Abstract
In this review the historical tenets and evidence-based clinical research in support of a bilirubin exchange threshold of >20 mg/dL for the healthy term neonate are revisited. In addition, a hypothesis is ventured that recent cases of kernicterus are related in part to changes in population factors coupled with genetic predispositions that have unmasked an unappreciated potential for marked neonatal hyperbilirubinemia.
It has been >20 years since an invited commentary titled “Bilirubin 20 mg/dL = Vigintiphobia” was published in Pediatrics.1 The article, based on literature available at the time, reinforced the premise set forth previously in the pediatric literature that hyperbilirubinemia among otherwise healthy term infants without hemolysis posed a lower risk for kernicterus than did hyperbilirubinemia secondary to hemolytic disease. The commentary also suggested that exchange transfusion at a total serum bilirubin (TSB) level of 20 mg/dL (340 μmol/L) under such circumstances might not be warranted. The commentary prompted a comprehensive detailed review and reanalysis of existing studies of nonhemolytic neonatal hyperbilirubinemia,2–4 which served as a forerunner to the 1994 American Academy of Pediatrics (AAP) practice parameter on the management of jaundice in the healthy term newborn.5 In the past decade, reported cases of severe hyperbilirubinemia and kernicterus6–8 reignited debate regarding the management of neonatal hyperbilirubinemia and the pathogenesis of kernicterus. The purpose of this article is threefold, ie, (1) to highlight the literature and commentary predating the publication of “Vigintiphobia,” to illustrate that an exchange threshold of >20 mg/dL (340 μmol/L) for healthy term newborns without hemolysis was neither new nor particularly radical; (2) to review the analysis of evidence-based clinical research leading to the 1994 AAP jaundice practice parameter; and (3) to hypothesize that current cases of kernicterus might be related in part to population factors that have changed since 1983, coupled with genetic predispositions.
THE ORIGIN OF THE DEBATE
Comment regarding the management of nonhemolytic jaundice among healthy term neonates has been longstanding, predating the publication of “Vigintiphobia” by ∼30 years. Its origin can be traced to the early 1950s, immediately after studies on exchange transfusion to prevent hyperbilirubinemic encephalopathy among infants with erythroblastosis fetalis.9–12 At that time, the applicability of a 20 mg/dL (340 μmol/L) exchange threshold to hyperbilirubinemic but otherwise healthy term infants without hemolysis became a focus of attention.13 Brown and Zuelzer14 were among the first to demonstrate that neonatal hyperbilirubinemia unrelated to isoimmunization could exceed what was considered “physiologic,” describing 8 term infants with TSB levels exceeding 20 mg/dL (340 μmol/L); 4 received an exchange transfusion (peak TSB range: 25.8–30.8 mg/dL [439–524 μmol/L]) and 4 did not (peak TSB range: 20.3–32.2 mg/dL [345–547 μmol/L]), and all reportedly recovered without neurologic sequelae. The authors commented,
No fixed values were regarded as indications for exchange, although in practice the level of 20 mg/dL was taken as a rough guide … Whether the use of this level as an indication for exchange is justifiable under these circumstances … is not known … Consideration must be given to the question of whether, or when, exchange transfusion should be done in hyperbilirubinemia in the absence of hemolytic disease.14
To address this issue more directly, Killander et al15 reported a consecutive series of term infants in which exchange transfusion was performed for every second infant when the serum bilirubin level reached 20 mg/dL (340 μmol/L; exchange: n = 46; control: n = 48). They observed no cases of kernicterus and no neurologic abnormalities in short-term15 and longer-term16 follow-up monitoring of both exchange-treated and non–exchange-treated cohorts and concluded,
In full term infants it is at present impossible to fix a critical bilirubin level at which exchange transfusion ought to be performed. It seems, however, reasonable to restrict exchange transfusion to those few infants who show excessive hyperbilirubinemia (bilirubin >25 mg per 100 mL).15
In a review of the article by Killander et al15 in the 1961–1962 Year Book of Pediatrics, as well as related studies in the 1962–1963 and 1966–1967 volumes, editor Sydney Gellis, MD, who was a frequent commentator on this management issue, ventured the following comments and recurrent theme.
