Correspondence

Phototherapy for Neonatal Jaundice

N Engl J Med 2008; 358:2522-2525June 5, 2008

Article

To the Editor:

In their Clinical Therapeutics article on phototherapy for neonatal jaundice, Maisels and McDonagh (Feb. 28 issue)1 describe various mechanisms for maximizing the efficacy of phototherapy. They state, “The dose and efficacy of phototherapy are also affected by the infant's distance from the light (the nearer the light source, the greater the irradiance).” However, this statement must be applied with great care. Indeed, guidelines from the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia specifically urge caution when halogen lamps, which can generate significant amounts of heat, are used.2 Placing these lamps as close as possible increases the risk of burns. Thus, physicians should be aware of this untoward side effect when positioning a halogen light to obtain maximum irradiance of a newborn with jaundice.

Roger Kapoor, M.D., M.B.A.
Stanford University, Palo Alto, CA 94305
rkapoor1@stanford.edu

2 References

1. 1

   Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920-928
   Full Text | Web of Science | Medline

2. 2

   American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316[Erratum, Pediatrics 2004;114:1138.]
   CrossRef | Web of Science | Medline

To the Editor:

In their review of phototherapy for neonatal jaundice, Maisels and McDonagh cite our work, suggesting that this form of therapy may influence the development of dysplastic nevi.1,2 We have now investigated the prevalence of melanocytic nevi among 11 monozygotic twin pairs in which one twin received phototherapy for neonatal jaundice and the other did not. Neonatal blue-light phototherapy was associated with a considerably higher number of common and clinically atypical nevi (Table 1Table 1Prevalence of Common and Clinically Atypical Melanocytic Nevi in 11 Monozygotic Twin Pairs in Which One Twin Received Neonatal Blue-Light Phototherapy (BLP) and the Other Twin Did Not.). The increased number of nevi on persons receiving phototherapy might well be due to the effects of light on neonatal skin. Ultraviolet A light has profound immunosuppressive effects and is sufficient to induce melanoma and melanoma precursors in animal models.3 Moreover, visible light has also been shown to exert indirect DNA damage through the generation of reactive oxygen species.4 In view of the immaturity of the skin and immune system in newborns, intensive neonatal phototherapy could markedly influence melanocytes and nevus development.

Zsanett Csoma, M.D., Ph.D.
Lajos Kemeny, M.D., Ph.D.
Judit Olah, M.D., Ph.D.
University of Szeged, 6720 Szeged, Hungary
csomazs@mail.derma.szote.u-szeged.hu

4 References

1. 1

   Csoma Z, Hencz P, Orvos H, et al. Neonatal blue-light phototherapy could increase the risk of dysplastic nevus development. Pediatrics 2007;119:1036-1037
   CrossRef | Web of Science | Medline

2. 2

   Csoma Z, Hencz P, Orvos H, et al. Neonatal blue-light phototherapy could increase the risk of dysplastic nevus development. Pediatrics 2007;119:1269-1269
   CrossRef | Web of Science | Medline

3. 3

   Wang SQ, Setlow R, Berwick M, et al. Ultraviolet A and melanoma: a review. J Am Acad Dermatol 2001;44:837-846
   CrossRef | Web of Science | Medline

4. 4

   Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of visible light on the skin. Photochem Photobiol 2008;84:450-462
   CrossRef | Web of Science | Medline

To the Editor:

The article by Maisels and McDonagh succinctly summarizes the mechanisms and application of phototherapy for jaundiced newborns. The authors promote the guidelines for using phototherapy that were published in 2004 by the American Academy of Pediatrics,1 which are based primarily on total serum bilirubin levels. They admit that these guidelines are not evidence-based, but rely primarily on expert opinion, and that “many infants are treated [2 to 3% of term or near-term infants and 150,000 to 250,000 premature infants each year] whose levels of total serum bilirubin would not have reached the threshold for exchange transfusion had phototherapy been withheld.”

The authors fail, however, to mention that theoretical considerations,2 substantial experimental data,3,4 and increasing evidence in human newborns5 all indicate that total serum bilirubin is a poor predictor of bilirubin-induced neurologic damage, whereas unbound (“free”) bilirubin levels correlate well with neurotoxicity. Establishing evidence-based guidelines for phototherapy (and exchange transfusion), with the use of unbound (free) bilirubin measurements, could significantly improve selection and reduce the number of infants requiring these treatments, as well as decrease hospital readmissions and the associated health care costs.

