ICTERICIA GUIA PEDIATRICa 2004

Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of
Gestation
Subcommittee on Hyperbilirubinemia
Pediatrics 2004;114;297-316
DOI: 10.1542/peds.114.1.297
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AMERICAN ACADEMY OF PEDIATRICS
CLINICAL PRACTICE GUIDELINE
Management of Hyperbilirubinemia in the Newborn Infant 35 or More

Weeks of Gestation
ABSTRACT. Jaundice occurs in most newborn infants. Hyperbilirubinemia”3 for a description of the meth-
Most jaundice is benign, but because of the potential odology, questions addressed, and conclusions of
toxicity of bilirubin, newborn infants must be monitored this report.) This guideline is intended for use by
to identify those who might develop severe hyperbili- hospitals and pediatricians, neonatologists, family
rubinemia and, in rare cases, acute bilirubin encephalop- physicians, physician assistants, and advanced prac-
athy or kernicterus. The focus of this guideline is to
reduce the incidence of severe hyperbilirubinemia and
tice nurses who treat newborn infants in the hospital
bilirubin encephalopathy while minimizing the risks of and as outpatients. A list of frequently asked ques-
unintended harm such as maternal anxiety, decreased tions and answers for parents is available in English
breastfeeding, and unnecessary costs or treatment. Al- and Spanish at www.aap.org/family/jaundicefaq.
though kernicterus should almost always be prevent- htm.
able, cases continue to occur. These guidelines provide a
framework for the prevention and management of DEFINITION OF RECOMMENDATIONS
hyperbilirubinemia in newborn infants of 35 or more
The evidence-based approach to guideline devel-
weeks of gestation. In every infant, we recommend that
clinicians 1) promote and support successful breastfeed- opment requires that the evidence in support of a
ing; 2) perform a systematic assessment before discharge policy be identified, appraised, and summarized and
for the risk of severe hyperbilirubinemia; 3) provide that an explicit link between evidence and recom-
early and focused follow-up based on the risk assess- mendations be defined. Evidence-based recommen-
ment; and 4) when indicated, treat newborns with pho- dations are based on the quality of evidence and the
totherapy or exchange transfusion to prevent the devel- balance of benefits and harms that is anticipated
opment of severe hyperbilirubinemia and, possibly, when the recommendation is followed. This guide-
bilirubin encephalopathy (kernicterus). Pediatrics 2004; line uses the definitions for quality of evidence and
114:297–316; hyperbilirubinemia, newborn, kernicterus, balance of benefits and harms established by the
bilirubin encephalopathy, phototherapy.
AAP Steering Committee on Quality Improvement
Management.4 See Appendix 1 for these definitions.
ABBREVIATIONS. AAP, American Academy of Pediatrics; TSB, The draft practice guideline underwent extensive
total serum bilirubin; TcB, transcutaneous bilirubin; G6PD, glu- peer review by committees and sections within the
cose-6-phosphate dehydrogenase; ETCOc, end-tidal carbon mon- AAP, outside organizations, and other individuals
oxide corrected for ambient carbon monoxide; B/A, bilirubin/
albumin; UB, unbound bilirubin. identified by the subcommittee as experts in the
field. Liaison representatives to the subcommittee
BACKGROUND were invited to distribute the draft to other represen-
tatives and committees within their specialty organi-
I
n October 1994, the Provisional Committee for
Quality Improvement and Subcommittee on Hy- zations. The resulting comments were reviewed by
perbilirubinemia of the American Academy of the subcommittee and, when appropriate, incorpo-
Pediatrics (AAP) produced a practice parameter rated into the guideline.
dealing with the management of hyperbilirubinemia
in the healthy term newborn.1 The current guideline BILIRUBIN ENCEPHALOPATHY AND
represents a consensus of the committee charged by KERNICTERUS
the AAP with reviewing and updating the existing Although originally a pathologic diagnosis charac-
guideline and is based on a careful review of the terized by bilirubin staining of the brainstem nuclei
evidence, including a comprehensive literature re- and cerebellum, the term “kernicterus” has come to
view by the New England Medical Center Evidence- be used interchangeably with both the acute and
Based Practice Center.2 (See “An Evidence-Based chronic findings of bilirubin encephalopathy. Biliru-
Review of Important Issues Concerning Neonatal bin encephalopathy describes the clinical central ner-
vous system findings caused by bilirubin toxicity to
the basal ganglia and various brainstem nuclei. To
The recommendations in this guideline do not indicate an exclusive course avoid confusion and encourage greater consistency
of treatment or serve as a standard of medical care. Variations, taking into
account individual circumstances, may be appropriate.
in the literature, the committee recommends that in
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- infants the term “acute bilirubin encephalopathy” be
emy of Pediatrics. used to describe the acute manifestations of bilirubin
PEDIATRICS Vol. 114 No. 1 July 2004 297

toxicity seen in the first weeks after birth and that the PRIMARY PREVENTION
term “kernicterus” be reserved for the chronic and In numerous policy statements, the AAP recom-
permanent clinical sequelae of bilirubin toxicity. mends breastfeeding for all healthy term and near-
See Appendix 1 for the clinical manifestations of term newborns. This guideline strongly supports this
acute bilirubin encephalopathy and kernicterus. general recommendation.
RECOMMENDATION 1.0: Clinicians should advise
mothers to nurse their infants at least 8 to 12 times per
FOCUS OF GUIDELINE
day for the first several days12 (evidence quality C: benefits
The overall aim of this guideline is to promote an exceed harms).
approach that will reduce the frequency of severe Poor caloric intake and/or dehydration associated
neonatal hyperbilirubinemia and bilirubin encepha- with inadequate breastfeeding may contribute to the
lopathy and minimize the risk of unintended harm development of hyperbilirubinemia.6,13,14 Increasing
such as increased anxiety, decreased breastfeeding, the frequency of nursing decreases the likelihood of
or unnecessary treatment for the general population subsequent significant hyperbilirubinemia in breast-
and excessive cost and waste. Recent reports of ker- fed infants.15–17 Providing appropriate support and
nicterus indicate that this condition, although rare, is advice to breastfeeding mothers increases the likeli-
still occurring.2,5–10 hood that breastfeeding will be successful.
Analysis of these reported cases of kernicterus Additional information on how to assess the ade-
suggests that if health care personnel follow the rec- quacy of intake in a breastfed newborn is provided in
ommendations listed in this guideline, kernicterus Appendix 1.
would be largely preventable. RECOMMENDATION 1.1: The AAP recommends
These guidelines emphasize the importance of uni- against routine supplementation of nondehydrated breast-
versal systematic assessment for the risk of severe fed infants with water or dextrose water (evidence quality
hyperbilirubinemia, close follow-up, and prompt in- B and C: harms exceed benefits).
tervention when indicated. The recommendations Supplementation with water or dextrose water
apply to the care of infants at 35 or more weeks of will not prevent hyperbilirubinemia or decrease TSB
gestation. These recommendations seek to further levels.18,19
the aims defined by the Institute of Medicine as
appropriate for health care:11 safety, effectiveness, SECONDARY PREVENTION
efficiency, timeliness, patient-centeredness, and eq- RECOMMENDATION 2.0: Clinicians should perform
uity. They specifically emphasize the principles of ongoing systematic assessments during the neonatal pe-
patient safety and the key role of timeliness of inter- riod for the risk of an infant developing severe hyperbil-
ventions to prevent adverse outcomes resulting from irubinemia.
neonatal hyperbilirubinemia.
The following are the key elements of the recom- Blood Typing
mendations provided by this guideline. Clinicians RECOMMENDATION 2.1: All pregnant women should
should: be tested for ABO and Rh (D) blood types and have a
serum screen for unusual isoimmune antibodies (evidence
1. Promote and support successful breastfeeding. quality B: benefits exceed harms).
2. Establish nursery protocols for the identification RECOMMENDATION 2.1.1: If a mother has not had
and evaluation of hyperbilirubinemia. prenatal blood grouping or is Rh-negative, a direct anti-
3. Measure the total serum bilirubin (TSB) or trans- body test (or Coombs’ test), blood type, and an Rh (D) type
cutaneous bilirubin (TcB) level on infants jaun- on the infant’s (cord) blood are strongly recommended
diced in the first 24 hours. (evidence quality B: benefits exceed harms).
4. Recognize that visual estimation of the degree of RECOMMENDATION 2.1.2: If the maternal blood is
jaundice can lead to errors, particularly in darkly group O, Rh-positive, it is an option to test the cord blood
pigmented infants. for the infant’s blood type and direct antibody test, but it
5. Interpret all bilirubin levels according to the in- is not required provided that there is appropriate surveil-
fant’s age in hours. lance, risk assessment before discharge, and follow-up20
6. Recognize that infants at less than 38 weeks’ (evidence quality C: benefits exceed harms).
gestation, particularly those who are breastfed,
are at higher risk of developing hyperbiliru- Clinical Assessment
binemia and require closer surveillance and RECOMMENDATION 2.2: Clinicians should ensure
monitoring. that all infants are routinely monitored for the develop-
7. Perform a systematic assessment on all infants ment of jaundice, and nurseries should have established
before discharge for the risk of severe hyperbil- protocols for the assessment of jaundice. Jaundice should
irubinemia. be assessed whenever the infant’s vital signs are measured
8. Provide parents with written and verbal infor- but no less than every 8 to 12 hours (evidence quality D:
mation about newborn jaundice. benefits versus harms exceptional).
9. Provide appropriate follow-up based on the time In newborn infants, jaundice can be detected by
of discharge and the risk assessment. blanching the skin with digital pressure, revealing
10. Treat newborns, when indicated, with photo- the underlying color of the skin and subcutaneous
therapy or exchange transfusion. tissue. The assessment of jaundice must be per-
298 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