The indications for exchange transfusion for nonhemolytic hyperbilirubinemia are not at all clear and universally accepted. Thus, we would at present refrain from treating any full term infant with exchange transfusion regardless of degree of hyperbilirubinemia once we have excluded excessive hemolysis due to erythroblastosis, sepsis etc, as its cause. We feel the risk of exchange transfusion is far greater then the risk of kernicterus in the full term infant.17(p30)
When hyperbilirubinemia occurs without hemolysis, we do not exchange full-term infants.17(p36)
We are exceedingly pleased with the fact that we have not altered our own guide to exchange transfusion which we outlined over a year ago. There was a time when the status of exchange transfusion and so-called physiologic hyperbilirubinemia almost called for weekly bulletins. Our loyal readers will recall that we adhere to a 20 mg level of unconjugated or indirect bilirubin for erythroblastotic infants and those with excessive hemolysis from other causes as the “critical” level at which exchange is conducted… . We have no critical level for full-term infants with nonhemolytic hyperbilirubinemia. We have seen no kernicterus.18(p34)
We have been even more conservative in regard to the full term infant, recommending that replacement transfusion be withheld regardless of the level of indirect bilirubin in those infants whose hyperbilirubinemia is nonhemolytic in origin and who show no neurologic signs.19(p37)
Dr Gellis continued,
The physician who has been taught that 20 mg/100 mL is the critical level of bilirubin in erythroblastosis has this level so firmly fixed in his mind that he is very reluctant to abandon it in any type of hyperbilirubinemia.19(p37)
Of note, these recommendations predated the use of phototherapy in the United States. After the introduction of phototherapy, Dr Gellis recommended its use if the serum bilirubin reaches 20 mg/dL, despite the fact that kernicterus in such infants is extremely rare … should phototherapy fail to hold the serum bilirubin of a full term infant below 25 mg/dL, I'd proceed with exchange transfusion.20(p32)
Neurodevelopmental follow-up investigations from the late 1960s and early 1970s suggested that (1) moderate degrees of hyperbilirubinemia (15–24 mg/dL TSB [255–408 μmol/L]) had no particular implications for hearing or motor impairment among otherwise healthy term neonates21 and (2) only infants whose TSB levels exceeded 25 mg/dL exhibited coordination disturbances or sensorineural hearing loss.22 Dr Gellis stated in review that “mild to moderate indirect hyperbilirubinemia poses little to no threat to the term infant who is otherwise well.”23(p427)
In summary, contrary to the assumption that a TSB of ≥20 mg/dL (340 μmol/L) was accepted widely as dangerous to the health of term infants with nonhemolytic hyperbilirubinemia, the literature of the 1950s, 1960s, and 1970s demonstrates both debate and a lack of consensus on the appropriateness of a 20 mg/dL (340 μmol/L) exchange threshold for such neonates. It is from this rich collection of clinical investigation and discourse that the commentary “Vigintiphobia” evolved.
