Published online October 1, 2004
PEDIATRICS Vol. 114 No. 4 October 2004, pp. 1086-1088 (doi:10.1542/peds.2004-1753)

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COMMENTARY

Management of Hyperbilirubinemia: Quality of Evidence and Cost

Neil A. Holtzman, MD, MPH

Department of Pediatrics and Institute of Genetic Medicine
Johns Hopkins University School of Medicine
Baltimore, MD 21205

Abbreviations: AAP, American Academy of Pediatrics

Kernicterus is associated with early hospital discharge, reduced concern about jaundice in otherwise healthy newborns, and breastfeeding.^1–3 To compensate for early discharge, the American Academy of Pediatrics (AAP) recommends that newborns be seen by a qualified health professional by 5 days of age (see "Recommendation 6.1.2" in ref 4). Providing this rapid follow-up to the estimated 70% of all infants now discharged before 48 hours of age would probably cost more than $10 million to prevent 1 case of kernicterus, as Suresh et al⁵ describe in this issue of Pediatrics. Here I address 2 questions: (1) Is the evidence sufficient to justify the recommendation? (2) Is the cost too high?

Of the 30 recommendations on the management of hyperbilirubinemia for which the AAP guidelines indicated "evidence quality," none were in the highest category ("well-designed, randomized, controlled trials or diagnostic studies on relevant populations"^4(p308)), 10 were in the lowest category ("expert opinion, case reports, reasoning from first principles"^4(p308)), and 15 were in the next to the lowest of the 4 possible categories (see "Appendix 1" in ref 4 for further definition of evidence categories). We still don’t know the incidence of kernicterus, whether it is rising, or how neonatal hyperbilirubinemia can best be managed in healthy infants who face early discharge. In addition to rapid follow-up of all infants, options include predischarge serum or transcutaneous bilirubin on all infants (see AAP "Recommendation 5.1.1" in ref 4), either postponing discharge for those whose bilirubin exceeds a threshold value or requiring that they receive a home visit (see below) within 2 days that would include a repeat bilirubin, and additional visits or readmission as necessary. A randomized, controlled trial comparing these or other options for the likelihood of reducing peak bilirubin, or some other short-term proxy outcome for kernicterus, is badly needed.

The recommendations were also based on a literature review requested by the AAP. The review concluded that "there is no strong evidence to suggest neurologic abnormalities in children with neonatal bilirubin levels higher than 20 mg/dL when followed up to 7 years of age."⁶ That is not to say that the association between hyperbilirubinemia and kernicterus does not exist. Rather, it indicates that the vast majority of infants with hyperbilirubinemia do not develop neurologic abnormalities. In an accompanying commentary, Ip et al⁷ noted that 2000 newborns with a total serum bilirubin 20 mg/dL (a higher concentration than the cutoff in the AAP recommendations) would have to be treated to prevent 1 case of kernicterus if its incidence is 1 in 100 000. Ip et al concluded that "hyperbilirubinemia, in most cases, is a necessary but not sufficient condition to explain kernicterus."^7(p263) A randomized, controlled trial similar to the one mentioned above could also be used to examine factors that contribute to high peak values and early signs of acute bilirubin encephalopathy (see "Appendix 1" in ref 4).

Questions also arise about the efficacy of phototherapy. In a Kernicterus Registry study,⁸ 74 of 81 infants who developed kernicterus received phototherapy. At least 7 of the 14 infants seen by age 4 or 5 days after early discharge, in accord with the AAP’s recommendation, would have received phototherapy. Reports of other cases of kernicterus vary in the effects of phototherapy on behavioral and neurologic outcomes.⁶

The cost to prevent 1 case of kernicterus by a rapid follow-up of all healthy newborns is >1000 times higher than the cost per quality-adjusted life-year gained by introducing tandem mass spectrometry into routine newborn screening, and the false-positive/true-positive ratio of predicting kernicterus by bilirubin testing is 80 times higher.⁹ Nevertheless, the introduction of tandem mass spectrometry into newborn screening is still debated, partly on the basis of cost.¹⁰ Thus, implementing the recommendation for rapid follow-up of early-discharged infants seems exorbitantly expensive. However, there are 2 reasons why this might not be the case. First, the recommendation for follow-up within 48 hours of nursery discharge is multipurposed. Suresh et al⁵ concede that they did not include other benefits that might result from rapid follow-up in their analysis. For rapid follow-up, a home visit by a nurse has advantages over a visit to a pediatric office; maternal as well as infant health can be assessed. Moreover, noncompliance will be higher with an office visit.¹¹ At present, probably no more than one third of healthy infants are seen within 2 days of discharge. Low-income families, who are at greatest risk of postnatal problems, are overrepresented in the group without rapid follow-up.¹²

Second, some parents and health care providers will be unwilling to allow 1 case of kernicterus to occur if it could be prevented regardless of the cost or of forgoing alternative policies that could benefit a larger number of infants.¹³ If we could be confident that implementing the AAP’s recommendation of rapid follow-up for all early-discharged infants had the highest yield per dollar in preventing kernicterus, then investing in it might be justified. I lack that confidence.

	FOOTNOTES

 
Accepted Aug 11, 2004.

Address correspondence to Neil A. Holtzman, MD, MPH. E-mail: nholtzma{at}jhsph.edu

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