Fig 1. Algorithm for the management of jaundice in the newborn nursery.
AMERICAN ACADEMY OF PEDIATRICS 299

formed in a well-lit room or, preferably, in daylight Cause of Jaundice
at a window. Jaundice is usually seen first in the face RECOMMENDATION 4.1: The possible cause of
and progresses caudally to the trunk and extremi- jaundice should be sought in an infant receiving
ties,21 but visual estimation of bilirubin levels from phototherapy or whose TSB level is rising rapidly (ie,
the degree of jaundice can lead to errors.22–24 In most crossing percentiles [Fig 2]) and is not explained by
infants with TSB levels of less than 15 mg/dL (257 the history and physical examination (evidence qual-
␮mol/L), noninvasive TcB-measurement devices can ity D: benefits versus harms exceptional).
provide a valid estimate of the TSB level.2,25–29 See RECOMMENDATION 4.1.1: Infants who have an ele-
Appendix 1 for additional information on the clinical vation of direct-reacting or conjugated bilirubin should
evaluation of jaundice and the use of TcB measure- have a urinalysis and urine culture.32 Additional labora-
ments. tory evaluation for sepsis should be performed if indicated
RECOMMENDATION 2.2.1: Protocols for the assess- by history and physical examination (evidence quality C:
ment of jaundice should include the circumstances in benefits exceed harms).
which nursing staff can obtain a TcB level or order a TSB See Appendix 1 for definitions of abnormal levels
measurement (evidence quality D: benefits versus harms of direct-reacting and conjugated bilirubin.
exceptional). RECOMMENDATION 4.1.2: Sick infants and those who
are jaundiced at or beyond 3 weeks should have a mea-
Laboratory Evaluation surement of total and direct or conjugated bilirubin to
RECOMMENDATION 3.0: A TcB and/or TSB measure- identify cholestasis (Table 1) (evidence quality D: benefit
ment should be performed on every infant who is jaun- versus harms exceptional). The results of the newborn
diced in the first 24 hours after birth (Fig 1 and Table 1)30 thyroid and galactosemia screen should also be checked in
(evidence quality C: benefits exceed harms). The need for these infants (evidence quality D: benefits versus harms
and timing of a repeat TcB or TSB measurement will exceptional).
depend on the zone in which the TSB falls (Fig 2),25,31 the RECOMMENDATION 4.1.3: If the direct-reacting or
age of the infant, and the evolution of the hyperbiliru- conjugated bilirubin level is elevated, additional evalua-
binemia. Recommendations for TSB measurements after tion for the causes of cholestasis is recommended (evidence
the age of 24 hours are provided in Fig 1 and Table 1. quality C: benefits exceed harms).
See Appendix 1 for capillary versus venous biliru- RECOMMENDATION 4.1.4: Measurement of the glu-
bin levels. cose-6-phosphate dehydrogenase (G6PD) level is recom-
RECOMMENDATION 3.1: A TcB and/or TSB measure- mended for a jaundiced infant who is receiving photother-
ment should be performed if the jaundice appears excessive apy and whose family history or ethnic or geographic
for the infant’s age (evidence quality D: benefits versus origin suggest the likelihood of G6PD deficiency or for an
harms exceptional). If there is any doubt about the degree infant in whom the response to phototherapy is poor (Fig
of jaundice, the TSB or TcB should be measured. Visual 3) (evidence quality C: benefits exceed harms).
estimation of bilirubin levels from the degree of jaundice G6PD deficiency is widespread and frequently un-
can lead to errors, particularly in darkly pigmented in- recognized, and although it is more common in the
fants (evidence quality C: benefits exceed harms). populations around the Mediterranean and in the
RECOMMENDATION 3.2: All bilirubin levels should be Middle East, Arabian peninsula, Southeast Asia, and
interpreted according to the infant’s age in hours (Fig 2) Africa, immigration and intermarriage have trans-
(evidence quality C: benefits exceed harms). 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 TSB
Jaundice appears excessive for infant’s age Measure TcB and/or TSB
Infant receiving phototherapy or TSB rising Blood type and Coombs’ test, if not obtained
rapidly (ie, crossing percentiles with cord blood
[Fig 2]) and unexplained by history Complete blood count and smear
and physical examination Measure direct or conjugated bilirubin
It is an option to perform reticulocyte count,
G6PD, and ETCOc, if available
Repeat TSB in 4–24 h depending on infant’s
age and TSB level
TSB concentration approaching exchange levels Perform reticulocyte count, G6PD, albumin,
or not responding to phototherapy ETCOc, if available
Elevated direct (or conjugated) bilirubin level Do urinalysis and urine culture. Evaluate for
sepsis if indicated by history and physical
examination
Jaundice present at or beyond age 3 wk, or Total and direct (or conjugated) bilirubin
sick infant level
If direct bilirubin elevated, evaluate for
causes of cholestasis
Check results of newborn thyroid and
galactosemia screen, and evaluate infant
for signs or symptoms of hypothyroidism

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 more
or 35 or more weeks’ gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin 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% low-risk zone (Fig 2) is at very low risk of developing
of African Americans, and kernicterus has occurred severe hyperbilirubinemia.5,38
in some of these infants.5,33 In a recent report, G6PD Table 2 lists those factors that are clinically signif-
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 TABLE 2. Risk Factors for Development of Severe Hyperbil-
information on G6PD deficiency.) irubinemia in Infants of 35 or More Weeks’ Gestation (in Approx-
imate Order of Importance)
Risk Assessment Before Discharge Major risk factors

Predischarge TSB or TcB level in the high-risk zone (Fig 2)25,31
RECOMMENDATION 5.1: Before discharge, every new- Jaundice observed in the first 24 h30
born should be assessed for the risk of developing severe Blood group incompatibility with positive direct antiglobulin
hyperbilirubinemia, and all nurseries should establish pro- test, other known hemolytic disease (eg, G6PD deficiency),
tocols for assessing this risk. Such assessment is particu- elevated ETCOc
Gestational age 35–36 wk39,40
larly important in infants who are discharged before the Previous sibling received phototherapy40,41
age of 72 hours (evidence quality C: benefits exceed Cephalohematoma or significant bruising39
harms). Exclusive breastfeeding, particularly if nursing is not going
RECOMMENDATION 5.1.1: The AAP recommends 2 well and weight loss is excessive39,40
East Asian race39*
clinical options used individually or in combination for the Minor risk factors
systematic assessment of risk: predischarge measurement Predischarge TSB or TcB level in the high intermediate-risk
of the bilirubin level using TSB or TcB and/or assessment zone25,31
of clinical risk factors. Whether either or both options are Gestational age 37–38 wk39,40
used, appropriate follow-up after discharge is essential Jaundice observed before discharge40
Previous sibling with jaundice40,41
(evidence quality C: benefits exceed harms). Macrosomic infant of a diabetic mother42,43
The best documented method for assessing the Maternal age ⱖ25 y39
risk of subsequent hyperbilirubinemia is to measure Male gender39,40
the TSB or TcB level25,31,35–38 and plot the results on Decreased risk (these factors are associated with decreased risk of
significant jaundice, listed in order of decreasing importance)
a nomogram (Fig 2). A TSB level can be obtained at TSB or TcB level in the low-risk zone (Fig 2)25,31
the time of the routine metabolic screen, thus obvi- Gestational age ⱖ41 wk39
ating the need for an additional blood sample. Some Exclusive bottle feeding39,40
authors have suggested that a TSB measurement Black race38*
should be part of the routine screening of all new- Discharge from hospital after 72 h40,44
borns.5,31 An infant whose predischarge TSB is in the * Race as defined by mother’s description.