REANALYSIS OF THE LITERATURE
The first more-comprehensive analysis focused on term infants without hemolytic disease was designed to estimate the effects of peak TSB levels on 3 clinical outcome variables, namely, cognitive development, abnormalities in neurologic examinations, and hearing.2 This detailed analysis by Newman and Maisels2 demonstrated that most smaller clinical studies reported no association between serum bilirubin levels and neurologic outcomes, whereas the results of the Collaborative Perinatal Project, with its enormous sample size, showed some statistically significant associations that were not considered clinically relevant, ie, the effect sizes were trivial. A subsequent separate reanalysis of the Collaborative Perinatal Project data focused on infants with birth weights of >2500 g and negative Coombs test results and confirmed that neonatal bilirubin levels within the studied range had little effect on IQ levels, definite neurologic abnormalities, or hearing loss.4 Higher bilirubin levels were associated with minor motor abnormalities but, as stated by the authors, “The clinical importance of this finding is limited by the weakness of the association, the mild nature of the abnormalities, and the lack of evidence that they are prevented by treatment.”4 These collective findings do not mean that bilirubin is benign but they do provide good evidence that term infants are not at risk of mental or physical impairment until serum bilirubin levels rise well above 20 mg/dL (340 μmol/L).2,4 The clinical management implications were explored more thoroughly in a seminal article titled “Evaluation and Treatment of Jaundice in the Term Newborn: A Kinder, Gentler Approach.”3 The article addressed problems associated with previous management recommendations, specifically, the lack of data supporting the traditional approach, the lack of evidence of treatment efficacy, and the fact that treatment is not risk free.3 New treatment recommendations that were less aggressive than those recommended previously were set forth, including a goal of keeping bilirubin levels below 400 to 500 μmol/L (23.4–29.2 mg/dL) among healthy term infants without hemolytic disease, with either phototherapy (treatment threshold: 300–375 μmol/L [17.5–22 mg/dL]) or exchange transfusion (treatment threshold: 425–500 μmol/L [25–29 mg/dL]).3 In contrast to many previous jaundice management recommendations, serum bilirubin treatment thresholds were given as ranges rather than as single numbers, to “reflect more accurately our current uncertainty about when to treat.”3 The proposal for a kinder gentler approach generated a vigorous response24–31 and engendered additional debate, as well as a call on the part of at least 2 respondents for the development of an informed consensus and new recommendations by the AAP.25,28
1994 AAP PRACTICE PARAMETER
In 1994, the AAP published a clinical management guideline for hyperbilirubinemia among healthy term infants that reflected the findings of the more detailed review and reanalysis of existing studies on nonhemolytic neonatal hyperbilirubinemia.2–5 Criteria were set forth indicating that otherwise healthy term (≥38 weeks' gestation) infants >48 hours of age should undergo exchange when their TSB levels were ≥30 mg/dL (510 μmol/L), or ≥25 mg/dL (425 μmol/L) if intensive phototherapy failed.5 For the first time, an authoritative review compiled by multiple clinicians and investigators from different institutions and perspectives provided recommendations that called for an exchange level of 25 mg/dL (425 μmol/L) for otherwise healthy term neonates. Moreover, the AAP practice parameter differed from previous guidelines in that the practice parameter contemplated exchange transfusion only when intensive phototherapy failed, unless the first TSB level obtained was ≥30 mg/dL.5 It was suggested subsequently that, by establishing these particular treatment thresholds, the practice parameter “lessened concern” for neonatal jaundice,6,8,32–34 perhaps an unintended consequence of the guideline. Indeed, as stated in the rationale for the parameter, “Important in the development of these guidelines is the general belief that therapeutic interventions for hyperbilirubinemia in the healthy term infant may carry significant risk relative to the uncertain risk of hyperbilirubinemia.”5 However, the practice parameter also recommended specifically that (1) infants ≤24 hours of age be excluded from the parameter because jaundice occurring before 24 hours is “generally considered pathologic and requires further evaluation,” including measurement of TSB,5 and (2) follow-up monitoring for all neonates discharged <48 hours after birth be performed by a health care professional in an office, in a clinic, or at home within 2 to 3 days after discharge,5 echoing previous recommendations by the AAP.35 Moreover, the parameter noted that “decreasing gestational age, breastfeeding, and large weight loss after birth” are conditions that increase the risk for hyperbilirubinemia significantly, and it emphasized that near-term neonates are at particular risk.5 Therefore, even by today's standards, the 1994 practice parameter provided sound, reasoned, evidence-based guidelines when appropriate data existed and expert consensus regarding treatment of jaundiced term neonates. Similar treatment guidelines had been published in the United Kingdom,36,37 and a similar exchange threshold was used in Greece.38
