Pediatrics AAP

AMERICAN ACADEMY OF PEDIATRICS

CLINICAL PRACTICE GUIDELINE

Subcommittee on Hyperbilirubinemia

Management of Hyperbilirubinemia in the Newborn Infant 35 or MoreWeeks of Gestation

ABSTRACT. Jaundice occurs in most newborn infants.Most jaundice is benign, but because of the potentialtoxicity of bilirubin, newborn infants must be monitoredto identify those who might develop severe hyperbili-rubinemia and, in rare cases, acute bilirubin encephalop-athy or kernicterus. The focus of this guideline is toreduce the incidence of severe hyperbilirubinemia andbilirubin encephalopathy while minimizing the risks ofunintended harm such as maternal anxiety, decreasedbreastfeeding, and unnecessary costs or treatment. Al-though kernicterus should almost always be prevent-able, cases continue to occur. These guidelines provide aframework for the prevention and management ofhyperbilirubinemia in newborn infants of 35 or moreweeks of gestation. In every infant, we recommend thatclinicians 1) promote and support successful breastfeed-ing; 2) perform a systematic assessment before dischargefor the risk of severe hyperbilirubinemia; 3) provideearly and focused follow-up based on the risk assess-ment; and 4) when indicated, treat newborns with pho-totherapy or exchange transfusion to prevent the devel-opment of severe hyperbilirubinemia and, possibly,bilirubin encephalopathy (kernicterus). Pediatrics 2004;114:297316; hyperbilirubinemia, newborn, kernicterus,bilirubin encephalopathy, phototherapy.

ABBREVIATIONS. AAP, American Academy of Pediatrics; TSB,total serum bilirubin; TcB, transcutaneous bilirubin; G6PD, glu-cose-6-phosphate dehydrogenase; ETCOc, end-tidal carbon mon-oxide corrected for ambient carbon monoxide; B/A, bilirubin/albumin; UB, unbound bilirubin.

BACKGROUND

In October 1994, the Provisional Committee forQuality Improvement and Subcommittee on Hy-perbilirubinemia of the American Academy ofPediatrics (AAP) produced a practice parameterdealing with the management of hyperbilirubinemiain the healthy term newborn.1 The current guidelinerepresents a consensus of the committee charged bythe AAP with reviewing and updating the existingguideline and is based on a careful review of theevidence, including a comprehensive literature re-view by the New England Medical Center Evidence-Based Practice Center.2 (See An Evidence-BasedReview of Important Issues Concerning Neonatal

Hyperbilirubinemia3 for a description of the meth-odology, questions addressed, and conclusions ofthis report.) This guideline is intended for use byhospitals and pediatricians, neonatologists, familyphysicians, physician assistants, and advanced prac-tice nurses who treat newborn infants in the hospitaland as outpatients. A list of frequently asked ques-tions and answers for parents is available in Englishand Spanish at www.aap.org/family/jaundicefaq.htm.

DEFINITION OF RECOMMENDATIONSThe evidence-based approach to guideline devel-

opment requires that the evidence in support of apolicy be identified, appraised, and summarized andthat an explicit link between evidence and recom-mendations be defined. Evidence-based recommen-dations are based on the quality of evidence and thebalance of benefits and harms that is anticipatedwhen the recommendation is followed. This guide-line uses the definitions for quality of evidence andbalance of benefits and harms established by theAAP Steering Committee on Quality ImprovementManagement.4 See Appendix 1 for these definitions.

The draft practice guideline underwent extensivepeer review by committees and sections within theAAP, outside organizations, and other individualsidentified by the subcommittee as experts in thefield. Liaison representatives to the subcommitteewere invited to distribute the draft to other represen-tatives and committees within their specialty organi-zations. The resulting comments were reviewed bythe subcommittee and, when appropriate, incorpo-rated into the guideline.

BILIRUBIN ENCEPHALOPATHY ANDKERNICTERUS

Although originally a pathologic diagnosis charac-terized by bilirubin staining of the brainstem nucleiand cerebellum, the term kernicterus has come tobe used interchangeably with both the acute andchronic findings of bilirubin encephalopathy. Biliru-bin encephalopathy describes the clinical central ner-vous system findings caused by bilirubin toxicity tothe basal ganglia and various brainstem nuclei. Toavoid confusion and encourage greater consistencyin the literature, the committee recommends that ininfants the term acute bilirubin encephalopathy beused to describe the acute manifestations of bilirubin

The recommendations in this guideline do not indicate an exclusive courseof treatment or serve as a standard of medical care. Variations, taking intoaccount individual circumstances, may be appropriate.PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Acad-emy of Pediatrics.

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toxicity seen in the first weeks after birth and that theterm kernicterus be reserved for the chronic andpermanent clinical sequelae of bilirubin toxicity.

See Appendix 1 for the clinical manifestations ofacute bilirubin encephalopathy and kernicterus.

FOCUS OF GUIDELINEThe overall aim of this guideline is to promote an

approach that will reduce the frequency of severeneonatal hyperbilirubinemia and bilirubin encepha-lopathy and minimize the risk of unintended harmsuch as increased anxiety, decreased breastfeeding,or unnecessary treatment for the general populationand excessive cost and waste. Recent reports of ker-nicterus indicate that this condition, although rare, isstill occurring.2,510

Analysis of these reported cases of kernicterussuggests that if health care personnel follow the rec-ommendations listed in this guideline, kernicteruswould be largely preventable.

These guidelines emphasize the importance of uni-versal systematic assessment for the risk of severehyperbilirubinemia, close follow-up, and prompt in-tervention when indicated. The recommendationsapply to the care of infants at 35 or more weeks ofgestation. These recommendations seek to furtherthe aims defined by the Institute of Medicine asappropriate for health care:11 safety, effectiveness,efficiency, timeliness, patient-centeredness, and eq-uity. They specifically emphasize the principles ofpatient safety and the key role of timeliness of inter-ventions to prevent adverse outcomes resulting fromneonatal hyperbilirubinemia.

The following are the key elements of the recom-mendations provided by this guideline. Cliniciansshould:

1. Promote and support successful breastfeeding.2. Establish nursery protocols for the identification

and evaluation of hyperbilirubinemia.3. Measure the total serum bilirubin (TSB) or trans-

cutaneous bilirubin (TcB) level on infants jaun-diced in the first 24 hours.

4. Recognize that visual estimation of the degree ofjaundice can lead to errors, particularly in darklypigmented infants.

5. Interpret all bilirubin levels according to the in-fants age in hours.

6. Recognize that infants at less than 38 weeksgestation, particularly those who are breastfed,are at higher risk of developing hyperbiliru-binemia and require closer surveillance andmonitoring.

7. Perform a systematic assessment on all infantsbefore discharge for the risk of severe hyperbil-irubinemia.

8. Provide parents with written and verbal infor-mation about newborn jaundice.

9. Provide appropriate follow-up based on the timeof discharge and the risk assessment.

10. Treat newborns, when indicated, with photo-therapy or exchange transfusion.

PRIMARY PREVENTIONIn numerous policy statements, the AAP recom-mends breastfeeding for all healthy term and near-term newborns. This guideline strongly supports thisgeneral recommendation.RECOMMENDATION 1.0: Clinicians should advisemothers to nurse their infants at least 8 to 12 times perday for the first several days12 (evidence quality C: benefitsexceed harms).

Poor caloric intake and/or dehydration associatedwith inadequate breastfeeding may contribute to thedevelopment of hyperbilirubinemia.6,13,14 Increasingthe frequency of nursing decreases the likelihood ofsubsequent significant hyperbilirubinemia in breast-fed infants.1517 Providing appropriate support andadvice to breastfeeding mothers increases the likeli-hood that breastfeeding will be successful.

Additional information on how to assess the ade-quacy of intake in a breastfed newborn is provided inAppendix 1.RECOMMENDATION 1.1: The AAP recommendsagainst routine supplementation of nondehydrated breast-fed infants with water or dextrose water (evidence qualityB and C: harms exceed benefits).