icant and most frequently associated with an in- Follow-up Assessment
crease in the risk of severe hyperbilirubinemia. But, RECOMMENDATION 6.1.4: The follow-up assessment
because these risk factors are common and the risk of should include the infant’s weight and percent change
hyperbilirubinemia is small, individually the factors from birth weight, adequacy of intake, the pattern of void-
are of limited use as predictors of significant hyper- ing and stooling, and the presence or absence of jaundice
bilirubinemia.39 Nevertheless, if no risk factors are (evidence quality C: benefits exceed harms). Clinical judg-
present, the risk of severe hyperbilirubinemia is ex- ment should be used to determine the need for a bilirubin
tremely low, and the more risk factors present, the measurement. If there is any doubt about the degree of
greater the risk of severe hyperbilirubinemia.39 The jaundice, the TSB or TcB level should be measured. Visual
important risk factors most frequently associated estimation of bilirubin levels can lead to errors, particu-
with severe hyperbilirubinemia are breastfeeding,
larly in darkly pigmented infants (evidence quality C:
gestation below 38 weeks, significant jaundice in a
benefits exceed harms).
previous sibling, and jaundice noted before dis-
See Appendix 1 for assessment of the adequacy of
charge.39,40 A formula-fed infant of 40 or more
weeks’ gestation is at very low risk of developing intake in breastfeeding infants.
severe hyperbilirubinemia.39
TREATMENT
Hospital Policies and Procedures
Phototherapy and Exchange Transfusion
RECOMMENDATION 6.1: All hospitals should provide
written and verbal information for parents at the time of RECOMMENDATION 7.1: Recommendations for treat-
discharge, which should include an explanation of jaun- ment are given in Table 3 and Figs 3 and 4 (evidence
dice, the need to monitor infants for jaundice, and advice quality C: benefits exceed harms). If the TSB does not fall
on how monitoring should be done (evidence quality D: or continues to rise despite intensive phototherapy, it is
benefits versus harms exceptional). very likely that hemolysis is occurring. The committee’s
An example of a parent-information handout is recommendations for discontinuing phototherapy can be
available in English and Spanish at www.aap.org/ found in Appendix 2.
family/jaundicefaq.htm. RECOMMENDATION 7.1.1: In using the guidelines for
phototherapy and exchange transfusion (Figs 3 and 4), the
Follow-up direct-reacting (or conjugated) bilirubin level should not
RECOMMENDATION 6.1.1: All infants should be ex- be subtracted from the total (evidence quality D: benefits
amined by a qualified health care professional in the first versus harms exceptional).
few days after discharge to assess infant well-being and the In unusual situations in which the direct bilirubin
presence or absence of jaundice. The timing and location of level is 50% or more of the total bilirubin, there are
this assessment will be determined by the length of stay in no good data to provide guidance for therapy, and
the nursery, presence or absence of risk factors for hyper- consultation with an expert in the field is recom-
bilirubinemia (Table 2 and Fig 2), and risk of other neo- mended.
natal problems (evidence quality C: benefits exceed RECOMMENDATION 7.1.2: If the TSB is at a level at
harms). which exchange transfusion is recommended (Fig 4) or if
the TSB level is 25 mg/dL (428 ␮mol/L) or higher at any
Timing of Follow-up time, it is a medical emergency and the infant should be
RECOMMENDATION 6.1.2: Follow-up should be pro- admitted immediately and directly to a hospital pediatric
vided as follows: service for intensive phototherapy. These infants should
not be referred to the emergency department, because it
Infant Discharged Should Be Seen by Age
delays the initiation of treatment54 (evidence quality C:
Before age 24 h 72 h benefits exceed harms).
Between 24 and 47.9 h 96 h RECOMMENDATION 7.1.3: Exchange transfusions
Between 48 and 72 h 120 h
should be performed only by trained personnel in a neo-
For some newborns discharged before 48 hours, 2 fol- natal intensive care unit with full monitoring and resus-
low-up visits may be required, the first visit between 24 citation capabilities (evidence quality D: benefits versus
and 72 hours and the second between 72 and 120 hours. harms exceptional).
Clinical judgment should be used in determining follow- RECOMMENDATION 7.1.4: In isoimmune hemolytic
up. Earlier or more frequent follow-up should be provided disease, administration of intravenous ␥-globulin (0.5-1
for those who have risk factors for hyperbilirubinemia g/kg over 2 hours) is recommended if the TSB is rising
(Table 2), whereas those discharged with few or no risk despite intensive phototherapy or the TSB level is within 2
factors can be seen after longer intervals (evidence quality to 3 mg/dL (34-51 ␮mol/L) of the exchange level (Fig
C: benefits exceed harms). 4).55 If necessary, this dose can be repeated in 12 hours
RECOMMENDATION 6.1.3: If appropriate follow-up (evidence quality B: benefits exceed harms).
cannot be ensured in the presence of elevated risk for Intravenous ␥-globulin has been shown to reduce
developing severe hyperbilirubinemia, it may be necessary the need for exchange transfusions in Rh and ABO
to delay discharge either until appropriate follow-up can hemolytic disease.55–58 Although data are limited, it
be ensured or the period of greatest risk has passed (72-96 is reasonable to assume that intravenous ␥-globulin
hours) (evidence quality D: benefits versus harms excep- will also be helpful in the other types of Rh hemolytic
tional). disease such as anti-C and anti-E.

TABLE 3. Example of a Clinical Pathway for Management of the Newborn Infant Readmitted for
Phototherapy or Exchange Transfusion
Treatment
Use 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 levels
Blood type (ABO, Rh)
Direct antibody test (Coombs’)
Serum albumin
Complete blood cell count with differential and smear for red cell morphology
Reticulocyte count
ETCOc (if available)
G6PD if suggested by ethnic or geographic origin or if poor response to phototherapy
Urine for reducing substances
If history and/or presentation suggest sepsis, perform blood culture, urine culture, and
cerebrospinal fluid for protein, glucose, cell count, and culture
Interventions
If TSB ⱖ25 mg/dL (428 ␮mol/L) or ⱖ20 mg/dL (342 ␮mol/L) in a sick infant or infant ⬍38 wk
gestation, obtain a type and crossmatch, and request blood in case an exchange transfusion is
necessary
In infants with isoimmune hemolytic disease and TSB level rising in spite of intensive
phototherapy or within 2–3 mg/dL (34–51 ␮mol/L) of exchange level (Fig 4), administer
intravenous immunoglobulin 0.5–1 g/kg over 2 h and repeat in 12 h if necessary
If infant’s weight loss from birth is ⬎12% or there is clinical or biochemical evidence of
dehydration, recommend formula or expressed breast milk. If oral intake is in question, give
intravenous fluids.
For infants receiving intensive phototherapy
Breastfeed or bottle-feed (formula or expressed breast milk) every 2–3 h
If TSB ⱖ25 mg/dL (428 ␮mol/L), repeat TSB within 2–3 h
If TSB 20–25 mg/dL (342–428 ␮mol/L), repeat within 3–4 h. If TSB ⬍20 mg/dL (342 ␮mol/L),
repeat in 4–6 h. If TSB continues to fall, repeat in 8–12 h
If 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 for
exchange transfusion recommendations)
When TSB is ⬍13–14 mg/dL (239 ␮mol/L), discontinue phototherapy
Depending on the cause of the hyperbilirubinemia, it is an option to measure TSB 24 h after
discharge to check for rebound
Serum Albumin Levels and the Bilirubin/Albumin diced and manifests the signs of the intermediate to ad-
Ratio vanced stages of acute bilirubin encephalopathy61,62 (hy-
RECOMMENDATION 7.1.5: It is an option to measure pertonia, arching, retrocollis, opisthotonos, fever, high-
the serum albumin level and consider an albumin level of pitched cry) even if the TSB is falling (evidence quality D:
less than 3.0 g/dL as one risk factor for lowering the benefits versus risks exceptional).
threshold for phototherapy use (see Fig 3) (evidence qual-
ity D: benefits versus risks exceptional.). Phototherapy
RECOMMENDATION 7.1.6: If an exchange transfusion RECOMMENDATION 7.2: All nurseries and services
is being considered, the serum albumin level should be treating infants should have the necessary equipment to
measured and the bilirubin/albumin (B/A) ratio used in provide intensive phototherapy (see Appendix 2) (evidence
conjunction with the TSB level and other factors in deter- quality D: benefits exceed risks).
mining the need for exchange transfusion (see Fig 4)
(evidence quality D: benefits versus harms exceptional). Outpatient Management of the Jaundiced Breastfed
The recommendations shown above for treating Infant
hyperbilirubinemia are based primarily on TSB lev-
els and other factors that affect the risk of bilirubin RECOMMENDATION 7.3: In breastfed infants who re-
encephalopathy. This risk might be increased by a quire phototherapy (Fig 3), the AAP recommends that,
prolonged (rather than a brief) exposure to a certain if possible, breastfeeding should be continued (evidence
TSB level.59,60 Because the published data that ad- quality C: benefits exceed harms). It is also an option to
dress this issue are limited, however, it is not possi- interrupt temporarily breastfeeding and substitute for-
ble to provide specific recommendations for inter- mula. This can reduce bilirubin levels and/or enhance
vention based on the duration of hyperbilirubinemia. the efficacy of phototherapy63–65 (evidence quality B: ben-
See Appendix 1 for the basis for recommendations efits exceed harms). In breastfed infants receiving photo-
7.1 through 7.1.6 and for the recommendations pro- therapy, supplementation with expressed breast milk or
vided in Figs 3 and 4. Appendix 1 also contains a formula is appropriate if the infant’s intake seems inade-
discussion of the risks of exchange transfusion and quate, weight loss is excessive, or the infant seems dehy-
the use of B/A binding. drated.
Acute Bilirubin Encephalopathy IMPLEMENTATION STRATEGIES

RECOMMENDATION 7.1.7: Immediate exchange The Institute of Medicine11 recommends a dra-
transfusion is recommended in any infant who is jaun- matic change in the way the US health care system

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 potential 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
␮W/cm2 per nm (measured at the infant’s skin 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 intensive phototherapy, and of light
sources 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 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.
ensures the safety of patients. The perspective of • Checklists or reminders associated with risk fac-
safety as a purely individual responsibility must be tors, age at discharge, and laboratory test results
replaced by the concept of safety as a property of that provide guidance for appropriate follow-up.
systems. Safe systems are characterized by a shared • Explicit educational materials for parents (a key
knowledge of the goal, a culture emphasizing safety, component of all AAP guidelines) concerning the
the ability of each person within the system to act in identification of newborns with jaundice.
a manner that promotes safety, minimizing the use of
memory, and emphasizing the use of standard pro- FUTURE RESEARCH
cedures (such as checklists), and the involvement of Epidemiology of Bilirubin-Induced Central Nervous
patients/families as partners in the process of care. System Damage
These principles can be applied to the challenge of
There is a need for appropriate epidemiologic data
preventing severe hyperbilirubinemia and ker-
to document the incidence of kernicterus in the new-
nicterus. A systematic approach to the implementa-
born population, the incidence of other adverse ef-
tion of these guidelines should result in greater
fects attributable to hyperbilirubinemia and its man-
safety. Such approaches might include
agement, and the number of infants whose TSB
• The establishment of standing protocols for nurs- levels exceed 25 or 30 mg/dL (428-513 ␮mol/L).
ing assessment of jaundice, including testing TcB Organizations such as the Centers for Disease Con-
and TSB levels, without requiring physician or- trol and Prevention should implement strategies for
ders. appropriate data gathering to identify the number of

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 is
recommended if the TSB rises to these levels despite intensive phototherapy. For readmitted infants, if the TSB level is above the exchange
level, repeat TSB measurement every 2 to 3 hours and consider exchange if the TSB remains above the levels indicated after intensive
phototherapy 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 need
for exchange transfusion52:
Risk Category B/A Ratio at Which Exchange Transfusion

