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CLINICAL PRACTICE GUIDELINE |
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ABSTRACT |
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Key Words: hyperbilirubinemia • newborn • kernicterus • bilirubin encephalopathy • phototherapy
Abbreviations: AAP, American Academy of Pediatrics • TSB, total serum bilirubin • TcB, transcutaneous bilirubin • G6PD, glucose-6-phosphate dehydrogenase • ETCOc, end-tidal carbon monoxide corrected for ambient carbon monoxide • B/A, bilirubin/albumin • UB, unbound bilirubin
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BACKGROUND |
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DEFINITION OF RECOMMENDATIONS |
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The draft practice guideline underwent extensive peer review by committees and sections within the AAP, outside organizations, and other individuals identified by the subcommittee as experts in the field. Liaison representatives to the subcommittee were invited to distribute the draft to other representatives and committees within their specialty organizations. The resulting comments were reviewed by the subcommittee and, when appropriate, incorporated into the guideline.
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BILIRUBIN ENCEPHALOPATHY AND KERNICTERUS |
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See Appendix 1 for the clinical manifestations of acute bilirubin encephalopathy and kernicterus.
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FOCUS OF GUIDELINE |
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Analysis of these reported cases of kernicterus suggests that if health care personnel follow the recommendations listed in this guideline, kernicterus would be largely preventable.
These guidelines emphasize the importance of universal systematic assessment for the risk of severe hyperbilirubinemia, close follow-up, and prompt intervention 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 equity. They specifically emphasize the principles of patient safety and the key role of timeliness of interventions to prevent adverse outcomes resulting from neonatal hyperbilirubinemia.
The following are the key elements of the recommendations provided by this guideline. Clinicians should:
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PRIMARY PREVENTION |
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RECOMMENDATION 1.0: Clinicians should advise mothers to nurse their infants at least 8 to 12 times per day for the first 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 breastfed infants.15–17 Providing appropriate support and advice to breastfeeding mothers increases the likelihood that breastfeeding will be successful.
Additional information on how to assess the adequacy of intake in a breastfed newborn is provided in Appendix 1.
RECOMMENDATION 1.1: The AAP recommends against routine supplementation of nondehydrated breastfed 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
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SECONDARY PREVENTION |
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Blood Typing
RECOMMENDATION 2.1: All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.1: If a mother has not had prenatal blood grouping or is Rh-negative, a direct antibody test (or Coombs’ test), blood type, and an Rh (D) type on the infant’s (cord) blood are strongly recommended (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.2: If the maternal blood is group O, Rh-positive, it is an option to test the cord blood for the infant’s blood type and direct antibody test, but it is not required provided that there is appropriate surveillance, 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 development of jaundice, and nurseries should have established protocols for the assessment of jaundice. Jaundice should be assessed whenever the infant’s vital 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 performed 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 extremities,21 but visual estimation of bilirubin levels from the degree of jaundice can lead to errors.22–24 In most infants with TSB levels of less than 15 mg/dL (257 µmol/L), noninvasive TcB-measurement devices can provide a valid estimate of the TSB level.2,25–29 See Appendix 1 for additional information on the clinical evaluation of jaundice and the use of TcB measurements.
RECOMMENDATION 2.2.1: Protocols for the assessment 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 measurement should be performed on every infant who is jaundiced 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 hyperbilirubinemia. Recommendations for TSB measurements after the age of 24 hours are provided in Fig 1 and Table 1.
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RECOMMENDATION 3.1: A TcB and/or TSB measurement should be performed if the jaundice appears excessive for the infant’s age (evidence quality D: benefits 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, particularly in darkly pigmented infants (evidence quality C: benefits exceed harms).
RECOMMENDATION 3.2: All bilirubin levels should be interpreted according to the infant’s age in hours (Fig 2) (evidence quality C: benefits 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 quality D: benefits versus harms exceptional).
RECOMMENDATION 4.1.1: Infants who have an elevation of direct-reacting or conjugated bilirubin should have a urinalysis and urine culture.32 Additional laboratory evaluation for sepsis should be performed if indicated by history and physical examination (evidence quality C: benefits exceed harms).
