After completing this article, readers should be able to: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.Ever since the 1950s, when Sister Ward of Rochford General Hospital in Essex noted that a jaundiced baby’s 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 liver’s 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 tungsten-halogen 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 infant’s other side, 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 mother-infant 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 lipoprotein 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.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 infant’s serum can be diluted by overhydration to reduce total bilirubin level is not supported by any studies.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 Rh- and ABO-sensitized infants results from destruction of neonatal red blood cells that have been coated by 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 hyper-bilirubinemic, 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 Uetani’s 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 infant’s 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 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 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 . An alternative therapeutic approach to the control of neonatal hyperbilirubinemia 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 (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 metalloporphyrins—a 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.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. 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 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.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.
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