AMERICAN ACADEMY OF PEDIATRICS
CLINICAL PRACTICE GUIDELINE
Subcommittee on Hyperbilirubinemia
Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation
ABSTRACT. Jaundice occurs in most newborn infants. Most jaundice is benign, but because of the potential toxicity of bilirubin, newborn infants must be monitored to identify those who might develop severe hyperbili- rubinemia and, in rare cases, acute bilirubin encephalop- athy or kernicterus. The focus of this guideline is to reduce the incidence of severe hyperbilirubinemia and bilirubin encephalopathy while minimizing the risks of unintended harm such as maternal anxiety, decreased breastfeeding, and unnecessary costs or treatment. Al- though kernicterus should almost always be prevent- able, cases continue to occur. These guidelines provide a framework for the prevention and management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation. In every infant, we recommend that clinicians 1) promote and support successful breastfeed- ing; 2) perform a systematic assessment before discharge for the risk of severe hyperbilirubinemia; 3) provide early and focused follow-up based on the risk a ssess- 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; 114:297-316; 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 for Quality lmprovement and Subcommittee on Hy- perbilirubinemia of the American Academy of Pediatrics (AAP) produced a practice parameter dealing with the management of hyperbilirubinemia in the healthy term newborn.1 The current guideline represents a consensus of the committee charged by the AAP with reviewing and updating the existing guideline and is based on a careful review of the evidence, including a comprehensive literature re- view by the New England Medical Center Evidence- Based Practice Center.2 (See "An Evidence-Based Review of Important Issues Concerning Neonatal Hyperbilirubinemia"3 for a description of the meth- odology, questions addressed, and conclusions of this report.) This guideline is intended for use by hospitals and pediatricians, neonatologists, family physicians, physician assistants, and advanced prac- tice nurses who treat newborn infants in the hospital and as outpatients. A list of frequently asked ques- tions and answers for parents is available in English and Spanish at www.aap.org/family/jaundicefaq.htm.
DEFINITION OF RECOMMENDATIONS
The evidence-based approach to guideline devel- opment requires that the evidence in support of a policy be identified, appraised, and summarized and that an explicit link between evidence and recom- mendations be defined. Evidence-based recommen- dations are based on the quality of evidence and the balance of benefits and harms that is anticipated when the recommendation is followed. This guide- line uses the definitions for quality of evidence and balance of benefits and harms established by the AAP Steering Committee on Quality Improvement Management.4 See Appendix 1 for these definitions.
BILIRUBIN ENCEPHALOPATHY AND KERNICTERUS
Although originally a pathologic diagnosis charac- terized by bilirubin staining of the brainstem nuclei and cerebellum, the term "kernicterus" has come to be used interchangeably with both the acute and chronic findings of bilirubin encephalopathy. Biliru- bin encephalopathy describes the clinical central ner- vous system findings caused by bilirubin toxicity to the basal ganglia and various brainstem nuclei. To avoid confusion and encourage greater consistency in the literature, the committee recommends that in infants the term "acute bilirubin encephalopathy" be emy of Pediatrics used to describe the acute manifestations of bilirubin toxicity seen in the first weeks after birth and that the term "kernicterus” be reserved for the chronic and permanent clinical sequelae of bilirubin toxicity.
See Appendix 1for the clinical manifestations of acute bilirubin encephalopathy and kernicterus.
FOCUS OF GUIDELINE
The overall aim of this guideline is to promote an approach that will reduce the frequency of severe neonatal hyperbilirubinemia and bilirubin encepha- lopathy and minimize the risk of unintended harm such as increased anxiety, decreased breastfeeding, or unnecessary treatment for the general population and excessive cost and waste. Recent reports of ker- nicterus indicate that this condition, although rare, is still occurring.2,5-10
Analysis of these reported cases of kernicterus suggests that if health care personnel follow the rec- ommendations listed in this guideline, kernicterus would be largely preventable.
These guidelines emphasize the importance of uni- versal systematic assessment for the risk of severe hyperbilirubinemia, close follow-up, and prompt in- tervention when indicated . The recommendations apply to the care of infants at 35 or more weeks of gestation. These recommendations seek to further the aims defined by the Institute of Medicine as appropriate for health care:11 safety, effectiveness, efficiency, timeliness, patient-centeredness, and eq- uity. They specifically emphasize the principles of patient safety and the key role of timeliness of inter- ventions to prevent adverse outcomes resulting from neonatal hyperbilirubinemia.
The following are the key elements of the recom- mendations provided by this guideline. Clinicians should:
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 of jaund ice can lead to errors, particularly in darkly pigmented infants.
5.Interpret all bilirubin levels according to the in- fant's age in hours.