Supplementation with water or dextrose waterwill not prevent hyperbilirubinemia or decrease TSBlevels.18,19

SECONDARY PREVENTIONRECOMMENDATION 2.0: Clinicians should performongoing systematic assessments during the neonatal pe-riod for the risk of an infant developing severe hyperbil-irubinemia.

Blood TypingRECOMMENDATION 2.1: All pregnant women shouldbe tested for ABO and Rh (D) blood types and have aserum screen for unusual isoimmune antibodies (evidencequality B: benefits exceed harms).RECOMMENDATION 2.1.1: If a mother has not hadprenatal blood grouping or is Rh-negative, a direct anti-body test (or Coombs test), blood type, and an Rh (D) typeon the infants (cord) blood are strongly recommended(evidence quality B: benefits exceed harms).RECOMMENDATION 2.1.2: If the maternal blood isgroup O, Rh-positive, it is an option to test the cord bloodfor the infants blood type and direct antibody test, but itis not required provided that there is appropriate surveil-lance, risk assessment before discharge, and follow-up20(evidence quality C: benefits exceed harms).

Clinical AssessmentRECOMMENDATION 2.2: Clinicians should ensurethat all infants are routinely monitored for the develop-ment of jaundice, and nurseries should have establishedprotocols for the assessment of jaundice. Jaundice shouldbe assessed whenever the infants vital signs are measuredbut no less than every 8 to 12 hours (evidence quality D:benefits versus harms exceptional).

In newborn infants, jaundice can be detected byblanching the skin with digital pressure, revealingthe underlying color of the skin and subcutaneoustissue. The assessment of jaundice must be per-

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formed in a well-lit room or, preferably, in daylightat a window. Jaundice is usually seen first in the faceand progresses caudally to the trunk and extremi-ties,21 but visual estimation of bilirubin levels fromthe degree of jaundice can lead to errors.2224 In mostinfants with TSB levels of less than 15 mg/dL (257mol/L), noninvasive TcB-measurement devices canprovide a valid estimate of the TSB level.2,2529 SeeAppendix 1 for additional information on the clinicalevaluation of jaundice and the use of TcB measure-ments.RECOMMENDATION 2.2.1: Protocols for the assess-ment of jaundice should include the circumstances inwhich nursing staff can obtain a TcB level or order a TSBmeasurement (evidence quality D: benefits versus harmsexceptional).

Laboratory EvaluationRECOMMENDATION 3.0: A TcB and/or TSB measure-ment should be performed on every infant who is jaun-diced in the first 24 hours after birth (Fig 1 and Table 1)30(evidence quality C: benefits exceed harms). The need forand timing of a repeat TcB or TSB measurement willdepend on the zone in which the TSB falls (Fig 2),25,31 theage of the infant, and the evolution of the hyperbiliru-binemia. Recommendations for TSB measurements afterthe age of 24 hours are provided in Fig 1 and Table 1.

See Appendix 1 for capillary versus venous biliru-bin levels.RECOMMENDATION 3.1: A TcB and/or TSB measure-ment should be performed if the jaundice appears excessivefor the infants age (evidence quality D: benefits versusharms exceptional). If there is any doubt about the degreeof jaundice, the TSB or TcB should be measured. Visualestimation of bilirubin levels from the degree of jaundicecan lead to errors, particularly in darkly pigmented in-fants (evidence quality C: benefits exceed harms).RECOMMENDATION 3.2: All bilirubin levels should beinterpreted according to the infants age in hours (Fig 2)(evidence quality C: benefits exceed harms).

Cause of JaundiceRECOMMENDATION 4.1: The possible cause ofjaundice should be sought in an infant receivingphototherapy or whose TSB level is rising rapidly (ie,crossing percentiles [Fig 2]) and is not explained bythe history and physical examination (evidence qual-ity D: benefits versus harms exceptional).RECOMMENDATION 4.1.1: Infants who have an ele-vation of direct-reacting or conjugated bilirubin shouldhave a urinalysis and urine culture.32 Additional labora-tory evaluation for sepsis should be performed if indicatedby history and physical examination (evidence quality C:benefits exceed harms).

See Appendix 1 for definitions of abnormal levelsof direct-reacting and conjugated bilirubin.RECOMMENDATION 4.1.2: Sick infants and those whoare jaundiced at or beyond 3 weeks should have a mea-surement of total and direct or conjugated bilirubin toidentify cholestasis (Table 1) (evidence quality D: benefitversus harms exceptional). The results of the newbornthyroid and galactosemia screen should also be checked inthese infants (evidence quality D: benefits versus harmsexceptional).RECOMMENDATION 4.1.3: If the direct-reacting orconjugated bilirubin level is elevated, additional evalua-tion for the causes of cholestasis is recommended (evidencequality C: benefits exceed harms).RECOMMENDATION 4.1.4: Measurement of the glu-cose-6-phosphate dehydrogenase (G6PD) level is recom-mended for a jaundiced infant who is receiving photother-apy and whose family history or ethnic or geographicorigin suggest the likelihood of G6PD deficiency or for aninfant in whom the response to phototherapy is poor (Fig3) (evidence quality C: benefits exceed harms).

G6PD deficiency is widespread and frequently un-recognized, and although it is more common in thepopulations around the Mediterranean and in theMiddle East, Arabian peninsula, Southeast Asia, andAfrica, immigration and intermarriage have trans-formed G6PD deficiency into a global problem.33,34

TABLE 1. Laboratory Evaluation of the Jaundiced Infant of 35 or More Weeks Gestation

Indications Assessments

Jaundice in first 24 h Measure TcB and/or TSBJaundice appears excessive for infants age Measure TcB and/or TSBInfant receiving phototherapy or TSB rising

rapidly (ie, crossing percentilesBlood type and Coombs test, if not obtained

with cord blood[Fig 2]) and unexplained by history Complete blood count and smearand physical examination Measure direct or conjugated bilirubin

It is an option to perform reticulocyte count,G6PD, and ETCOc, if available

Repeat TSB in 424 h depending on infantsage and TSB level

TSB concentration approaching exchange levelsor not responding to phototherapy

Perform reticulocyte count, G6PD, albumin,ETCOc, if available

Elevated direct (or conjugated) bilirubin level Do urinalysis and urine culture. Evaluate forsepsis if indicated by history and physicalexamination

Jaundice present at or beyond age 3 wk, orsick infant

Total and direct (or conjugated) bilirubinlevel

If direct bilirubin elevated, evaluate forcauses of cholestasis

Check results of newborn thyroid andgalactosemia screen, and evaluate infantfor signs or symptoms of hypothyroidism


Furthermore, G6PD deficiency occurs in 11% to 13%of African Americans, and kernicterus has occurredin some of these infants.5,33 In a recent report, G6PDdeficiency was considered to be the cause of hyper-bilirubinemia in 19 of 61 (31.5%) infants who devel-oped kernicterus.5 (See Appendix 1 for additionalinformation on G6PD deficiency.)

Risk Assessment Before DischargeRECOMMENDATION 5.1: Before discharge, every new-born should be assessed for the risk of developing severehyperbilirubinemia, and all nurseries should establish pro-tocols for assessing this risk. Such assessment is particu-larly important in infants who are discharged before theage of 72 hours (evidence quality C: benefits exceedharms).RECOMMENDATION 5.1.1: The AAP recommends 2clinical options used individually or in combination for thesystematic assessment of risk: predischarge measurementof the bilirubin level using TSB or TcB and/or assessmentof clinical risk factors. Whether either or both options areused, appropriate follow-up after discharge is essential(evidence quality C: benefits exceed harms).

The best documented method for assessing therisk of subsequent hyperbilirubinemia is to measurethe TSB or TcB level25,31,3538 and plot the results ona nomogram (Fig 2). A TSB level can be obtained atthe time of the routine metabolic screen, thus obvi-ating the need for an additional blood sample. Someauthors have suggested that a TSB measurementshould be part of the routine screening of all new-borns.5,31 An infant whose predischarge TSB is in the

low-risk zone (Fig 2) is at very low risk of developingsevere hyperbilirubinemia.5,38

Table 2 lists those factors that are clinically signif-

Fig 2. Nomogram for designation of risk in 2840 well newborns at 36 or more weeks gestational age with birth weight of 2000 g or moreor 35 or more weeks gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values. The serumbilirubin level was obtained before discharge, and the zone in which the value fell predicted the likelihood of a subsequent bilirubin levelexceeding the 95th percentile (high-risk zone) as shown in Appendix 1, Table 4. Used with permission from Bhutani et al.31 See Appendix1 for additional information about this nomogram, which should not be used to represent the natural history of neonatal hyperbiliru-binemia.

