Journal of Perinatology (2009) 29, S20–S24. doi:10.1038/jp.2008.212

Kernicterus in the 21st century: frequently asked questions

V K Bhutani1 and L Johnson2

  1. 1Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Stanford, CA, USA
  2. 2Pennsylvania Center for Kernicterus, Philadelphia, PA, USA

Correspondence: Dr VK Bhutani, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, 750 Welch Ave no. 315; Stanford, CA 94304, USA. E-mail:



Acute kernicterus remains a clinical emergency and its delayed management represents an easily preventable neonatal brain injury. Yet, practitioners encounter recurrent questions regarding the risk and timing of bilirubin-related neurotoxicity. These include the following: does bilirubin damage the brain of healthy infants? Is there a re-emergence of kernicterus in the United States? Was kernicterus previously prevented in the United States? What was the public health impact of 1994 American Academy of Pediatrics Guidelines? What is the current incidence of kernicterus and severe neonatal hyperbilirubinemia? What is the estimated risk of kernicterus in infants with excessive hyperbilirubinemia? Is there a specific bilirubin threshold total serum bilirubin (TSB) value for neurotoxicity? Are there sequelae of severe or prolonged moderate hyperbilirubinemia in the absence of recognized acute bilirubin encephalopathy? Can we define a bilirubin level that is safe in newborns? We address these questions in the context of available data and evidence, and estimate the current risk of chronic kernicterus is about one in seven in infants with TSB >30mg per 100ml (513μmoll−1).


newborn jaundice, kernicterus, bilirubin, hyperbilirubinemia, well babies, bilirubin-induced neurological dysfunction



An American clinical emergency is the occurrence of acute kernicterus in the 21st century. Unmonitored common signs of newborn jaundice and hyperbilirubinemia (otherwise easily treated with phototherapy), unrecognized or untreated in a timely manner, can cause serious and often irreversible post-icteric outcomes. Neonatal hyperbilirubinemia occurs in all newborn infants and may be recognized as jaundice in about 60% of healthy newborns in the United States. Most infants are cared for at home at the age of >72h during the usual peak hyperbilirubinemia (age: 72 to 120h). Jaundice and hyperbilirubinemia should be benign and resolved by the age of 2 to 3. Significant hyperbilirubinemia (>95th percentile for age in hours) occurs in 8 to 11% of infants.1, 2 The etiological basis for progressive hyperbilirubinemia is multifactorial and due to excessive bilirubin production and/or decrease its elimination is influenced by both constitutional and environmental factors. In 1994, the Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP) published a practice parameter to manage hyperbilirubinemia in the healthy term newborns.3 Updated 2004 clinical practice guidelines address concerns regarding the risk of kernicterus and represent a consensus of the committee charged by the AAP with a careful review of evidence and literature.4, 5 A number of questions impact daily clinical practice. Governed by concerns for patient safety, clinical practice needs to range from reassurance, alerts and concerns of alarm for target populations in the continuum of progressive hyperbilirubinemia. Some of the questions that clinicians have been asked are addressed below in the context of available evidence.


Frequently asked questions

Question I: Does bilirubin damage the brain of healthy infants?

Yes. Prior to publication of the 1994 AAP recommendations, the ‘lack of evidence’ of bilirubin neurotoxicity in term apparently healthy babies in the pediatric literature promoted a kinder, gentler, demedicalized management of neonatal hyperbilirubinemia.6, 7, 8 These assertions excluded infants with Crigler–Najjar syndrome who were healthy at birth but subsequently progressed to severe hyperbilirubinemia and some sustained kernicterus. At present, documented cases of classic kernicterus in breast-fed infants discharged as healthy from their birth hospitals confirm that bilirubin can be neurotoxic in the absence of hemolytic disease.9, 10

Question 2: Is there a re-emergence of kernicterus in the United States?

Possibly, yes. Soon after publications of articles7, 8 questioning the occurrence of kernicterus in term infants without hemolytic disease (as discussed above), reports of kernicterus in term healthy newborns appeared.9 Due to the absence of formal reporting for incidence of kernicterus or of its surrogate, extreme hyperbilirubinemia, it has been a challenge to gauge the magnitude of its reemergence. Clinical reports from the Pilot USA Kernicterus Registry presented in this supplement provide evidence for the ‘tip of the iceberg’ of the adverse outcomes of unrecognized and unmonitored neonatal hyperbilirubinemia.10

Question 3: Was kernicterus previously prevented in the United States?