6.Recognize that infants at less than 38 weeks' gestation, particularly those who are breastfed, are at higher risk of developing hyperbiliru- binemia and require closer surveillance and monitoring.
7.Perform a systematic assessment on all infants before 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 time of discharge and the risk assessment.
10.Treat newborns, when indicated, with photo- therapy or exchange transfusion.
PRIMARY PREVENTION
In numerous policy statements, the AAP recom- mends breastfeeding for all healthy term and near- term newborns. This guideline strongly supports this general recommendation.
RECOMMENDATION 1.0: Clinicians should advise mothers to nurse their infants at least 8 to 12 times per day for thefirst several days12 (evidence quality C: benefits exceed harms).
Poor caloric intake and/or dehydration associated with inadequate breastfeeding may contribute to the development of hyperbilirubinemia .6,13,14 Increasing the frequency of nursing decreases the likelihood of subsequent significant hyperbilirubinemia in breast- fed infants.15-17 Providing appropriate support and advice 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 in Appendix 1.
RECOMMENDATION 1.1: The AAP recommends against routine supplementation of nondehydrated breast- f ed infants with water or dextrose water (evidence quality B and C: harms exceed benefits).
Supplementation with water or dextrose water will not prevent hyperbilirubinemia or decrease TSB levels.18,19
SECONDARY PREVENTION
RECOMMENDATION 2.0: Clinicians should perform ongoing systematic assessments during the neonatal pe- riod for the risk of an infant developing severe hyperbil- irubinemia.
Blood Typing
RECOMMENDATION 2.1: All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screenfor unusual isoimmune antibodies (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.1: If a mother has not had prenatal blood groupi ng or is Rh-negative, a direct anti-body test (or Coombs'test), blood type, and an Rh (D) type on the 呐nt 's (cord) blood are strongly recommended (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.2：If the maternal blood is group 0,Rh-positive, it is an option to test the cord blood f or the infant's blood type and direct antibody test, but it is not required provided that there is appro priate surveil-lance, risk assessment before discharge, and follow-up20 (evidence quality C: benefits exceed harms).
Clinical Assessment
RECOMMENDATION 2.2: Clinicians should ensure that all infants are routinely monitored for the develop- ment of jaundice , and nurseries should have established protocols for the assessment of jaundice. Jaundice should be assessed whenever the infant'svital signs are measured but no less than every 8 to 12 hours (evidence quality D: benefits versus harms exceptional).
In newborn infants, jaundice can be detected by blanching the skin with digital pressure, revealing the underlying color of the skin and subcutaneous tissue. The assessment of jaundice must be per-formed in a well-lit room or, preferably, in daylight at a window. Jaundice is usually seen first in the face and progresses caudally to the trunk and extremi- ties,21 but visual estimation of bilirubin levels from the degree of jaundice can lead to errors.22-24 Inmost infants with TSB levels of less than 15 mg/dL (257μmol/L), noninvasive TcB-measurement devices can provide a valid estimate of the TSB level.2,25-29 See Appendix 1for additional information on the clinical evaluation of jaundice and the use of TcB measure- ments.
RECOMMENDATION 2.2.1: Protocols for the assess-ment of jaundice should include the circumstances in which nursing staff can obtain a TcB level or order a TSB measurement (evidence quality D: benefits versus harms exceptional).
Laboratory Evaluation
RECOMMENDATION 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 for and timing of a repeat TcB or TSB measurement will depend on the zone in which the TSB falls (Fig 2),25,31 the age of the infant，and the evolution of the hyperbiliru- binemia. Recommendations for TSB measurements after the age of 24 hours are provided in Fig 1 and Table 1.
See Appendix 1for capillary versus venous biliru- bin levels.
RECOMMENDAT ION 3.1: A TcB and/or TSB measure- ment should be performed if thejaundice appears excessive for the infant's age (evidence quality D: benφts versus harms exceptional) .If there is any doubt about the degree of jaundice, the TSB or TcB should be measured. Visual estimation of bilirubin levels from the degree of jaundice can lead to errors, particularl y in darkly pigmented in-fants (evidence quality C: benefits exceed harms).
RECOMMENDAT ION 3.2: All bilirubin levels should be interpreted according to the infant’s age in hours (Fig 2) (evidence quality C: ben fits exceed harms).
Cause of Jaundice
RECOMMENDATION 4.1: The possible cause of jaundice should be sought in an infant receiving phototherapy or whose TSB level is rising rapidly (ie, crossing percentiles [Fig 2] and is not explained by the 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 should have a urinalysis and urine culture.32 Additional labora-tory evaluation for sepsis should be performed if indicated by history and physical examination (evidence quality C: benefits exceed harms).