TABLE 2. Risk Factors for Development of Severe Hyperbil-irubinemia in Infants of 35 or More Weeks Gestation (in Approx-imate Order of Importance)

Major risk factorsPredischarge TSB or TcB level in the high-risk zone (Fig 2)25,31Jaundice observed in the first 24 h30Blood group incompatibility with positive direct antiglobulin

test, other known hemolytic disease (eg, G6PD deficiency),elevated ETCOc

Gestational age 3536 wk39,40Previous sibling received phototherapy40,41Cephalohematoma or significant bruising39Exclusive breastfeeding, particularly if nursing is not going

well and weight loss is excessive39,40East Asian race39*

Minor risk factorsPredischarge TSB or TcB level in the high intermediate-risk

zone25,31Gestational age 3738 wk39,40Jaundice observed before discharge40Previous sibling with jaundice40,41Macrosomic infant of a diabetic mother42,43Maternal age 25 y39Male gender39,40

Decreased risk (these factors are associated with decreased risk ofsignificant jaundice, listed in order of decreasing importance)

TSB or TcB level in the low-risk zone (Fig 2)25,31Gestational age 41 wk39Exclusive bottle feeding39,40Black race38*Discharge from hospital after 72 h40,44

* Race as defined by mothers description.


icant and most frequently associated with an in-crease in the risk of severe hyperbilirubinemia. But,because these risk factors are common and the risk ofhyperbilirubinemia is small, individually the factorsare of limited use as predictors of significant hyper-bilirubinemia.39 Nevertheless, if no risk factors arepresent, the risk of severe hyperbilirubinemia is ex-tremely low, and the more risk factors present, thegreater the risk of severe hyperbilirubinemia.39 Theimportant risk factors most frequently associatedwith severe hyperbilirubinemia are breastfeeding,gestation below 38 weeks, significant jaundice in aprevious sibling, and jaundice noted before dis-charge.39,40 A formula-fed infant of 40 or moreweeks gestation is at very low risk of developingsevere hyperbilirubinemia.39

Hospital Policies and ProceduresRECOMMENDATION 6.1: All hospitals should providewritten and verbal information for parents at the time ofdischarge, which should include an explanation of jaun-dice, the need to monitor infants for jaundice, and adviceon how monitoring should be done (evidence quality D:benefits versus harms exceptional).

An example of a parent-information handout isavailable in English and Spanish at www.aap.org/family/jaundicefaq.htm.

Follow-upRECOMMENDATION 6.1.1: All infants should be ex-amined by a qualified health care professional in the firstfew days after discharge to assess infant well-being and thepresence or absence of jaundice. The timing and location ofthis assessment will be determined by the length of stay inthe nursery, presence or absence of risk factors for hyper-bilirubinemia (Table 2 and Fig 2), and risk of other neo-natal problems (evidence quality C: benefits exceedharms).

Timing of Follow-upRECOMMENDATION 6.1.2: Follow-up should be pro-vided as follows:

Infant Discharged Should Be Seen by Age

Before age 24 h 72 hBetween 24 and 47.9 h 96 hBetween 48 and 72 h 120 h

For some newborns discharged before 48 hours, 2 fol-low-up visits may be required, the first visit between 24and 72 hours and the second between 72 and 120 hours.Clinical judgment should be used in determining follow-up. Earlier or more frequent follow-up should be providedfor those who have risk factors for hyperbilirubinemia(Table 2), whereas those discharged with few or no riskfactors can be seen after longer intervals (evidence qualityC: benefits exceed harms).RECOMMENDATION 6.1.3: If appropriate follow-upcannot be ensured in the presence of elevated risk fordeveloping severe hyperbilirubinemia, it may be necessaryto delay discharge either until appropriate follow-up canbe ensured or the period of greatest risk has passed (72-96hours) (evidence quality D: benefits versus harms excep-tional).

Follow-up AssessmentRECOMMENDATION 6.1.4: The follow-up assessmentshould include the infants weight and percent changefrom birth weight, adequacy of intake, the pattern of void-ing and stooling, and the presence or absence of jaundice(evidence quality C: benefits exceed harms). Clinical judg-ment should be used to determine the need for a bilirubinmeasurement. If there is any doubt about the degree ofjaundice, the TSB or TcB level should be measured. Visualestimation of bilirubin levels can lead to errors, particu-larly in darkly pigmented infants (evidence quality C:benefits exceed harms).

See Appendix 1 for assessment of the adequacy ofintake in breastfeeding infants.

TREATMENT

Phototherapy and Exchange TransfusionRECOMMENDATION 7.1: Recommendations for treat-ment are given in Table 3 and Figs 3 and 4 (evidencequality C: benefits exceed harms). If the TSB does not fallor continues to rise despite intensive phototherapy, it isvery likely that hemolysis is occurring. The committeesrecommendations for discontinuing phototherapy can befound in Appendix 2.RECOMMENDATION 7.1.1: In using the guidelines forphototherapy and exchange transfusion (Figs 3 and 4), thedirect-reacting (or conjugated) bilirubin level should notbe subtracted from the total (evidence quality D: benefitsversus harms exceptional).

In unusual situations in which the direct bilirubinlevel is 50% or more of the total bilirubin, there areno good data to provide guidance for therapy, andconsultation with an expert in the field is recom-mended.RECOMMENDATION 7.1.2: If the TSB is at a level atwhich exchange transfusion is recommended (Fig 4) or ifthe TSB level is 25 mg/dL (428 mol/L) or higher at anytime, it is a medical emergency and the infant should beadmitted immediately and directly to a hospital pediatricservice for intensive phototherapy. These infants shouldnot be referred to the emergency department, because itdelays the initiation of treatment54 (evidence quality C:benefits exceed harms).RECOMMENDATION 7.1.3: Exchange transfusionsshould be performed only by trained personnel in a neo-natal intensive care unit with full monitoring and resus-citation capabilities (evidence quality D: benefits versusharms exceptional).RECOMMENDATION 7.1.4: In isoimmune hemolyticdisease, administration of intravenous -globulin (0.5-1g/kg over 2 hours) is recommended if the TSB is risingdespite intensive phototherapy or the TSB level is within 2to 3 mg/dL (34-51 mol/L) of the exchange level (Fig4).55 If necessary, this dose can be repeated in 12 hours(evidence quality B: benefits exceed harms).

Intravenous -globulin has been shown to reducethe need for exchange transfusions in Rh and ABOhemolytic disease.5558 Although data are limited, itis reasonable to assume that intravenous -globulinwill also be helpful in the other types of Rh hemolyticdisease such as anti-C and anti-E.


Serum Albumin Levels and the Bilirubin/AlbuminRatioRECOMMENDATION 7.1.5: It is an option to measurethe serum albumin level and consider an albumin level ofless than 3.0 g/dL as one risk factor for lowering thethreshold for phototherapy use (see Fig 3) (evidence qual-ity D: benefits versus risks exceptional.).RECOMMENDATION 7.1.6: If an exchange transfusionis being considered, the serum albumin level should bemeasured and the bilirubin/albumin (B/A) ratio used inconjunction with the TSB level and other factors in deter-mining the need for exchange transfusion (see Fig 4)(evidence quality D: benefits versus harms exceptional).

The recommendations shown above for treatinghyperbilirubinemia are based primarily on TSB lev-els and other factors that affect the risk of bilirubinencephalopathy. This risk might be increased by aprolonged (rather than a brief) exposure to a certainTSB level.59,60 Because the published data that ad-dress this issue are limited, however, it is not possi-ble to provide specific recommendations for inter-vention based on the duration of hyperbilirubinemia.

