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Screening and Follow-Up for Neonatal Hyperbilirubinemia: A Review

Anthony E. Burgos, Valerie J. Flaherman and Thomas B. Newman CLIN PEDIATR 2012 51: 7 originally published online 27 February 2011 DOI: 10.1177/0009922811398964 The online version of this article can be found at: http://cpj.sagepub.com/content/51/1/7

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Commentary

Screening and Follow-Up for Neonatal Hyperbilirubinemia: A Review

Clinical Pediatrics 51(1) 716 The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922811398964 http://cpj.sagepub.com

Anthony E. Burgos, MD, MPH1, Valerie J. Flaherman, MD, MPH2, and Thomas B. Newman, MD, MPH2 Introduction
The term hyperbilirubinemia describes an excess of bilirubin in the blood. This becomes clinically apparent as jaundice, a yellow coloration of the skin and whites of the eyes, which occurs in newborns at serum bilirubin levels >5 mg/dL. Hyperbilirubinemia is caused both by increased production of bilirubin as the heme in red blood cells is broken down and by decreased bilirubin excretion due to inadequate hepatic conjugation and increased enterohepatic reabsorption. Jaundice is common: When carefully sought it may be noted in up to 80% of newborn infants.1 The clinical importance of hyperbilirubinemia derives primarily from its potential to cause kernicterus, a form of brain damage that can cause death or long-term sequelae, including cerebral palsy and hearing loss. Whereas hyperbilirubinemia and resultant jaundice are common, hyperbilirubinemia severe enough to cause kernicterus is rare. Population-based studies of its incidence have only recently become available.2 Estimates in developed countries range about from about 0.4 to 2 per 100000 (Table 1).3-9 Case series from referral hospitals suggest that the incidence may be much higher in developing countries, at least partly because of higher rates of glucose 6-phosphate dehydrogenase (G6PD) deficiency and sepsis.10-12 Lower levels of hyperbilirubinemia may also have some significance as a predictor of outcomes other than kernicterus in very premature infants; however, this area is still under active investigation.13-15 For the purposes of this review, we will focus on hyperbilirubinemia in term and late preterm infants. Treatment options for hyperbilirubinemia include exchange transfusion, phototherapy, and replacing breastfeeding with formula. Exchange transfusion consists of replacing a portion of the newborns blood with donor blood. This treatment has significant morbidity and mortality16-19 and is generally reserved for the most severe cases of hyperbilirubinemia. Phototherapy with light of wavelength in the 430 to 490 nm spectrum is much safer than exchange transfusion, although it leads to expense and separation of mother and infant. In addition, in vitro studies and some epidemiologic studies suggest the as yet unconfirmed possibility of late adverse effects.20-23 Rehospitalization for jaundice, which almost always includes phototherapy, occurs in 1% to 2% of all newborns, at an average cost of more than $3000 per admission (in 2008).24 Although population-based data on the frequency of exchange transfusion are not available, there has been a significant decline in use of exchange transfusions.25-27 Surveys of pediatricians indicate significant variability in the bilirubin levels at which exchange transfusion and phototherapy are recommended.28-31 This article reviews current evidence and recommendations for screening and follow-up for neonatal hyperbilirubinemia. Because most of the research and guidelines relate to total bilirubin, we focus on total bilirubin levels with the understanding that significant or prolonged elevation of bilirubin levels should trigger additional evaluation, including fractionation. The 2 main types of bilirubin measurements used clinicallytotal serum bilirubin (TSB) and transcutaneous bilirubin (TcB) are discussed in the accompanying boxed feature. Recommendations for treatment with phototherapy or exchange transfusion are not discussed but can be found in the American Academy of Pediatrics (AAP) guideline,32 or a guideline with similar recommendations (accompanied by a massive evidence synthesis) produced by the United Kingdoms National Institute for Health and Clinical Excellence (NICE).33

Screening for Hyperbilirubinemia

Screening is often defined as the application of a test to detect a disease or a risk factor for disease among people with no known signs or symptoms of that disease or risk
1 2

Stanford University, Palo Alto, CA, USA University of California, San Francisco, San Francisco, CA, USA

Corresponding Author: Anthony E. Burgos, Department of Pediatrics, Stanford University, 770 Welch Road, Suite 100, Palo Alto, CA 94304, USA Email: tony.burgos@stanford.edu

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8
Table 1. Population-Based Estimates of Kernicterus Incidence Author(s) (Year) Country Years Ascertainment Case Definition No. of Cases 8

Clinical Pediatrics 51(1)

Denominator 576000

Rate 1.4/100000

Bjerre and Denmark Ebbesen (2006)8 Bjerre et al (2008)7 Denmark

Manning et al (2007)6

United Kingdom

Sgro et al (2006)5

Canada

Sgro (2009)4

Canada

Burke (2009)

