Pediatr Clin N Am 51 (2004) 843 – 861

Diagnosis and management of

hyperbilirubinemia in the term neonate: for a
safer first week
Vinod K. Bhutani, MD, FAAPa,*,
Lois H. Johnson, MD, FAAPa,b, Ron Keren, MD, MPHa,c
a
Department of Pediatrics, University of Pennsylvania School of Medicine, 800 Spruce Street,
Philadelphia, PA 19107, USA
b
Section on Newborn Pediatrics, Pennsylvania Hospital, Philadelphia, PA, USA
c
Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Newborn jaundice due to severe hyperbilirubinemia, with its potential for

producing brain damage, remains a continuing problem for pediatricians. Most
practitioners have been fortunate to not witness adverse effects consequent to
excessive hyperbilirubinemia, and it remains unrecognized as a threat to their
practice of newborn care. Long term correlation of severe hyperbilirubinemia to
subtle neurologic consequences is unknown and limited by a paucity of prospec-
tive studies. A prevailing understanding is that newborn jaundice is mostly benign,
and that occurrence of kernicterus is extremely unusual. The apparent lack of
evidence that bilirubin could cause brain damage in healthy newborns has, in
multiple instances, led to a lack of concern about bilirubin neurotoxicity. This
attitude is one of the root causes of the recent re-emergence of kernicterus [1,2].
These healthy infants who develop kernicterus and an increased expert concern
that kernicterus is a ‘‘tip of the iceberg’’ of bilirubin-induced neurologic dysfunc-
tion (BIND) has altered our perception; we now realize that the usual benign
neonatal experience of newborn jaundice is unsafe for some in the United States.
Recent reports and evaluation of safety data have demonstrated visual
assessment of jaundice as an unreliable and unsafe indicator to initiate a concern
for severe hyperbilirubinemia [2,3]. Several predischarge screening strategies
based on total serum bilirubin, transcutaneous bilirubin, or clinical risk factor
scoring have now been suggested as strategies to identify an at-risk group of
infants to be tracked more closely [4 –8]. In addition, there have been calls to

* Corresponding author. University of Pennsylvania School of Medicine, Center for Research

on Reproduction and Women’s Health, 1315 Biomedical Research Building 11/111, 421 Curie
Boulevard, Philadelphia, PA 19104.
E-mail address: vkbdev@aol.com (V.K. Bhutani).

0031-3955/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcl.2004.03.011
844 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

adjust the recommendations for interventions with phototherapy or exchange

transfusions to include lowered total serum bilirubin (TSB) thresholds in the
more vulnerable population: near-term (<38 weeks’ gestation) infants, those at
earlier postnatal ages (< 72 hours), and those who have hypoalbuminemia or
presence of comorbidities [9,10]. All of these safety recommendations are
amenable to a system-based approach in which babies who are most likely to
have a benign experience with newborn jaundice are distinguished early from
those in whom the course is less predictable or potentially unsafe.
Structural practice changes that would facilitate a system-based approach
include: (1) predischarge bilirubin management, (2) follow-up bilirubin manage-
ment, and (3) lactational support and nutritional management. We, as pediatri-
cians, can facilitate and implement these practices by screening and validating
specific safety concerns, and by addressing the known root causes for the re-
emergence of kernicterus. To meet these objectives, we have proposed a practical,
family-centered, safety-oriented, system-based approach (as practiced at Penn-
sylvania Hospital over the past decade) to manage newborn hyperbilirubinemia
and prevent kernicterus [11].

Scope of neonatal hyperbilirubinemia

Over 60% of the 3.5 million healthy babies admitted to well-baby nurseries in
the United States will develop jaundice and be diagnosed with hyperbilirubine-
mia during the first week after birth. About 25% of these well babies who have
TSB levels above the 75th percentile or with postnatal age in hours will be
classified as being at high risk for developing TSB above the 95th percentile
(severe hyperbilirubinemia). At this point, most babies are about 96 hours old,
have already been discharged from the birthing hospital, and are being cared for
by their parents at home. In the vast majority of cases, the outcome is benign;
however, severe neonatal jaundice ( > 95th percentile) can progress in some
cases to dangerous levels (> 99.99th percentile). These excessively jaundiced but
otherwise healthy babies are at risk of bilirubin-related brain damage (kernic-
terus) within the first 2 weeks after birth. As determined in large, prospectively
studied US and multinational study populations, severe hyperbilirubinemia
occurs in 8.1% to 9% of healthy and near-term well babies who have hour-
specific TSB values above the 95th percentile (high-risk zone) during the first

Table 1
Incidence of severe hyperbilirubinemia in term and near-term infants
Severe hyperbilirubinemia Incidence
TSB level > 95 percentile > 17 mg/dL 8.1 to 10% 1 in 9
TSB level > 98 percentile TSB level > 20 mg/dL 1 to 2% 1 in 50
TSB level > 99.9 percentile TSB level > 25 mg/dL 0.16% 1 in 700
TSB level > 99.99 percentile TSB level > 30 mg/dL 0 to 0.032% 1 in 10,000
Data from Ref. [4,7,8,18,22].
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 845

7 postnatal days. Known incidences of progressively severe hyperbilirubinemia

to excessive hyperbilirubinemia have been estimated from several studies and
are listed in Table 1.

