez JC. 1998.81:485– 497 Keenan WJ. Eur J Pediatr. Albrecht K. Fetterly KL.06 mmol/L (Յ13 g/dL). Present after 24 hours of life with a total hemoglobin level Ͼ8. Ueda K. 2012 . A special fiberoptic pad used alone is considered first-line therapy. Control of hyperbilirubinemia in glucose-6-phosphate dehydrogenase deficient newborns using an inhibitor of bilirubin production. Acta Paediatr Scand. They are competitive inhibitors of heme oxygenase. Antioxidant and cytotoxic effects of bilirubin on neonatal erythrocytes. Present after 24 hours of life with a total hemoglobin Յ8. Okamoto O. Is exchange transfusion for hyperbilirubinemia in danger of becoming extinct? Pediatr Res. Pediatr Res. 1989. Yamamoto Y. Mcdonagh AF. 1980. Novak KK. Dennery PA.35: 713–719 Yu Z. They are competitive inhibitors of glucuronosyl transferase. Stevenson DK. 1995. http://www. Exhibit clinically significant jaundice within the first 24 hours of life.17:327–330 Rubo J. Kernicterus in otherwise healthy breast-fed term newborns. Mechanism of intravenous immune globulin therapy in antibody mediated autoimmune diseases. Pediatr Res. Drummond GS. Bryla DA. N Engl J Med. Nakamura H. J Pediatr. 45:355–362 Rubaltelli FF. C. 1. B. Lasch P. D. Morbidity and mortality associated with exchange transfusion. They work by improving elimination of bilirubin that already has been formed. Bronze baby syndrome: a new porphyrin related disorder. 1 No. 1985.31:171–176 Valaes T.44: 809 – 809 Warshaw JB. Reddi E. Is bilirubin good for you? Clin Perinatol. 1997. Exhibit an increase in bilirubin of Ն17 mcmol/L (Ն1 mg/dL) per hour during the first day of life. Pediatrics. 1999. 2 February 2000 Downloaded from http://neoreviews. Which statement about protoporphyrins is most accurate? A. E. High dose intravenous gamma globulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Exhibit minimal jaundice within the first 24 hours of life. Lowe LS. Pediatr Res. et al. 1988. Pediatr Res. 1999. 1995. Arch Pediatr Adolesc Med. 2.17:359 –369 Mireles LC. Adv Pediatr.99:e13 Uetani Y. Decreased response to phototherapy for neonatal jaundice in breast fed infants.125:607– 612 Tan KL.

org/ at Indonesia:AAP Sponsored on May 4. tables) or in its entirety can be found online at: /site/misc/Permissions.1.aappublications.xhtml Information about ordering reprints can be found online: /site/misc/reprints.aappublications.1542/neo. 2012 .e19 DOI: 10.org/content/1/2/e19 This article cites 38 articles.aappublications. can be found at: http://neoreviews. 11 of which you can access for free at: http://neoreviews.org/content/1/2/e19#BIBL Information about reproducing this article in parts (figures.Recent Developments in the Management of Neonatal Hyperbilirubinemia Cathy Hammerman and Michael Kaplan Neoreviews 2000.1-2-e19 Updated Information & Services References including high resolution figures.xhtml Permissions & Licensing Reprints Downloaded from http://neoreviews.

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