See Appendix 1 for 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 measurement of total and direct or conjugated bilirubin to identify cholestasis (Table 1) (evidence quality D: benefit versus harms exceptional). 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 evaluation for the causes of cholestasis is recommended (evidence quality C: benefits exceed harms).
RECOMMENDATION 4.1.4: Measurement of the glucose-6-phosphate dehydrogenase (G6PD) level is recommended for a jaundiced infant who is receiving phototherapy and whose family history or ethnic or geographic origin suggest the likelihood of G6PD deficiency or for an infant in whom the response to phototherapy is poor (Fig 3) (evidence quality C: benefits exceed harms).
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Risk Assessment Before Discharge
RECOMMENDATION 5.1: Before discharge, every newborn should be assessed for the risk of developing severe hyperbilirubinemia, and all nurseries should establish protocols for assessing this risk. Such assessment is particularly important in infants who are discharged before the age of 72 hours (evidence quality C: benefits exceed harms).
RECOMMENDATION 5.1.1: The AAP recommends 2 clinical options used individually or in combination for 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, appropriate follow-up after discharge is essential (evidence quality C: benefits exceed harms).
The best documented method for assessing the risk of subsequent hyperbilirubinemia is to measure the TSB or TcB level25,31,35–38 and plot the results on a nomogram (Fig 2). A TSB level can be obtained at the time of the routine metabolic screen, thus obviating the need for an additional blood sample. Some authors have suggested that a TSB measurement should be part of the routine screening of all newborns.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 significant and most frequently associated with an increase 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 hyperbilirubinemia.39 Nevertheless, if no risk factors are present, the risk of severe hyperbilirubinemia is extremely low, and the more risk factors present, the greater the risk of severe hyperbilirubinemia.39 The important risk factors most frequently associated with severe hyperbilirubinemia are breastfeeding, gestation below 38 weeks, significant jaundice in a previous sibling, and jaundice noted before discharge.39,40 A formula-fed infant of 40 or more weeks’ gestation is at very low risk of developing severe hyperbilirubinemia.39
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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 examined by a qualified health care professional in the first few days after 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 hyperbilirubinemia (Table 2 and Fig 2), and risk of other neonatal problems (evidence quality C: benefits exceed harms).
Timing of Follow-up
RECOMMENDATION 6.1.2: Follow-up should be provided as follows:
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For some newborns discharged before 48 hours, 2 follow-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. Earlier or more frequent follow-up 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).
RECOMMENDATION 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-up can be ensured or the period of greatest risk has passed (72-96 hours) (evidence quality D: benefits versus harms exceptional).
Follow-up Assessment
RECOMMENDATION 6.1.4: The follow-up assessment should include the infant’s weight and percent change from birth weight, adequacy of intake, the pattern of voiding and stooling, and the presence or absence of jaundice (evidence quality C: benefits exceed harms). Clinical judgment 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, particularly in darkly pigmented infants (evidence quality C: benefits exceed harms).
See Appendix 1 for assessment of the adequacy of intake in breastfeeding infants.
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TREATMENT |
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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 recommended.
RECOMMENDATION 7.1.2: If the TSB is at a level at which exchange transfusion is recommended (Fig 4) or if the TSB level is 25 mg/dL (428 µmol/L) or higher at any time, it is a medical emergency and the infant should be admitted immediately and directly to a hospital pediatric service for intensive phototherapy. 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 neonatal intensive care unit with full monitoring and resuscitation capabilities (evidence quality D: benefits versus harms exceptional).
RECOMMENDATION 7.1.4: In isoimmune hemolytic disease, administration of intravenous 
-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 µmol/L) of the exchange level (Fig 4).55 If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms).
Intravenous -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 -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 level and consider an albumin level of less than 3.0 g/dL as one risk factor for lowering the threshold for phototherapy use (see Fig 3) (evidence quality D: benefits versus risks exceptional.).
RECOMMENDATION 7.1.6: If an exchange transfusion is being considered, the serum albumin level should be measured and the bilirubin/albumin (B/A) ratio used in conjunction with the TSB level and other factors in determining 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 levels 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 address this issue are limited, however, it is not possible to provide specific recommendations for intervention based on the duration of hyperbilirubinemia.