The hour-specific bilirubin nomogram

The hour-specific bilirubin nomogram (Fig. 1) provides a more appropriate
understanding of the magnitude of hyperbilirubinemia in the contexts of postnatal
age in hours and the percentile level as defined for healthy infants. It was
developed using bilirubin data from term and near-term infants who did not have
evidence of hemolytic disease or other illness requiring neonatal intensive care
unit (NICU) admission [4,12]. This nomogram was not specifically designed to
be used in premature infants or infants with comorbidities requiring intensive
neonatal care. These infants, who are not considered healthy, are at higher risk of
developing bilirubin toxicity and of developing kernicterus at lower bilirubin
levels. In term or near-term infants, the nomogram may be helpful in identifying
infants who have early hyperbilirubinemia (those in the high-risk zone or with a
rapid rate of rise) and who require further evaluation for a cause of their
hyperbilirubinemia. Once it is known that an infant has an ABO blood type
incompatibility or glucose 6-phospho-dehydrogenase (G6PD) deficiency, how-
ever, the nomogram may not be used to accurately predict the degree of risk
for subsequent hyperbilirubinemia. Nevertheless, it serves as a useful clinical
guide for management because, by general consensus and by the American
Academy of Pediatrics (AAP) guidelines [13], the patterns of severity in mg/dL

25

hrs)
Serum Bilirubin (mg/dl)

e in
20 k (ag
bin Trac
Biliru
Risk
High
15 ise
SB r
t e of T /dL/hr)
a
R 2m g
)
= 0.
age in hrs
10 rack (
Bilirubin T
isk
Low R )/hr
5 0.1 mg/dL
rise =
f TSB
Rate o

0
0 12 24 36 48 60 72 84 96 108 120
Age (hours)

Fig. 1. Hour-specific bilirubin nomogram for term and near-term healthy babies that illustrates
the rate of TSB rise, between 24 to 60 hours of age, for: the high-risk track (95th percentile) at
0.20 mg/dL/h; the intermediate-risk track (75th percentile) at 0.15 mg/dL/h; and the low-risk track
(40th percentile) at 0.10 mg/dL/h.
846 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

at the 95th percentile and at the 99th percentile in our mixed population could
define the threshold for consideration and recommendations for consideration of
need for interventions.

Clinical manifestations of neonatal hyperbilirubinemia

Serial observations of the clinical manifestations of jaundice and hyperbili-
rubinemia indicate two patterns from a management perspective, irrespective of
the specific etiology of hyperbilirubinemia. Early-onset severe hyperbilirubinemia
is generally associated with increased bilirubin production, whereas late-onset
hyperbilirubinemia is likely to be associated with delayed bilirubin elimination
that may or may not be complicated with increased bilirubin production. Both are
described below in the context of the authors’ bedside observations [11].

Early-onset hyperbilirubinemia
In the authors’ observations, TSB values >75th percentile before 72 hours age
represented a particularly high-risk clinical state characterized by potential
adverse events. Babies manifested an acute and rapid rise in TSB values; some
reached levels well above the 95th percentile within the first 12 hours after birth
(Fig. 2). Identification of these babies was uniformly dependent on the recogni-
tion of jaundice by pediatric nurses. The interval between recognition of jaundice
and initiation of intensive phototherapy was originally dependent on obtaining a

G6PD Deficiency
Exchange Transfusion
30
Serum Bilirubin (mg/dl)

Jaundice noted

20
95th percentile
75th percentile
40th percentile
10

Intensive phototherapy
4D 5D 6D 7D 8D 9D
0
0 24 48 72 96 120 144 168 192 216
Age (hours)