See Appendix 1 for the basis for recommendations7.1 through 7.1.6 and for the recommendations pro-vided in Figs 3 and 4. Appendix 1 also contains adiscussion of the risks of exchange transfusion andthe use of B/A binding.

Acute Bilirubin EncephalopathyRECOMMENDATION 7.1.7: Immediate exchangetransfusion is recommended in any infant who is jaun-

diced and manifests the signs of the intermediate to ad-vanced stages of acute bilirubin encephalopathy61,62 (hy-pertonia, arching, retrocollis, opisthotonos, fever, high-pitched cry) even if the TSB is falling (evidence quality D:benefits versus risks exceptional).

PhototherapyRECOMMENDATION 7.2: All nurseries and servicestreating infants should have the necessary equipment toprovide intensive phototherapy (see Appendix 2) (evidencequality D: benefits exceed risks).

Outpatient Management of the Jaundiced BreastfedInfantRECOMMENDATION 7.3: In breastfed infants who re-quire phototherapy (Fig 3), the AAP recommends that,if possible, breastfeeding should be continued (evidencequality C: benefits exceed harms). It is also an option tointerrupt temporarily breastfeeding and substitute for-mula. This can reduce bilirubin levels and/or enhancethe efficacy of phototherapy6365 (evidence quality B: ben-efits exceed harms). In breastfed infants receiving photo-therapy, supplementation with expressed breast milk orformula is appropriate if the infants intake seems inade-quate, weight loss is excessive, or the infant seems dehy-drated.

IMPLEMENTATION STRATEGIESThe Institute of Medicine11 recommends a dra-

matic change in the way the US health care system

TABLE 3. Example of a Clinical Pathway for Management of the Newborn Infant Readmitted forPhototherapy or Exchange Transfusion

TreatmentUse intensive phototherapy and/or exchange transfusion as indicated in Figs 3 and 4 (see

Appendix 2 for details of phototherapy use)Laboratory tests

TSB and direct bilirubin levelsBlood type (ABO, Rh)Direct antibody test (Coombs)Serum albuminComplete blood cell count with differential and smear for red cell morphologyReticulocyte countETCOc (if available)G6PD if suggested by ethnic or geographic origin or if poor response to phototherapyUrine for reducing substancesIf history and/or presentation suggest sepsis, perform blood culture, urine culture, and

cerebrospinal fluid for protein, glucose, cell count, and cultureInterventions

If TSB 25 mg/dL (428 mol/L) or 20 mg/dL (342 mol/L) in a sick infant or infant 38 wkgestation, obtain a type and crossmatch, and request blood in case an exchange transfusion isnecessary

In infants with isoimmune hemolytic disease and TSB level rising in spite of intensivephototherapy or within 23 mg/dL (3451 mol/L) of exchange level (Fig 4), administerintravenous immunoglobulin 0.51 g/kg over 2 h and repeat in 12 h if necessary

If infants weight loss from birth is 12% or there is clinical or biochemical evidence ofdehydration, recommend formula or expressed breast milk. If oral intake is in question, giveintravenous fluids.

For infants receiving intensive phototherapyBreastfeed or bottle-feed (formula or expressed breast milk) every 23 hIf TSB 25 mg/dL (428 mol/L), repeat TSB within 23 hIf TSB 2025 mg/dL (342428 mol/L), repeat within 34 h. If TSB 20 mg/dL (342 mol/L),

repeat in 46 h. If TSB continues to fall, repeat in 812 hIf TSB is not decreasing or is moving closer to level for exchange transfusion or the

TSB/albumin ratio exceeds levels shown in Fig 4, consider exchange transfusion (see Fig 4 forexchange transfusion recommendations)

When TSB is 1314 mg/dL (239 mol/L), discontinue phototherapyDepending on the cause of the hyperbilirubinemia, it is an option to measure TSB 24 h after

discharge to check for rebound


ensures the safety of patients. The perspective ofsafety as a purely individual responsibility must bereplaced by the concept of safety as a property ofsystems. Safe systems are characterized by a sharedknowledge of the goal, a culture emphasizing safety,the ability of each person within the system to act ina manner that promotes safety, minimizing the use ofmemory, and emphasizing the use of standard pro-cedures (such as checklists), and the involvement ofpatients/families as partners in the process of care.

These principles can be applied to the challenge ofpreventing severe hyperbilirubinemia and ker-nicterus. A systematic approach to the implementa-tion of these guidelines should result in greatersafety. Such approaches might include

The establishment of standing protocols for nurs-ing assessment of jaundice, including testing TcBand TSB levels, without requiring physician or-ders.

Checklists or reminders associated with risk fac-tors, age at discharge, and laboratory test resultsthat provide guidance for appropriate follow-up.

Explicit educational materials for parents (a keycomponent of all AAP guidelines) concerning theidentification of newborns with jaundice.

FUTURE RESEARCH

Epidemiology of Bilirubin-Induced Central NervousSystem Damage

There is a need for appropriate epidemiologic datato document the incidence of kernicterus in the new-born population, the incidence of other adverse ef-fects attributable to hyperbilirubinemia and its man-agement, and the number of infants whose TSBlevels exceed 25 or 30 mg/dL (428-513 mol/L).Organizations such as the Centers for Disease Con-trol and Prevention should implement strategies forappropriate data gathering to identify the number of

Fig 3. Guidelines for phototherapy in hospitalized infants of 35 or more weeks gestation.Note: These guidelines are based on limited evidence and the levels shown are approximations. The guidelines refer to the use of

intensive phototherapy which should be used when the TSB exceeds the line indicated for each category. Infants are designated as higherrisk because of the potential negative effects of the conditions listed on albumin binding of bilirubin,4547 the blood-brain barrier,48 andthe susceptibility of the brain cells to damage by bilirubin.48

Intensive phototherapy implies irradiance in the blue-green spectrum (wavelengths of approximately 430490 nm) of at least 30W/cm2 per nm (measured at the infants skin directly below the center of the phototherapy unit) and delivered to as much of the infantssurface area as possible. Note that irradiance measured below the center of the light source is much greater than that measured at theperiphery. Measurements should be made with a radiometer specified by the manufacturer of the phototherapy system.

See Appendix 2 for additional information on measuring the dose of phototherapy, a description of intensive phototherapy, and of lightsources used. If total serum bilirubin levels approach or exceed the exchange transfusion line (Fig 4), the sides of the bassinet, incubator,or warmer should be lined with aluminum foil or white material.50 This will increase the surface area of the infant exposed and increasethe efficacy of phototherapy.51

If the total serum bilirubin does not decrease or continues to rise in an infant who is receiving intensive phototherapy, this stronglysuggests the presence of hemolysis.

Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubin level (cholestatic jaundice) may developthe bronze-baby syndrome. See Appendix 2 for the use of phototherapy in these infants.


infants who develop serum bilirubin levels above 25or 30 mg/dL (428-513 mol/L) and those who de-velop acute and chronic bilirubin encephalopathy.This information will help to identify the magnitudeof the problem; the number of infants who need to bescreened and treated to prevent 1 case of kernicterus;and the risks, costs, and benefits of different strate-gies for prevention and treatment of hyperbiliru-binemia. In the absence of these data, recommenda-tions for intervention cannot be considereddefinitive.

Effect of Bilirubin on the Central Nervous System

The serum bilirubin level by itself, except when itis extremely high and associated with bilirubin en-cephalopathy, is an imprecise indicator of long-termneurodevelopmental outcome.2 Additional studiesare needed on the relationship between central ner-vous system damage and the duration of hyperbil-irubinemia, the binding of bilirubin to albumin, andchanges seen in the brainstem auditory evoked re-sponse. These studies could help to better identify

Fig 4. Guidelines for exchange transfusion in infants 35 or more weeks gestation.Note that these suggested levels represent a consensus of most of the committee but are based on limited evidence, and the levels shown

are approximations. See ref. 3 for risks and complications of exchange transfusion. During birth hospitalization, exchange transfusion isrecommended if the TSB rises to these levels despite intensive phototherapy. For readmitted infants, if the TSB level is above the exchangelevel, repeat TSB measurement every 2 to 3 hours and consider exchange if the TSB remains above the levels indicated after intensivephototherapy for 6 hours.