Should be Considered
TSB mg/dL/Alb, g/dL TSB ␮mol/L/Alb, ␮mol/L
Infants ⱖ38 0/7 wk 8.0 0.94
Infants 35 0/7–36 6/7 wk and well or ⱖ38 0/7 wk 7.2 0.84
if higher risk or isoimmune hemolytic disease
or G6PD deficiency
Infants 35 0/7–37 6/7 wk if higher risk or 6.8 0.80
isoimmune hemolytic disease or G6PD deficiency
If the TSB is at or approaching the exchange level, send blood for immediate type and crossmatch. Blood for exchange transfusion is
modified whole blood (red cells and plasma) crossmatched against the mother and compatible with the infant.53
infants who develop serum bilirubin levels above 25 Effect of Bilirubin on the Central Nervous System
or 30 mg/dL (428-513 ␮mol/L) and those who de-
velop acute and chronic bilirubin encephalopathy. The serum bilirubin level by itself, except when it
This information will help to identify the magnitude is extremely high and associated with bilirubin en-
of the problem; the number of infants who need to be cephalopathy, is an imprecise indicator of long-term
screened and treated to prevent 1 case of kernicterus; neurodevelopmental outcome.2 Additional studies
and the risks, costs, and benefits of different strate- are needed on the relationship between central ner-
gies for prevention and treatment of hyperbiliru- vous system damage and the duration of hyperbil-
binemia. In the absence of these data, recommenda- irubinemia, the binding of bilirubin to albumin, and
tions for intervention cannot be considered changes seen in the brainstem auditory evoked re-
definitive. sponse. These studies could help to better identify

risk, clarify the effect of bilirubin on the central ner- lirubinemia, close follow-up, and prompt interven-
vous system, and guide intervention. tion, when necessary.
Identification of Hemolysis M. Jeffrey Maisels, MB, BCh, Chairperson
Because of their poor specificity and sensitivity, Richard D. Baltz, MD
the standard laboratory tests for hemolysis (Table 1) Vinod K. Bhutani, MD
are frequently unhelpful.66,67 However, end-tidal Thomas B. Newman, MD, MPH
carbon monoxide, corrected for ambient carbon Heather Palmer, MB, BCh
Warren Rosenfeld, MD
monoxide (ETCOc), levels can confirm the presence
David K. Stevenson, MD
or absence of hemolysis, and measurement of ETCOc Howard B. Weinblatt, MD
is the only clinical test that provides a direct mea-
surement of the rate of heme catabolism and the rate Consultant
of bilirubin production.68,69 Thus, ETCOc may be Charles J. Homer, MD, MPH, Chairperson
helpful in determining the degree of surveillance American Academy of Pediatrics Steering
needed and the timing of intervention. It is not yet Committee on Quality Improvement and
known, however, how ETCOc measurements will Management
affect management.
Staff
Carla T. Herrerias, MPH
Nomograms and the Measurement of Serum and TcB
ACKNOWLEDGMENTS
It would be useful to develop an age-specific (by
hour) nomogram for TSB in populations of newborns M.J.M. received grant support from Natus Medical, Inc, for
multinational study of ambient carbon monoxide; WellSpring
that differ with regard to risk factors for hyperbiliru- Pharmaceutical Corporation for study of Stannsoporfin (tin-meso-
binemia. There is also an urgent need to improve the porphyrin); and Minolta, Inc, for study of the Minolta/Hill-Rom
precision and accuracy of the measurement of TSB in Air-Shields transcutaneous jaundice meter model JM-103. V.K.B.
the clinical laboratory.70,71 Additional studies are received grant support from WellSpring Pharmaceutical Corpora-
tion for study of Stannsoporfin (tin-mesoporphyrin) and Natus
also needed to develop and validate noninvasive Medical, Inc, for multinational study of ambient carbon monoxide
(transcutaneous) measurements of serum bilirubin and is a consultant (volunteer) to SpectrX (BiliChek transcutane-
and to understand the factors that affect these mea- ous bilirubinometer). D.K.S. is a consultant to and holds stock
surements. These studies should also assess the cost- options through Natus Medical, Inc.
effectiveness and reproducibility of TcB measure- The American Academy of Pediatrics Subcommittee on Hyper-
bilirubinemia gratefully acknowledges the help of the following
ments in clinical practice.2 organizations, committees, and individuals who reviewed drafts
of this guideline and provided valuable criticisms and commen-
tary: American Academy of Pediatrics Committee on Nutrition;
Pharmacologic Therapy American Academy of Pediatrics Committee on Practice and Am-
There is now evidence that hyperbilirubinemia can bulatory Medicine; American Academy of Pediatrics Committee
be effectively prevented or treated with tin-mesopor- on Child Health Financing; American Academy of Pediatrics
Committee on Medical Liability; American Academy of Pediatrics
phyrin,72–75 a drug that inhibits the production of Committee on Fetus and Newborn; American Academy of Pedi-
heme oxygenase. Tin-mesoporphyrin is not ap- atrics Section on Perinatal Pediatrics; Centers for Disease Control
proved by the US Food and Drug Administration. If and Prevention; Parents of Infants and Children With Kernicterus
approved, tin-mesoporphyrin could find immediate (PICK); Charles Ahlfors, MD; Daniel Batton, MD; Thomas Bojko,
application in preventing the need for exchange MD; Sarah Clune, MD; Sudhakar Ezhuthachan, MD; Lawrence
Gartner, MD; Cathy Hammerman, MD; Thor Hansen, MD; Lois
transfusion in infants who are not responding to Johnson, MD; Michael Kaplan, MB, ChB; Tony McDonagh, PhD;
phototherapy.75 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-
Dissemination and Monitoring tham Suresh, MD; Margot VandeBor, MD; Hank Vreman, PhD;
Research should be directed toward methods for Philip Walson, MD; Jon Watchko, MD; Richard Wennberg, MD;
disseminating the information contained in this and Chap-Yung Yeung, MD.
guideline to increase awareness on the part of phy- REFERENCES
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30. Newman TB, Liljestrand P, Escobar GJ. Jaundice noted in the first 24 ease. J Pediatr. 1992;121:93–97
hours after birth in a managed care organization. Arch Pediatr Adolesc 58. Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous
Med. 2002;156:1244 –1250 immune globulin in neonatal ABO isoimmunization: factors associated
31. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge with clinical efficacy. Biol Neonate. 1996;70:69 –74
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binemia in healthy term and near-term newborns. Pediatrics. 1999;103: indications for treatment. In: Odell GB, Schaffer R, Simopoulos AP, eds.
6 –14 Phototherapy in the Newborn: An Overview. Washington, DC: National
32. Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinary Academy of Sciences; 1974:122–149
tract infection in infancy. Pediatrics. 2002;109:846 – 851 60. Ozmert E, Erdem G, Topcu M. Long-term follow-up of indirect hyper-
33. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a po- bilirubinemia in full-term Turkish infants. Acta Paediatr. 1996;85:
tential complication of glucose-6-phosphate dehydrogenase deficiency. 1440 –1444
Clin Perinatol. 1998;25:575–590 61. Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia, PA: W. B.
34. Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate Saunders; 2001
dehydrogenase deficiency: pathogenesis and global epidemiology. Acta 62. Harris M, Bernbaum J, Polin J, Zimmerman R, Polin RA. Developmental
Paediatr Suppl. 1994;394:58 –76 follow-up of breastfed term and near-term infants with marked hyper-
35. Alpay F, Sarici S, Tosuncuk HD, Serdar MA, Inanç N, Gökçay E. The bilirubinemia. Pediatrics. 2001;107:1075–1080
value of first-day bilirubin measurement in predicting the development 63. Osborn LM, Bolus R. Breast feeding and jaundice in the first week of
of significant hyperbilirubinemia in healthy term newborns. Pediatrics. life. J Fam Pract. 1985;20:475– 480

64. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the ences. In this guideline, the term “should” implies
breast-fed newborn: a controlled trial of four interventions. Pediatrics.
1993;91:470 – 473
a recommendation by the committee.
65. Amato M, Howald H, von Muralt G. Interruption of breast-feeding • Option: either the quality of the evidence that ex-
versus phototherapy as treatment of hyperbilirubinemia in full-term ists is suspect or well-performed studies have
infants. Helv Paediatr Acta. 1985;40:127–131 shown little clear advantage to one approach over
66. Maisels MJ, Gifford K, Antle CE, Leib GR. Jaundice in the healthy another. Patient preference should have a substan-
newborn infant: a new approach to an old problem. Pediatrics. 1988;81:
505–511
tial role in influencing clinical decision-making
67. Newman TB, Easterling MJ. Yield of reticulocyte counts and blood when a policy is described as an option.
smears in term infants. Clin Pediatr (Phila). 1994;33:71–76 • No recommendation: there is a lack of pertinent
68. Herschel M, Karrison T, Wen M, Caldarelli L, Baron B. Evaluation of the evidence and the anticipated balance of benefits
direct antiglobulin (Coombs’) test for identifying newborns at risk for
hemolysis as determined by end-tidal carbon monoxide concentration
and harms is unclear.
(ETCOc); and comparison of the Coombs’ test with ETCOc for detecting
significant jaundice. J Perinatol. 2002;22:341–347 Anticipated Balance Between Benefits and Harms
69. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin production The presence of clear benefits or harms supports
in neonates. Pediatrics. 1997;100:252–254
70. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin
stronger statements for or against a course of action.
measurements. Clin Chem. 1996;42:869 – 873 In some cases, however, recommendations are made
71. Lo S, Doumas BT, Ashwood E. Performance of bilirubin determinations when analysis of the balance of benefits and harms
in US laboratories—revisited. Clin Chem. 2004;50:190 –194 provides an exceptional dysequilibrium and it would
72. Kappas A, Drummond GS, Henschke C, Valaes T. Direct comparison of
Sn-mesoporphyrin, an inhibitor of bilirubin production, and photother-
be unethical or impossible to perform clinical trials to
apy in controlling hyperbilirubinemia in term and near-term newborns. “prove” the point. In these cases the balance of ben-
Pediatrics. 1995;95:468 – 474 efit and harm is termed “exceptional.”
73. Martinez JC, Garcia HO, Otheguy L, Drummond GS, Kappas A. Control
of severe hyperbilirubinemia in full-term newborns with the inhibitor of Clinical Manifestations of Acute Bilirubin
bilirubin production Sn-mesoporphyrin. Pediatrics. 1999;103:1–5
74. Suresh G, Martin CL, Soll R. Metalloporphyrins for treatment of uncon-
Encephalopathy and Kernicterus
jugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev. Acute Bilirubin Encephalopathy
2003;2:CD004207
75. Kappas A, Drummond GS, Munson DP, Marshall JR. Sn-mesoporphy-
In the early phase of acute bilirubin encephalopa-
rin interdiction of severe hyperbilirubinemia in Jehovah’s Witness new- thy, severely jaundiced infants become lethargic and
borns as an alternative to exchange transfusion. Pediatrics. 2001;108: hypotonic and suck poorly.2,3 The intermediate
1374 –1377 phase is characterized by moderate stupor, irritabil-
ity, and hypertonia. The infant may develop a fever
APPENDIX 1: Additional Notes and high-pitched cry, which may alternate with
Definitions of Quality of Evidence and Balance of
drowsiness and hypotonia. The hypertonia is mani-
Benefits and Harms
fested by backward arching of the neck (retrocollis)
and trunk (opisthotonos). There is anecdotal evi-
The Steering Committee on Quality Improvement dence that an emergent exchange transfusion at this
and Management categorizes evidence quality in 4 stage, in some cases, might reverse the central ner-
levels: vous system changes.4 The advanced phase, in which
1. Well-designed, randomized, controlled trials or central nervous system damage is probably irrevers-
diagnostic studies on relevant populations ible, is characterized by pronounced retrocollis-opis-
2. Randomized, controlled trials or diagnostic stud- thotonos, shrill cry, no feeding, apnea, fever, deep
ies with minor limitations; overwhelming, consis- stupor to coma, sometimes seizures, and death.2,3,5
tent evidence from observational studies
3. Observational studies (case-control and cohort de- Kernicterus
sign) In the chronic form of bilirubin encephalopathy,
4. Expert opinion, case reports, reasoning from first surviving infants may develop a severe form of ath-
principles etoid cerebral palsy, auditory dysfunction, dental-
The AAP defines evidence-based recommenda- enamel dysplasia, paralysis of upward gaze, and,
tions as follows:1 less often, intellectual and other handicaps. Most
infants who develop kernicterus have manifested
• Strong recommendation: the committee believes some or all of the signs listed above in the acute
that the benefits of the recommended approach phase of bilirubin encephalopathy. However, occa-
clearly exceed the harms of that approach and that sionally there are infants who have developed very
the quality of the supporting evidence is either high bilirubin levels and, subsequently, the signs of
excellent or impossible to obtain. Clinicians should kernicterus but have exhibited few, if any, anteced-
follow these recommendations unless a clear and ent clinical signs of acute bilirubin encephalopa-
compelling rationale for an alternative approach is thy.3,5,6
present.
• Recommendation: the committee believes that the Clinical Evaluation of Jaundice and TcB Measurements
benefits exceed the harms, but the quality of evi- Jaundice is usually seen in the face first and
dence on which this recommendation is based is progresses caudally to the trunk and extremities,7
not as strong. Clinicians should also generally fol- but because visual estimation of bilirubin levels from
low these recommendations but should be alert to the degree of jaundice can lead to errors,8 –10 a low
new information and sensitive to patient prefer- threshold should be used for measuring the TSB.

Devices that provide a noninvasive TcB measure- mg/dL (17.1 ␮mol/L) is generally considered abnor-
ment have proven very useful as screening tools,11 mal. For TSB values higher than 5 mg/dL (85 ␮mol/
and newer instruments give measurements that pro- L), a direct bilirubin of more than 20% of the TSB is
vide a valid estimate of the TSB level.12–17 Studies considered abnormal. If the hospital laboratory mea-
using the new TcB-measurement instruments are sures conjugated bilirubin using the Vitros (formerly
limited, but the data published thus far suggest that Ektachem) system (Ortho-Clinical Diagnostics, Rari-
in most newborn populations, these instruments tan, NJ), any value higher than 1 mg/dL is consid-
generally provide measurements within 2 to 3 ered abnormal.
mg/dL (34 –51 ␮mol/L) of the TSB and can replace a
measurement of serum bilirubin in many circum- Assessment of Adequacy of Intake in Breastfeeding
stances, particularly for TSB levels less than 15 Infants
mg/dL (257 ␮mol/L).12–17 Because phototherapy The data from a number of studies27–34 indicate
“bleaches” the skin, both visual assessment of jaun- that unsupplemented, breastfed infants experience
dice and TcB measurements in infants undergoing their maximum weight loss by day 3 and, on aver-
phototherapy are not reliable. In addition, the ability age, lose 6.1% ⫾ 2.5% (SD) of their birth weight.
of transcutaneous instruments to provide accurate Thus, ⬃5% to 10% of fully breastfed infants lose 10%
measurements in different racial groups requires ad- or more of their birth weight by day 3, suggesting
ditional study.18,19 The limitations of the accuracy that adequacy of intake should be evaluated and the
and reproducibility of TSB measurements in the clin- infant monitored if weight loss is more than 10%.35
ical laboratory20 –22 must also be recognized and are Evidence of adequate intake in breastfed infants also
discussed in the technical report.23 includes 4 to 6 thoroughly wet diapers in 24 hours
and the passage of 3 to 4 stools per day by the fourth
Capillary Versus Venous Serum Bilirubin day. By the third to fourth day, the stools in ade-
Measurement quately breastfed infants should have changed from
Almost all published data regarding the relation- meconium to a mustard yellow, mushy stool.36 The
ship of TSB levels to kernicterus or developmental above assessment will also help to identify breastfed
outcome are based on capillary blood TSB levels. infants who are at risk for dehydration because of
Data regarding the differences between capillary and inadequate intake.
venous TSB levels are conflicting.24,25 In 1 study the
capillary TSB levels were higher, but in another they Nomogram for Designation of Risk
were lower than venous TSB levels.24,25 Thus, obtain- Note that this nomogram (Fig 2) does not describe
ing a venous sample to “confirm” an elevated capil- the natural history of neonatal hyperbilirubinemia,
lary TSB level is not recommended, because it will particularly after 48 to 72 hours, for which, because
delay the initiation of treatment. of sampling bias, the lower zones are spuriously
elevated.37 This bias, however, will have much less
Direct-Reacting and Conjugated Bilirubin effect on the high-risk zone (95th percentile in the
Although commonly used interchangeably, direct- study).38
reacting bilirubin is not the same as conjugated bili-
rubin. Direct-reacting bilirubin is the bilirubin that G6PD Dehydrogenase Deficiency
reacts directly (without the addition of an accelerat- It is important to look for G6PD deficiency in
ing agent) with diazotized sulfanilic acid. Conju- infants with significant hyperbilirubinemia, because
gated bilirubin is bilirubin made water soluble by some may develop a sudden increase in the TSB. In
binding with glucuronic acid in the liver. Depending addition, G6PD-deficient infants require intervention
on the technique used, the clinical laboratory will at lower TSB levels (Figs 3 and 4). It should be noted
report total and direct-reacting or unconjugated and also that in the presence of hemolysis, G6PD levels
conjugated bilirubin levels. In this guideline and for can be elevated, which may obscure the diagnosis in
clinical purposes, the terms may be used inter- the newborn period so that a normal level in a he-
changeably. molyzing neonate does not rule out G6PD deficien-
cy.39 If G6PD deficiency is strongly suspected, a re-
Abnormal Direct and Conjugated Bilirubin Levels peat level should be measured when the infant is 3
Laboratory measurement of direct bilirubin is not months old. It is also recognized that immediate
precise,26 and values between laboratories can vary laboratory determination of G6PD is generally not
widely. If the TSB is at or below 5 mg/dL (85 ␮mol/ available in most US hospitals, and thus translating
L), a direct or conjugated bilirubin of more than 1.0 the above information into clinical practice is cur-
TABLE 4. Risk Zone as a Predictor of Hyperbilirubinemia39