Fig. 2. Early-onset severe hyperbilirubinemia (TSB level > 75th percentile before 60 hours of age) due
to G6PD deficiency.
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 847

physician order, blood sampling, assay for TSB, and physician response. The use
of transcutaneous bilirubin (TcB) allowed for a reduction of this interval. It was
appreciably shortened from an average interval of about 3 hours to a point-of-care
assessment with the institutional policy that allowed for nurses to obtain a TcB/
TSB measure upon visual recognition of jaundice. A combination of the nursing
policy and the universal predischarge bilirubin screening allowed for identifica-
tion of babies with an hour-specific TSB values >75th percentile track by both
nurses and physicians. Most of these babies had evidence of hemolysis based on
ABO incompatibility, though the precise confirmation of hemolysis was elusive
by available laboratory tests. Use of exhaled carbon monoxide testing has been of
value in the recent years, but was not used during this study period. Positive
Coombs tests were recorded in 7.1% of the well-baby population (range 5.6% to
10% of the well babies). Babies who had ABO incompatibility, with or without a
positive Coombs test, accounted for about 18.4% (ranges: 14.4% to 21%) of the
well-baby population, and 9.9% of these babies had a predischarge TSB level
above the 95th percentile for age in hours. Nearly 55% of these severely
hyperbilirubinemic babies who have ABO incompatibility need intensive photo-
therapy. Of the total 16 exchange transfusions performed, 11 (68.8%) occurred in
babies who had early-onset hyperbilirubinemia due to ABO incompatibility
(1:553 babies who had ABO incompatibility).

Late-onset hyperbilirubinemia
TSB values >95th percentile track beyond 72 hours age can be predicted by
universal predischarge bilirubin screening [11]. Babies who have predischarge
TSB values below the 40th percentile track are followed and jaundice is clinically
monitored. Repeat TSB measurements have not appeared to be necessary for
these babies. Application of these policies was associated with a significant
decline in hospital readmission for intensive phototherapy. Overall, our experi-
ence suggests that the repeat postdischarge TSB measurements are targeted to
babies who have predischarge TSB values above the 75th percentile track, and
represent about 30% of the well-baby population. Those who have TSB values
above the 95th percentile track have repeated TSB measurements based on the
need for medical interventions. Late-onset hyperbilirubinemia, especially in
breast-fed babies, is likely to be complicated by G6PD deficiency and babies
who have familial or ethnic risk factors (siblings who have jaundice, East Asian
or Mediterranean descent, Gilbert’s syndrome, and as yet unrecognized genetic
polymorphisms of the glucoronyl transferase gene) as well as babies who have
increased entero-hepatic of bilirubin secondary to breast feeding without ade-
quate or appropriate lactational counseling. The etiology for severe hyperbili-
rubinemia remains elusive in a significant number of cases, and must be
considered idiopathic pending future generic investigations (Fig. 3). Recent
studies have reported that the incidence of G6PD deficiency in the well-baby
population discharged from Pennsylvania Hospital is about 1.7%, and may be a
reflection of an ethnically diverse population [14]. Unfortunately, in the United
848 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

PhotoRx
Term: 4012g, AA female,
Total Serum Bilirubin (mg/dl)

30 SVD, no bruising, no sepsis Exchange Transfusion

Mom: B pos, Baby: B pos,
Wt gain: 50g, breast feeding, No hematological
Hct: 45.7%, Retic: 1.6%, signs of hemolysis
S. Albumin: 3.6, UB: 1.01
20
95th %ile
Jaundice noted 75th %ile

40th %ile
10
G6PD: normal

4D 5D 6D 7D 8D 9D
0
0 24 48 72 96 120 144 168 192 216
Postnatal Age (hours)

Fig. 3. Late-onset severe hyperbilirubinemia (TSB level > 95th percentile after 72 hours of age) due to
idiopathic causes (see text).

States, results of G6PD screening tests are not available at nursery discharge. This
and other risk factors may be ascertained by details of a family history.

Acute bilirubin encephalopathy

The classic signs of acute bilirubin encephalopathy (ABE) in the severely
hyperbilirubinemic term infant include increasing hypertonia, especially of
extensor muscles, with retrocollis and opisthotonus, in association with varying
degrees of drowsiness, poor feeding, hypotonia, and alternating tone [15 – 17].
These signs can be described in terms of the infant’s mental status, muscle tone,
and cry. To facilitate the accurate documentation of progression of ABE, a
schema for grading the severity of ABE has been described by Volpe [16]. This
has also been used as a clinical tool in a retrospective study and may help
clinicians understand the progression of BIND [2]. Increasing scores are
indicative of worsening BIND and may be of prognostic value. The earliest
signs of ABE are subtle and nonspecific, and may be missed. They need to be
elicited by direct questioning of parents and by close clinical observation. During
the early phases of BIND, prompt and effective intervention can prevent chronic
kernicteric sequelae. BIND abnormalities with progression to scores between
4 and 6 are often reversible. These signs include early hypertonia and retrocollis,
which increase in severity and are usually accompanied by a shrill cry; and an
unexplained irritability alternating with increasing lethargy. Advanced signs are
cessation of feeding, bicycling movements, inconsolable irritability and crying,
possible seizures, fever, and coma. These are late findings and ominous
predictors of the likelihood of severe kernicteric sequelae, even with intensive
treatment. The extent of brain damage is likely to be reduced by the rapid
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 849

reduction of the bilirubin load (a combination of intensive phototherapy and

exchange transfusion). The rate of progression of clinical signs depends on the
rate of bilirubin rise, the duration of hyperbilirubinemia, the adequacy of albumin
binding reserves, the level of unbound bilirubin, host-susceptibility, and the
presence of comorbidities. Death from acute kernicterus is due to respiratory
failure and progressive coma or intractable seizures.