The following B/A ratios can be used together with but in not in lieu of the TSB level as an additional factor in determining the needfor exchange transfusion52:

Risk Category B/A Ratio at Which Exchange TransfusionShould be Considered

TSB mg/dL/Alb, g/dL TSB mol/L/Alb, mol/L

Infants 38 0/7 wk 8.0 0.94Infants 35 0/736 6/7 wk and well or 38 0/7 wk

if higher risk or isoimmune hemolytic diseaseor G6PD deficiency

7.2 0.84

Infants 35 0/737 6/7 wk if higher risk orisoimmune hemolytic disease or G6PD deficiency

6.8 0.80

If the TSB is at or approaching the exchange level, send blood for immediate type and crossmatch. Blood for exchange transfusion ismodified whole blood (red cells and plasma) crossmatched against the mother and compatible with the infant.53


risk, clarify the effect of bilirubin on the central ner-vous system, and guide intervention.

Identification of HemolysisBecause of their poor specificity and sensitivity,

the standard laboratory tests for hemolysis (Table 1)are frequently unhelpful.66,67 However, end-tidalcarbon monoxide, corrected for ambient carbonmonoxide (ETCOc), levels can confirm the presenceor absence of hemolysis, and measurement of ETCOcis the only clinical test that provides a direct mea-surement of the rate of heme catabolism and the rateof bilirubin production.68,69 Thus, ETCOc may behelpful in determining the degree of surveillanceneeded and the timing of intervention. It is not yetknown, however, how ETCOc measurements willaffect management.

Nomograms and the Measurement of Serum and TcBIt would be useful to develop an age-specific (by

hour) nomogram for TSB in populations of newbornsthat differ with regard to risk factors for hyperbiliru-binemia. There is also an urgent need to improve theprecision and accuracy of the measurement of TSB inthe clinical laboratory.70,71 Additional studies arealso needed to develop and validate noninvasive(transcutaneous) measurements of serum bilirubinand to understand the factors that affect these mea-surements. These studies should also assess the cost-effectiveness and reproducibility of TcB measure-ments in clinical practice.2

Pharmacologic TherapyThere is now evidence that hyperbilirubinemia can

be effectively prevented or treated with tin-mesopor-phyrin,7275 a drug that inhibits the production ofheme oxygenase. Tin-mesoporphyrin is not ap-proved by the US Food and Drug Administration. Ifapproved, tin-mesoporphyrin could find immediateapplication in preventing the need for exchangetransfusion in infants who are not responding tophototherapy.75

Dissemination and MonitoringResearch should be directed toward methods for

disseminating the information contained in thisguideline to increase awareness on the part of phy-sicians, residents, nurses, and parents concerning theissues of neonatal hyperbilirubinemia and strategiesfor its management. In addition, monitoring systemsshould be established to identify the impact of theseguidelines on the incidence of acute bilirubin en-cephalopathy and kernicterus and the use of photo-therapy and exchange transfusions.

CONCLUSIONSKernicterus is still occurring but should be largely

preventable if health care personnel follow the rec-ommendations listed in this guideline. These recom-mendations emphasize the importance of universal,systematic assessment for the risk of severe hyperbi-

lirubinemia, close follow-up, and prompt interven-tion, when necessary.

Subcommittee on HyperbilirubinemiaM. Jeffrey Maisels, MB, BCh, ChairpersonRichard D. Baltz, MDVinod K. Bhutani, MDThomas B. Newman, MD, MPHHeather Palmer, MB, BChWarren Rosenfeld, MDDavid K. Stevenson, MDHoward B. Weinblatt, MD

ConsultantCharles J. Homer, MD, MPH, Chairperson

American Academy of Pediatrics SteeringCommittee on Quality Improvement andManagement

StaffCarla T. Herrerias, MPH

ACKNOWLEDGMENTSM.J.M. received grant support from Natus Medical, Inc, for

multinational study of ambient carbon monoxide; WellSpringPharmaceutical Corporation for study of Stannsoporfin (tin-meso-porphyrin); and Minolta, Inc, for study of the Minolta/Hill-RomAir-Shields transcutaneous jaundice meter model JM-103. V.K.B.received grant support from WellSpring Pharmaceutical Corpora-tion for study of Stannsoporfin (tin-mesoporphyrin) and NatusMedical, Inc, for multinational study of ambient carbon monoxideand is a consultant (volunteer) to SpectrX (BiliChek transcutane-ous bilirubinometer). D.K.S. is a consultant to and holds stockoptions through Natus Medical, Inc.

The American Academy of Pediatrics Subcommittee on Hyper-bilirubinemia gratefully acknowledges the help of the followingorganizations, committees, and individuals who reviewed draftsof this guideline and provided valuable criticisms and commen-tary: American Academy of Pediatrics Committee on Nutrition;American Academy of Pediatrics Committee on Practice and Am-bulatory Medicine; American Academy of Pediatrics Committeeon Child Health Financing; American Academy of PediatricsCommittee on Medical Liability; American Academy of PediatricsCommittee on Fetus and Newborn; American Academy of Pedi-atrics Section on Perinatal Pediatrics; Centers for Disease Controland Prevention; Parents of Infants and Children With Kernicterus(PICK); Charles Ahlfors, MD; Daniel Batton, MD; Thomas Bojko,MD; Sarah Clune, MD; Sudhakar Ezhuthachan, MD; LawrenceGartner, MD; Cathy Hammerman, MD; Thor Hansen, MD; LoisJohnson, MD; Michael Kaplan, MB, ChB; Tony McDonagh, PhD;Gerald Merenstein, MD; Mary OShea, MD; Max Perlman, MD;Ronald Poland, MD; Alex Robertson, MD; Firmino Rubaltelli, MD;Steven Shapiro, MD; Stanford Singer, MD; Ann Stark, MD; Gau-tham Suresh, MD; Margot VandeBor, MD; Hank Vreman, PhD;Philip Walson, MD; Jon Watchko, MD; Richard Wennberg, MD;and Chap-Yung Yeung, MD.

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24. Tayaba R, Gribetz D, Gribetz I, Holzman IR. Noninvasive estimation ofserum bilirubin. Pediatrics. 1998;102(3). Available at: www.pediatrics.org/cgi/content/full/102/3/e28

25. Bhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson LH.Noninvasive measurement of total serum bilirubin in a multiracialpredischarge newborn population to assess the risk of severe hyperbi-lirubinemia. Pediatrics. 2000;106(2). Available at: www.pediatrics.org/cgi/content/full/106/2/e17

26. Yasuda S, Itoh S, Isobe K, et al. New transcutaneous jaundice devicewith two optical paths. J Perinat Med. 2003;31:8188

27. Maisels MJ, Ostrea EJ Jr, Touch S, et al. Evaluation of a new transcuta-neous bilirubinometer. Pediatrics. 2004;113:16381645

28. Ebbesen F, Rasmussen LM, Wimberley PD. A new transcutaneousbilirubinometer, bilicheck, used in the neonatal intensive care unit andthe maternity ward. Acta Paediatr. 2002;91:203211

29. Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubinmeasurement: a multicenter evaluation of a new device. Pediatrics.2001;107:12641271

30. Newman TB, Liljestrand P, Escobar GJ. Jaundice noted in the first 24hours after birth in a managed care organization. Arch Pediatr AdolescMed. 2002;156:12441250

31. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischargehour-specific serum bilirubin for subsequent significant hyperbiliru-binemia in healthy term and near-term newborns. Pediatrics. 1999;103:614

32. Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinarytract infection in infancy. Pediatrics. 2002;109:846851

33. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a po-tential complication of glucose-6-phosphate dehydrogenase deficiency.Clin Perinatol. 1998;25:575590

34. Valaes T. Severe neonatal jaundice associated with glucose-6-phosphatedehydrogenase deficiency: pathogenesis and global epidemiology. ActaPaediatr Suppl. 1994;394:5876

35. Alpay F, Sarici S, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. Thevalue of first-day bilirubin measurement in predicting the developmentof significant hyperbilirubinemia in healthy term newborns. Pediatrics.