The higher serum bilirubin threshold for exchange transfusion in the 1994 AAP practice parameter held the potential to reduce the number of infants undergoing exchange transfusion. Although some studies suggested that the risks of exchange transfusion are extremely low among healthy term neonates and are confined to laboratory abnormalities that are asymptomatic and treatable,39–41 none of those analyses was large enough to detect an effect size of 3 to 4 adverse events per 1000 exchanges, a frequently cited morbidity and/or mortality risk42 that a recent meta-analysis concluded is germane to term infants without serious hemolytic disease.43 The largest study (n = 502 infants) of exchange transfusions involving mainly healthy infants born at term (70% of the cohort) was published in 1969 and demonstrated an equivalent mortality rate when analysis was confined to this group.38 This rate may not be generalizable to the current era, however, if the frequency of performance is an important determinant of risk (as for most procedures), because experience with exchange transfusion is decreasing.44,45
Evidence from the literature suggests that the application of the 1994 practice parameter guideline within the pediatric community, like that of many such guidelines,46 has been far from uniform and has not translated into substantive changes in clinical practice.47,48 In fact, studies documented that only ∼50% of healthy term newborns for whom the AAP practice parameter recommends phototherapy receive it,48 only approximately two thirds of pediatricians reported any familiarity with the guidelines,47 and, of those, only 28% reported a change in management practices as a result of the guideline.47 These findings mirror those reported by McMillan et al49 with respect to the Canadian Medical Association published guideline on the use of phototherapy for newborns with hyperbilirubinemia, underscoring the difficulty of securing high levels of adherence to guidelines in practice.48 The AAP is working actively on an implementation program to increase the level of practitioner adherence to hyperbilirubinemia management guidelines.50
KERNICTERUS: CURRENT STATUS
Incidence and Possible Causes
Recent reports demonstrate that kernicterus, although a rare event, continues to occur in the United States and abroad, meriting our attention.6,7,43,51–59 The lack of population-based studies in the United States precludes an objective assessment regarding whether such cases represent a basal level, resurgence, or reemergence of kernicterus.7,43,59 A population-based Danish report, however, suggests that cases have occurred recently that have not been seen for a few decades.56 Why is there an increase now? An analysis published in the Joint Commission on Accreditation of Healthcare Organizations Sentinel Event Alert on kernicterus identified issues in patient care processes as being operative in the current risk for kernicterus.60 These included matters related to (1) patient assessment (problems related to jaundice assessment among neonates or failure to measure bilirubin levels for infants who are jaundiced in the first 24 hours of life), (2) continuum of care (early discharge without timely follow-up monitoring or failure to provide ongoing lactation support), (3) family education (failure to provide appropriate information to parents about jaundice or to respond to parental concerns about jaundice), and (4) treatment (failure to treat severe hyperbilirubinemia aggressively).60 These risk factors reveal important differences between the circumstances attendant to the care of neonates today and 20 to 30 years ago, which might contribute materially to a greater risk of developing marked hyperbilirubinemia. The differences include, among others, (1) shortened hospital stays, necessitating outpatient surveillance for identification and management of neonatal jaundice, and (2) both increased advocacy for and prevalence of breastfeeding.61 In the 1970s, however, most infants were still discharged on approximately day 3 (before they were 72 hours of age), ∼30% to 35% were breastfed, and it was standard practice for the first follow-up visit to occur at 2 weeks of life. The prevalence of glucose-6-phosphate dehydrogenase deficiency must have been similar to that today, and mothers rarely received special instructions about jaundice. Although there were fewer breastfed infants, there was still a population at risk; therefore, it is of interest why we never saw or heard of an infant with a TSB level of 35 to 45 mg/dL (595–765 μmol/L) or a case of kernicterus during that era.