See Appendix 1 for 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 jaundiced and manifests the signs of the intermediate to advanced stages of acute bilirubin encephalopathy61,62 (hypertonia, arching, retrocollis, opisthotonos, fever, high-pitched cry) even if the TSB is falling (evidence quality D: benefits versus risks exceptional).
Phototherapy
RECOMMENDATION 7.2: All nurseries and services treating infants should have the necessary equipment to provide intensive phototherapy (see Appendix 2) (evidence quality D: benefits exceed risks).
Outpatient Management of the Jaundiced Breastfed Infant
RECOMMENDATION 7.3: In breastfed infants who require phototherapy (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 efficacy of phototherapy63–65 (evidence quality B: benefits exceed harms). In breastfed infants receiving phototherapy, supplementation with expressed breast milk or formula is appropriate if the infant’s intake seems inadequate, weight loss is excessive, or the infant seems dehydrated.
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IMPLEMENTATION STRATEGIES |
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These principles can be applied to the challenge of preventing severe hyperbilirubinemia and kernicterus. A systematic approach to the implementation of these guidelines should result in greater safety. Such approaches might include
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FUTURE RESEARCH |
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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 nervous 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 nervous 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 determining the degree of surveillance needed and the timing 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 hyperbilirubinemia. 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 measurements. 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-mesoporphyrin,72–75 a drug that inhibits the production of heme oxygenase. Tin-mesoporphyrin is not approved 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 disseminating the information contained in this guideline to increase awareness on the part of physicians, residents, nurses, and parents concerning the issues of neonatal hyperbilirubinemia and strategies for its management. In addition, monitoring systems should be established to identify the impact of these guidelines on the incidence of acute bilirubin encephalopathy and kernicterus and the use of phototherapy and exchange transfusions.
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CONCLUSIONS |
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SUBCOMMITTEE ON HYPERBILIRUBINEMIA
M. Jeffrey Maisels, MB, BCh, Chairperson
Richard D. Baltz, MD
Vinod K. Bhutani, MD
Thomas B. Newman, MD, MPH
Heather Palmer, MB, BCh
Warren Rosenfeld, MD
David K. Stevenson, MD
Howard B. Weinblatt, MD
CONSULTANT
Charles J. Homer, MD, MPH, Chairperson
American Academy of Pediatrics Steering Committee on Quality Improvement and Management
STAFF
Carla T. Herrerias, MPH
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APPENDIX 1: Additional Notes |
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The AAP defines evidence-based recommendations as follows:1
Anticipated Balance Between Benefits and Harms
The presence of clear benefits or harms supports stronger statements for or against a course of action. In some cases, however, recommendations are made when analysis of the balance of benefits and harms provides an exceptional dysequilibrium and it would be unethical or impossible to perform clinical trials to "prove" the point. In these cases the balance of benefit and harm is termed "exceptional."
Clinical Manifestations of Acute Bilirubin Encephalopathy and Kernicterus
Acute Bilirubin Encephalopathy
In the early phase of acute bilirubin encephalopathy, severely jaundiced infants become lethargic and hypotonic and suck poorly.2,3 The intermediate phase is characterized by moderate stupor, irritability, and hypertonia. The infant may develop a fever and high-pitched cry, which may alternate with drowsiness and hypotonia. The hypertonia is manifested by backward arching of the neck (retrocollis) and trunk (opisthotonos). There is anecdotal evidence that an emergent exchange transfusion at this stage, in some cases, might reverse the central nervous system changes.4 The advanced phase, in which central nervous system damage is probably irreversible, is characterized by pronounced retrocollis-opisthotonos, shrill cry, no feeding, apnea, fever, deep stupor to coma, sometimes seizures, and death.2,3,5