See Appendix 1for definitions of abnormal levels of direct-reacting and conjugated bilirubin.
RECOMMENDATION 4.1.2: Sick infants and those who are jaundiced at or beyond 3 weeks should have a mea- surement of total and direct or conjugated bilirubin to identify cholestasis (Table 1) (evidence quality D: benefit versus harms exceptiona l) . The results of the newborn thyroid and galactosemia screen should also be checked in these infants (evidence quality D: benefits versus harms exceptional).
RECOMMENDATION 4.1.3: If the direct-reacting or conjugated bilirubin level is elevated, additional evalua- tionfor the causes of cholestasis is recommended (evidence quality 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 famil y history or ethnic or geographic origin suggest the likelihood of G6PD deficiency or for an infant in whom the response to photothera py is poor (Fig 3)(evidence quality C: benefits exceed harms).
G6PD deficiency is widespread and frequently un- recognized, and although it is more common in the populations around the Mediterranean and in the Middle East, Arabian peninsula, Southeast Asia, and Africa, immigration 缸1d intermarriage have trans- formed G6PD deficiency into a global problem.33,34
Fig 2. Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with birth weiht of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or more based 0n the hour-specific serum bilirubm values. The serum bilirubin level was obtained before discharge, and the zone in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile (high-risk zone) as shown in Appendix 1, Table 4. Used with permission from Bhutani et al.31 See Appendix 1 for additional information about this nomogram, which should not be used to represent the natural history of neonatal hyperbiliru- binemia.
Furthermore, G6PD deficiency occurs in 11% to 13% of African Americans, and kernicterus has occurred in some of these infants.5,33 In a recent report, G6PD deficiency 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 additional information on G6PD deficiency .)
Risk Assessment Before Discharge
RECOMMENDAT ION 5.1: Before discharge, every new- born should be assessed for the risk of developing severe hyperbilirubinemia, and all nurseries should establish pro- tocols for assessing this risk. Such assessment is particu-larly important in infants who are discharged before the age of 72 hours (evidence quality C: benefits exceed harms).
RECOMMENDAT ION 5.1.1: The AAP recommends 2 clinical options used individually or in combinationfor the systematic assessment of risk: predischarge measurement of the bilirubin level using TSB or TcB and/or assessment of clinical risk factors. Whether either or both options are used, appro priate follow-u p after discharge is essential (evidence quality C: ben fits exceed harms).
The best documented method for assessing the risk of subsequent hyperbilirubinemia is to measure the TSB or TcB leve25,31,35-38 and plot the results on a nomogram (Fig 2). A TSB level can be obtained at the time of the routine metabolic screen, thus obvi- ating the need for an additional blood sample. Some authors have suggested that a TSB measurement should 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 developing severe hyperbilirubinemia.5,38
Table 2 lists those factors that are clinically signif-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 of hyperbilirubinemia is small, individually the factors are of limited use as predictors of significant hyper- bilirubinemia39 Nevertheless, if no risk factors are present, the risk of severe perbilirubinemia is ex- tremely low, and the more risk factors prese时 the greater the risk of severe hyperbilirubinemia.39 The important risk factors most frequently associated with severe hyperbilirubinemia are breastfeeding, gestation below 38 weeks, signi自cant jaundice in a previous sibling, and jaundice noted before dis- charge39,40 A formula-fed infant of 40 or more weeks' gestation is at very low risk of developing severe hyperbilirubinemia.39
Hospital Policies and Procedures
RECOMM ENDATION 6.1: All hospitals should provide written and verbal information for parents at the time of discharge, which should include an explanation of jaun- dice, the need to monitor infants for jaundice, and advice on how monitoring should be done (evidence quality D: benefits versus harms exceptional).
An example of a parent-information handout is available in English and Spanish at www.aap.org/family/jaundicefaq.htm.
Follow-up
RECOMMENDATION 6.1.1: All infants should be ex- amined by a qualified health care professional in the first few days ifter discharge to assess infant well-being and the presence or absence of jaundice. The timing and location of this assessment will be determined by the length of stay in the 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 exceed harms).
Timing of Follow-up
RECOMMENDATION 6.1.2: Follow-u p should be pro- vided as follows:
For some newborns discharged before 48 hours, 2 fol low-up visits may be required, the first visit between 24 and 72 hours and the second between 72 and 120 hours. Clinical judgment should be used in determining follow up. Earltet’ or morefrequent follow-u p should be provided for those who have risk factors for hyperbilirubinemia (Table 2)，whereas those discharged with few or no risk factors can be seen after longer intervals (evidence quality C: benefits exceed harms) .