Clinical management of neonatal hyperbilirubinemia

The primary goal for effective and efficient management of neonatal hyper-
bilirubinemia is to prevent ABE. Of the preventive clinical strategies, implemen-
tation of either the existing AAP guidelines or those enhanced by a system-based
approach may be used. There are no comparative studies of these two approaches
thus far, and both are likely to be effective, provided all babies are screened
before discharge and uniformly followed postdischarge. We have practiced and
implemented a system-based approach at Pennsylvania Hospital to achieve safer
individualized care in an efficient and robust manner, so as to accommodate a
clinician’s concerns, an informed participation of the family, and a monitoring of
the progression of hyperbilirubinemia in at-risk newborns [11].

Clinical approach
The practice parameters developed by the AAP [6,13] provide useful guide-
lines for the management of term healthy newborns, provided they are followed
diligently and with concern for unexpected differences in appearance of jaundice
and vulnerability to its skin-tone effects. These guidelines are predominantly
based upon visual recognition of jaundice and identification of clinical and
epidemiologic risk factors for severe hyperbilirubinemia. This risk-based strategy
has been the basis of clinical practice for several years, and has been popular
among pediatricians. The approach is based on consensus, but is recognized to
have a limited evidentiary validation; thus concerns for newborn safety had been
questioned. Newman et al have further studied the traditional risk-based evalua-
tion to provide an evidence-based ranking of individual factors and for potential
use as a predictive instrument. In their study, a risk index or score incorporates
clinical predictors of hyperbilirubinemia obtained from medical history and
physical examination [18]. Eight clinical predictors were identified from a
multivariate logistic regression model. These include early onset of jaundice, a
sibling who has a history of jaundice, exclusive breast feeding, bruising, east
Asian background, cephalhematoma, maternal age, and earlier gestation. These
factors were weighted to approximately equal the odds ratio for each of the risk
factors in the logistic regression model, in order to predict the development of a
total serum bilirubin of 25 mg/dL: a threshold to consider intensive phototherapy
and possible exchange transfusion in an intensive care nursery. In a recent
preliminary analysis of a cohort from our previous report [4] Keren identified
850 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

three major risk factors: large for gestational age, vacuum or forceps delivery
and exclusive breast feeding. The superiority of clinical risk factors has yet to
be validated.

System-based screening approach

In view of shortened hospital stay after normal birthing, the need for universal
postdischarge follow-up is obvious; however, the postbirthing newborn follow-up
programs are not mandated, are often nonreimbursable, and are not seamless.
Predischarge screening with a targeted follow-up visit within 24 to 48 hours of
discharge may help promote successful breast feeding and address concerns for
the visual assessment of jaundice.
We explored and evaluated [2,3,11,12] a system-based strategy (in addition to
the clinical approach) to prevent ABE and kernicterus. The fundamental elements
of this system-based approach included universal predischarge TSB screening,
risk-based targeted follow-up of newborns to monitor the trajectory and rate of
rise, safe and effective treatment to reduce the bilirubin load, and systematic
evaluation and documentation of signs indicating progressive ABE. Our method
for predicting risk of developing severe neonatal hyperbilirubinemia (TSB level
>95th percentile; a threshold to consider phototherapy) relies simply on an
infant’s predischarge, hour-specific bilirubin value. According to this approach, a
predischarge, hour-specific TSB value is plotted on the hour-specific bilirubin
nomogram that provides clinicians with a percentile-based estimate of the
bilirubin value and stratifies patients according to risk of developing severe
neonatal hyperbilirubinemia (see Figs. 2, 3). This approach also corrects the root
causes that have been associated with the morbidity and mortality associated with
re-emergence of Kernicterus [2,19].
A system-based approach should be used to identify infants at risk of
developing severe hyperbilirubinemia. This will enable the provider to cost-
effectively target infants most likely to benefit from closer clinical and laboratory
follow-up (or new prophylactic therapies), while avoiding the cost and potential
harm of intervention for low-risk infants.