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36. Carbonell X, Botet F, Figueras J, Riu-Godo A. Prediction of hyperbiliru-binaemia in the healthy term newborn. Acta Paediatr. 2001;90:166170

37. Kaplan M, Hammerman C, Feldman R, Brisk R. Predischarge bilirubinscreening in glucose-6-phosphate dehydrogenase-deficient neonates.Pediatrics. 2000;105:533537

38. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbil-irubinemia in near-term and term infants. Pediatrics. 2001;108:3139

39. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and pre-vention of extreme neonatal hyperbilirubinemia in a mature healthmaintenance organization. Arch Pediatr Adolesc Med. 2000;154:11401147

40. Maisels MJ, Kring EA. Length of stay, jaundice, and hospital readmis-sion. Pediatrics. 1998;101:995998

41. Gale R, Seidman DS, Dollberg S, Stevenson DK. Epidemiology of neo-natal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr.1990;10:8286

42. Berk MA, Mimouni F, Miodovnik M, Hertzberg V, Valuck J. Macroso-mia in infants of insulin-dependent diabetic mothers. Pediatrics. 1989;83:10291034

43. Peevy KJ, Landaw SA, Gross SJ. Hyperbilirubinemia in infants of dia-betic mothers. Pediatrics. 1980;66:417419

44. Soskolne El, Schumacher R, Fyock C, Young ML, Schork A. The effect ofearly discharge and other factors on readmission rates of newborns.Arch Pediatr Adolesc Med. 1996;150:373379

45. Ebbesen F, Brodersen R. Risk of bilirubin acid precipitation in preterminfants with respiratory distress syndrome: considerations of blood/brain bilirubin transfer equilibrium. Early Hum Dev. 1982;6:341355

46. Cashore WJ, Oh W, Brodersen R. Reserve albumin and bilirubin toxicityindex in infant serum. Acta Paediatr Scand. 1983;72:415419

47. Cashore WJ. Free bilirubin concentrations and bilirubin-binding affinityin term and preterm infants. J Pediatr. 1980;96:521527

48. Bratlid D. How bilirubin gets into the brain. Clin Perinatol. 1990;17:449465

49. Wennberg RP. Cellular basis of bilirubin toxicity. N Y State J Med.1991;91:493496

50. Eggert P, Stick C, Schroder H. On the distribution of irradiation inten-sity in phototherapy. Measurements of effective irradiance in an incu-bator. Eur J Pediatr. 1984;142:5861

51. Maisels MJ. Why use homeopathic doses of phototherapy? Pediatrics.1996;98:283287

52. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns.Pediatrics. 1994;93:488494

53. American Association of Blood Banks Technical Manual Committee.Perinatal issues in transfusion practice. In: Brecher M, ed. TechnicalManual. Bethesda, MD: American Association of Blood Banks; 2002:497515

54. Garland JS, Alex C, Deacon JS, Raab K. Treatment of infants withindirect hyperbilirubinemia. Readmission to birth hospital vs nonbirthhospital. Arch Pediatr Adolesc Med. 1994;148:13171321

55. Gottstein R, Cooke R. Systematic review of intravenous immunoglob-ulin in haemolytic disease of the newborn. Arch Dis Child Fetal NeonatalEd. 2003;88:F6F10

56. Sato K, Hara T, Kondo T, Iwao H, Honda S, Ueda K. High-doseintravenous gammaglobulin therapy for neonatal immune haemolyticjaundice due to blood group incompatibility. Acta Paediatr Scand. 1991;80:163166

57. Rubo J, Albrecht K, Lasch P, et al. High-dose intravenous immuneglobulin therapy for hyperbilirubinemia caused by Rh hemolytic dis-ease. J Pediatr. 1992;121:9397

58. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenousimmune globulin in neonatal ABO isoimmunization: factors associatedwith clinical efficacy. Biol Neonate. 1996;70:6974

59. Johnson L, Boggs TR. Bilirubin-dependent brain damage: incidence andindications for treatment. In: Odell GB, Schaffer R, Simopoulos AP, eds.Phototherapy in the Newborn: An Overview. Washington, DC: NationalAcademy of Sciences; 1974:122149

60. Ozmert E, Erdem G, Topcu M. Long-term follow-up of indirect hyper-bilirubinemia in full-term Turkish infants. Acta Paediatr. 1996;85:14401444

61. Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia, PA: W. B.Saunders; 2001

62. Harris M, Bernbaum J, Polin J, Zimmerman R, Polin RA. Developmentalfollow-up of breastfed term and near-term infants with marked hyper-bilirubinemia. Pediatrics. 2001;107:10751080

63. Osborn LM, Bolus R. Breast feeding and jaundice in the first week oflife. J Fam Pract. 1985;20:475480


64. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in thebreast-fed newborn: a controlled trial of four interventions. Pediatrics.1993;91:470473

65. Amato M, Howald H, von Muralt G. Interruption of breast-feedingversus phototherapy as treatment of hyperbilirubinemia in full-terminfants. Helv Paediatr Acta. 1985;40:127131

66. Maisels MJ, Gifford K, Antle CE, Leib GR. Jaundice in the healthynewborn infant: a new approach to an old problem. Pediatrics. 1988;81:505511

67. Newman TB, Easterling MJ. Yield of reticulocyte counts and bloodsmears in term infants. Clin Pediatr (Phila). 1994;33:7176

68. Herschel M, Karrison T, Wen M, Caldarelli L, Baron B. Evaluation of thedirect antiglobulin (Coombs) test for identifying newborns at risk forhemolysis as determined by end-tidal carbon monoxide concentration(ETCOc); and comparison of the Coombs test with ETCOc for detectingsignificant jaundice. J Perinatol. 2002;22:341347

69. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin productionin neonates. Pediatrics. 1997;100:252254

70. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubinmeasurements. Clin Chem. 1996;42:869873

71. Lo S, Doumas BT, Ashwood E. Performance of bilirubin determinationsin US laboratoriesrevisited. Clin Chem. 2004;50:190194

72. Kappas A, Drummond GS, Henschke C, Valaes T. Direct comparison ofSn-mesoporphyrin, an inhibitor of bilirubin production, and photother-apy in controlling hyperbilirubinemia in term and near-term newborns.Pediatrics. 1995;95:468474

73. Martinez JC, Garcia HO, Otheguy L, Drummond GS, Kappas A. Controlof severe hyperbilirubinemia in full-term newborns with the inhibitor ofbilirubin production Sn-mesoporphyrin. Pediatrics. 1999;103:15

74. Suresh G, Martin CL, Soll R. Metalloporphyrins for treatment of uncon-jugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev.2003;2:CD004207

75. Kappas A, Drummond GS, Munson DP, Marshall JR. Sn-mesoporphy-rin interdiction of severe hyperbilirubinemia in Jehovahs Witness new-borns as an alternative to exchange transfusion. Pediatrics. 2001;108:13741377

APPENDIX 1: Additional Notes

Definitions of Quality of Evidence and Balance ofBenefits and Harms

The Steering Committee on Quality Improvementand Management categorizes evidence quality in 4levels:1. Well-designed, randomized, controlled trials or

diagnostic studies on relevant populations2. Randomized, controlled trials or diagnostic stud-

ies with minor limitations; overwhelming, consis-tent evidence from observational studies

3. Observational studies (case-control and cohort de-sign)

4. Expert opinion, case reports, reasoning from firstprinciples

The AAP defines evidence-based recommenda-tions as follows:1

Strong recommendation: the committee believesthat the benefits of the recommended approachclearly exceed the harms of that approach and thatthe quality of the supporting evidence is eitherexcellent or impossible to obtain. Clinicians shouldfollow these recommendations unless a clear andcompelling rationale for an alternative approach ispresent.

Recommendation: the committee believes that thebenefits exceed the harms, but the quality of evi-dence on which this recommendation is based isnot as strong. Clinicians should also generally fol-low these recommendations but should be alert tonew information and sensitive to patient prefer-

ences. In this guideline, the term should impliesa recommendation by the committee.