RECOMM ENDATION 6.1.3：If appropriate follow-up cannot be ensured in the presence of elevated risk for developing severe hyperbilirubinemia , it may be necessary to delay discharge either until appropriate follow-u p can be ensured or the period of greates t risk has pass ed (72-96 hours) (evidence quality 0: benefits versus harms excep tional).
Follow-up Assessment
RECOMMENDATION 6.1.4: The follow-up assessment should include the infant 's weight and percent change from birth weight, dequacy 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 bilirubin measurement. If there is any doubt about the degree of jaundice , the TSB or TcB level should be measured. Visual estimation of bilirubin levels can lead to errors, particu larly in darkly pigmented infants (evidence quality C:benefits exceed harms).
See Appendix 1for assessment of the adequacy of intake in breastfeeding infants.
TREATMENT
Phototherapy and Exchange Transfusion
RECOMMENDATION 7.1: Recommendations for treat ment are given in Table 3 and Figs 3 and 4 (evidence quality C: benefits exceed harms). If the TSB does not fall or continues to rise despite intensive photothera py, it is very likely that hemolysis is occurring. The committee's recommendations for discontinuing photothera py can be found in Appendix 2.
RECOMMENDATION 7.1.1: In using the guidelines for photothera py and exchange transfusion （Figs 3 and 4),the direct reacting (or conjugated ) bilirubin level should not be subtracted from the total (evidence quality 0: benefits versus harms exceptional).
In unusual situations in which the direct bilirubin level is 50% or more of the total bilirubin, there are no good data to provide guidance for therapy, and consultation with an expert in the field is recom mended.
RECOMMENDATION 7.1.2：If the TSB is at a level at which exchange transfusion is recommend ed (Fig 4) or if the TSB level is 25 mg/d L (428 µmol/L) or higher at any time, it is a medical emergency and the infant should be admitted immediately and directly to a hosp ital pediatric service for intensive phototh erapy . These infants should not be referred to the emergency department，because it delays the initiation of treatment54(evidence quality C:benefits exceed harms).
RECOMMENDATION 7.1.3: Exchange transfusions should be performed only by trained personnel in a neo natal intensive care unit withfull monitoring and resus citation capabilities (evidence quality 0: benefits versus harms exceptional ).
RECOMMENDATION 7.1.4: In isoimmune hemolytic disease, administration of intravenous γ-globulin (0.5-1g/kg over 2 hours) is recommended if the TSB is rising despit e intensive photothera py or the TSB level is within 2 to 3 mg/dL (34-51 µmol/L) of the exchange level (Fig 4).55 If necessa,this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms).
Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease.55-58 Although data are limited, it is reasonable to assume that intravenous γ-globulin will also be helpful in the other types of Rh hemolytic disease such as anti-C and anti-E.
Serum Albumin Levels and the Bilirubin/Albumin Ratio
RECOMMENDATION 7.1.5: It is an option to measure the serum albumin leevel and consider an albumin level of less than 3.0 g/dL as one risk factor for lowering the threshold for photothera py use (see Fig 3) (evidence quality D: benefits versus risks exceptional.).
RECOMM ENDATION 7.1.6: If an exchange transfusion is being considered, the serum albumin level should be measured and the bilirubin I albumin (BIA) ratio used in conjunction with the TSB level and otherfactors in deter mining the need for exchange transfusion (see Fig 4) (evidence quality D: benefits versus harms exceptional).
The recommendations shown above for treating hyperbilirubinemia are based primarily on TSB lev els and other factors that affect the risk of bilirubin encephalopathy. This risk might be increased by a prolonged (rather than a brief) exposure to a certain TSB 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 1for the basis for recommendations
7.1 through 7.1.6 and for the recommendations provided in Figs 3 and 4. Appendix 1 also contains a discussion of the risks of exchange transfusion and the use of B/A binding.
Acute Bilirubin Encephalopathy
RECOMMENDATION 7.1.7: Immediate exchange transfusion 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(hypertonia, arching, retrocollis, opisthotonos, fever, highpitched cry)even if the TSB isfalling (evidence quality D:benefits versus risks exceptional).
Phototherapy
RECOMM ENDATION 7.2: All nurseries and services treating infants should have the necessary equipment to provide intensive photothera py (see Appendix 2) (evidence quality D: benefits exceed risks).
Outpatient Management of the Jaundiced Breastfed Infant
RECOMM ENDATION 7.3: In breastfed infants who re quire photothera py (Fig 3)，the AAP recommends that, if possible, breastfeeding should be continued (evidence quality C: benefits exceed harms). It is also an option to interrupt temporarily breastfeeding and substitute formula. This can reduce bilirubin levels and/or enhance the effcacy of phototherapy63-65(evidence quality B: ben φts exceed harms). In breastfed infants receiving phototherapy, supplementation with expressed breast milk or formula is appropriate if the infant's intake seems inade quate, weight loss is excessi时 or the infant seems dehy drated.