The assumption has been made that a major portion (if not all) of kernicterus cases are iatrogenic in nature, a result of alleged inadequate and/or delayed follow-up monitoring and a “lack of concern” on the part of health care providers.8,32–34 Although the Joint Commission on Accreditation of Healthcare Organizations analysis of recent kernicterus cases suggested that such factors might be important contributors in many cases, this might not be the case for all. The observation of newborns for whom TSB levels increased to 35 to 45 mg/dL (595–765 μmol/L) or higher within a few days of life, who were discharged without clinical jaundice and with no overt evidence of hemolysis, suggests that important physiologic factors must also have been operative in the development of their severe hyperbilirubinemia. Recent clinical observations suggest the same, including (1) the finding that essentially every reported newborn affected with kernicterus has been breastfed,6,7,43,59 (2) the observation that breastfeeding, combined with polymorphisms for the genes encoding the hepatic bilirubin-conjugating enzyme uridine diphosphate glucuronosyltransferase 1A1 (UDP-GT1A1) and/or organic anion transporter protein 2 (OATP-2) (purported to be involved in hepatic uptake of unconjugated bilirubin62), substantially increases the risk for TSB levels of >20 mg/dL (370 μmol/L),63,64 and (3) the noteworthy population prevalence of UDP-GT1A1 gene polymorphisms that underlie hepatic bilirubin-conjugating deficiencies.65,66 Exploration of the molecular and biochemical bases of marked neonatal hyperbilirubinemia would complement the important, clinically focused efforts of identifying at-risk newborns and reducing their risk for kernicterus,7,67 by defining more completely the biological mechanisms through which infants are able to generate such high TSB levels and the physiologic and environmental circumstances that attend their occurrence.
Breastfeeding and Jaundice
It is likely no coincidence that almost all reported cases of kernicterus in the past 2 decades have involved breastfed infants. What does this observation imply with respect to the cause of marked neonatal jaundice? Numerous studies have reported an association between breastfeeding and increased incidence and severity of hyperbilirubinemia, both during the first few days of life and in the genesis of prolonged neonatal jaundice.68–72 A pooled analysis of a dozen studies including >8000 neonates demonstrated a threefold greater incidence of TSB levels of ≥12.0 mg/dL (205 μmol) and a sixfold greater incidence of levels of ≥15 mg/dL (257 μmol) among breastfed infants, compared with their formula-fed counterparts.71 Others, however, reported that, if adequate breastfeeding is established and sufficient lactation support is in place, then breastfed infants should be at no greater risk for hyperbilirubinemia than their formula-fed counterparts.73–76 The latter studies suggest that many breastfed infants who develop marked neonatal jaundice do so in the context of delays in lactation or varying degrees of lactation failure. Indeed, appreciable proportions of the breastfed infants who develop kernicterus have been noted to have inadequate intake and variable but substantial degrees of dehydration and weight loss.7,53
Inadequate breast milk intake, in addition to contributing to varying degrees of dehydration, can enhance hyperbilirubinemia by increasing the enterohepatic circulation of bilirubin and the resultant hepatic bilirubin load. The enterohepatic circulation of bilirubin is already exaggerated in the neonatal period, in part because the newborn intestinal tract is not yet colonized with bacteria that convert conjugated bilirubin to urobilinogen and because intestinal β-glucuronidase activity is high.77,78 Earlier studies among human and primate newborns confirmed that the enterohepatic circulation of bilirubin accounts for up to 50% of the hepatic bilirubin load in neonates.79,80 Moreover, fasting hyperbilirubinemia is attributable largely to intestinal reabsorption of unconjugated bilirubin,81,82 which suggests an additional mechanism through which inadequate lactation and/or poor enteral intake may contribute to the genesis of marked hyperbilirubinemia for some neonates. Indeed, in the context of the limited hepatic conjugation capacity in the immediate postnatal period, any additional increase in hepatic bilirubin load would likely result in more marked hyperbilirubinemia. Studies confirmed that early breastfeeding-associated jaundice is associated with a state of relative caloric deprivation83 and resultant enhanced enterohepatic circulation of bilirubin.83,84 Breastfeeding-associated jaundice is not associated with increased bilirubin production.85,86 While recognizing the relationship between breastfeeding and jaundice, it is important to emphasize that the benefits of breastfeeding far outweigh the related risk of hyperbilirubinemia.