Guidelines for a system-based management of hyperbilirubinemia

Predischarge management
A system-based approach (Table 2) addresses parental education, clinical
recognition of jaundice, and predischarge risk assessment with multidisciplinary
strategies to

 Recognize the clinical significance of jaundice within the first 24 hours

after birth
 Recognize the limitations of visual recognition of jaundice
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 851

 Recognize and document clinical jaundice and document severity of

hyperbilirubinemia by a bilirubin measurement before discharge from
the hospital
 Ensure postdischarge follow-up based on the severity of predischarge
hyperbilirubinemia
 Respond to parental concerns of newborn jaundice, poor feeding, lactational
difficulties, and change in behavior and activity
 Provide ongoing lactational support in breast-feeding babies to ensure ade-
quacy of intake
 Recognize the impact of race, ethnicity, and family history on the severity
of newborn jaundice
 Diagnose the cause of severe hyperbilirubinemia
 Institute intervention strategies to prevent severe hyperbilirubinemia when
bilirubin is rising more rapidly than expected
 Consider the level of serum albumin in babies who have TSB levels above
the 95th percentile to gauge susceptibility to neurotoxicity
 Aggressively treat increasingly severe hyperbilirubinemia with intensive
phototherapy or exchange transfusion
 Educate parents and health care providers about the potential risks of
jaundice during the newborn period

Use of hour-specific bilirubin nomogram to guide follow-up

The primary purpose of the bilirubin nomogram (Table 3) is to provide a
simple and accurate method for quantifying the risk that a newborn will develop
hyperbilirubinemia requiring treatment after discharge from the nursery. There
are currently no evidence-based recommendations for how to manage infants
who have a specified probability of developing hyperbilirubinemia after hospital
discharge. Opinions will likely vary based on the experience of the provider,
practice settings, and parental preferences. We recommend that infants in the low-
risk zone, particularly those discharged from the hospital before 72 hours of life
and breast-fed infants, be seen by a health care provider (office or home visit) on
day 4 to 5 of life to evaluate their nutritional status (hydration, weight loss, breast
feeding), and to observe for obvious jaundice. Depending on the prior probability
of developing hyperbilirubinemia, infants who have predischarge TSBs in the
lower intermediate-risk zone can be managed similarly to the low-risk infants.
Physicians who have access to transcutaneous bilirubin meters might consider
measuring a transcutaneous bilirubin in these infants at the time of follow-up. For
infants who have predischarge TSBs in the upper intermediate-risk zone, the
clinician has a couple of options. The simplest option is to repeat the TSB in 24
hours. Alternatively, if the infant will not be discharged for another several hours,
a repeat TSB can be sent within 4 to 8 hours, and the rate of rise of bilirubin can
be used to recommend subsequent course. Infants who have a rate of rise greater
than 0.20 mg/dL/h, particularly if they are crossing the 95th percentile track,
852 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

Table 2
Predischarge jaundice management of term and near-term infants
Clinical assessment after birthing
Visual assessment Monitor as a vital sign every 8 hours
of jaundice Document cephalo-caudal progression
Clinical and biologic Prematurity (<38 weeks), exclusive
risk factors breast feeding, bruising, race and
ethnicity, mode of delivery, maternal
diabetes, etc.
Bilirubin testing TSB/TcB testing at time of routine
metabolic screen
Hemolysis assessment Especially in infants with TSB
levels >75 percentile track
Assessment for targeted TSB >95 percentile
follow-up for discharge
at <72 hours age TSB >75 percentile
(age 2 days)
TSB >40 percentile
TSB <40 percentile
Recommendations
Obtain TcB/TSB if jaundice
evident < 36 hours age
Obtain TcB/TSB at discharge
for progressive jaundice
Closer follow-up
Assess for TSB levels
‘‘jumping’’ tracks
Detailed discussion with
family regarding risk of
bilirubin toxicity
Consider use of risk score
Plot on hour-specific
bilirubin nomogram for risk
assessment (see Fig. 1)
Family history
Maternal and neonatal
blood type
Exhaled carbon monoxide
(ETCOc) measurement,
if available
Consider G6PD evaluation
Assess for hemolysis and
intervention
Assess for hemolysis, and
TSB follow-up within 8 to
24 hours
TSB follow-up within
48 hours
Clinical follow-up within
48 hours, and optional
TSB follow-up