J. Donald Ostrow, M.D.
Richard P. Wennberg, M.D., Ph.D.
University of Washington School of Medicine, Seattle, WA 98195-6424
jdostrow@medicine.washington.edu

Claudio Tiribelli, M.D., Ph.D.
University of Trieste, 34012 Trieste, Italy

5 References

1. 1

   American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316[Erratum, Pediatrics 2004;114:1138.]
   CrossRef | Web of Science | Medline

2. 2

   Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med 2004;10:65-70
   CrossRef | Web of Science | Medline

3. 3

   Calligaris SD, Bellarosa C, Giraudi P, Wennberg RP, Ostrow JD, Tiribelli C. Cytotoxicity is predicted by unbound and not total bilirubin concentration. Pediatr Res 2007;62:576-580
   CrossRef | Web of Science | Medline

4. 4

   Ahlfors CE, Shapiro SM. Auditory brainstem response and unbound bilirubin in jaundiced (jj) Gunn rat pups. Biol Neonate 2001;80:158-162
   CrossRef | Medline

5. 5

   Wennberg RP, Ahlfors CE, Bhutani VK, Johnson LH, Shapiro SM. Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 2006;117:474-485[Erratum, Pediatrics 2006;117:1467.]
   CrossRef | Web of Science | Medline

Author/Editor Response

Kapoor draws attention to an important issue. Halogen and tungsten lights should not be placed closer to the baby than recommended by the manufacturer because of the danger of a burn. We noted this in our article (Figure 3 legend), and it is also a recommendation of the American Academy of Pediatrics guidelines.1

As noted by Csoma et al., the development of dysplastic nevi is a concern requiring further investigation. It is difficult to evaluate their findings because of a lack of information about the spectral emission of the phototherapy lights, particularly their ultraviolet output; the distribution of the nevi; and the patients' skin types. Properly shielded fluorescent lamps emit little radiation (<400 nm),2 and blue light-emitting-diode (LED) lights none at all. Although the findings in twin pairs might appear to be persuasive, the untreated twin is not an adequate control for the effects of phototherapy light on the treated twin. Proper sibling controls would need to be treated identically to their twins but not exposed to blue light or, alternatively, exposed to the same fixtures containing lamps with only long-wavelength visible emission. In the absence of proper controls, the results reported could equally well be attributed, for example, to effects of electromagnetic-field radiation from the light-fixture ballasts as to effects of the phototherapy light. Reassuringly, to our knowledge, there are no reports of increased nevus formation in patients with the Crigler–Najjar syndrome who have received daily phototherapy since birth.

It is well known that the total bilirubin concentration alone is a poor predictor of kernicterus. Nevertheless, the risk of bilirubin encephalopathy increases with the bilirubin concentration at high bilirubin levels. Kernicterus in term and late-preterm infants is almost always associated with bilirubin concentrations higher than 25 mg per deciliter (428 μmol per liter) and rarely occurs at lower concentrations. Therefore, the total bilirubin concentration, which is readily measured, is not to be ignored. The idea that unbound (“free”) bilirubin levels are useful in improving the selection of infants requiring treatment is a long-standing hypothesis that requires validation. Currently, such measurements are not offered by clinical laboratories in the United States, and there is concern that bilirubin photoisomers may complicate their interpretation.3 Alternatives are the bilirubin:albumin molar ratio and the reserve bilirubin-binding capacity of albumin in serum,4,5 which are more easily measured and might also facilitate identification of infants at greatest risk. Currently, attempts are being made to refine the American Academy of Pediatrics guidelines and reduce unnecessary treatment.

M. Jeffrey Maisels, M.B., B.Ch.
William Beaumont Hospital, Royal Oak, MI 48073
jmaisels@beaumont.edu

Antony F. McDonagh, Ph.D.
University of California at San Francisco, San Francisco, CA 94143

5 References

1. 1

   American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316[Erratum, Pediatrics 2004;114:1138.]
   CrossRef | Web of Science | Medline

2. 2

   Gies HP, Roy CR. Bilirubin phototherapy and potential UVR hazards. Health Phys 1990;58:313-320
   CrossRef | Web of Science | Medline

3. 3

   McDonagh AF, Wong RJ, Vreman HJ. Photoisomers — obfuscating factors in clinical peroxidase measurements of unbound bilirubin. Pediatrics (in press).
   

4. 4

   Brown AK, Eisinger J, Blumberg WE, Flores J, Boyle G, Lamola AA. A rapid fluorometric method for determining bilirubin levels and binding in the blood of neonates: comparisons with a diazo method and with 2-(4'-hydroxybenzene) azobenzoic acid dye binding. Pediatrics 1980;65:767-776
   Web of Science | Medline

5. 5

   Ash KO, Hentschel WM, Chan GM, Wu JT. Reserve bilirubin binding capacity assessed by difference spectroscopy: assay statistics and results on newborn sera. Clin Chim Acta 1980;104:309-318
   CrossRef | Web of Science | Medline