Kernicterus
In the chronic form of bilirubin encephalopathy, surviving infants may develop a severe form of athetoid cerebral palsy, auditory dysfunction, dental-enamel dysplasia, paralysis of upward gaze, and, less often, intellectual and other handicaps. Most infants who develop kernicterus have manifested some or all of the signs listed above in the acute phase of bilirubin encephalopathy. However, occasionally there are infants who have developed very high bilirubin levels and, subsequently, the signs of kernicterus but have exhibited few, if any, antecedent clinical signs of acute bilirubin encephalopathy.3,5,6
Clinical Evaluation of Jaundice and TcB Measurements
Jaundice is usually seen in the face first and progresses caudally to the trunk and extremities,7 but because visual estimation of bilirubin levels from the degree of jaundice can lead to errors,8–10 a low threshold should be used for measuring the TSB. Devices that provide a noninvasive TcB measurement have proven very useful as screening tools,11 and newer instruments give measurements that provide a valid estimate of the TSB level.12–17 Studies using the new TcB-measurement instruments are limited, but the data published thus far suggest that in most newborn populations, these instruments generally provide measurements within 2 to 3 mg/dL (34–51 µmol/L) of the TSB and can replace a measurement of serum bilirubin in many circumstances, particularly for TSB levels less than 15 mg/dL (257 µmol/L).12–17 Because phototherapy "bleaches" the skin, both visual assessment of jaundice and TcB measurements in infants undergoing phototherapy are not reliable. In addition, the ability of transcutaneous instruments to provide accurate measurements in different racial groups requires additional study.18,19 The limitations of the accuracy and reproducibility of TSB measurements in the clinical laboratory20–22 must also be recognized and are discussed in the technical report.23
Capillary Versus Venous Serum Bilirubin Measurement
Almost all published data regarding the relationship of TSB levels to kernicterus or developmental outcome are based on capillary blood TSB levels. Data regarding the differences between capillary and venous TSB levels are conflicting.24,25 In 1 study the capillary TSB levels were higher, but in another they were lower than venous TSB levels.24,25 Thus, obtaining a venous sample to "confirm" an elevated capillary TSB level is not recommended, because it will delay the initiation of treatment.
Direct-Reacting and Conjugated Bilirubin
Although commonly used interchangeably, direct-reacting bilirubin is not the same as conjugated bilirubin. Direct-reacting bilirubin is the bilirubin that reacts directly (without the addition of an accelerating agent) with diazotized sulfanilic acid. Conjugated bilirubin is bilirubin made water soluble by binding with glucuronic acid in the liver. Depending on the technique used, the clinical laboratory will report total and direct-reacting or unconjugated and conjugated bilirubin levels. In this guideline and for clinical purposes, the terms may be used interchangeably.
Abnormal Direct and Conjugated Bilirubin Levels
Laboratory measurement of direct bilirubin is not precise,26 and values between laboratories can vary widely. If the TSB is at or below 5 mg/dL (85 µmol/L), a direct or conjugated bilirubin of more than 1.0 mg/dL (17.1 µmol/L) is generally considered abnormal. For TSB values higher than 5 mg/dL (85 µmol/L), a direct bilirubin of more than 20% of the TSB is considered abnormal. If the hospital laboratory measures conjugated bilirubin using the Vitros (formerly Ektachem) system (Ortho-Clinical Diagnostics, Raritan, NJ), any value higher than 1 mg/dL is considered abnormal.
Assessment of Adequacy of Intake in Breastfeeding Infants
The data from a number of studies27–34 indicate that unsupplemented, breastfed infants experience their maximum weight loss by day 3 and, on average, 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, suggesting that adequacy of intake should be evaluated and the infant monitored if weight loss is more than 10%.35 Evidence of adequate intake in breastfed infants also includes 4 to 6 thoroughly wet diapers in 24 hours and the passage of 3 to 4 stools per day by the fourth day. By the third to fourth day, the stools in adequately breastfed infants should have changed from meconium to a mustard yellow, mushy stool.36 The above assessment will also help to identify breastfed infants who are at risk for dehydration because of inadequate intake.