United States California

Brooks et al (in press)3

1994-2002 Registry; voluntary reports; 35 weeks gestation; TSB 31.1 mg/dL; symptoms of chronic bilirubin encephalopathy 1994-2002 National laboratory information system linked to medical reports; 35 weeks gestation and 28 days of age; TSB 26.5 mg/dL and advanced phase symptoms of bilirubin encephalopathy 2003-2005 Voluntary reports; > 35 weeks gestation and <1 month of age; TSB 30 mg/dL; death OR postmortem examination OR typical sequelae at 12-month follow-up 2002-2004 Surveillance program; voluntary reports; 35 weeks gestation and 60 days of age TSB 25 mg/dL and/or exchange transfusion AND clinically important neurologic abnormalities at final discharge 2007-2008 Surveillance program; voluntary reports; any child up to 6 years old; 35 weeks gestation at birth; TSB 25 mg/dL or exchange transfusion AND 2 or more signs/ symptoms of kernicterus; OR abnormal MRI with history of hyperbilirubinemia 1988-2005 Hospital discharge abstracts; 30 days of age; ICD-9 for kernicterus AND CPT for phototherapy or exchange transfusion 1988-1997 State registry for developmental services; ICD-9 for kernicterus

249308a

0.4/100000a

1500052

0.46/100000

13

640000

2/100000

22

900000

2.4/100000

436

Not stated

2.7/100000

25

5697147

0.49/100000

Abbreviations: TSB, total serum bilirubin; MRI, magnetic resonance imaging; ICD-9, International Statistical Classification of DiseasesNinth Revision; CPT, Current Procedural Terminology. a Rate is dependent on whether patients without acute symptoms who are lost to follow-up are included in the denominator.

factor.34,35 Screening for hyperbilirubinemia functions in both ways because it detects infants with total bilirubin levels that already require treatment and detects bilirubin levels that do not yet require treatment but predict an increased risk of future significant hyperbilirubinemia. Hyperbilirubinemia screening programs also differ slightly from the traditional definition of screening because all infants are considered to have received screening for hyperbilirubinemia after total bilirubin testing, even if providers had noticed jaundice at the time of testing.

Screening to Diagnose Existing Hyperbilirubinemia

Because the alternative to screening to diagnose existing hyperbilirubinemia requiring treatment is to measure bilirubin levels only on those infants believed to be jaundiced enough to warrant that test, studies that can inform this indication for screening examine the accuracy of physical examination for significant jaundice. Multiple studies have examined the accuracy of visual estimation of bilirubin levels. This estimation can use the

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Burgos et al. progression of jaundice from the face to the extremities (cephalo-caudal progression) as bilirubin levels rise.36,37 Correlation coefficients between bilirubin levels estimated from physical examination by observers at various levels of training and TSB levels have been fair (0.4 to 0.7), but these studies have included mostly newborns with TSB levels of 12 to 15 mg/dL or less and have not directly addressed how frequently TSB levels high enough to warrant treatment at older ages would be missed.36,38-41 Several studies suggest that the vast majority (>95%) of newborns with levels of 12 mg/dL or more will have jaundice below the level of the nipples, although many infants with lower TSB levels will, too.37,40-42 Dark pigmentation adds an additional degree of difficulty in visual estimation in some studies.36,40 Because the level of bilirubin at which treatment is indicated is much lower in younger infants, visual estimation of bilirubin levels is not sufficient to guide treatment decisions in the youngest infants. The AAP guidelines and all available evidence indicate that any newborn who appears jaundiced in the first 24 hours should have a total bilirubin measured. The NICE guideline goes further, recommending measurement of TcB levels in all jaundiced infants regardless of age. We agree that a TcB is reasonable, if available, in jaundiced newborns of any age, as the discomfort, time, and cost involved are trivial once the instrument is available. However, we are not convinced that a TSB is necessary in every jaundiced infant. For example, in low-risk infants 4 or more days old, phototherapy is not recommended by the AAP unless the TSB is 20 mg/dL or more. Available studies suggest that in infants of this age a bilirubin level that high can often be ruled out by clinical examination with enough confidence to make the cost-effectiveness of requiring a TSB level in all such infants questionable.

9 chest level, it is prudent to confirm with a total bilirubin. Since the sensitivity and specificity of early TSB measurement for prediction of future hyperbilirubinemia may be lower than similar values for more reliable screening tests, controversy remains regarding both the effectiveness and the cost-effectiveness of bilirubin screening for the prediction of future hyperbilirubinemia. Nevertheless, evolving evidence has encouraged many providers and institutions to institute a screening program.46 Early hour-specific TSB, when related to its percentile distribution for postnatal age, has been shown to be useful in defining risk of hyperbilirubinemia.47 In the classic study,47 a TSB in the high-risk zone for age in hours had a positive predictive value for significant hyperbilirubinemia of 40% and negative predictive value of 98%, with a sensitivity of 54% and specificity of 96%. Although results of this study have proven useful, it is important to note that the percentile labels on this hour-specific nomogram are biased by differential follow-up48 and may not be generalizeable to other populations. For example, the 95th percentile for TcB levels in a recent study from Michigan was between the 40th and 75th percentiles on the Bhutani nomogram.49 Nonetheless, the risk stratification produced by the nomogram has been validated in subsequent studies by other investigators and is used clinically by some providers.36,50,51 For those infants from whom at least 2 successive TSB or TcB measurements are obtained, it is helpful to plot the data on an hour-specific nomogram to assess the rate of rise. A rate of rise greater than 0.2 mg/dL/h is sufficient to cross percentiles on the hour-specific nomogram, should be considered rapid, and requires further testing and follow-up.32,52 After 48 hours of age a rate of rise as low as 0.1 mg/dL/h may cross percentile curves into a higher risk zone,53 and further testing should be considered. When only one total postnatal bilirubin value is available, it may be useful to consider the mean cord bilirubin value, which ranges from 1.4 to 1.9 mg/dL,54 as the initial data point. If total bilirubin screening is not used, it is particularly important to assess the infants clinical risk factors for developing hyperbilirubinemia.32 The major risk factors for development of severe hyperbilirubinemia are jaundice observed in the first 24 hours, blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease such as G6PD deficiency, gestational age 35 to 36 weeks, family history of a sibling who received phototherapy, cephalohematoma, or significant bruising, exclusive breastfeeding, and East Asian race. Minor risk factors include gestational age 37 to 38 weeks, jaundice observed before discharge, previous sibling with jaundice, macrosomic infant of a diabetic mother,