IMPLEMENTATION STRATEGIES
The Institute of Medicine11 recommends a dra matic change in the way the US health care system ensures the safety of patients. The perspective of safety as a purely individual responsibility must be replaced by the concept of safety as a property of systems. Safe systems are characterized by a shared knowledge of the goal, a culture emphasizing safety, the ability of each person within the system to act in a manner that promotes safety, minimizing the use of memory, and emphasizing the use of standard pro cedures (such as checklists), and the involvement of patients/families as partners in the process of care.
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 "higher risk" because of the potentia l negative effects of the conditions listed on albumin binding of bilirubin,45-47 the blood-brain barrier,48 and the susceptibility of the brain cells to damage by bilirubin.48
"Intensive phototherapy" implies irradiance in the blue-green spectrum (wavelengths of approximately 430-490 nm) of at least 30 µW /cm2 per nm (measured at the infant’Sskin directly below the center of the phototherapy unit) and delivered to as much of the infant's surface area as possible. Note that irradiance measured below the center of the light source is much greater than that measured at the periphery. 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 mtensive phototherapy,and of light sources used. If total serun 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 increase the 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 strongly suggests the presence of hemolysis.
Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubin level (cholestatic jaundice) may develop the bronze-baby syndrome. See Appendix 2 for the use of phototherapy in these infants.
These principles can be applied to the challenge of preventing severe hyperbilirubinemia and kernicterus. A systematic approach to the implementa tion of these guidelines should result in greater safety. Such approaches might include
The establishment of standing protocols for nurs ing assessment of jaundice, including testing TcB and TSB levels, without requiring physician or ders.
Checklists or reminders associated with risk factors, age at discharge, and laboratory test results that provide guidance for appropriate follow-up.
Explicit educational materials for parents (a key component of all AAP guidelines) concerning the identification of newborns with jaundice .
FUTURE RESEARCH
Epidemiology of Bilirubin-Induced Central Nervous System Damage
There is a need for appropriate epidemiologic data to 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 TSB levels exceed 25 or 30 mg/dL (428-513 µmol/L). Organizations such as the Centers for Disease Con trol and Prevention should implement strategies for appropriate data gathering to identify the number of infants who develop serum bilirubin levels above 25 or 30 mg/dL (428-513 µmol/L) and those who de velop acute and chronic bilirubin encephalopathy . This information will help to identify the magnitude of the problem; the number of infants who need to be screened and treated to prevent 1case 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 considered definitive.
Effect of Bilirubin on the Central Nervous System
The serum bilirubin level by itself, except when it is extremely high and associated with bilirubin encephalopathy, is an imprecise indicator of long-term neurodevelopmental outcome.2 Additional studies are needed on the relationship between central ner vous system damage and the duration of hyperbilirubinemia, the binding of bilirubin to albumin, and changes seen in the brainstem auditory evoked response. These studies could help to better identify risk, clarify the effect of bilirubin on the central ner vous system, and guide intervention.
Identification of Hemolysis
Because of their poor specificity and sensitivity, the standard laboratory tests for hemolysis (Table 1) are frequently unhelpful.66,67 However, end-tidal carbon monoxide, corrected for ambient carbon monoxide (ETCOc), levels can confirm the presence or absence of hemolysis, and measurement of ETCOc is the only clinical test that provides a direct measurement of the rate of heme catabolism and the rate of bilirubin production.68,69 Thus, ETCOc may be helpful in etermining the degree of surveillance needed and the tin吐ng of intervention. It is not yet known, however, how ETCOc measurements will affect management.
Nomograms and the Measurement of Serum and TcB
It would be useful to develop an age-specific (by hour) nomogram for TSB in populations of newborns that differ with regard to risk factors for hyperbiliru binemia. There is also an urgent need to improve the precision and accuracy of the measurement of TSB in the clinical laboratory.70,71 Additional studies are also needed to develop and validate noninvasive (transcutaneous) measurements of serum bilirubin and to understand the factors that affect these mea surements. These studies should also assess the cost effectiveness and reproducibility of TcB measurements in clinical practice.2
Pharmacologic Therapy
There is now evidence that hyperbilirubinemia can be effectively prevented or treated with tin-mesopor phyrin,72-75 a drug that inhibits the production of heme oxygenase. Tin-mesoporphyrin is not ap proved by the US Food and Drug Administration. If approved, tin-mesoporphyrin could find immediate application in preventing the need for exchange transfusion in infants who are not responding to phototherapy.75
Dissemination and Monitoring
Research should be directed toward methods for dissenlinating the information contained in this guideline to increase awareness on the part of phy sicians, residents, nurses, and parents concerning the issues of neonatal hyperbilirubinemia and strategies for its management. Inaddition, monitoring systems should be established to identify the impact of these guidelines on the incidence of acute bilirubin enephalopathy and kernicterus and the use of phototherapy and exchange transfusions.