Probably, yes. Ip et al.5 compiled voluntary reports of kernicterus in the pediatric literature for the past 5 decades. We juxtaposed the date of births of these infants to the prevalent and changing clinical practices in bilirubin management (Table 1). Prior to the introduction of exchange transfusion, severe neonatal hyperbilirubinemia was generally due to Rh hemolytic disease and perinatal sepsis, and often complicated with birth asphyxia. Kernicterus was one of the major pediatric problems in the early 20th century (prior to the 1950s). Over the ensuing five decades due to prenatal diagnosis of Rh isoimmunization and use of exchange transfusions as neonatal intensive care was refined, evidence-based management of Rh disease was delineated. Concurrently, the availability of Rhogam reduced the incidence of Rh isoimmunization and hemolysis. Advent of phototherapy and its liberal use in the United States in the late 1960s and early 1970s led to the effective management of severe neonatal hyperbilirubinemia.11 Unfortunately, evidence-based studies were not conducted to show its effectiveness in preventing kernicterus. The inherent ability of phototherapy to reduce bilirubin concentrations led to a widespread clinical practice for a staged approach of using phototherapy prior to exchange transfusion. As shown in Table 1, the least number of cases of kernicterus were reported in the pediatric literature from 1973 to 1982. During this time period, liberal phototherapy with white light devices was readily adopted and implemented by pediatricians who relied extensively on exchange transfusion for total serum bilirubin (TSB) levels >20mg per 100ml. Changing demographics, health-care practices and waning experiences of infants with severe hemolytic diseases in the newborn characterized the 1990s. A resurgence of kernicterus was reported in infants that were being cared for in a home environment, often with limited medical supervision, during the first week after birth.2, 4, 10, 11, 12

Question 4: What was the public health impact on the 1994 AAP Guidelines?

Implementation and surveillance strategies were not planned. No formal public health evaluation of the impact of the 1994 practice parameters was initiated to track national incidence of kernicterus or its surrogate, extreme hyperbilirubinemia. To track the cases of kernicterus encountered by colleagues, Dr Audrey K Brown initiated an informal voluntary registry of cases at the 1992 Kernicterus symposium (Pediatric Academic Societies). Evidence from this convenient sample led to a systems approach to manage newborn jaundice.10, 12 This inquiry of ‘numerators’ does not provide any incidence or prevalence of kernicterus in the US population, rather it provides insight into the occurrence for a condition where nationally recommended guidelines either were not implemented or failed to identify an infant with progressive severe hyperbilirubinemia.

Question 5: What is the current incidence of kernicterus and severe neonatal hyperbilirubinemia?

Approximately 1 in 650 to 1000 infants, >35 weeks of gestation can develop serum bilirubin values of 427μmoll−1 (>25mg per 100ml) and approximately 1 in 10000 have levels of 513μmoll−1 (>30mg per 100ml).13 There is a varying occurrence of infants with total bilirubin levels >25mg per 100ml from diverse communities and practices (Table 2). There are few population-based studies on the incidence of either acute bilirubin encephalopathy and/or chronic bilirubin encephalopathy (kernicterus). Incidence of chronic kernicterus in North America and Europe is listed in Table 3. In Denmark, there were no case reports of kernicterus in the 20 years prior to Ebbesen's report14 of 8 cases between 1994 and 2002 (incidence of 1.4/100000 live births). Between 2002 and 2005, with a more vigilant approach to newborn jaundice management, no more cases have been seen in Denmark, reducing the overall incidence to 1.1/100000 live births between 1994 and 2005.15 A 2004 UK surveillance study has reported an occurrence of kernicterus in 1 in 100000 live births.16 The frequency of catastrophic hyperbilirubinemia (serum bilirubin 513μmoll−1) was 1 in 14084 live births in the United Kingdom.16 A 2004 Canadian survey assessed the frequency of extreme hyperbilirubinemia (serum bilirubin >427μmoll−1) as 1 in 2840 live births, of which 13 (2/100000 live births) had abnormal neurological outcomes at the time of discharge.17 Use of phototherapy and exchange transfusion during the development and implementation of an institutional systems approach for newborn jaundice management is shown in Figure 1.18 Similarly, the use of phototherapy and exchange transfusion at a single-payor, regional health maintenance organization study is shown in Table 4.19, 20 These data from the United States compare to the Jerusalem experience with 1 in 4520 infants requiring an exchange transfusion, 1.9% requiring hospital-based intensive phototherapy and 0.41% being readmitted for phototherapy.21

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Rates of readmission for well babies pre-, during and subsequent to implementation of systems-based approach for newborn jaundice (from Bhutani et al.18).

Full figure and legend (67K)

Question 6: What is the estimated risk of kernicterus in infants with excessive hyperbilirubinemia?

