Preventing kernicterus: Almost there☆☆☆
Article Outline
Abbreviations: BIND , Bilirubin-induced neurologic dysfunction
See related article,p 396
The commentary by Johnson, Brown, and Bhutani in this issue of The Journal1 is an important contribution to our knowledge about neonatal hyperbilirubinemia and kernicterus, and it should lead to improvement in the care of newborns. Recognizing that the incidence of kernicterus in the United States was increasing after a long period when it appeared to be a rarity, they created a registry of cases in 1992 to study the root causes. This registry collected 90 cases in 8 years. In the process they identified lapses in care, but more importantly, they recognized problems with accepted recommendations that might have contributed to the increased incidence of kernicterus. They defined a new term, BIND (bilirubin-induced neurologic dysfunction), which is more clinically relevant and descriptive than “kernicterus.” Finally, they formulated thoughtful and practical recommendations for preventing BIND in the future.
What changes in the landscape of newborn care contributed to this resurgence in bilirubin-associated morbidity? First, hospital stays for newborn infants have become shorter. In the 1960s and 1970s, a 3- or 4-day stay was standard. Bilirubin concentrations would likely be higher before discharge. Thus, a larger number of caretakers would be involved and have a better chance to recognize jaundice and trigger the measurement of serum bilirubin and a plan of management. Today, hospital discharge at 24 hours is common, leading to fewer observations by professionals at a time when jaundice may just be at the threshold of visibility. Although it was widely believed that a bilirubin concentration >6 mg/dL should be visible to the trained eye, Tayaba et al2 found that when the serum bilirubin was between 6 mg/dL and 8 mg/dL, professional caretakers did not see jaundice in 20% to 40% of cases. Moyer et al3 found that medical/nursing estimates were similarly poor. The significance of early discharge is emphasized by the fact that only one of 61 infants in the Kernicterus Registry was born by cesarean delivery.
Another factor contributing to the increase in bilirubin-related problems is the (otherwise laudable) increase in the incidence of breast-feeding. Johnson et al1 reported that 59 of 61 registry infants readmitted for treatment of jaundice were breast-fed. In these cases, inadequate intake (most likely) and/or factors in breast milk that enhance the enterohepatic circulation of bilirubin or inhibit excretion of bilirubin might have resulted in higher concentrations.
Perhaps the most important factor, however, is the apparent change in thinking about neonatal jaundice in the pediatric community, influenced strongly by 2 publications. The first article was an entertaining and enlightening one-act play by Watchko and Oski4 entitled “Bilirubin 20 mg/dL = Vigintiphobia” that pointed out the lack of foundation for the notion that the bilirubin concentration should not exceed 20 mg/dL in healthy infants. They noted that the guideline came from a 1952 article by Hsia et al5 that examined the risks and benefits of exchange transfusion in infants with erythroblastosis fetalis. The implication was that many more infants were being exposed to the risks of exchange transfusion than were in danger of having kernicterus. In 1992, Newman and Maisels6 reported that neonatal serum bilirubin concentrations (from 0-29.2 mg/dL) did not correlate with long-term neurodevelopmental outcome. This conclusion was based on large population studies of otherwise healthy term newborn infants without hemolytic disease; they suggested that exchange transfusion be reserved for infants with serum bilirubin values >25 mg/dL.
It is not surprising that neurologic outcome correlates poorly with serum bilirubin concentrations. Bilirubin is a powerful cellular toxin, but infants have defenses against this toxicity. Their main defense is albumin, which protects by binding bilirubin tightly and keeping it out of cells.7 Only when available bilirubin-binding sites on albumin are saturated can bilirubin enter cells and cause toxicity and/or cell death.8 Therefore, there should be no linear relationship between the serum bilirubin concentration and brain damage. A threshold must be reached before any damage can ensue. Hsia et al5 reported kernicterus in 18% of infants with erythroblastosis and serum bilirubin concentrations between 16 mg/dL and 30 mg/dL and in only 50% of infants with a serum bilirubin concentration >30 mg/dL. This remarkable variation in host resistance accounts for the fact that almost any particular serum total bilirubin concentration is an inadequate predictor of brain damage.
Based primarily on the work of Newman and Maisels, the American Academy of Pediatrics published guidelines for the management of neonatal hyperbilirubinemia in “healthy term newborns” in 1994, recommending exchange transfusion for bilirubin concentrations >25 mg/dL to 30 mg/dL.9 This signaled an apparent shift in attitude about neonatal jaundice; physicians began to treat jaundiced infants less intensely, to measure bilirubin less often, and to rely exclusively on phototherapy for treatment, although phototherapy had never been shown to prevent brain damage. Infants with occult hemolysis, underfeeding, prematurity, or other problems that might not fit “healthy term infants” began to be treated with the same guidelines.
Based on their registry findings, Johnson et al1 now make recommendations that should all but eliminate the failures they found in our current system of newborn care. They recommend parental education about jaundice, universal predischarge bilirubin measurements plotted on their hour-specific nomogram, and individual follow-up plans based on the risk level that the hour-specific value defines. They also recommend that all infants be seen at 96 hours of age or earlier if the nomogram indicates higher risk. In addition, they recommend continuing education of the professionals who care for these infants. These recommendations should significantly improve case finding and care, and they will protect the great majority of infants from bilirubin toxicity in the future.
How can we improve on this? The current guidelines for treatment need to be reviewed. Johnson et al1 identified apparently healthy term infants with clinical evidence of bilirubin neurotoxicity, where peak documented bilirubin values were <25 mg/dL. On the other hand, we should not have to return to “vigintiphobia” and overtreatment. Infants who fall above the 75th percentile on the hour-specific bilirubin nomogram need to be investigated for factors that increase risk, such as hemolytic disease. Infants found to have additional risk factors must be treated more aggressively. Most important, we cannot rely on treatment guidelines based on the total bilirubin because that measure cannot tell us which babies are likely to have BIND. What we need is a practical measure of host defenses to help identify infants at high risk. The bilirubin:albumin concentration ratio provides a slight advantage over bilirubin alone in predicting risk, but the best information we have suggests that measuring unbound bilirubin or reserve albumin-binding capacity would be much more effective.
These techniques exist10, 11 and they have been validated to some extent.12, 13, 14 We need to use them in clinical practice and should no longer be satisfied with the total bilirubin as a guide to therapy. The total bilirubin has been shown beyond doubt not to estimate an individual infant's risk for devastating neurotoxicity.
In summary, Drs Johnson, Brown, and Bhutani have pointed the way toward a significant improvement in the care of newborn infants, which should almost eliminate the need for a kernicterus registry. If we can add to that the availability of a practical measure of host resistance, we could make BIND a rarity once again.
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☆ Reprint requests: Ronald L. Poland, Professor of Pediatrics, Children's Hospital of New Mexico ACC-3W, University of New Mexico School of Medicine, Albuquerque, NM 87131-5313.
☆☆ J Pediatr 2002;140:385-6.
PII: S0022-3476(02)27099-7
doi:10.1067/mpd.2002.124310
© 2002 Mosby, Inc. All rights reserved.
Refers to article:
- System-based approach to management of neonatal jaundice and prevention of kernicterus