Screening to Predict Future Hyperbilirubinemia

Bilirubin screening for prediction of future significant hyperbilirubinemia has been recommended by a panel of experts convened by the AAP,43 but the evidence was not sufficient to make it an AAP guideline recommendation.44 The United States Preventive Services Task Force recently undertook a systematic review of the effectiveness of universal bilirubin screening and concluded that there was insufficient evidence to recommend for or against it.45 As discussed above, the alternative to universal bilirubin screening is to rely on the physical examination, which may be a sufficient indicator of bilirubin level, if either the infant is not jaundiced at all or is at least a few days old. In cases of jaundice presenting below the

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10

Clinical Pediatrics 51(1)

Table 2. Studies Examining the Value of Adding Clinical Risk Factors to Bilirubin Levels for the Prediction of Subsequent Hyperbilirubinemia N With Predischarge Prediction Prediction Using Definition of Total N with Bilirubin in N With Using Total Total Bilirubin Subsequent predischarge High-Risk Subsequent Bilirubin Plus Clinical Risk Hyperbilirubinemia TSB Zone Hyperbilirubinemia Alone Factors TSB 20 mg/dL 5706 1424 270 C = 0.79 C = 0.86 for TSB for TSB z-score plus risk zone; partial clinical C = 0.83 risk index for TSB (included race, z-score maternal age 25 years, scalp injury diagnosis, male gender, and gestational age but not breastfeeding) C = 0.88 C = 0.96 for TSB for TSB risk zone + risk zone gestational age and percent weight loss first 2 days C = 0.77 C = 0.89 for for TcB TcB plus percentile gestational age group and exclusive breastfeeding

Author(s) (Year) Newman et al (2005)49

Measurement Method Serum

Keren et al (2008)35

Maisels et al (2009)59

TSB exceeded or was within 1 mg/dL of AAP phototherapy treatment threshold Transcutaneous TSB 17 mg/dL

Serum

751

82

48

11456

574

75

Abbreviations: TSB, total serum bilirubin; C, area under receiver operating characteristic curve; TcB, transcutaneous bilirubin; AAP, American Academy of Pediatrics.

maternal age 25 years, and male gender.32 These risk factors have long been documented to increase the risk of hyperbilirubinemia.55-59 In addition, the provider typically has additional clinical information with regard to other factors affecting bilirubin excretion, including breast milk supply, success of breastfeeding, stool color, and stool frequency. Several studies have compared the predictive accuracy of clinical factors with that of total bilirubin levels. Overall, clinical risk models have been shown to have predictive accuracy similar to that of the predischarge bilirubin risk zone used alone. However, the best prediction consistently comes from combining clinical factors, especially gestational age, and breastfeeding, with predischarge bilirubin levels.36,50,51,60 Gestational age has the best potential to increase the predictive ability of a total bilirubin level: An infant less than 38 weeks gestation with a total bilirubin above the 75th percentile would be considered high risk and has about a 42% probability of developing a TSB level 1 mg/dL below the AAP phototherapy threshold or higher36 (see Table 2).

Effects of Bilirubin Screening

A few recent studies have shown that predischarge screening is associated with a reduction in the incidence of severe hyperbilirubinemia, although the extent to which this is due to an increase in phototherapy use has been unclear61 or has varied across studies(Table 3).46,62 These studies have found implementation of universal bilirubin screening was associated with a 40% to 70% decrease in TBS levels 25 mg/dL, with suggestions of benefit of similar magnitude for TSB 30 mg/dL in all studies, which was statistically significant in the largest study.62 It is possible that some of the decrease in hyperbilirubinemia observed in these studies was not because of the screening itself but because of a greater level of awareness and concern about hyperbilirubinemia that accompanied institution of screening, which might also be accomplished without screening. However, the data from the Kaiser Permanente Medical Care Program suggested that at least some of the benefit was achieved through better detection of previously undiagnosed

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Burgos et al.
Table 3. Studies of the Effect of Universal Bilirubin Screening on Phototherapy Use and Frequency of Hyperbilirubinemia Baseline Rate per 100 with TSB 20.0-24.9 1.20

11

Author(s) (Year); System Eggert et al (2006)60 Intermountain Healthcare Kuzniewicz et al (2009)45 Northern California Kaiser Mah et al (2010)61 Hospital Corporation of America

N Births N Births Baseline Baseline Screened Phototherapy 48789

Change in Phototherapy

Baseline Baseline Rate per Rate per RRR 1000 TSB RRR 100000 RRR (%) 25.0-29.9 (%) TSB 30 (%) 45 0.55 66 10.3 44