CONCLUSIONS
Kernicterus 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-lirubinenlia, close follow-up, and prompt interven tion, when necessary.
ACKNOWLEDGMENTS
M.J.M. received grant support from Natus Medical, Inc, for multinational study of ambient carbon monoxide; Wel!Spring Pharmaceutical Corporation for study of Stannsoporfin (tin-meso porphyrin); and Minolta, Inc, for study of the Minolta /Hill-Rom Air-Shields transcutaneous jaundic e meter model JM-103. V.K.B. received grant support from Wel!Spring Pharmaceutical Corpora tion for study of Stannsoporfin (tin-mesoporphyrin) and Natus Medical, Inc, for multinational study of ambient carbon monoxide and is a consultant (volunteer) to SpectrX (BiliChek transcutane ous bilirubinometer). D.K.S. is a consultant to and holds stock options through Natus Medical, Inc.
The American Academy of Pediatrics Subcommittee on Hyper bilirubinemia gratefully acknowledges the help of the following organizations, committees, and individuals who reviewed drafts of 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 Committee on Child Health Financing; American Academy of Pediatrics Committee on Medical Liability; American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pedi atrics Section on Perinatal Pediatrics; Centers for Disease Control and Prevention; Parents of Infants and Children With Kernicterus (PICK); Charles Ahlfors, MD; Daniel Batton, MD; Thomas Bojko, MD; Sarah Clune, MD; Sudhakar Ezhuthachan, MD; Lawrence Gartner, MD; Cathy Hammerman, MD; Thor Hansen, MD; Lois Johnson, MD; Michael Kaplan, MB, ChB; Tony McDonagh, PhD; Gerald Merenstein, MD; Mary O'Shea, 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.
REFERENCES
1. American Academy of Pediatrics, Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilir ubinernia in the healthy term newborn. Pediatrics. 1994;94:558-562
2. Ip S, Glicken S, Kulig J, Obrien R, Sege R, Lau J. Management of Neonatal Hyperbilirubinemia. Rockville, MD: US Department of Health and Hu man Services, Agency for Healthcare Research and Quality; 2003 AHRQ Publication 03-EOll
3. Ip S, Chung M, Kulig J. et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;113(6) Available at: www.pediatrics.org/cgi/content/full/113/ 6/e644
4. American Academy of Pediatrics, Steering Committee on Quality Im provement and Management. A taxonomy of recommendation s. Pedi atrics. 2004; In press
5. Johnson LH, Bhutani VK, Brown AK. System-based approach to man agement of neonatal jaundice and prevention of kernicterus. J Pediatr. 2002;140:396-403
6. Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics. 1995;96:730-733
7. MacDonald M. Hidden risks: early discharge and bilirubin toxicity due to glucose-6-phosphate dehydrogenase deficiency. Pediatrics. 1995;96 734-738
8. Penn AA, Enzman DR, Hahn JS, Stevenson DK. Kernicterus in a full term infant. Pediatrics. 1994;93:1003-1006
9. Washington EC, Ector W, Abboud M, Ohning B, Holden K. Hemolytic jaundice due to G6PD deficiency causing kernicterus in a female new born. South Med J. 1995;88:776-779
10. Ebbesen F. Recurrence of kernicterus in term and near term infants in Denmark. Acta Paediatr. 2000;89:1213-1217
11. Institue of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001
12. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care. 5th ed. Elk Grove Vil lage, IL: American Academy of Pediatrics; 2002:220-224
13. Bertini G, Dani C, Trochin M, Rubaltelli F. Is breastfeeding really favoring early neonatal jaundice? Pediatrics. 2001;107(3). Available at: www.pediatrics.org/cgi/content/full/107/3/e41
14. Maisels MJ, Gifford K. Normal serum bilirubin levels in the newborn and the effect of breast-feeding. Pediatrics. 1986;78:837-843
15. Yamauchi Y, Yamanouchi I.Breast-feeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics,1990;86:171-175
16. De Carvalho M, Klaus MH, Merkatz RB. Frequency of breastfeeding and serum bilirubin concentration. Am J Dis Child. 1982;136:737-738
17. Varimo P, Simila S, Wendt L, Kolvisto M. Frequency of breast feeding and hyperbilirubinemia [letter]. Clin Pediatr (Phi/a). 1986;25:112
18. De Carvalho M, Holl M, Harvey D. Effects of water supplementation on physiological jaundice in breast fed babies. Arch Dis Child. 1981;56: 568-569