There has been an historic concern that untreated TSB greater than or equal to30mg per 100ml was more likely to be associated with irreversible kernicterus. We estimate the risk of kernicterus in infants with extreme hyperbilirubinemia using contemporary population-based data from Canada and Denmark. In Canada, the incidence of TSB >25mg per 100ml is 1 in 2840 and the concurrent incidence of chronic kernicterus is 1 in 50000. Thus, risk of kernicterus in infants with TSB >25mg per 100ml may be calculated as 50000/2840 or 1 in 17.6. In Denmark, the incidence of TSB >25mg per 100ml was 1 in 4320 for a concurrent incidence of kernicterus as 1 in 70000. Thus, risk of kernicterus in infants with TSB >25mg per 100ml in Denmark was estimated as 1 in 16.2 (70000/4320). The British and Danish studies define incidences of TSB greater than or equal to30mg per 100ml as 1 in 14084 and 1 in 10000 live births and kernicterus incidence of 1 and 1.4/10000 live births, respectively. Thus, the risk of kernicterus in infants with TSB >30mg per 100ml is about one in seven.15, 16, 17 The risk is 1 in 5.5, assuming 2 of the 11 infants with TSB >30mg per 100ml ‘lost to follow-up’ in the California data have kernicterus.24 None of these retrospective data provide any insight to signs of acute kernicterus in infants with TSB <25mg per 100ml.

Question 7: Is there a specific threshold TSB value for bilirubin related neurotoxicity?

As discussed in a recent review, previous investigators have unsuccessfully attempted to correlate the occurrence of kernicterus to a specific or threshold TSB level.25 In this supplement, the report from the Pilot USA Kernicterus Registry also fails to identify a specific TSB level that is associated with the onset of bilirubin neurotoxicity. It appears that bilirubin levels of >35mg per 100ml (598μmoll−1) can have profoundly deleterious effect. Data are needed to document clinical signs of acute kernicterus to a range of TSB levels and unbound bilirubin levels.

Question 8: Are there sequelae of severe or prolonged moderate hyperbilirubinemia in the absence of recognized acute bilirubin encephalopathy?

To date, no convincing evidence has been provided. Clinical concerns remain but are unproven.26, 27 In their article, Soorani-Lunsing et al.28 prospectively observed a dose–response relationship increase in minor neurological dysfunction throughout the first year of life to the degree of hyperbilirubinemia (13.6 to 25mg per 100ml; 233 to 444μmoll−1). Are moderate degrees of hyperbilirubinemia really safe for the brain? This question remains unanswered. Minor neurological abnormalities have been described as abnormal postural behavior, high-frequency tremors and deviancies in muscle tone regulation at ages 3 and 12 months. These may continue beyond puberty as muscle tone dysregulation, choreiform dyskinesia, manipulative disability, coordination problems, gait abnormalities, awkwardness, tremors or exaggerated extrapyramidal reflexes. Their correlation to moderate or severe hyperbilirubinemia without concurrent signs of acute bilirubin encephalopathy has been sought but not proven. Prospective long-term clinical studies are needed to allay these concerns.

Question 9: Can we define a bilirubin level that is safe?

Evidence needs to be determined. To assure a safe approach to manage newborn hyperbilirubinemia in a changing health-care environment, optimal operational thresholds for intervention need to be delineated. Consensus and evidence-based guidelines have been established and need to be implemented.4 Clinical experience and practices indicate that kernicterus can almost always be prevented in infants >35 weeks of gestation. Our experience with universal pre-discharge bilirubin screening in the well-baby nursery indicates that hour-specific TSB levels <40th percentile appear to be safe in terms of the magnitude of hyperbilirubinemia and the potential risk for subsequent adverse outcome during the first week after birth.18

Question 10: Can we prevent kernicterus by a practical approach?

In infants >35 weeks GA, kernicterus should be unacceptable. Prevention of kernicterus should be a public health goal. As the 2004 guidelines12 is implemented, success for reduction in the incidence of severe hyperbilirubinemia and possibly kernicterus has yet to be shown through national surveillance.

The ensuing articles and a report from the Pilot USA Kernicterus Registry, presented in this supplement, provide a current perspective on these questions and inform strategies to transform management of newborn jaundice.



The authors have declared no financial interests.



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  2. Bhutani VK, Johnson LH, Maisels MJ, Newman TB, Phibbs C, Stark AR et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004; 24(10): 650–662. | Article | PubMed |
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  4. American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia, Maisels MJ, Baltz RD, Bhutani VK, Newman TB, Palmer H, Rosenfeld W et al. Clinical Practice Guideline: management of hyperbilirubinemia in the newborn infant 35 weeks of gestation. Pediatrics 2004; 114: 297–316. Available at; 114/1/297. | Article | PubMed | ISI |
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