38182

52483 Not stated; Not stated; 22% readmissions decrease in for jaundice readmissions 0.55% for jaundice 319904 4.20% 117% increase

2.00

32

1.20

74

12.0

57

129345

899472

4.40%

5% to 16% increase

0.56

40

0.43

38

8.5

65

Abbreviations: TSB, total serum bilirubin (mg/dL); RRR, relative risk reduction

hyperbilirubinemia, because the frequency of infants identified with peak TSB levels of 15.0 to 19.9 mg/dL increased during the study period, whereas the frequency of infants with TSB levels 20 mg/dL decreased.46 An additional benefit of universal screening is the assurance that bilirubin levels warranting immediate treatment will be identified. Although most such newborns would likely be significantly jaundiced, universal screening offers a backup to the physical examination so that no newborn will be missed because of inadequate physical assessment. Discovery of significant hyperbilirubinemia in a jaundiced infant may alter the management of that infant. If the total bilirubin level is above the recommended levels for phototherapy or rising rapidly compared with a previous value, there is considerable evidence that phototherapy can lower bilirubin levels and/or keep them from rising.2,22,63 Hyperbilirubinemia requiring phototherapy or rising rapidly should also prompt the provider to consider possible causes. Unconjugated hyperbilirubinemia can either be a result of increased bilirubin production, decreased conjugation of bilirubin, increased reabsorption of bilirubin from the intestine, or some combination of the three. Decreased conjugation may be because of delay in the maturation of the activity of the enzyme that conjugates bilirubin (uridine 5'-diphospho-glucuronosyl transferase) or to genetic variation in the activity of that enzyme, which leads to racial differences in the frequency of unconjugated hyperbilirubinemia.64 Similarly, increased bilirubin production may be due to hemolysis from maternalinfant blood type incompatibility, G6PD deficiency, cephalohematoma or other factors.

Recommendations for Newborn Follow-Up

Because bilirubin levels commonly peak at 3 to 5 days of age, the AAP 2004 hyperbilirubinemia guideline recommends that most newborns be examined by a health care provider within 48 to 72 hours after discharge, with the timing of the follow-up visit determined by the length of birth hospital stay, risk factors for hyperbilirubinemia, and other clinical risk factors. In particular, late-preterm infants are at greater risk for morbidity and mortality than term infants and are more likely to require rehospitalization for jaundice, feeding difficulties, dehydration, and suspected sepsis.65 Infants with few or no risk factors and infants discharged after 72 to 96 hours of age can be examined after a longer interval. Infants delivered by Cesarean section have decreased risk of jaundice and of readmission for hyperbilirubinemia.66 Potential reasons for the protective effect of Cesarean delivery include the greater initial length of stay, leading to increased recognition and treatment of jaundice during the birth hospitalization, early formula supplementation, less placental transfusion, and stress prior to delivery prompting induction of conjugating enzymes or metabolism of bilirubin as an antioxidant.66,67 Specific follow-up recommendations are available that explicitly consider the screening bilirubin level obtained prior to hospital discharge, the gestational age, and the presence of additional hyperbilirubinemia risk factors.43 Although the AAP did not consider the evidence to support these recommendations sufficient to make them part of a new guideline, they do seem reasonable to us.

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12 However, it is important to note that neither their efficacy nor cost-efficacy has been established, and that the experiences of the authors might lead them to be overly conservative.44 After follow-up is planned, parent education plays an important role in hyperbilirubinemia prevention, ensuring that the provider is contacted if concerning signs arise prior to the scheduled visit and also ensuring that the infant arrives at the scheduled visit. Frequency of breastfeeding, frequency of voiding and stooling, progression of jaundice, and signs of illness can all be monitored by the engaged parent and shared with the provider. These historical items can then be complemented by the percentage change in weight and the presence or absence and level of jaundice on exam. Parents of jaundiced infants may be informed that although sunlight through a window may help reduce bilirubin levels, it will only work to the extent that the baby is unclothed, which can make it difficult to ensure the babys temperature is controlled. Furthermore, because of the bleaching effect of sunlight on the skin, parents and providers may be falsely reassured about resolution of jaundice. Examining a covered area, such as under the diaper, may be useful. Frequent breastfeeding may be helpful in preventing and/or treating jaundice, and formula feeding has been shown to reduce the risk of jaundice.68,69 As such, some experts may recommend formula for infants with significant hyperbilirubinemia. However, because formula use may compromise breastfeeding, and because breastfeeding offers so many health benefits for infants, formula use may be helpful in the context of excellent lactation support, but should not be casually recommended. Home remedies have not been shown to be useful and can be dangerous; providers should provide anticipatory guidance discouraging home remedies.