It is also reasonable to hypothesize that the few breastfed infants who develop severe hyperbilirubinemia may carry UDP-GT1A1 gene polymorphisms for promoter or coding sequence mutations that are associated with diminished conjugating capacity. Breastfeeding may act as a modifier that, for an individual genotype, may predispose the infant to the development of marked neonatal jaundice.64 A recent report lent credence to this possibility, demonstrating that the risk of developing a TSB level of ≥20 mg/dL (342 μmol/L) in association with breastfeeding was enhanced 22-fold when breastfeeding was combined with a genetic polymorphism for a coding sequence mutation of the UDP-GT1A1 or OATP-2 gene63 and 88-fold when it was combined with genetic polymorphisms for both UDP-GT1A1 and OATP-2.63 Others reported previously an association between prolonged (>14 days) breastfeeding-associated jaundice and Gilbert's syndrome.87,88
Genetics and Neonatal Jaundice
Recognition of a genetic predisposition to neonatal hyperbilirubinemia dates back to the description of the Crigler-Najjar syndrome in 195289 and now includes, among others, both promoter and coding sequence mutations of the UDP-GT1A1 gene.65,66,90–98 Crigler-Najjar syndrome type I is secondary to a nonsense or stop mutation of the UDP-GT1A1 coding sequence and is associated frequently with marked hyperbilirubinemia and kernicterus, which emphasizes that the risk for kernicterus should not be thought of as being limited to infants with hemolytic disease. Far more prevalent UDP-GT1A1 gene polymorphisms identified since the middle 1980s have provided important insights into the genetic underpinnings of neonatal jaundice.65,66,90–98 The Gilbert genotype is characterized by a variant UDP-GT1A1 promoter sequence that contains a 2-base pair addition (TA) in the TATAA promoter element, giving rise to 7 (A[TA]7TAA), rather than the more usual 6 (A[TA]6TAA), repeats among affected subjects.90 This extra TA repeat (A[TA]7TAA) impairs proper message transcription and accounts for reduced UDP-GT1A1 activity.90 Subjects with Gilbert's syndrome are homozygous for the A[TA]7TAA variant promoter, which provides a unique genetic marker for this disorder. The gene frequency for the expanded A[TA]7TAA motif is 0.3, resulting in 9% of the general population being homozygous and 42% being heterozygous for the variant promoter.91 Therefore, approximately one half of the general population carries a Gilbert promoter on ≥1 allele.91 The importance of the Gilbert genotype in the genesis of neonatal jaundice is particularly apparent when affected newborns have either (1) an increased bilirubin load as a result of increased bilirubin production (eg, glucose-6-phosphate dehydrogenase deficiency65,66,92) and/or enhanced enterohepatic circulation, or (2) additional coinherited defects in bilirubin conjugation.65,66,91 A few recent studies highlight this fact. Kaplan et al92 demonstrated a dose-dependent genetic interaction between glucose-6-phosphate dehydrogenase deficiency and Gilbert syndrome that contributes to the development of neonatal hyperbilirubinemia; similarly a combination of the Gilbert genotype with hereditary spherocytosis93 or ABO hemolytic disease94 appreciably increases the risk for marked neonatal jaundice.