should be treated like high-risk infants. Infants who have a rate of rise less than
0.20 mg/dL/h, particularly if their hour-specific TSB is trending down below the
75th percentile, can be treated as lower intermediate-risk infants. Infants who
have predischarge TSBs in the high-risk zone should give the provider pause,
prompting her to explore causes for the relative hyperbilirubinemia (eg, feeding
problems, ABO incompatibility, G6PD deficiency, cephalohematoma or bruis-
ing). In addition to the options discussed for upper intermediate-risk infants, the
provider may consider pre-emptive phototherapy before the infant reaches
absolute TSB levels traditionally used as cutoffs for initiating phototherapy,
particularly if a repeat TSB shows a rate of rise >0.20 mg/dL/hour or a trajectory
that will result in a bilirubin level requiring readmission and phototherapy in
24 hours. If the rate of rise is less than 0.20 mg/dL/hour and there is no evidence
of hemolysis, the infant may simply require lactation support if breast feeding,
and close follow-up in 24 hours to re-evaluate nutritional status and the TSB
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861
Table 3
Postdischarge and follow-up based on predischarge TSB (mg/dL) level (based on the hour-specific bilirubin nomogram)
Follow-up within TSB recheck optional (unless indicated
Discharge only if TSB level is 24 hours 48 hours by clinical risk factors)
Predischarge TSB level
at postnatal age (hour-specific) <95 percentile >75 percentile <75 percentile < 40 percentile
41 – 44 hours <12.3 >10.0 <10.0 <7.9
45 – 48 hours <12.7 >10.4 <10.4 <8.2
49 – 56 hours <13.2 >11.0 <11.0 <8.7
57 – 64 hours <14.7 >12.2 <12.2 <9.4
65 – 72 hours <15.5 >13.0 <13.0 <10.3
>72 hours <15.5 >14.0 <14.0 <11.0

853
854 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

Table 4
Suggested strategies for observation and interventions for increasing severity of hyperbilirubinemia
Follow rate of TSB
Severe hyperbilirubinemia at >72 hours age rise and B:A ratio Interventions
TSB level >75 percentile TSB level And <0.20 mg/dL/h Nutritional support
>14 mg/dL
TSB level >95 percentile TSB level And >0.20 mg/dL/h Phototherapy
17 mg/dL
TSB level >98 percentile TSB level And B:A ratio <7.0 Intensive phototherapy
20 mg/dL
TSB level >99.9 percentile TSB level And/or B:A ratio Intensive phototherapy
25 mg/dL 7.0 mg/g and prepare for an
exchange transfusion
TSB level >99.99 percentile TSB level And/or B:A ratio Intensive phototherapy
30 mg/dL 7.0 mg/g and perform an
exchange transfusion

trajectory. Table 4 summarizes the management options that we recommend for

various predischarge TSB levels.

Postdischarge follow-up management

A seamless continuation of care to provide the following services (see
Tables 3, 4):

Outpatient follow-up appointments

All babies discharged from a birthing site should have mandatory follow-up
appointments with a physician or nurse who has pediatric credentials within
48 hours (within 24 hours when deemed at high risk) when discharged at less
than 72 hours age. For those babies discharged at 4 to 5 days age (such as when
there is a delay in maternal discharge), a follow-up at 1 week age would be
considered safe. This follow-up should include careful observation for jaundice
and its confirmation with TcB/TSB measurement. Follow-up staff and personnel
should be alerted to those babies at high risk for subsequent development of
hyperbilirubinemia, so that they may be followed more closely and monitored
for noncompliance.

Outpatient phone assessment of a jaundiced newborn

Several questions should be asked when parents note jaundice in their
newborn. Has the baby’s feeding decreased? Is the baby arousable? Is there
excessive sleepiness and irritability on waking? Has the baby’s feeding pattern
deteriorated? What are the stooling patterns: color, frequency, and amount of
bowel movements? What is the color, frequency, and amount of urine output?
Does the baby lie with the head tilted back? Are there any signs of arching of the
body? Has the cry pattern changed? Has Is it become more shrill?
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 855

Table 5
Modes of phototherapy
Home-based (blanket) Hospital-based (intensive)a
Source of light Fiber optic Bank of tube lights
Color of light White/blue ‘‘Super-blue’’
Spectral reflectance (425 to Wide Narrow and specific
475 nm range)
Irradiance (at skin surface) <20 mwatts/cm2/nm 25 to 35 mwatts/cm2/nm
Surface area (exposed) Torso is wrapped; eye Entire body surface (exclude eye
patches not needed patches and diaper area)
a
May be complemented with white halogen lights to cover a wider a surface area (avoid shadows
with multiple lights).

Rapid emergency room/office intervention plan

Severely jaundiced babies and symptomatic babies may often be first seen
at the pediatrician’s office or in the emergency room. The front office and triage
staff should be familiar with an intensive ‘‘crash-cart’’ approach to managing
ABE (as described below). Phototherapy lights in (Phillips F-20 T12/BB) in
the 425 to 475 nm range should be easily and rapidly accessible, and periodi-
cally inspected and maintained to ensure proper functioning (Table 5). If photo-
therapy lights are not available, providers should periodically review mechanisms
for rapid transfer of hyperbilirubinemic infants to neonatal intensive care units
for swift intervention. Travel time should not exceed half an hour, and if travel
is unavoidable, arrangements for transport phototherapy should be considered.
Transport should be planned via direct communication with a responsible
neonatologist, so that care plans might be initiated before and during the trans-
port interval.