Clinical Pediatrics 51(1) measurement of total bilirubin (serum or transcutaneous), or some combination of both. When this assessment includes a total bilirubin measurement, it is commonly referred to as universal bilirubin screening. This general approach assumes that risk assessment prevents hyperbilirubinemia and kernicterus and that there are clear alterations in management that are indicated in newborns with different bilirubin levels, taking into account clinical risk factors for jaundice. Although these assumptions are not proven, they seem reasonable to us. Although the evidence for universal bilirubin screening for prevention of kernicterus may not be strong, the evidence for decreasing the incidence of total bilirubin levels >25 mg/dL seems sufficient. Furthermore, universal screening is also useful in the setting of clinical jaundice, when a total bilirubin measurement will indicate whether or not an infant has developed hyperbilirubinemia that requires either treatment or further investigation as to the cause or both. In younger infants it is even more important to rely on measurements of total bilirubin to determine treatment, rather than on visual estimation of the level of jaundice. For those providers and institutions that decide to implement universal screening, many tools and toolkits are available to aid with implementation of a bilirubin screening strategy.70-72 Since effective treatment for hyperbilirubinemia is easily available in developed countries and is believed to be effective in preventing kernicterus, and since the implementation of universal screening is likely to identify more cases of hyperbilirubinemia, the argument against universal screening is unlikely to be lack of efficacy, but rather the potentially high number of infants that need to be tested and possibly treated to prevent a rare outcome. Implementation of universal bilirubin screening may be costly, and estimating cost-effectiveness is difficult given the unknown incidence of kernicterus, practice variability, and unknown costs related to policies, information exchange, and technology. Whether or not universal screening is implemented, the ultimate success of any risk assessment strategy depends on appropriate follow up of infants identified to be at risk for hyperbilirubinemia or identified to have significant hyperbilirubinemia.

Conclusions
Based on the above review, we recommend the following with regard to bilirubin screening in newborn infant: First, infants with any jaundice noted at less than 24 hours of age should have an immediate bilirubin level. Second, infants who appear jaundiced prior to discharge from the birth hospitalization should have a TSB or TcB performed prior to discharge. Finally, infants 3 to 5 days old or older with only minimal jaundice and no other clinical risk factors may not need another bilirubin measured. When caring for infants not significantly jaundiced in the first 24 to 48 hours of life, the providers main goal (with respect to hyperbilirubinemia) should be to identify infants that warrant closer follow-up and, perhaps, future bilirubin measurement. According to the AAP guidelines, this predischarge risk assessment for hyperbilirubinemia, required for all newborns, can be done by evaluation of clinical risk factors,

Future Perspective
Although much has been learned about prevention of hyperbilirubinemia and kernicterus, there are still many topics deserving of future research. Among the most important is the extent to which increasing efforts to identify and treat hyperbilirubinemia will translate into reductions in kernicterus, and how this can be accomplished most efficiently. We do have strong evidence

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Burgos et al. from observational studies that universal screening is temporally related to reductions in the frequency of TSB 25 mg/dL, and 1 study showing and 2 consistent with a reduction in TSB levels 30 mg/dL. Although this seems likely to translate into fewer kernicterus cases, it is not clear that, for example, a 60% reduction of TSB levels 30 mg/dL will translate in to a 60% reduction in the risk of kernicterus. It is possible that the cases of very high TSB levels so prevented were not those most likely to cause kernicterus. Many cases of kernicterus are due to sepsis or G6PD deficiency73; at least the latter can cause sudden and dramatic rises in TSB in spite of treatment, and thus might be more difficult to prevent with a screening program.10 In areas where G6PD deficiency is prevalent, screening for that disorder and identifying modifiable triggers of hemolysis may be able to reduce the risk of kernicterus.74 As screening for genetic variants such as G6PD deficiency and Gilberts disease becomes quicker and less expensive, it may become feasible to obtain these tests to provide additional guidance for bilirubin follow-up and treatment decisions Given the rarity of kernicterus, comparative studies to estimate the efficiency of various strategies for monitoring and treating hyperbilirubinemia will rely on the surrogate outcome of very high bilirubin levels for the foreseeable future. There remains much work to be done to identify which infants really need bilirubin levels, phototherapy and exchange transfusions. For example the recent NICE guidelines for phototherapy and exchange transfusion33 differ significantly from those of the AAP, especially in the first 72 hours after birth. Because there is significant practice variation in treating hyperbilirubinemia,28,72,75 observational studies of the comparative efficacy of different follow-up, phototherapy, and exchange transfusion practices should be possible. These studies will allow us to continue to our treatment of hyperbilirubinemia in newborns in a more evidence-based fashion.

13 standard show promise in reducing this variability, with coefficients of variation reduced to less than 5%.78,79 It is important to be aware of the method of testing used in each clinical laboratory. The Vitros method in particular has been shown to result in higher bilirubin values than traditional methods, especially when total bilirubin values are >14 mg/dL.79 This is an important point when interpreting bilirubin results. Clinicians who do not know the method used in their laboratory can inquire with the directors of the clinical laboratories they use. One clue is how the result is reported. While traditional methods measure and report total, direct, and indirect bilirubin levels (where indirect = total direct), laboratories using the Vitros method will generally report total, conjugated and unconjugated bilirubin levels. Both types of analyzers may report neonatal total bilirubin, which has been shown to be interchangeable with total bilirubin in newborns.80 While total bilirubin measures all fractions of bilirubin and the neonatal bilirubin does not include -bilirubin (which is covalently bound to albumin), -bilirubin levels are very low in most newborns. Studies of transcutaneous (TcB) measurements with various devices have found them to correlate closely with TSB levels, generally within 2 to 3 mg/dL.81-84 However, most of the infants in these studies had only moderate elevations of bilirubin levels, and there is some evidence that the transcutaneous instruments are less accurate at higher bilirubin levels (>15 mg/dL).84,85 In addition, our anecdotal experience is that even among instruments made by the same manufacturer, not all of these instruments perform equally well. Before buying such an instrument, users should make sure it can be returned if it does not function properly, and should document the accuracy compared with total bilirubin levels before relying on it. Although both instruments are easy to use, the JM-103 (Konica Minolta, Tokyo, Japan) device tends to overestimate bilirubin levels in dark-skinned infants,82 and the BiliChek (Respironics, Marietta, GA) may underestimate the total serum value in Hispanic infants.81,84 Additional unreliability may occur with TcB measurements taken on the forehead because of exposure to ambient light, especially sunlight. Therefore, TcB should be measured on the sternum.86 The AAP hyperbilirubinemia guidelines recommend either TSB or TcB (interchangeably) for screening purposes. However, once total bilirubin is documented to be 15 mg/dL or rising rapidly, TSB is recommended. TSB is also required once infants begin phototherapy, because TcB may result in falsely low measurements.