19. Nicoll A, Ginsburg R, Tripp JH. Supplementary feeding and jaundice m newborns. Acta Paediatr Scand. 1982;71:759-761
20. Madlon-Ka y DJ. Identifying ABO incompatibility in newborns: selective vs automatic testing. J Fam Pract. 1992;35:278 280
21. Kramer LI. Ad vancement of dermal icterus in the jaundiced newborn. Am J Dis Child. 1969;118:454-458
22. Moyer VA, Ahn C, Sneed S. Accuracy of clinical jud gment in neonatal jaundice. Arch Pediatr Adolesc Med. 2000;154:391-394
23. Davidson LT, Merritt KK, Weech AA. Hyperbilirubinernia in the new born. Am J Dis Child. 1941;61:958-980
24. Tayaba R, Gribetz D, Gribetz I,Holzman IR.Noninvasive estimation of serum bilirubin. Pediatrics. 1998;102(3).Available at: www.pediatrics.org/cgi/content/full/102/3Ie28
25. Bhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge 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, ltoh S, lsobe K, et al. New transcutaneous jaundice device with hwo optical paths. J Perinat Med. 2003;31:81 88
27. Maisels MJ, Ostrea EJ Jr, Touch S, et al. Evaluation of a new transcuta- neous bilirubinom eter. Pediatrics. 2004;113:1638-1645
28. Ebbesen F, Rasmussen LM, Wimberley PD. A new transcutaneous bilirubinometer, bilicheck, used in the neonatal intensive care unit and the maternity ward. Acta Paediatr. 2002;91:203-211
29. Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubm measurement: a multicenter evaluation of a new device Pediatrics 2001;107:1264-1271
30. Newman TB, Liljestrand P, Escobar GJ. Jaundice noted in the first 24 hours after birth in a managed care organization. Arch Pediatr Adolesc Med. 2002;156:1244-1250
31. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbiliru binemia in healthy term and near-term newborns. Pediatrics. 1999;103:6-14
32. Garcia FJ，Nager AL. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics. 2002;109:846-851
33. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a po tential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol. 1998;25:575-590
34. Valaes T. Severe neonataljaundic e associated with glucose 6 phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl.1994;394:58-76
35. Alpay F, Sarici S, Tosuncuk HD, Serdar MA, Inan, N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinernia in healthy term newborns. Pediatrics 2000;106(2). Available at: www.pediatrics.org/cgi/content/full/106/2/el6
36. Carbonell X, Botet F, Figueras J, Riu Godo A. Prediction of hyperbiliru binaemia in the healthy term newborn. Acta Paediatr. 2001;90:166-170
37. Kaplan M, Hammerman C, Feldman R, Brisk R. Predischarge bilirubin screening in glucose-6-phosphate dehydrogenase-deficient neonates Pediatrics. 2000;105:533-537
38. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbil irubinemia in near-term and term infants. Pediatrics. 2001;108:31-39
39. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and pre vention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000;154:1140-1147
40. Maisels MJ, Kring EA. Length of stay, jaundice, and hospital readmis sion. Pediatrics. 1998;101:995-998
41. Gale R, Seidman DS, Dollberg S, Stevenson DK. Epidemiology of neo natal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr.1990;10:82-86
42. Berk MA, Mimouni F, Miodovnik M, Hertzberg V, Valuck J. Macroso mia in infants of insulin-dependent diabetic mothers. Pediatr ics. 1989; 83:1029-1034
43. Peevy KJ，Landaw SA, Gross SJ. Hyperbilirubinemia in infants of diabetic mothers. Pediatrics . 1980;66:417-419
44. Soskolne El, Schumacher R,Fyock C, Young ML, Schork A. The effect of early discharge and other factors on readmission rates of newborns Arch Pediatr Adolesc Med. 1996;150:373-379
45. Ebbesen F, Brodersen R. Risk of bilirubin acid precipitation in preterm infants with respiratory distress syndrome: considerations of blood/ brain bilirubin transfer equilibrium. Early H um Dev. 1982;6:341-355
46. Cashore WJ, Oh W, Brodersen R. Reserve albumin and bilirubin toxicity index in infant serum. Acta Paediatr Scand. 1983;72:415 419
47. Cashore WJ. Free bilirubin concentrations and bilirubin-binding affinity in term and preterm infants. J Pediatr. 1980;96:521-527
48. Bratlid D. How bilirubin gets into the brain. Clin Perinatol . 1990;17·449-465
49. Wennberg RP. Cellular basis of bilirubin toxicity. N Y State J M ed.1991;91:493-496
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;142:58-61