Intensive and preventive approach

Strategies to rapidly reduce the bilirubin load are described in the AAP
Practice Parameters [13] and a recent review article by Dennery et al [20].
Attention to the following additional aggressive steps will facilitate effective,
safe, and efficient management of severely hyperbilirubinemic infant presenting
with only early, nonspecific signs of possible ABE:

1. assess for clinical signs of acute bilirubin encephalopathy (as shown in

Table 1) or an abnormal ABR (one may also use an automated auditory
brainstorm response [ABR] and its pass-or-fail response). In the presence
of specific signs of ABE, an exchange transfusion is recommended
irrespective of the TSB level.
2. Immediately obtain a transcutaneous bilirubin measurement (if available)
and send a blood sample to the laboratory for total bilirubin, serum
albumin, electrolytes, calcium, and type, and cross-match for 170 mL/kg of
blood (for double-volume exchange transfusion).
856 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

3. Admit directly to the intensive care nursery and start intensive photo-
therapy. Perform all procedures while the infant is under intensive
phototherapy. Irradiance and intensity of phototherapy units should be
previously configured as a routine maintenance policy.
4. Prepare for an exchange transfusion by assessing for vascular access
through cannulation of either central (if umbilical vessels are accessible) or
peripheral vessels (arterial and venous).
5. Evaluate for hydration and consider enteral feeds to decrease entero-hepatic
circulation and increase intestinal clearance of bilirubin.
6. Other concurrent preventive and therapeutic options to reduce the bilirubin
load (Fig. 4) may be initiated based on clinical needs.

Lactation support and nutritional management

The lactation program at Pennsylvania Hospital is organized and supervised
by lactation counselors who have concurrently developed an institutional
program to promote, support, and provide follow-up services to optimize
successful lactational nutrition. As a component of this program, restructured
in 1996, all breast-fed babies are evaluated soon after birth and during hospital-
ization with a lactational attachment (LATCH) score as an objective instrument
for bedside counseling and promoting of maternal breast-pumping (especially
of mothers who delivered by cesarean sections or assisted vaginal deliveries,
or those with lactational difficulties). Mothers of infants who have greater
than 8% weight loss are provided individualized instructions to supplement
feeds with expressed breast milk (or if necessary, a breast-milk substitute), and
advised regarding the importance of urine output and stooling patterns.
Nearly 65 to 70% of the patients attempt breast feeding while in the hospital,

Heme-Oxygenase Inhibitors Phenobarbital, Phototherapy

Bilirubin Bilirubin
production elimination

TSBt = TSB0 + [a (t) + b (t) – c (t)] t

Formula Charcoal,
supplementation Bilirubin agar, etc
entero-hepatic
circulation

Fig. 4. The bilirubin equation with sites for potential therapeutic interventions; bilirubin at any given
time (t) is the sum of bilirubin production and bilirubin reabsorbed from the enterohepatic circulation,
subtracted from the bilirubin that has been eliminated. (Adapted from Valaes T. Problems with
prediction of neonatal hyperbilirubinemia. Pediatrics 2001;108:176; with permission.) [23].
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 857

and are counseled by both salaried and volunteer lactation consultants, nurses,
and physicians.

Management of acute bilirubin encephalopathy

‘‘Crash-cart’’ approach to ABE in babies who have severe hyperbilirubinemia

Once specific signs of ABE are recognized, the goal of therapy is a prompt,
expeditious, and safe reduction of the bilirubin load. Strategies to accomplish this
have also been detailed in the AAP Practice Parameters [13]. Our ‘‘crash-cart’’
approach is based on the following considerations:

1. Presently, only an exchange transfusion can accomplish rapid and effective

clearance of bilirubin in a symptomatic neonate to minimize brain damage.
2. The risk of a performing an exchange transfusion (in experienced hands)
must be weighed against the potential risk of ABE itself (see Table 6 for
incidence of severe adverse events due to an exchange transfusion).
3. Babies who have ABE should be treated with intensive phototherapy
(confirmed irradiance of >30 mwatts/cm2/nm) to the entire body surface
area, with a goal of reducing the bilirubin load by >0.5 mg/dL/hr while
preparations are being made for an urgent exchange transfusion.
4. Exchange transfusion is performed as an isovolumic procedure with
concurrent withdrawal from an arterial line and infusion through a venous
line. Double volume exchange (170 mL/kg) is ideal, but in the event of
technical difficulties, a single volume exchange transfusion may be
adequate if supplemented with intensive phototherapy. The entire process
should be accomplished within 3 to 4 hours.
5. Exchange transfusion should also be considered when there are no specific
signs of ABE, but there are significant concerns of neurotoxicity. These
include: TSB levels >30 mg/dL [13]; intensive phototherapy fails to
produce a dramatic TSB drop of <0.5 mg/dL/hour or <2 mg/dL drop in
4 hours; or an infant who had a successful universal hearing screen and now
fails an automated ABR screen.
6. Before an exchange transfusion, one may consider an albumin infusion
(1 g/kg), especially if serum albumin is low (<3.4 g/dL); or immune
globulin (IVIG), when the hyperbilirubinemia is attributed to ABO
sensitization [21].