Measurement Options: Serum Bilirubin and Transcutaneous Bilirubin

Total serum bilirubin measured in a clinical laboratory is considered the gold standard for bilirubin level, but even this supposed gold standard may not be accurate. Significant interlaboratory variability in TSB measurements, with coefficients of variation across laboratories of 10% to 15%, has been reported.76,77 (The coefficient of variation is defined as the ratio of the standard deviation to the mean. It is a unitless measure of dispersion of data points.) However, more recent studies using a more appropriate

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14 Declaration of Conflicting Interests

The author(s) declared a potential conflict of interest (eg, a financial relationship with the commercial organizations or products discussed in this article) as follows: Dr Newman has served as a consultant in medical malpractice cases related to hyperbilirubinemia. Dr Burgos is cofounder and President of BiliTool, Inc, which is currently run as a notfor-profit organization. The authors have no additional relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflicts with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was used in the production of this article.

Clinical Pediatrics 51(1)

10. Nair PA, Al Khusaiby SM. Kernicterus and G6PD deficiencya case series from Oman. J Trop Pediatr. 2003;49:74-77. 11. Yeung CY. Kernicterus in term infants. Aust Paediatr J. 1985;21:273-274. 12. Owa JA, Ogunlesi TA. Why we are still doing so many exchange blood transfusion for neonatal jaundice in Nigeria. World J Pediatr. 2009;5:51-55. 13. van de Bor M, van Zeben-van der Aa TM, VerlooveVanhorick SP, Brand R, Ruys JH. Hyperbilirubinemia in preterm infants and neurodevelopmental outcome at 2 years of age: results of a national collaborative survey. Pediatrics. 1989;83:915-920. 14. van de Bor M, Ens-Dokkum M, Schreuder AM, Veen S, Brand R, Verloove-Vanhorick SP. Hyperbilirubinemia in low birth weight infants and outcome at 5 years of age. Pediatrics. 1992;89:359-364. 15. Oh W, Tyson JE, Fanaroff AA, et al. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics. 2003;112: 773-779. 16. Sanpavat S. Exchange transfusion and its morbidity in tenyear period at King Chulalongkorn Hospital. J Med Assoc Thai. 2005;88:588-592. 17. Patra K, Storfer-Isser A, Siner B, Moore J, Hack M. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr. 2004;144:626-631. 18. Jackson J. Adverse events associated with exchange transfusion in healthy and ill newborn. Pediatrics. 1997;99:e7. 19. Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbidity and mortality associated with exchange transfusion. Pediatrics. 1985;75(2 Pt 2):417-421. 20. Aspberg S, Dahlquist G, Kahan T, Kallen B. Confirmed association between neonatal phototherapy or neonatal icterus and risk of childhood asthma. Pediatr Allergy Immunol. 2010;21(4 Pt 2):e733-e739. 21. Aspberg S, Dahlquist G, Kahan T, Kallen B. Is neonatal phototherapy associated with an increased risk for hospitalized childhood bronchial asthma? Pediatr Allergy Immunol. 2007;18:313-319. 22. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358:920-928. 23. Dahlquist G, Kallen B. Indications that phototherapy is a risk factor for insulin-dependent diabetes. Diabetes Care. 2003;26:247-248. 24. Burgos AE, Schmitt SK, Stevenson DK, Phibbs CS. Readmission for neonatal jaundice in California, 19912000: trends and implications. Pediatrics. 2008;121: e864-e869. 25. Seidman DS, Paz I, Armon Y, Ergaz Z, Stevenson DK, Gale R. Effect of publication of the Practice parameter for the management of hyperbilirubinemia on treatment of neonatal jaundice. Acta Paediatr. 2001;90:292-295.

Funding
The authors received no financial support for the research and/ or authorship of this article.