51. Maisels MJ. Why use homeopa thic doses of phototherapy? Pediatncs.1996;98:283-287
52. Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns Pediatrics. 1994;93:488-494
53. American Association of Blood Banks Technical Manual Committee. Perinatal issues in transfusion practice. In: Brecher M, ed. Technical Manual. Bethesda , MD: American Association of Blood Banks; 2002 497-515
54. Garland JS, Alex C, Deacon JS, Raab K. Treatment of infants with indirect hyperbil irubinemia. Readmission to birth hospital vs nonbirth hospital. Arch Pediatr Adolesc Med. 1994;148:1317- 1321
55. Gottstein R, Cooke R. Systematic review of intravenous immunoglob ulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonata l Ed. 2003;88:F6-F10
56. Sato K, Hara T, Kondo T, Twao H, Honda S, Ueda K. High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand . 1991;
80:163-166
57. Rubo J, Albrecht K, Lasch P, et al. High dose intravenous unmune globulin therapy for hyperbilirubinemia caused by Rh hemolytic dis ease. J Pediatr. 1992;121:93-97
58. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous in1mmune globulin in neonatal ABO isoin1munization: factors associated with clinical efficacy. Biol Neonate. 1996;70:69 -74
59. Johnson L, Boggs TR. Bilirubin-dependent brain damage: incidence and indications for treatment. In: Odell GB, Schaffer R, Simopoulos AP, eds. Phototherapy in the Newborn: An Overview. Washington, DC: National Academy of Sciences; 1974:122-149
60. Ozmert E, Erdem G, Topcu M. Long-term follow-up of indirect hyper bilirubinemia in full-term Turkish infants. Acta Paediatr. 1996;85: 1440-1444
61. Volpe JJ. Neuro!ogi; of the Newborn. 4th ed. Philadelphia, PA: W.B.Saunders; 2001
62. Harris M, Bernbaum J, Polin J, Zin1merman R, Polin RA. Developmental follow-up of breastfed term and near-term infants with marked hyper bilirubinemia. Pediat rics. 2001;107:1075-1080
63. Osborn LM, Bolus R. Breast feeding and jaundice in the first week of life. J Fam Pract. 1985;20:475-480
64. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics 1993;91:470-473
65. Amato M, Howald H, von Murali G. Interruption of breast-feeding versus phototherapy as treatrnent of hyperbilirubinernia in full-term infants. Helv Paediatr Acta. 1985;40:127-131
66. 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
67. Newman TB, Easterling MJ. Yield of reticulocyte counts and blood smears in term infants. Clin Pediatr (Pilila). 1994;33:71-76
68. Herschel M, Karrison T, Wen M,Caldarelli L, Baron B. Evaluation of the direct antiglobulin (Coombs'） test for identifying newborns at risk for hemolysis as determined by end-tidal carbon monoxide concentration (ETCOc); and comparison of the Coombs' test with ETCOc for detecting significant jaundice. J Perinatal. 2002;22:341-347
69. Stevenson DK, Vrernan HJ. Carbon monoxide and bilirubin production in neonates. Pediatrics. 1997;100:252-254
70. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubm measurements. Clin Chem. 1996;42:869-873
Lo S, Doumas BT, Ashwood E. Performance of bilirubin determinations in US laboratories-revisited. Clin Cllem. 2004;50:190 194
72. Kappas A, Drummond GS, Henschke C, Valaes T. Direct comparison of Sn mesoporphyrin, an inhibitor of bilirubin production ,and photother apy in controlling hyperbilirubinemia in term and near-term newborns. Pediatrics. 1995;95:468-474
73. Martinez JC, Garcia HO, Otheguy L, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newbornswith the inhibitor of bilirubin production Sn-mesoporph yrin. Pediatrics. 1999;103:l 5
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 Jehovah’s Witness new borns as an alternative to exchange transfusion. Pediatrics. 2001;108 1374-1377
APPENDIX 1: Additional Notes
Definitions of Quality of Evidence and Balance of Benefits and Harms
The Steering Committee on Quality Improvement and Management categorizes evidence quality in 4 levels:
l. Well-designed, randomized, controlled trials or diagnostic studies on relevant populations
2. Randomized, controlled trials or diagnostic stud ies with minor limitations; overwhelming, consis tent evidence from observational studies
3. Observational studies (case-control and cohort design)
4. Expert opinion, case reports, reasoning from first principles
The AAP defines evidence-based recommenda tions as follow