TSB Before Discharge Newborns Newborns Who Subsequently
(Total ⫽ 2840), Developed a TSB Level
n (%) ⬎95th 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- TSB levels.57,58 Intervention for these infants is
minded to consider the diagnosis of G6PD deficiency based on this risk as well as extrapolations from
in infants with severe hyperbilirubinemia, particu- more premature, lower birth-weight infants who
larly if they belong to the population groups in do have a higher risk of bilirubin toxicity.52,53
which this condition is prevalent. This is important • For all newborns, treatment is recommended at
in the African American population, because these lower TSB levels at younger ages because one of
infants, as a group, have much lower TSB levels than the primary goals of treatment is to prevent addi-
white or Asian infants.40,41 Thus, severe hyperbiliru- tional increases in the TSB level.
binemia in an African American infant should al-
ways raise the possibility of G6PD deficiency. Subtle Neurologic Abnormalities Associated With
Hyperbilirubinemia
There are several studies demonstrating measur-
Basis for the Recommendations 7.1.1 Through 7.1.6 and able transient changes in brainstem-evoked poten-
Provided in Figs 3 and 4 tials, behavioral patterns, and the infant’s cry59 – 63
Ideally, recommendations for when to implement associated with TSB levels of 15 to 25 mg/dL (257–
phototherapy and exchange transfusions should be 428 ␮mol/L). In these studies, the abnormalities
based on estimates of when the benefits of these identified were transient and disappeared when the
interventions exceed their risks and cost. The evi- serum bilirubin levels returned to normal with or
dence for these estimates should come from random- without treatment.59,60,62,63
ized trials or systematic observational studies. Un- A few cohort studies have found an association
fortunately, there is little such evidence on which to between hyperbilirubinemia and long-term adverse
base these recommendations. As a result, treatment neurodevelopmental effects that are more subtle
guidelines must necessarily rely on more uncertain than kernicterus.64 – 67 Current studies, however, sug-
estimates and extrapolations. For a detailed discus- gest that although phototherapy lowers the TSB lev-
sion of this question, please see “An Evidence-Based els, it has no effect on these long-term neurodevel-
Review of Important Issues Concerning Neonatal opmental outcomes.68 –70
Hyperbilirubinemia.”23
The recommendations for phototherapy and ex- Risks of Exchange Transfusion
change transfusion are based on the following prin- Because exchange transfusions are now rarely per-
ciples: formed, the risks of morbidity and mortality associ-
ated with the procedure are difficult to quantify. In
• The main demonstrated value of phototherapy is addition, the complication rates listed below may not
that it reduces the risk that TSB levels will reach a be generalizable to the current era if, like most pro-
level at which exchange transfusion is recom- cedures, frequency of performance is an important
mended.42– 44 Approximately 5 to 10 infants with determinant of risk. Death associated with exchange
TSB levels between 15 and 20 mg/dL (257–342 transfusion has been reported in approximately 3 in
␮mol/L) will receive phototherapy to prevent the 1000 procedures,71,72 although in otherwise well in-
TSB in 1 infant from reaching 20 mg/dL (the num- fants of 35 or more weeks’ gestation, the risk is
ber needed to treat).12 Thus, 8 to 9 of every 10 probably much lower.71–73 Significant morbidity (ap-
infants with these TSB levels will not reach 20 nea, bradycardia, cyanosis, vasospasm, thrombosis,
mg/dL (342 ␮mol/L) even if they are not treated. necrotizing enterocolitis) occurs in as many as 5% of
Phototherapy has proven to be a generally safe exchange transfusions,71 and the risks associated
procedure, although rare complications can occur with the use of blood products must always be con-
(see Appendix 2). sidered.74 Hypoxic-ischemic encephalopathy and ac-
• Recommended TSB levels for exchange transfu- quired immunodeficiency syndrome have occurred
sion (Fig 4) are based largely on the goal of keep- in otherwise healthy infants receiving exchange
ing TSB levels below those at which kernicterus transfusions.73,75
has been reported.12,45– 48 In almost all cases, ex-
change transfusion is recommended only after Serum Albumin Levels and the B/A Ratio
phototherapy has failed to keep the TSB level be- The legends to Figs 3 and 4 and recommendations
low the exchange transfusion level (Fig 4). 7.1.5 and 7.1.6 contain references to the serum albu-
• The recommendations to use phototherapy and min level and the B/A ratio as factors that can be
exchange transfusion at lower TSB levels for in- considered in the decision to initiate phototherapy
fants of lower gestation and those who are sick are (Fig 3) or perform an exchange transfusion (Fig 4).
based on limited observations suggesting that sick Bilirubin is transported in the plasma tightly bound
infants (particularly those with the risk factors to albumin, and the portion that is unbound or
listed in Figs 3 and 4)49 –51 and those of lower loosely bound can more readily leave the intravas-
gestation51–54 are at greater risk for developing cular space and cross the intact blood-brain barrier.76
kernicterus at lower bilirubin levels than are well Elevations of unbound bilirubin (UB) have been as-
infants of more than 38 6/7 weeks’ gestation. Nev- sociated with kernicterus in sick preterm new-
ertheless, other studies have not confirmed all of borns.77,78 In addition, elevated UB concentrations
these associations.52,55,56 There is no doubt, how- are more closely associated than TSB levels with
ever, that infants at 35 to 37 6/7 weeks’ gestation transient abnormalities in the audiometric brainstem
are at a much greater risk of developing very high response in term79 and preterm80 infants. Long-term

studies relating B/A binding in infants to develop- 16. Ebbesen F, Rasmussen LM, Wimberley PD. A new transcutaneous
bilirubinometer, bilicheck, used in the neonatal intensive care unit and
mental outcome are limited and conflicting.69,81,82 In
the maternity ward. Acta Paediatr. 2002;91:203–211
addition, clinical laboratory measurement of UB is 17. Rubaltelli FF, Gourley GR, Loskamp N, et al. Transcutaneous bilirubin
not currently available in the United States. measurement: a multicenter evaluation of a new device. Pediatrics.
The ratio of bilirubin (mg/dL) to albumin (g/dL) 2001;107:1264 –1271
does correlate with measured UB in newborns83 and 18. Engle WD, Jackson GL, Sendelbach D, Manning D, Frawley W. Assess-
ment of a transcutaneous device in the evaluation of neonatal hyperbi-
can be used as an approximate surrogate for the lirubinemia in a primarily Hispanic population. Pediatrics. 2002;110:
measurement of UB. It must be recognized, however, 61– 67
that both albumin levels and the ability of albumin to 19. Schumacher R. Transcutaneous bilirubinometry and diagnostic tests:
bind bilirubin vary significantly between new- “the right job for the tool.” Pediatrics. 2002;110:407– 408
borns.83,84 Albumin binding of bilirubin is impaired 20. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin
measurements. Clin Chem. 1996;42:869 – 873
in sick infants,84 – 86 and some studies show an in- 21. Doumas BT, Eckfeldt JH. Errors in measurement of total bilirubin: a
crease in binding with increasing gestational86,87 and perennial problem. Clin Chem. 1996;42:845– 848
postnatal87,88 age, but others have not found a sig- 22. Lo S, Doumas BT, Ashwood E. Performance of bilirubin determinations
nificant effect of gestational age on binding.89 Fur- in US laboratories—revisited. Clin Chem. 2004;50:190 –194
23. Ip S, Chung M, Kulig J. et al. An evidence-based review of important
thermore, the risk of bilirubin encephalopathy is un-
issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;113(6).
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of both (ie, the total amount of bilirubin available are they really different? Am J Dis Child. 1987;141:1199 –1200
[the miscible pool of bilirubin] as well as the ten- 25. Eidelman AI, Schimmel MS, Algur N, Eylath U. Capillary and venous
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1989;143:642
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susceptibility of the cells of the central nervous sys- bilirubin analyses in Australia and New Zealand. J Clin Pathol. 1982;35:
tem to damage by bilirubin.90 It is therefore a clinical 52–58
option to use the B/A ratio together with, but not in 27. Bertini G, Dani C, Trochin M, Rubaltelli F. Is breastfeeding really
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APPENDIX 2: Phototherapy
1982;100:624 – 626 There is no standardized method for delivering
64. Soorani-Lunsing I, Woltil H, Hadders-Algra M. Are moderate degrees phototherapy. Phototherapy units vary widely, as do
of hyperbilirubinemia in healthy term neonates really safe for the brain?
the types of lamps used in the units. The efficacy of
Pediatr Res. 2001;50:701–705
65. Grimmer I, Berger-Jones K, Buhrer C, Brandl U, Obladen M. Late
phototherapy depends on the dose of phototherapy
neurological sequelae of non-hemolytic hyperbilirubinemia of healthy administered as well as a number of clinical factors
term neonates. Acta Paediatr. 1999;88:661– 663 (Table 5).1
66. Seidman DS, Paz I, Stevenson DK, Laor A, Danon YL, Gale R. Neonatal
hyperbilirubinemia and physical and cognitive performance at 17 years
of age. Pediatrics. 1991;88:828 – 833 Measuring the Dose of Phototherapy
67. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long- Table 5 shows the radiometric quantities used in
term outcome: another look at the collaborative perinatal project. Pedi- measuring the phototherapy dose. The quantity most
atrics. 1993;92:651– 657
68. Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy
commonly reported in the literature is the spectral
for neonatal hyperbilirubinemia: six-year follow-up of the National irradiance. In the nursery, spectral irradiance can be
Institute of Child Health and Human Development clinical trial. Pedi- measured by using commercially available radiome-
atrics. 1990;85:455– 463 ters. These instruments take a single measurement
69. Scheidt PC, Graubard BI, Nelson KB, et al. Intelligence at six years in
relation to neonatal bilirubin levels: follow-up of the National Institute
across a band of wavelengths, typically 425 to 475 or
of Child Health and Human Development Clinical Trial of Photother- 400 to 480 nm. Unfortunately, there is no standard-
apy. Pediatrics. 1991;87:797– 805 ized method for reporting phototherapy dosages in
70. Seidman DS, Paz I, Stevenson DK, Laor A, Danon YL, Gale R. Effect of the clinical literature, so it is difficult to compare
phototherapy for neonatal jaundice on cognitive performance. J Perina- published studies on the efficacy of phototherapy
tol. 1994;14:23–28
71. Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbid-
and manufacturers’ data for the irradiance produced
ity and mortality associated with exchange transfusion. Pediatrics. 1985; by different systems.2 Measurements of irradiance
75:417– 421 from the same system, using different radiometers,