Option: either the quality of the evidence that ex-ists is suspect or well-performed studies haveshown little clear advantage to one approach overanother. Patient preference should have a substan-tial role in influencing clinical decision-makingwhen a policy is described as an option.

No recommendation: there is a lack of pertinentevidence and the anticipated balance of benefitsand harms is unclear.

Anticipated Balance Between Benefits and HarmsThe presence of clear benefits or harms supports

stronger statements for or against a course of action.In some cases, however, recommendations are madewhen analysis of the balance of benefits and harmsprovides an exceptional dysequilibrium and it wouldbe unethical or impossible to perform clinical trials toprove the point. In these cases the balance of ben-efit and harm is termed exceptional.

Clinical Manifestations of Acute BilirubinEncephalopathy and Kernicterus

Acute Bilirubin EncephalopathyIn the early phase of acute bilirubin encephalopa-

thy, severely jaundiced infants become lethargic andhypotonic and suck poorly.2,3 The intermediatephase is characterized by moderate stupor, irritabil-ity, and hypertonia. The infant may develop a feverand high-pitched cry, which may alternate withdrowsiness and hypotonia. The hypertonia is mani-fested by backward arching of the neck (retrocollis)and trunk (opisthotonos). There is anecdotal evi-dence that an emergent exchange transfusion at thisstage, in some cases, might reverse the central ner-vous system changes.4 The advanced phase, in whichcentral nervous system damage is probably irrevers-ible, is characterized by pronounced retrocollis-opis-thotonos, shrill cry, no feeding, apnea, fever, deepstupor to coma, sometimes seizures, and death.2,3,5

KernicterusIn the chronic form of bilirubin encephalopathy,

surviving infants may develop a severe form of ath-etoid cerebral palsy, auditory dysfunction, dental-enamel dysplasia, paralysis of upward gaze, and,less often, intellectual and other handicaps. Mostinfants who develop kernicterus have manifestedsome or all of the signs listed above in the acutephase of bilirubin encephalopathy. However, occa-sionally there are infants who have developed veryhigh bilirubin levels and, subsequently, the signs ofkernicterus but have exhibited few, if any, anteced-ent clinical signs of acute bilirubin encephalopa-thy.3,5,6

Clinical Evaluation of Jaundice and TcB MeasurementsJaundice is usually seen in the face first and

progresses caudally to the trunk and extremities,7but because visual estimation of bilirubin levels fromthe degree of jaundice can lead to errors,810 a lowthreshold should be used for measuring the TSB.


Devices that provide a noninvasive TcB measure-ment have proven very useful as screening tools,11and newer instruments give measurements that pro-vide a valid estimate of the TSB level.1217 Studiesusing the new TcB-measurement instruments arelimited, but the data published thus far suggest thatin most newborn populations, these instrumentsgenerally provide measurements within 2 to 3mg/dL (3451 mol/L) of the TSB and can replace ameasurement of serum bilirubin in many circum-stances, particularly for TSB levels less than 15mg/dL (257 mol/L).1217 Because phototherapybleaches the skin, both visual assessment of jaun-dice and TcB measurements in infants undergoingphototherapy are not reliable. In addition, the abilityof transcutaneous instruments to provide accuratemeasurements in different racial groups requires ad-ditional study.18,19 The limitations of the accuracyand reproducibility of TSB measurements in the clin-ical laboratory2022 must also be recognized and arediscussed in the technical report.23

Capillary Versus Venous Serum BilirubinMeasurement

Almost all published data regarding the relation-ship of TSB levels to kernicterus or developmentaloutcome are based on capillary blood TSB levels.Data regarding the differences between capillary andvenous TSB levels are conflicting.24,25 In 1 study thecapillary TSB levels were higher, but in another theywere lower than venous TSB levels.24,25 Thus, obtain-ing a venous sample to confirm an elevated capil-lary TSB level is not recommended, because it willdelay the initiation of treatment.

Direct-Reacting and Conjugated BilirubinAlthough commonly used interchangeably, direct-

reacting bilirubin is not the same as conjugated bili-rubin. Direct-reacting bilirubin is the bilirubin thatreacts directly (without the addition of an accelerat-ing agent) with diazotized sulfanilic acid. Conju-gated bilirubin is bilirubin made water soluble bybinding with glucuronic acid in the liver. Dependingon the technique used, the clinical laboratory willreport total and direct-reacting or unconjugated andconjugated bilirubin levels. In this guideline and forclinical purposes, the terms may be used inter-changeably.

Abnormal Direct and Conjugated Bilirubin LevelsLaboratory measurement of direct bilirubin is not

precise,26 and values between laboratories can varywidely. If the TSB is at or below 5 mg/dL (85 mol/L), a direct or conjugated bilirubin of more than 1.0

mg/dL (17.1 mol/L) is generally considered abnor-mal. For TSB values higher than 5 mg/dL (85 mol/L), a direct bilirubin of more than 20% of the TSB isconsidered abnormal. If the hospital laboratory mea-sures conjugated bilirubin using the Vitros (formerlyEktachem) system (Ortho-Clinical Diagnostics, Rari-tan, NJ), any value higher than 1 mg/dL is consid-ered abnormal.

Assessment of Adequacy of Intake in BreastfeedingInfants

The data from a number of studies2734 indicatethat unsupplemented, breastfed infants experiencetheir maximum weight loss by day 3 and, on aver-age, lose 6.1% 2.5% (SD) of their birth weight.Thus, 5% to 10% of fully breastfed infants lose 10%or more of their birth weight by day 3, suggestingthat adequacy of intake should be evaluated and theinfant monitored if weight loss is more than 10%.35Evidence of adequate intake in breastfed infants alsoincludes 4 to 6 thoroughly wet diapers in 24 hoursand the passage of 3 to 4 stools per day by the fourthday. By the third to fourth day, the stools in ade-quately breastfed infants should have changed frommeconium to a mustard yellow, mushy stool.36 Theabove assessment will also help to identify breastfedinfants who are at risk for dehydration because ofinadequate intake.

Nomogram for Designation of RiskNote that this nomogram (Fig 2) does not describe

the natural history of neonatal hyperbilirubinemia,particularly after 48 to 72 hours, for which, becauseof sampling bias, the lower zones are spuriouslyelevated.37 This bias, however, will have much lesseffect on the high-risk zone (95th percentile in thestudy).38

G6PD Dehydrogenase DeficiencyIt is important to look for G6PD deficiency in

infants with significant hyperbilirubinemia, becausesome may develop a sudden increase in the TSB. Inaddition, G6PD-deficient infants require interventionat lower TSB levels (Figs 3 and 4). It should be notedalso that in the presence of hemolysis, G6PD levelscan be elevated, which may obscure the diagnosis inthe newborn period so that a normal level in a he-molyzing neonate does not rule out G6PD deficien-cy.39 If G6PD deficiency is strongly suspected, a re-peat level should be measured when the infant is 3months old. It is also recognized that immediatelaboratory determination of G6PD is generally notavailable in most US hospitals, and thus translatingthe above information into clinical practice is cur-

TABLE 4. Risk Zone as a Predictor of Hyperbilirubinemia39

TSB Before Discharge Newborns(Total 2840),

n (%)

Newborns Who SubsequentlyDeveloped a TSB Level95th Percentile, n (%)

High-risk zone (95th percentile) 172 (6.0) 68 (39.5)High intermediate-risk zone 356 (12.5) 46 (12.9)Low intermediate-risk zone 556 (19.6) 12 (2.26)Low-risk zone 1756 (61.8) 0


rently difficult. Nevertheless, practitioners are re-minded to consider the diagnosis of G6PD deficiencyin infants with severe hyperbilirubinemia, particu-larly if they belong to the population groups inwhich this condition is prevalent. This is importantin the African American population, because theseinfants, as a group, have much lower TSB levels thanwhite or Asian infants.40,41 Thus, severe hyperbiliru-binemia in an African American infant should al-ways raise the possibility of G6PD deficiency.