Nomogram for Designation of Risk
Note that this nomogram (Fig 2) does not describe the natural history of neonatal hyperbilirubinemia, particularly after 48 to 72 hours, for which, because of sampling bias, the lower zones are spuriously elevated.37 This bias, however, will have much less effect on the high-risk zone (95th percentile in the study).38
G6PD Dehydrogenase Deficiency
It is important to look for G6PD deficiency in infants with significant hyperbilirubinemia, because some may develop a sudden increase in the TSB. In addition, G6PD-deficient infants require intervention at lower TSB levels (Figs 3 and 4). It should be noted also that in the presence of hemolysis, G6PD levels can be elevated, which may obscure the diagnosis in the newborn period so that a normal level in a hemolyzing neonate does not rule out G6PD deficiency.39 If G6PD deficiency is strongly suspected, a repeat level should be measured when the infant is 3 months old. It is also recognized that immediate laboratory determination of G6PD is generally not available in most US hospitals, and thus translating the above information into clinical practice is currently difficult. Nevertheless, practitioners are reminded to consider the diagnosis of G6PD deficiency in infants with severe hyperbilirubinemia, particularly if they belong to the population groups in which this condition is prevalent. This is important in the African American population, because these infants, as a group, have much lower TSB levels than white or Asian infants.40,41 Thus, severe hyperbilirubinemia in an African American infant should always raise the possibility of G6PD deficiency.
Basis for the Recommendations 7.1.1 Through 7.1.6 and Provided in Figs 3 and 4
Ideally, recommendations for when to implement phototherapy and exchange transfusions should be based on estimates of when the benefits of these interventions exceed their risks and cost. The evidence for these estimates should come from randomized trials or systematic observational studies. Unfortunately, there is little such evidence on which to base these recommendations. As a result, treatment guidelines must necessarily rely on more uncertain estimates and extrapolations. For a detailed discussion of this question, please see "An Evidence-Based Review of Important Issues Concerning Neonatal Hyperbilirubinemia."23
The recommendations for phototherapy and exchange transfusion are based on the following principles:
Subtle Neurologic Abnormalities Associated With Hyperbilirubinemia
There are several studies demonstrating measurable transient changes in brainstem-evoked potentials, behavioral patterns, and the infant’s cry59–63 associated with TSB levels of 15 to 25 mg/dL (257–428 µmol/L). In these studies, the abnormalities identified were transient and disappeared when the serum bilirubin levels returned to normal with or without treatment.59,60,62,63
A few cohort studies have found an association between hyperbilirubinemia and long-term adverse neurodevelopmental effects that are more subtle than kernicterus.64–67 Current studies, however, suggest that although phototherapy lowers the TSB levels, it has no effect on these long-term neurodevelopmental outcomes.68–70
Risks of Exchange Transfusion
Because exchange transfusions are now rarely performed, the risks of morbidity and mortality associated with the procedure are difficult to quantify. In addition, the complication rates listed below may not be generalizable to the current era if, like most procedures, frequency of performance is an important determinant of risk. Death associated with exchange transfusion has been reported in approximately 3 in 1000 procedures,71,72 although in otherwise well infants of 35 or more weeks’ gestation, the risk is probably much lower.71–73 Significant morbidity (apnea, bradycardia, cyanosis, vasospasm, thrombosis, necrotizing enterocolitis) occurs in as many as 5% of exchange transfusions,71 and the risks associated with the use of blood products must always be considered.74 Hypoxic-ischemic encephalopathy and acquired immunodeficiency syndrome have occurred in otherwise healthy infants receiving exchange transfusions.73,75
Serum Albumin Levels and the B/A Ratio
The legends to Figs 3 and 4 and recommendations 7.1.5 and 7.1.6 contain references to the serum albumin level and the B/A ratio as factors that can be considered in the decision to initiate phototherapy (Fig 3) or perform an exchange transfusion (Fig 4). Bilirubin is transported in the plasma tightly bound to albumin, and the portion that is unbound or loosely bound can more readily leave the intravascular space and cross the intact blood-brain barrier.76 Elevations of unbound bilirubin (UB) have been associated with kernicterus in sick preterm newborns.77,78 In addition, elevated UB concentrations are more closely associated than TSB levels with transient abnormalities in the audiometric brainstem response in term79 and preterm80 infants. Long-term studies relating B/A binding in infants to developmental outcome are limited and conflicting.69,81,82 In addition, clinical laboratory measurement of UB is not currently available in the United States.