TABLE 5. Factors That Affect the Dose and Efficacy of Phototherapy
Factor Mechanism/Clinical Implementation and Clinical Application
Relevance Rationale
Spectrum of light emitted Blue-green spectrum is Special blue fluorescent Use special blue tubes or LED light
most effective. At these tubes or other light source with output in blue-green
wavelengths, light sources that have spectrum for intensive PT.
penetrates skin well most output in the
and is absorbed blue-green spectrum
maximally by bilirubin. and are most
effective in lowering
TSB.
Spectral irradiance (irradiance 1 irradiance 3 Irradiance is measured If special blue fluorescent tubes are
in certain wavelength 1 rate of decline in TSB with a radiometer as used, bring tubes as close to
band) delivered to surface ␮W/cm2 per nm. infant as possible to increase
of infant Standard PT units irradiance (Fig 6). Note: This
deliver 8–10 ␮W/ cannot be done with halogen
cm2 per nm (Fig 6). lamps because of the danger of
Intensive PT requires burn. Special blue tubes 10–15
⬎30 ␮W/cm2 per cm above the infant will produce
nm. an irradiance of at least 35 ␮W/
cm2 per nm.
Spectral power (average 1 surface area exposed For intensive PT, Place lights above and fiber-optic
spectral irradiance across 3 1 rate of decline in expose maximum pad or special blue fluorescent
surface area) TSB surface area of infant tubes* below the infant. For
to PT. maximum exposure, line sides of
bassinet, warmer bed, or
incubator with aluminum foil.
Cause of jaundice PT is likely to be less When hemolysis is present, start
effective if jaundice is PT at lower TSB levels. Use
due to hemolysis or if intensive PT. Failure of PT
cholestasis is present. suggests that hemolysis is the
(1 direct bilirubin) cause of jaundice. If 1 direct
bilirubin, watch for bronze baby
syndrome or blistering.
TSB level at start of PT The higher the TSB, the Use intensive PT for higher TSB
more rapid the decline levels. Anticipate a more rapid
in TSB with PT. decrease in TSB when TSB ⬎20
mg/dL (342 ␮mol/L).
PT indicates phototherapy; LED, light-emitting diode.
* Available in the Olympic BiliBassinet (Olympic Medical, Seattle, WA).
can also produce significantly different results. The Is It Necessary to Measure Phototherapy Doses
width of the phototherapy lamp’s emissions spec- Routinely?
trum (narrow versus broad) will affect the measured Although it is not necessary to measure spectral
irradiance. Measurements under lights with a very irradiance before each use of phototherapy, it is im-
focused emission spectrum (eg, blue light-emitting portant to perform periodic checks of phototherapy
diode) will vary significantly from one radiometer to units to make sure that an adequate irradiance is
another, because the response spectra of the radiom- being delivered.
eters vary from manufacturer to manufacturer.
Broader-spectrum lights (fluorescent and halogen) The Dose-Response Relationship of Phototherapy
have fewer variations among radiometers. Manufac-
turers of phototherapy systems generally recom- Figure 5 shows that there is a direct relationship
mend the specific radiometer to be used in measur- between the irradiance used and the rate at which
ing the dose of phototherapy when their system is the serum bilirubin declines under phototherapy.4
used. The data in Fig 5 suggest that there is a saturation
It is important also to recognize that the measured point beyond which an increase in the irradiance
irradiance will vary widely depending on where the produces no added efficacy. We do not know, how-
measurement is taken. Irradiance measured below ever, that a saturation point exists. Because the con-
the center of the light source can be more than dou- version of bilirubin to excretable photoproducts is
ble that measured at the periphery, and this dropoff partly irreversible and follows first-order kinetics,
at the periphery will vary with different photother- there may not be a saturation point, so we do not
apy units. Ideally, irradiance should be measured at know the maximum effective dose of phototherapy.
multiple sites under the area illuminated by the unit
and the measurements averaged. The International Effect on Irradiance of the Light Spectrum and the
Electrotechnical Commission3 defines the “effective Distance Between the Infant and the Light Source
surface area” as the intended treatment surface that Figure 6 shows that as the distance between the
is illuminated by the phototherapy light. The com- light source and the infant decreases, there is a cor-
mission uses 60 ⫻ 30 cm as the standard-sized sur- responding increase in the spectral irradiance.5 Fig 6
face. also demonstrates the dramatic difference in irradi-

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-stand-
ing 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 recom-
mended, maximal efficiency must be sought. The
most effective light sources currently commercially
Fig 5. Relationship between average spectral irradiance and de- available for phototherapy are those that use special
crease in serum bilirubin concentration. Term infants with nonhe-
molytic hyperbilirubinemia were exposed to special blue lights
blue fluorescent tubes7 or a specially designed light-
(Phillips TL 52/20W) of different intensities. Spectral irradiance emitting diode light (Natus Inc, San Carlos, CA).6
was measured as the average of readings at the head, trunk, and The special blue fluorescent tubes are labeled
knees. Drawn from the data of Tan.4 Source: Pediatrics. 1996;98: F20T12/BB (General Electric, Westinghouse, Sylva-
283-287. nia) or TL52/20W (Phillips, Eindhoven, The Nether-
lands). It is important to note that special blue tubes
ance produced within the important 425- to 475-nm provide much greater irradiance than regular blue
band by different types of fluorescent tubes. tubes (labeled F20T12/B) (Fig 6). Special blue tubes
are most effective because they provide light pre-
What is Intensive Phototherapy? dominantly in the blue-green spectrum. At these
Intensive phototherapy implies the use of high wavelengths, light penetrates skin well and is ab-
levels of irradiance in the 430- to 490-nm band (usu- sorbed maximally by bilirubin.7
ally 30 ␮W/cm2 per nm or higher) delivered to as There is a common misconception that ultraviolet
much of the infant’s surface area as possible. How light is used for phototherapy. The light systems
this can be achieved is described below. used do not emit significant ultraviolet radiation,
and the small amount of ultraviolet light that is
Using Phototherapy Effectively emitted by fluorescent tubes and halogen bulbs is in
Light Source longer wavelengths than those that cause erythema.
The spectrum of light delivered by a phototherapy In addition, almost all ultraviolet light is absorbed by
unit is determined by the type of light source and the glass wall of the fluorescent tube and the Plexi-
glas cover of the phototherapy unit.
Distance From the Light

As can be seen in Fig 6, the distance of the light
source from the infant has a dramatic effect on the
spectral irradiance, and this effect is most significant
when special blue tubes are used. To take advantage
of this effect, the fluorescent tubes should be placed
as close to the infant as possible. To do this, the infant
should be in a bassinet, not an incubator, because the
top of the incubator prevents the light from being
brought sufficiently close to the infant. In a bassinet,
it is possible to bring the fluorescent tubes within
approximately 10 cm of the infant. Naked term in-
fants do not become overheated under these lights. It
is important to note, however, that the halogen spot
Fig 6. Effect of light source and distance from the light source to
the infant on average spectral irradiance. Measurements were phototherapy lamps cannot be positioned closer to
made across the 425- to 475-nm band by using a commercial the infant than recommended by the manufacturers
radiometer (Olympic Bilimeter Mark II) and are the average of without incurring the risk of a burn. When halogen
measurements taken at different locations at each distance (irra- lamps are used, manufacturers recommendations
diance at the center of the light is much higher than at the periph- should be followed. The reflectors, light source, and
ery). The phototherapy unit was fitted with eight 24-in fluorescent
tubes. 䡲 indicates special blue, General Electric 20-W F20T12/BB transparent light filters (if any) should be kept clean.
tube; 䉬, blue, General Electric 20-W F20T12/B tube; Œ, daylight
blue, 4 General Electric 20-W F20T12/B blue tubes and 4 Sylvania Surface Area
20-W F20T12/D daylight tubes; •, daylight, Sylvania 20-W A number of systems have been developed to pro-
F20T12/D daylight tube. Curves were plotted by using linear
curve fitting (True Epistat, Epistat Services, Richardson, TX). The vide phototherapy above and below the infant.8,9
best fit is described by the equation y ⫽ AeBx. Source: Pediatrics. One commercially available system that does this is
1996;98:283-287. the BiliBassinet (Olympic Medical, Seattle, WA). This