References
1. Keren R, Tremont K, Luan X, Cnaan A. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94:F317-F322. 2. Ip S, Chung M, Kulig J, et al; American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. An evidencebased review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;114:e130-e153. 3. Brooks JC, Fisher-Owens SA, Wu YW, Strauss DJ, Newman TB. Evidence suggests there was not a resurgence of kernicterus in the 1990s. Pediatrics. In press. 4. Sgro M. Kernicterus, January 2007 to December, 2008. CPSP Canadian Paediatroc Surveillance Program. Ottawa, Ontario, Canada: Public Health Agency of Canada; 2009: 41-43. 5. Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ. 2006;175:587-590. 6. Manning D, Todd P, Maxwell M, Platt M. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed. 2007;92:342-346. 7. Bjerre JV, Petersen JR, Ebbesen F. Surveillance of extreme hyperbilirubinaemia in Denmark. A method to identify the newborn infants. Acta Paediatr. 2008;97:1030-1034. 8. Bjerre JV, Ebbesen F. Incidence of kernicterus in newborn infants in Denmark [in Danish]. Ugeskr Laeger. 2006;168: 686-691. 9. Burke BL, Robbins JM, Bird TM, Hobbs CA, Nesmith C, Tilford JM. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988-2005. Pediatrics. Feb 2009;123(2):524-532.

Downloaded from cpj.sagepub.com by guest on February 8, 2014

Burgos et al.
26. Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG. A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality. Pediatrics. 2007;120:27-32. 27. Maisels M. Is exchange transfusion for hyperbilirubinemia in danger of becoming extinct? [Abstract]. Pediatr Res. 1999;45:210A. 28. Rennie JM, Sehgal A, De A, Kendall GS, Cole TJ. Range of UK practice regarding thresholds for phototherapy and exchange transfusion in neonatal hyperbilirubinaemia. Arch Dis Child Fetal Neonatal Ed. 2009;94:F323-327. 29. Petrova A, Mehta R, Birchwood G, Ostfeld B, Hegyi T. Management of neonatal hyperbilirubinemia: pediatricians practices and educational needs. BMC Pediatr. 2006;6:6. 30. Gartner L. Practice patterns in neonatal hyperbilirubinemia. Pediatrics. 1998;101:25-31. 31. Hansen T. Therapeutic approaches to neonatal jaundice: an international survey. Clin Pediatr (Phila). 1996;35:309-316. 32. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. 33. Rennie J, Burman-Roy S, Murphy MS; Guideline Development Group. Neonatal jaundice: summary of NICE guidance. BMJ. 2010;340:c2409. 34. Newman TB, Kohn MA. Evidence-Based Diagnosis. New York, NY: Cambridge University Press; 2009. 35. Eddy D. Common Screening Tests. Philadelphia, PA: American College of Physicians; 1991. 36. Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics. 2008;121:e170-e179. 37. Kramer LI. Advancement of dermal icterus in the jaundiced newborn. Am J Dis Child. 1969;118:454-458. 38. Riskin A, Tamir A, Kugelman A, Hemo M, Bader D. Is visual assessment of jaundice reliable as a screening tool to detect significant neonatal hyperbilirubinemia? J Pediatr. 2008;152:782-787. 39. Riskin A, Kuglman A, Abend-Weinger M, Green M, Hemo M, Bader D. In the eye of the beholder: how accurate is clinical estimation of jaundice in newborns? Acta Paediatr. 2003;92:574-576. 40. Moyer VA, Ahn C, Sneed S. Accuracy of clinical judgment in neonatal jaundice. Arch Pediatr Adolesc Med. 2000;154: 391-394. 41. Madlon-Kay DJ. Recognition of the presence and severity of newborn jaundice by parents, nurses, physicians, and icterometer. Pediatrics. 1997;100:E3. 42. Ebbesen F. The relationship between the cephalo-pedal progress of clinical icterus and the serum bilirubin concentration in newborn infants without blood type sensitization. Acta Obstet Gynecol Scand. 1975;54:329-332.

15
43. Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Management of hyperbilirubinemia in the newborn infant 35 weeks gestationan update with clarifications. Pediatrics. 2009;124:1193-1198. 44. Newman TB. Universal bilirubin screening, guidelines, and evidence. Pediatrics. 2009;124:1199-1202. 45. Trikalinos T, Chung M, Lau J, Ip S. Systematic review of screening for bilirubin encephalopathy in neonates. Pediatrics. 2009;124:1162-1171. 46. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics. 2009;124: 1031-1039. 47. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and nearterm newborns. Pediatrics. 1999;103:6-14. 48. Maisels MJ, Newman TB. Predicting hyperbilirubinemia in newborns: the importance of timing. Pediatrics. 1999;103:493-495. 49. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of > or = 35 weeks gestation. Pediatrics. 2006;117: 1169-1173. 50. Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med. 2005;159:113-119. 51. Keren R, Bhutani VK, Luan X, Nihtianova S, Cnaan A, Schwartz JS. Identifying newborns at risk of significant hyperbilirubinaemia: a comparison of two recommended approaches. Arch Dis Child. 2005;90:415-421. 52. Bhutani VK, Johnson LH. Urgent clinical need for accurate and precise bilirubin measurements in the United States to prevent kernicterus. Clin Chem. 2004;50:477-480. 53. De Luca D, Jackson GL, Tridente A, Carnielli VP, Engle WD. Transcutaneous bilirubin nomograms: a systematic review of population differences and analysis of bilirubin kinetics. Arch Pediatr Adolesc Med. 2009;163: 1054-1059. 54. Maisels MJ. Jaundice. In: MacDonald M, Seshia M, Mullett M, eds. Neonatology: Pathophysiology and Management of the Newborn. 6th ed. Philadelphia, PA: JB Lippincott; 2005:768-846. 55. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000;154:1140-1147. 56. Maisels MJ, Gifford K, Antle CE, Leib GR. Jaundice in the healthy newborn infant: a new approach to an old problem. Pediatrics. 1988;81:505-511 57. Gale R, Seidman DS, Dollberg S, Stevenson DK. Epidemiology of neonatal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr. 1990;10:82-86.