Basis for the Recommendations 7.1.1 Through 7.1.6 andProvided in Figs 3 and 4

Ideally, recommendations for when to implementphototherapy and exchange transfusions should bebased on estimates of when the benefits of theseinterventions exceed their risks and cost. The evi-dence for these estimates should come from random-ized trials or systematic observational studies. Un-fortunately, there is little such evidence on which tobase these recommendations. As a result, treatmentguidelines must necessarily rely on more uncertainestimates and extrapolations. For a detailed discus-sion of this question, please see An Evidence-BasedReview of Important Issues Concerning NeonatalHyperbilirubinemia.23

The recommendations for phototherapy and ex-change transfusion are based on the following prin-ciples:

The main demonstrated value of phototherapy isthat it reduces the risk that TSB levels will reach alevel at which exchange transfusion is recom-mended.4244 Approximately 5 to 10 infants withTSB levels between 15 and 20 mg/dL (257342mol/L) will receive phototherapy to prevent theTSB in 1 infant from reaching 20 mg/dL (the num-ber needed to treat).12 Thus, 8 to 9 of every 10infants with these TSB levels will not reach 20mg/dL (342 mol/L) even if they are not treated.Phototherapy has proven to be a generally safeprocedure, although rare complications can occur(see Appendix 2).

Recommended TSB levels for exchange transfu-sion (Fig 4) are based largely on the goal of keep-ing TSB levels below those at which kernicterushas been reported.12,4548 In almost all cases, ex-change transfusion is recommended only afterphototherapy has failed to keep the TSB level be-low the exchange transfusion level (Fig 4).

The recommendations to use phototherapy andexchange transfusion at lower TSB levels for in-fants of lower gestation and those who are sick arebased on limited observations suggesting that sickinfants (particularly those with the risk factorslisted in Figs 3 and 4)4951 and those of lowergestation5154 are at greater risk for developingkernicterus at lower bilirubin levels than are wellinfants of more than 38 6/7 weeks gestation. Nev-ertheless, other studies have not confirmed all ofthese associations.52,55,56 There is no doubt, how-ever, that infants at 35 to 37 6/7 weeks gestationare at a much greater risk of developing very high

TSB levels.57,58 Intervention for these infants isbased on this risk as well as extrapolations frommore premature, lower birth-weight infants whodo have a higher risk of bilirubin toxicity.52,53

For all newborns, treatment is recommended atlower TSB levels at younger ages because one ofthe primary goals of treatment is to prevent addi-tional increases in the TSB level.

Subtle Neurologic Abnormalities Associated WithHyperbilirubinemia

There are several studies demonstrating measur-able transient changes in brainstem-evoked poten-tials, behavioral patterns, and the infants cry5963associated with TSB levels of 15 to 25 mg/dL (257428 mol/L). In these studies, the abnormalitiesidentified were transient and disappeared when theserum bilirubin levels returned to normal with orwithout treatment.59,60,62,63

A few cohort studies have found an associationbetween hyperbilirubinemia and long-term adverseneurodevelopmental effects that are more subtlethan kernicterus.6467 Current studies, however, sug-gest that although phototherapy lowers the TSB lev-els, it has no effect on these long-term neurodevel-opmental outcomes.6870

Risks of Exchange TransfusionBecause exchange transfusions are now rarely per-

formed, the risks of morbidity and mortality associ-ated with the procedure are difficult to quantify. Inaddition, the complication rates listed below may notbe generalizable to the current era if, like most pro-cedures, frequency of performance is an importantdeterminant of risk. Death associated with exchangetransfusion has been reported in approximately 3 in1000 procedures,71,72 although in otherwise well in-fants of 35 or more weeks gestation, the risk isprobably much lower.7173 Significant morbidity (ap-nea, bradycardia, cyanosis, vasospasm, thrombosis,necrotizing enterocolitis) occurs in as many as 5% ofexchange transfusions,71 and the risks associatedwith the use of blood products must always be con-sidered.74 Hypoxic-ischemic encephalopathy and ac-quired immunodeficiency syndrome have occurredin otherwise healthy infants receiving exchangetransfusions.73,75

Serum Albumin Levels and the B/A RatioThe legends to Figs 3 and 4 and recommendations

7.1.5 and 7.1.6 contain references to the serum albu-min level and the B/A ratio as factors that can beconsidered in the decision to initiate phototherapy(Fig 3) or perform an exchange transfusion (Fig 4).Bilirubin is transported in the plasma tightly boundto albumin, and the portion that is unbound orloosely bound can more readily leave the intravas-cular space and cross the intact blood-brain barrier.76Elevations of unbound bilirubin (UB) have been as-sociated with kernicterus in sick preterm new-borns.77,78 In addition, elevated UB concentrationsare more closely associated than TSB levels withtransient abnormalities in the audiometric brainstemresponse in term79 and preterm80 infants. Long-term


studies relating B/A binding in infants to develop-mental outcome are limited and conflicting.69,81,82 Inaddition, clinical laboratory measurement of UB isnot currently available in the United States.

The ratio of bilirubin (mg/dL) to albumin (g/dL)does correlate with measured UB in newborns83 andcan be used as an approximate surrogate for themeasurement of UB. It must be recognized, however,that both albumin levels and the ability of albumin tobind bilirubin vary significantly between new-borns.83,84 Albumin binding of bilirubin is impairedin sick infants,8486 and some studies show an in-crease in binding with increasing gestational86,87 andpostnatal87,88 age, but others have not found a sig-nificant effect of gestational age on binding.89 Fur-thermore, the risk of bilirubin encephalopathy is un-likely to be a simple function of the TSB level or theconcentration of UB but is more likely a combinationof both (ie, the total amount of bilirubin available[the miscible pool of bilirubin] as well as the ten-dency of bilirubin to enter the tissues [the UB con-centration]).83 An additional factor is the possiblesusceptibility of the cells of the central nervous sys-tem to damage by bilirubin.90 It is therefore a clinicaloption to use the B/A ratio together with, but not inlieu of, the TSB level as an additional factor in deter-mining the need for exchange transfusion83 (Fig 4).

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36. Lawrence RA. Management of the mother-infant nursing couple. In: ABreastfeeding Guide for the Medical Profession. 4th ed. St Louis, MO:Mosby-Year Book, Inc; 1994:215-277

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39. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. Blood. 1994;84:36133636

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APPENDIX 2: PhototherapyThere is no standardized method for delivering

phototherapy. Phototherapy units vary widely, as dothe types of lamps used in the units. The efficacy ofphototherapy depends on the dose of phototherapyadministered as well as a number of clinical factors(Table 5).1

Measuring the Dose of PhototherapyTable 5 shows the radiometric quantities used in

measuring the phototherapy dose. The quantity mostcommonly reported in the literature is the spectralirradiance. In the nursery, spectral irradiance can bemeasured by using commercially available radiome-ters. These instruments take a single measurementacross a band of wavelengths, typically 425 to 475 or400 to 480 nm. Unfortunately, there is no standard-ized method for reporting phototherapy dosages inthe clinical literature, so it is difficult to comparepublished studies on the efficacy of phototherapyand manufacturers data for the irradiance producedby different systems.2 Measurements of irradiancefrom the same system, using different radiometers,


can also produce significantly different results. Thewidth of the phototherapy lamps emissions spec-trum (narrow versus broad) will affect the measuredirradiance. Measurements under lights with a veryfocused emission spectrum (eg, blue light-emittingdiode) will vary significantly from one radiometer toanother, because the response spectra of the radiom-eters vary from manufacturer to manufacturer.Broader-spectrum lights (fluorescent and halogen)have fewer variations among radiometers. Manufac-turers of phototherapy systems generally recom-mend the specific radiometer to be used in measur-ing the dose of phototherapy when their system isused.

It is important also to recognize that the measuredirradiance will vary widely depending on where themeasurement is taken. Irradiance measured belowthe center of the light source can be more than dou-ble that measured at the periphery, and this dropoffat the periphery will vary with different photother-apy units. Ideally, irradiance should be measured atmultiple sites under the area illuminated by the unitand the measurements averaged. The InternationalElectrotechnical Commission3 defines the effectivesurface area as the intended treatment surface thatis illuminated by the phototherapy light. The

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