The ratio of bilirubin (mg/dL) to albumin (g/dL) does correlate with measured UB in newborns83 and can be used as an approximate surrogate for the measurement of UB. It must be recognized, however, that both albumin levels and the ability of albumin to bind bilirubin vary significantly between newborns.83,84 Albumin binding of bilirubin is impaired in sick infants,84–86 and some studies show an increase in binding with increasing gestational86,87 and postnatal87,88 age, but others have not found a significant effect of gestational age on binding.89 Furthermore, the risk of bilirubin encephalopathy is unlikely to be a simple function of the TSB level or the concentration of UB but is more likely a combination of both (ie, the total amount of bilirubin available [the miscible pool of bilirubin] as well as the tendency of bilirubin to enter the tissues [the UB concentration]).83 An additional factor is the possible susceptibility of the cells of the central nervous system to damage by bilirubin.90 It is therefore a clinical option to use the B/A ratio together with, but not in lieu of, the TSB level as an additional factor in determining the need for exchange transfusion83 (Fig 4).
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APPENDIX 2: Phototherapy |
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It is important also to recognize that the measured irradiance will vary widely depending on where the measurement is taken. Irradiance measured below the center of the light source can be more than double that measured at the periphery, and this dropoff at the periphery will vary with different phototherapy units. Ideally, irradiance should be measured at multiple sites under the area illuminated by the unit and the measurements averaged. The International Electrotechnical Commission3 defines the "effective surface area" as the intended treatment surface that is illuminated by the phototherapy light. The commission uses 60 x 30 cm as the standard-sized surface.
Is It Necessary to Measure Phototherapy Doses Routinely?
Although it is not necessary to measure spectral irradiance before each use of phototherapy, it is important to perform periodic checks of phototherapy units to make sure that an adequate irradiance is being delivered.
The Dose-Response Relationship of Phototherapy
Figure 5 shows that there is a direct relationship between the irradiance used and the rate at which the serum bilirubin declines under phototherapy.4 The data in Fig 5 suggest that there is a saturation point beyond which an increase in the irradiance produces no added efficacy. We do not know, however, that a saturation point exists. Because the conversion of bilirubin to excretable photoproducts is partly irreversible and follows first-order kinetics, there may not be a saturation point, so we do not know the maximum effective dose of phototherapy.
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Using Phototherapy Effectively
Light Source
The spectrum of light delivered by a phototherapy unit is determined by the type of light source and any filters used. Commonly used phototherapy units contain daylight, cool white, blue, or "special blue" fluorescent tubes. Other units use tungsten-halogen lamps in different configurations, either free-standing or as part of a radiant warming device. Recently, a system using high-intensity gallium nitride light-emitting diodes has been introduced.6 Fiber-optic systems deliver light from a high-intensity lamp to a fiber-optic blanket. Most of these devices deliver enough output in the blue-green region of the visible spectrum to be effective for standard phototherapy use. However, when bilirubin levels approach the range at which intensive phototherapy is recommended, maximal efficiency must be sought. The most effective light sources currently commercially available for phototherapy are those that use special blue fluorescent tubes7 or a specially designed light-emitting diode light (Natus Inc, San Carlos, CA).6 The special blue fluorescent tubes are labeled F20T12/BB (General Electric, Westinghouse, Sylvania) or TL52/20W (Phillips, Eindhoven, The Netherlands). It is important to note that special blue tubes provide much greater irradiance than regular blue tubes (labeled F20T12/B) (Fig 6). Special blue tubes are most effective because they provide light predominantly in the blue-green spectrum. At these wavelengths, light penetrates skin well and is absorbed maximally by bilirubin.7
There is a common misconception that ultraviolet light is used for phototherapy. The light systems used do not emit significant ultraviolet radiation, and the small amount of ultraviolet light that is emi
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ABSTRACT
BACKGROUND
38 0/7 wk
indicates special blue, General Electric 20-W F20T12/BB tube; 
, blue, General Electric 20-W F20T12/B tube; 
, daylight blue, 4 General Electric 20-W F20T12/B blue tubes and 4 Sylvania 20-W F20T12/D daylight tubes; •, daylight, Sylvania 20-W F20T12/D daylight tube. Curves were plotted by using linear curve fitting (True Epistat, Epistat Services, Richardson, TX). The best fit is described by the equation y = AeBx. Source: Pediatrics. 1996;98:283-287.