Coinheritance of the Gilbert promoter and a structural mutation in the coding region of UDP-GT1A1 can also lead to jaundice.95–97 Of note, this is true not only for patients who are homozygous for the Gilbert genotype but also for compound heterozygotes with a Gilbert-type promoter and a structural region mutation of UDP-GT1A1.91 An example of the latter is a report of twin girls who developed marked neonatal hyperbilirubinemia (26.7 mg/dL [457 μmol/L] and 24.0 mg/dL [410 μmol/L]) and kernicterus and were found to be compound heterozygotes for the Gilbert-type TATAA element and a frameshift mutation in the coding region of the UDP-GT1A1 gene.91 The father was heterozygous for the coding region mutation, whereas the mother carried the Gilbert promoter genotype on 1 allele.91 UDP-GT1A1 activity in such cases is predicted to be 10% to 15% of normal, which produces bilirubin levels higher than those seen with Gilbert's syndrome but lower than those seen with Crigler-Najjar syndrome type I.91 Because ∼50% of the population carries a Gilbert-type promoter on ≥1 allele,91 heterozygous carriers of an UDP-GT1A1 coding region mutation have a relatively high probability of carrying a Gilbert-type promoter. On the basis of the gene frequencies for the Gilbert-type promoter and structural mutations of the UDP-GT1A1 gene, it can be predicted that at least 1:3300 infants are compound heterozygotes for Gilbert-type and UDP-GT1A1 coding region mutations and are at risk for significant hyperbilirubinemia.91
The role such mutations play in the genesis of severe hyperbilirubinemia remains unclear, although the small direct bilirubin fractions53 (an indication of conjugating capacity) and evidence of poor feeding and prominent weight loss (ie, a state resembling fasting) reported in cases of kernicterus53 suggest that coding sequence variants, Gilbert's syndrome, and/or compound heterozygosity for the Gilbert promoter and a structural mutation of the UDP-GT1A1 gene might underlie some cases of marked neonatal jaundice.65,66 An analogous UDP-GT1A1 coding sequence mutation (a guanine to adenine transition at nucleotide 211, the polymorphism known as G71R65,98) among East Asian infants may play a comparable role in that population of newborns.65,98 It is of interest that the frequency of compound heterozygosity for the Gilbert promoter and a structural mutation of the UDP-GT1A1 gene predicted above (1:3300) closely approximates the frequency of TSB levels of >30 mg/dL (>513 μmol/L) in recent reports.99,100 Apportioning a genetic contribution for the few infants who develop severe hyperbilirubinemia is a hypothesis that merits testing, not only because such a study might shed light on biological factors that predispose infants to or protect infants against the development of hyperbilirubinemic encephalopathy but also because such data might define additional risk factors that could be used to identify infants at greatest risk. In light of the large number of infants who develop neonatal jaundice, the very small fraction who proceed to develop severe hyperbilirubinemia, and the even smaller subset at risk for kernicterus, such studies are warranted.
The development of disease is ultimately a complex biological phenomenon determined by both genetic and environmental factors. It remains unclear whether the current prevalence of kernicterus is primarily iatrogenic and kernicterus can therefore be made a “never event.” It is unknown whether kernicterus was ever a never event43 or whether previous5 and recently revised clinical guidelines67 will make it so. What is clear is that the current population of neonates and the circumstances under which we care for them are not the same as those 2 or 3 decades ago. Indeed, kernicterus has manifested itself in temporal association with profound changes in maternal (enhanced prevalence of breastfeeding) and medical (early hospital discharge) behaviors. The resultant environmental changes might have unmasked a previously unappreciated potential for marked hyperbilirubinemia among a select and unfortunate few, the basis of which might be partly genetic. Clinical efforts to reduce this risk, including the use of predischarge risk assessment and/or bilirubin screening67 combined with hour-specific interpretation of assayed bilirubin levels7,67 and timely postdischarge follow-up monitoring and therapeutic intervention,7,67 hold great promise for avoiding the development of severe hyperbilirubinemia and kernicterus. Additional work is also needed, to clarify the physiologic, genetic, and environmental contributors to the development of marked neonatal hyperbilirubinemia.
Acknowledgments
In memory of Frank A. Oski, MD.
Footnotes
- Accepted November 16, 2004.
- Address correspondence to Jon F. Watchko, MD, Division of Neonatology and Developmental Biology, Department of Pediatrics, Magee-Womens Hospital, 300 Halket St, Pittsburgh, PA 15213. E-mail: jwatchko{at}mail.magee.edu
No conflict of interest declared.
REFERENCES
- Copyright © 2005 by the American Academy of Pediatrics
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