Quality improvement and peer-review program

The authors have maintained a surveillance program to monitor the occurrence
of ABE, readmission for a TSB level >25 mg/dL after 72 hours of age,
readmission for TSB level >20 mg/dL before 48 hours age, and exchange
transfusion in term and near-term babies. Clinical management is reviewed for
 858
V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861
Table 6
Serious adverse events attributed to exchange transfusion In term and near-term infants with hyperbilirubinemia
Gestational age (range) Death Resuscitation Sepsis/NEC Embolism Thrombocytopenia Arrhythmia Total
35 – 42 weeks (n = 26) 0 0 0 0 0 0 0%
33 – 34 weeks (n = 18) 0 0 1 0 1 0 12%
29 – 31 weeks (n = 13) 1a 0 0 0 0 0 8%
<28 weeks (n = 16) 0 0 3 0 2 0 26%
Data are based on experiences at Pennsylvania Hospital (1990 – 1998), previously reported as abstracts.
a
Infant with nonimmune hydrops.
 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861 859

any adverse events associated with either severe hyperbilirubinemia or the

procedures used to reduce the bilirubin load.

Long-term follow-up
The authors recommend that all babies who have TSB levels above 25 mg/dL,
those who receive an exchange transfusion, those who have had ABR abnor-
malities (even transient), and those who manifested the intermediate (or more)
clinical signs of ABE should be followed during infancy and childhood until
school age. The clinical follow-up should include a neurologic and neuro-
developmental evaluation (especially for extrapyramidal function and for pro-
cessing disorders) as well as auditory neuropathy. Neuroimaging with MRI can
be helpful, though there are limited data to recommend clinical correlation at a
specific age. In its most severe manifestation (Table 7), the chronic, irreversible
bilirubin encephalopathy (kernicterus) may include extrapyramidal movement
disorders (dystonia and athetosis), gaze abnormalities (especially upward gaze)
and other visual problems of focusing and recognition, auditory disturbances
(especially sensorineural hearing loss with central processing disorders or
auditory neuropathy), and enamel dysplasia of the deciduous teeth [2,15,16].
Although earlier reports described cognitive deficits, these are actually un-
common [2]. In retrospect, these assessments probably reflected, for the most
part, an inability to accurately assess intelligence in children who have hearing,
communication, and coordination problems. The neuromotor manifestations of
extrapyramidal damage, present to some degree in almost all cases, may
occasionally be apparent only with reinforcement and attempts at skilled move-
ments. Auditory disturbances are also almost always present, and are both central
(brain stem) and peripheral (auditory nerve) in origin and may be the only
apparent residual sequelae of ABE. They may be subtle, difficult to diagnose (as
is the case with auditory neuropathy), or delayed in clinical expression. Other

Table 7
Syndrome of bilirubin-induced neurologic dysfunction (BIND): clinical manifestations of posticteric
sequelae
Clinical signs During infancy During childhood (5 to 8 years)
Dystonia (with varying Present, often by 3 months age May improve with age
hypertonia/hypotonia)
Athetosis/Chorea and Present, often present by May improve with age
hyperkinetic signs 3 months age
Auditory Abnormal ABR, may be transient Neuropathy in variable
during the neonatal period manifestations
Ocular Upward gaze limitation May improve or is compensated
with maturity
Dental Enamel dysplasia May not be evident after eruption
of permanent teeth
860 V.K. Bhutani et al / Pediatr Clin N Am 51 (2004) 843–861

subtle manifestations observed during childhood in association with incremental

bilirubin levels [23] are listed below:

Awkwardness
Gait abnormality
Poorly coordinated movements
Failure of fine stereognosis
Gaze abnormalities
Exaggerated extrapyramidal reflexes

Summary
Bilirubin-induced neurologic dysfunction can occur in term and near-term
healthy babies. The term babies who are unwell, the preterm neonates, and the
infants who have multiple comorbidities constitute a group vulnerable to bilirubin
neurotoxicity. The current resources for clinical interventions that can drastically
and efficiently reduce the increased bilirubin load—intensive phototherapy and
exchange transfusions—are available for use in those infants who have excessive
hyperbilirubinemia (as judged by their postnatal age, wellness, and gestation);
however, these interventions leave a very narrow margin of safety for babies who
have rapid or unrecognized increases in their bilirubin load. Because most babies
are discharged before the hyperbilirubinemia reaches its peak during the first
week of life, preventive and system-based strategies offer a safer, kinder, and
gentler means to prevent BIND, including kernicterus.

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