Purpose of Report

The American Academy of Pediatrics (AAP) asked the Agency for Healthcare Research and Quality (AHRQ) to commission a report which would critically examine the available evidence regarding the effect of high levels of bilirubin on behavioral and neurodevelopmental outcomes, the role of various effect modifiers (e.g., sepsis and hemolysis) on neurodevelopment, the efficacy of phototherapy, the reliability of various strategies in predicting hyperbilirubinemia, and the accuracy of transcutaneous measurement of bilirubin. The report will be used by AAP in updating the 1994 AAP guidelines for the management of neonatal hyperbilirubinemia. This review focuses on otherwise healthy term or near-term (at least 34 weeks gestational age or at least 2,500 grams birth weight) infants with hyperbilirubinemia.

Background

High levels of serum bilirubin in the neonatal period have long been associated with the development of kernicterus, a rare condition characterized by hypertonicity, poor feeding, and high-pitched cry. Kernicterus was a frequent complication of hyperbilirubinemia caused by Rh incompatibility, a condition that also led to severe hemolytic anemia, and, in some cases, fetal demise due to hydrops fetalis. Over the past decades, improved obstetric and neonatal care has reduced the incidence of high bilirubin levels and kernicterus. Hydrops fetalis and severe hemolytic anemia caused by maternal-fetal Rh incompatibility have been dramatically reduced by the use of RhoGam™. Post-natal phototherapy has further reduced the incidence of hyperbilirubinemia.

Because of these advances, concerns were raised that the standards of therapy for hyperbilirubinemia in otherwise healthy term newborns were too aggressive leading to over-treatment of many newborns unnecessarily. In 1994, the American Academy of Pediatrics published a set of clinical practice guidelines for the management of hyperbilirubinemia in the healthy term newborn (Practice Parameter: Management of hyperbilirubinemia in the healthy term newborn. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia, American Academy of Pediatrics, 1994). The Subcommittee Task Force, relying on retrospective epidemiologic data primarily derived from North America and Europe and a 1990 report by Newman and Maisels (1990), issued a set of recommendations. These recommendations were based on evidence when appropriate data existed, and, when data was lacking, were based on expert consensus. There were no specific data concerning the relationship between specific levels of bilirubin and adverse neurodevelopmental outcomes. The AAP recommendations advocated an approach to the jaundiced infant that was less aggressive than previously recommended.

The AAP recommendations were specifically directed at evaluation and treatment of hyperbilirubinemia in healthy term newborns, i.e., only infants without signs of illness or apparent hemolytic disease. Some of the highlights in the recommendations included visual inspection of the skin to determine jaundice, use of total serum bilirubin (TSB) level as the relevant variable in determining treatment, and use of exchange transfusion only if intensive phototherapy fails to lower the TSB to less than 20 mg/dl between 24 to 48 hours of life, and below 25 mg/dl after 48 hours.

Criticisms regarding these recommendations included the fact that visual inspection of jaundice is not reliable. Criteria based on number of days since birth (instead of number of hours) is too coarse of a time interval for precise interpretation of the bilirubin level (a 25-hour-old baby with a bilirubin of 15 mg/dl is at a different percentile of bilirubin than a 48-hour-old baby with the same level of bilirubin, even though both of them would be classified as 2-day-old infants and would have fallen into the same category in the treatment guidelines). The adverse effects of phototherapy treatment on healthy term newborns are unknown, thus making the assessment of risks and benefits of the treatment difficult. Some authors have argued that only in the framework of randomized controlled trials will it be possible to adequately assess the relationship between bilirubin levels and development of adverse neurological sequelae (Seidman and Stevenson, 1995). More recently, continued reporting of new cases of kernicterus have raised the concern that standards for the treatment of hyperbilirubinemia have not been followed (Johnson, Bhutani, and Brown, 2002).

Neonatal Hyperbilirubinemia

Bilirubin has an affinity for neuronal membrane phospholipids and can interfere with ion exchange and nerve conduction, and is therefore potentially neurotoxic. Unconjugated free bilirubin can enter the central nervous system, although conjugated or albumin-bound bilirubin does not. Autopsy studies of infants with kernicterus demonstrated bilirubin staining of the basal ganglia. Thus, there is a plausible association of high bilirubin levels with clinical kernicterus.

Burden of Disease

Neither hyperbilirubinemia nor kernicterus are reportable diseases, and there are no reliable sources of information providing national incidence estimates. Since the advent of effective prevention of Rh incompatibility and treatment of elevated bilirubin levels with phototherapy, both kernicterus and hyperbilirubinemia have become uncommon. When laboratory records of a 1995-1996 birth cohort of over 50,000 California infants was examined, Newman, Escobar, Gonzales, et al. (1999) reported that 2 percent had total serum bilirubin levels over 20 mg/dl; 0.15 percent had levels over 25 mg/dl, and only 0.01 percent had levels over 30 mg/dl. (These data were from infants with identified hyperbilirubinemia, and as such, it represents a minimum estimate of the true incidence of extreme hyperbilirubinemia.) This is undoubtedly the result of both successful prevention of hemolytic anemia, and of the application of effective treatment of elevated serum bilirubin levels in accordance with currently accepted medical practice. Projecting the California estimates to the national birthrate of four million per year (National Vital Statistics Reports, 2002), we can expect 80,000, 6,000, and 400 newborns with bilirubin levels of greater than 20 mg/dl, 25 mg/dl, and 30 mg/dl, respectively.

However, there is continued concern that the rise in early hospital discharges, coupled with a rise in breastfeeding rates, has led to a rise in the rate of preventable kernicterus resulting from “unattended to” hyperbilirubinemia (Sentinel Event Alert, 2001). A report published in 2002 (Johnson, Bhutani, and Brown, 2002), based on a national registry established since 1992, reported only 90 cases, although the efficiency of case ascertainment is not clear. Thus, there are no data to reliably establish incidence trends for either hyperbilirubinemia or kernicterus.

Despite these constraints, there has been substantial research on the neurodevelopmental outcomes of hyperbilirubinemia and its prediction and treatment. Subsequent sections of this review describe in more detail the precise study questions and the existing published work in this area.