Downloaded from cpj.sagepub.com by guest on February 8, 2014

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58. Osborn LM, Lenarsky C, Oakes RC, Reiff MI. Phototherapy in full-term infants with hemolytic disease secondary to ABO incompatibility. Pediatrics. 1984;74: 371-374. 59. Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. Epidemiology of neonatal hyperbilirubinemia. Pediatrics. 1985;75:770-774. 60. Maisels MJ, Deridder JM, Kring EA, Balasubramaniam M. Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol. 2009;29: 612-617. 61. Eggert LD, Wiedmeier SE, Wilson J, Christensen RD. The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006;117:e855-e862. 62. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics. 2010;125:e1143-e1148. 63. Maisels MJ. Jaundice. In: Sinclair JC, Bracken MB. Effective Care of the Newborn Infant. Oxford, UK: Oxford University Press; 1992:507-561. 64. Chang PF, Lin YC, Liu K, Yeh SJ, Ni YH. Prolonged unconjugated hyperbiliriubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase. J Pediatr. 2009;155:860-863. 65. Engle WA, Tomashek KM, Wallman C. Late-preterm infants: a population at risk. Pediatrics. 2007;120:1390-1401. 66. Bertini G, Dani C, Tronchin M, Rubaltelli FF. Is breastfeeding really favoring early neonatal jaundice? Pediatrics. 2001;107:E41. 67. Wiedemann M, Kontush A, Finckh B, Hellwege HH, Kohlschtter A. Neonatal blood plasma is less susceptible to oxidation than adult plasma owing to its higher content of bilirubin and lower content of oxidizable fatty acids. Pediatr Res. 2003;53:843-849. 68. Kuzniewicz MW, Escobar GJ, Wi S, Liljestrand P, McCulloch C, Newman TB. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr. 2008;153:234-240. 69. Gourley GR, Kreamer B, Arend R. The effect of diet on feces and jaundice during the first 3 weeks of life. Gastroenterology. 1992;103:660-667. 70. Longhurst C, Turner S, Burgos AE. Development of a Web-based decision support tool to increase use of neonatal hyperbilirubinemia guidelines. Jt Comm J Qual Patient Saf. 2009;35:256-262. 71. Longhurst C, Turner S, Burgos AE. BiliTool. 2004. http:// www.bilitool.org. Accessed November 23, 2010.

Clinical Pediatrics 51(1)

72. Agulnik A, Ryumina II, Burgos AE. Hyperbilirubinemia guideline adherence in Russia illustrates universal challenges. Eur J Pediatr. 2009;168:1175-1180. 73. Bhutani VK, Johnson L. Synopsis report from the pilot USA Kernicterus Registry. J Perinatol. 2009;29(Suppl 1):S4-S7. 74. Mallouh AA, Imseeh G, Abu-Osba YK, Hamdan JA. Screening for glucose-6-phosphate dehydrogenase deficiency can prevent severe neonatal jaundice. Ann Trop Paediatr. 1992;12:391-395. 75. Atkinson L, Escobar G, Takayama J, Newman T. Phototherapy use in jaundiced newborns in a large managed care organization: do physicians adhere to the guideline? Pediatrics. 2003;111:e555-e561. 76. Schreiner R, Glick M. Interlaboratory bilirubin variability. Pediatrics. 1982;69:277-281. 77. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements. Clin Chem. 1996;42(6 Pt 1):869-873. 78. Lo SF, Doumas BT, Ashwood ER. Bilirubin proficiency testing using specimens containing unconjugated bilirubin and human serum: results of a College of American Pathologists study. Arch Pathol Lab Med. 2004;128:1219-1223. 79. Lo SF, Doumas BT, Ashwood ER. Performance of bilirubin determinations in US laboratoriesrevisited. Clin Chem. 2004;50:190-194. 80. Lo SF, Jendrzejczak B, Doumas BT. Total or neonatal bilirubin assays in the Vitros 5,1 FS: hemoglobin interference, hemolysis, icterus index. Clin Chem. 2007;53:799-800. 81. Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics. 2000;106:E17. 82. Maisels MJ, Ostrea EM Jr, Cepeda E, et al. Evaluation of the the Minolta Model 103 transcutaneous bilirubinometer. Pediatr Res. 2002;51:341A. 83. Janjindamai W, Tansantiwong T. Accuracy of transcutaneous bilirubinometer estimates using BiliCheck in Thai neonates. J Med Assoc Thai. 2005;88:187-190. 84. Engle WD, Jackson GL, Sendelbach D, Manning D, Frawley WH. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics. 2002;110(1 Pt 1):61-67. 85. Maisels MJ, Ostrea EM Jr, Touch S, et al. Evaluation of a new transcutaneous bilirubinometer. Pediatrics. 2004;113: 1628-1635. 86. Poland RL, Hartenberger C, McHenry H, Hsi A. Comparison of skin sites for estimating serum total bilirubin in in-patients and out-patients: chest is superior to brow. J Perinatol. 2004;24:541-543.

Downloaded from cpj.sagepub.com by guest on February 8, 2014