unit provides special blue fluorescent tubes above products responsible for the decline in serum biliru-
and below the infant. An alternative is to place fiber- bin are excreted in urine and bile,18 maintaining
optic pads below an infant with phototherapy lamps adequate hydration and good urine output should
above. One disadvantage of fiber-optic pads is that help to improve the efficacy of phototherapy. Unless
they cover a relatively small surface area so that 2 or there is evidence of dehydration, however, routine
3 pads may be needed.5 When bilirubin levels are intravenous fluid or other supplementation (eg, with
extremely high and must be lowered as rapidly as dextrose water) of term and near-term infants receiv-
possible, it is essential to expose as much of the ing phototherapy is not necessary.
infant’s surface area to phototherapy as possible. In
these situations, additional surface-area exposure When Should Phototherapy Be Stopped?
can be achieved by lining the sides of the bassinet There is no standard for discontinuing photother-
with aluminum foil or a white cloth.10 apy. The TSB level for discontinuing phototherapy
In most circumstances, it is not necessary to re- depends on the age at which phototherapy is initi-
move the infant’s diaper, but when bilirubin levels ated and the cause of the hyperbilirubinemia.13 For
approach the exchange transfusion range, the diaper infants who are readmitted after their birth hospital-
should be removed until there is clear evidence of a ization (usually for TSB levels of 18 mg/dL [308
significant decline in the bilirubin level. ␮mol/L] or higher), phototherapy may be discontin-
ued when the serum bilirubin level falls below 13 to
What Decline in the Serum Bilirubin Can You Expect? 14 mg/dL (239-239 ␮mol/L). Discharge from the
The rate at which the bilirubin declines depends hospital need not be delayed to observe the infant for
on the factors listed in Table 5, and different re- rebound.13,19,20 If phototherapy is used for infants
sponses can be expected depending on the clinical with hemolytic diseases or is initiated early and dis-
circumstances. When bilirubin levels are extremely continued before the infant is 3 to 4 days old, a
high (more than 30 mg/dL [513 ␮mol/L]), and in- follow-up bilirubin measurement within 24 hours
tensive phototherapy is used, a decline of as much as after discharge is recommended.13 For infants who
10 mg/dL (171 ␮mol/L) can occur within a few are readmitted with hyperbilirubinemia and then
hours,11 and a decrease of at least 0.5 to 1 mg/dL per discharged, significant rebound is rare, but a repeat
hour can be expected in the first 4 to 8 hours.12 On TSB measurement or clinical follow-up 24 hours after
average, for infants of more than 35 weeks’ gestation discharge is a clinical option.13
readmitted for phototherapy, intensive phototherapy
can produce a decrement of 30% to 40% in the initial Home Phototherapy
bilirubin level by 24 hours after initiation of photo- Because the devices available for home photother-
therapy.13 The most significant decline will occur in apy may not provide the same degree of irradiance
the first 4 to 6 hours. With standard phototherapy or surface-area exposure as those available in the
systems, a decrease of 6% to 20% of the initial bili- hospital, home phototherapy should be used only in
rubin level can be expected in the first 24 hours.8,14 infants whose bilirubin levels are in the “optional
phototherapy” range (Fig 3); it is not appropriate for
Intermittent Versus Continuous Phototherapy infants with higher bilirubin concentrations. As with
Clinical studies comparing intermittent with con- hospitalized infants, it is essential that serum biliru-
tinuous phototherapy have produced conflicting re- bin levels be monitored regularly.
sults.15–17 Because all light exposure increases biliru-
bin excretion (compared with darkness), no plausible Sunlight Exposure
scientific rationale exists for using intermittent pho- In their original description of phototherapy, Cre-
totherapy. In most circumstances, however, photo- mer et al21 demonstrated that exposure of newborns
therapy does not need to be continuous. Photother- to sunlight would lower the serum bilirubin level.
apy may be interrupted during feeding or brief Although sunlight provides sufficient irradiance in
parental visits. Individual judgment should be exer- the 425- to 475-nm band to provide phototherapy,
cised. If the infant’s bilirubin level is approaching the practical difficulties involved in safely exposing a
the exchange transfusion zone (Fig 4), phototherapy naked newborn to the sun either inside or outside
should be administered continuously until a satisfac- (and avoiding sunburn) preclude the use of sunlight
tory decline in the serum bilirubin level occurs or as a reliable therapeutic tool, and it therefore is not
exchange transfusion is initiated. recommended.
Hydration Complications
There is no evidence that excessive fluid adminis- Phototherapy has been used in millions of infants
tration affects the serum bilirubin concentration. for more than 30 years, and reports of significant
Some infants who are admitted with high bilirubin toxicity are exceptionally rare. Nevertheless, photo-
levels are also mildly dehydrated and may need therapy in hospital separates mother and infant, and
supplemental fluid intake to correct their dehydra- eye patching is disturbing to parents. The most im-
tion. Because these infants are almost always breast- portant, but uncommon, clinical complication occurs
fed, the best fluid to use in these circumstances is a in infants with cholestatic jaundice. When these in-
milk-based formula, because it inhibits the enterohe- fants are exposed to phototherapy, they may develop
patic circulation of bilirubin and should help to a dark, grayish-brown discoloration of the skin, se-
lower the serum bilirubin level. Because the photo- rum, and urine (the bronze infant syndrome).22 The

pathogenesis of this syndrome is unknown, but it 8. Garg AK, Prasad RS, Hifzi IA. A controlled trial of high-intensity
double-surface phototherapy on a fluid bed versus conventional pho-
may be related to an accumulation of porphyrins and
totherapy in neonatal jaundice. Pediatrics. 1995;95:914 –916
other metabolites in the plasma of infants who de- 9. Tan KL. Phototherapy for neonatal jaundice. Clin Perinatol. 1991;18:
velop cholestasis.22,23 Although it occurs exclusively 423– 439
in infants with cholestasis, not all infants with cho- 10. Eggert P, Stick C, Schroder H. On the distribution of irradiation inten-
lestatic jaundice develop the syndrome. sity in phototherapy. Measurements of effective irradiance in an incu-
This syndrome generally has had few deleterious bator. Eur J Pediatr. 1984;142:58 – 61
11. Hansen TW. Acute management of extreme neonatal jaundice—the
consequences, and if there is a need for photother- potential benefits of intensified phototherapy and interruption of en-
apy, the presence of direct hyperbilirubinemia terohepatic bilirubin circulation. Acta Paediatr. 1997;86:843– 846
should not be considered a contraindication to its 12. Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of
use. This is particularly important in sick neonates. 30 mg/dL or more in a large managed care organization. Pediatrics.
Because the products of phototherapy are excreted in 2003;111(6 Pt 1):1303–1311
13. Maisels MJ, Kring E. Bilirubin rebound following intensive photother-
the bile, the presence of cholestasis will decrease the
apy. Arch Pediatr Adolesc Med. 2002;156:669 – 672
efficacy of phototherapy. Nevertheless, infants with 14. Tan KL. Comparison of the efficacy of fiberoptic and conventional
direct hyperbilirubinemia often show some response phototherapy for neonatal hyperbilirubinemia. J Pediatr. 1994;125:
to phototherapy. In infants receiving phototherapy 607– 612
who develop the bronze infant syndrome, exchange 15. Rubaltelli FF, Zanardo V, Granati B. Effect of various phototherapy
regimens on bilirubin decrement. Pediatrics. 1978;61:838 – 841
transfusion should be considered if the TSB is in the
16. Maurer HM, Shumway CN, Draper DA, Hossaini AA. Controlled trial
intensive phototherapy range and phototherapy comparing agar, intermittent phototherapy, and continuous photother-
does not promptly lower the TSB. Because of the apy for reducing neonatal hyperbilirubinemia. J Pediatr. 1973;82:73–76
paucity of data, firm recommendations cannot be 17. Lau SP, Fung KP. Serum bilirubin kinetics in intermittent phototherapy
made. Note, however, that the direct serum bilirubin of physiological jaundice. Arch Dis Child. 1984;59:892– 894
should not be subtracted from the TSB concentration 18. McDonagh AF, Lightner DA. ‘Like a shrivelled blood orange’—
bilirubin, jaundice, and phototherapy. Pediatrics. 1985;75:443– 455
in making decisions about exchange transfusions 19. Yetman RJ, Parks DK, Huseby V, Mistry K, Garcia J. Rebound bilirubin
(see Fig 4). levels in infants receiving phototherapy. J Pediatr. 1998;133:705–707
Rarely, purpura and bullous eruptions have been 20. Lazar L, Litwin A, Merlob P. Phototherapy for neonatal nonhemolytic
described in infants with severe cholestatic jaundice hyperbilirubinemia. Analysis of rebound and indications for discon-
receiving phototherapy,24,25 and severe blistering tinuing therapy. Clin Pediatr (Phila). 1993;32:264 –267
21. Cremer RJ, Perryman PW, Richards DH. Influence of light on the
and photosensitivity during phototherapy have oc- hyperbilirubinemia of infants. Lancet. 1958;1(7030):1094 –1097
curred in infants with congenital erythropoietic por- 22. Rubaltelli FF, Jori G, Reddi E. Bronze baby syndrome: a new porphyrin-
phyria.26,27 Congenital porphyria or a family history related disorder. Pediatr Res. 1983;17:327–330
of porphyria is an absolute contraindication to the 23. Meisel P, Jahrig D, Theel L, Ordt A, Jahrig K. The bronze baby
use of phototherapy, as is the concomitant use of syndrome: consequence of impaired excretion of photobilirubin? Pho-
tobiochem Photobiophys. 1982;3:345–352
drugs or agents that are photosensitizers.28
24. Mallon E, Wojnarowska F, Hope P, Elder G. Neonatal bullous eruption
as a result of transient porphyrinemia in a premature infant with
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2001;21(suppl 1):S93–S97 BB. Purpuric phototherapy-induced eruption in transfused neonates:
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3. International Electrotechnical Commission. Medical electrical equip- 26. Tonz O, Vogt J, Filippini L, Simmler F, Wachsmuth ED, Winterhalter
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Accessed June 7, 2004 diatr Acta. 1975;30:47–56
4. Tan KL. The pattern of bilirubin response to phototherapy for neonatal 27. Soylu A, Kavukcu S, Turkmen M. Phototherapy sequela in a child with
hyperbilirubinemia. Pediatr Res. 1982;16:670 – 674 congenital erythropoietic porphyria. Eur J Pediatr. 1999;158:526 –527
5. Maisels MJ. Why use homeopathic doses of phototherapy? Pediatrics. 28. Kearns GL, Williams BJ, Timmons OD. Fluorescein phototoxicity in a
1996;98:283–287 premature infant. J Pediatr. 1985;107:796 –798
6. Seidman DS, Moise J, Ergaz Z, et al. A new blue light-emitting photo-
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neonatal jaundice. Clin Perinatol. 1990;17:467– 481 reaffirmed, revised, or retired at or before that time.

Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of
Gestation
Pediatrics 2004;114;297-316
DOI: 10.1542/peds.114.1.297
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Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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CLINICAL PRACTICE GUIDELINE

Management of Hyperbilirubinemia in the Newborn Infant 35 or More

PEDIATRICS Vol. 114 No. 1 July 2004 297

298 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

AMERICAN ACADEMY OF PEDIATRICS 299

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

300 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

Risk Assessment Before Discharge Major risk factors

AMERICAN ACADEMY OF PEDIATRICS 301

302 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

Acute Bilirubin Encephalopathy IMPLEMENTATION STRATEGIES

AMERICAN ACADEMY OF PEDIATRICS 303

304 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

Risk Category B/A Ratio at Which Exchange Transfusion

AMERICAN ACADEMY OF PEDIATRICS 305

306 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

AMERICAN ACADEMY OF PEDIATRICS 307

308 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

TABLE 4. Risk Zone as a Predictor of Hyperbilirubinemia39

AMERICAN ACADEMY OF PEDIATRICS 309

310 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

AMERICAN ACADEMY OF PEDIATRICS 311

312 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

AMERICAN ACADEMY OF PEDIATRICS 313

Distance From the Light

314 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

AMERICAN ACADEMY OF PEDIATRICS 315

316 MANAGEMENT OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

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