Original Article

Neurodevelopmental Outcome of Severe Neonatal

Hemolytic Hyperbilirubinemia
Wen-Xiong Chen, MD; Virginia C.N. Wong, MBBS, FHKAM, FHKCPaed, FRCPCH, FRCP (London, Edinburgh),
DCH (London, Glasgow); Kar-Yin Wong, MBBS, FHKAM, FHKCPaed, MRCP (UK)

ABSTRACT
We recruited 128 neonates with hyperbilirubinemia over a 5-year period (19952000) to study the short- and long-term
effects of hemolytic hyperbilirubinemia on the auditory brainstem pathway and neurodevelopmental status. These children were divided into two groups: (1) a hemolytic group (n = 29; ABO incompatibility [n = 19], Rh incompatibility [n =
1], glucose-6-phosphate dehydrogenase deficiency [n = 8] and both ABO incompatibility and glucose-6-phosphate dehydrogenase deficiency [n = 1]) and (2) a nonhemolytic group (n = 99). All received phototherapy. Exchange transfusions
were performed for four (13.8%) in the hemolytic group and three (3%) in the nonhemolytic group. The brainstem auditory evoked potential was recorded at a mean age of 3.2 months in the hemolytic group and 3.1 months in the nonhemolytic
group. Serial brainstem auditory evoked potential assessments were performed until 2 years of age (3 in the hemolytic
group and 18 in the nonhemolytic group). All had regular physical, neurologic, visual, and auditory evaluation until 3 years
of age. The rate of exchange transfusion was significantly higher in the hemolytic group than in the nonhemolytic group
(P < .05). Brainstem auditory evoked potential abnormalities at the initial assessment occurred in three (10.4%) in the
hemolytic group (all related to ABO incompatibility) and nine (9.1%) in the nonhemolytic group. At 2 years, the brainstem
auditory evoked potential returned to normal except in three cases with a slightly increased hearing threshold (one [3.5%]
in the hemolytic group at 60 dB nHL and two [2%] in the nonhemolytic group at 50 dB nHL]). There were no significant
differences in the rate of brainstem auditory evoked potential abnormalities at the initial or subsequent assessments
between both groups. All except five cases had a normal neurodevelopmental outcome at 3 years (three [two with ABO
incompatibility and one with glucose-6-phosphate dehydrogenase deficiency] in the hemolytic group [10.4%] and two [2%]
in the nonhemolytic group). All had mild motor delay and hypotonia, which returned to normal at 3 years. The rate of
abnormal neurodevelopmental outcome was higher in the hemolytic group than in the nonhemolytic group, although with
no significant difference between both groups (P = .08). All five cases in both groups with abnormal neurodevelopment
had a normal brainstem auditory evoked potential at the initial assessment. There was no relationship between the abnormal initial brainstem auditory evoked potential and the final neurodevelopmental outcome. The toxic effect of
hyperbilirubinemia on the auditory brainstem pathway and neurodevelopmental status in our cohort was transient. The
prognosis of neonatal hemolytic hyperbilirubinemia in our Chinese cohort is excellent, possibly owing to an aggressive
early-intervention approach. (J Child Neurol 2006;21:474479; DOI 10.2310/7010.2006.00107).

Received March 4, 2005. Received revised May 25, 2005. Accepted for publication June 16. 2005.
From the Division of Neurodevelopmental Paediatrics (Drs Chen and Wong
and Prof Wong), Department of Paediatrics and Adolescent Medicine, Queen
Mary Hospital, The University of Hong Kong, Hong Kong, China.
Address correspondence to Prof Virginia C. N. Wong, Division of
Neurodevelopmental Paediatrics, Department of Paediatrics and Adolescent
Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Tel: 852-2855-4485; fax: 852-2855-1523; e-mail: vcnwong@hkucc.hku.hk.

474

The prevalence of neonatal jaundice is 50% to 60% in term and 80%

in preterm infants.1 Neonatal hyperbilirubinemia can result in cerebral palsy (choreoathetotic type), sensorineural hearing impairment,
psychologic impairment, and disturbances of visual perception or
gaze paralysis.25 The incidence of kernicterus in untreated neonates
with severe hemolytic hyperbilirubinemia is much higher than in
those without hemolytic disease.611
The brainstem auditory evoked potential has been demonstrated to be a useful tool in detecting the acute neurotoxicity of
hyperbilirubinemia in the peripheral and central auditory path-

Neurodevelopment Outcome of Severe Neonatal Hemolytic Hyperbilirubinemia / Chen et al

ways.1219 Nwaesei et al evaluated the acute effect of bilirubin with

serial brainstem auditory evoked potential assessments in nine term
infants with hemolytic hyperbilirubinemia and all showed improvement after exchange transfusion.18
There were no studies on the short- or long-term effects of
hyperbilirubinemia on the auditory brainstem pathway and neurodevelopmental status in Chinese neonates. We aimed to evaluate the effects of hyperbilirubinemia on the auditory brainstem
pathway and neurodevelopmental status in Chinese term neonates
with hemolytic hyperbilirubinemia.
PATIENTS AND METHODS

475

Our brainstem auditory evoked potential protocol consisted of testing at an intensity of 80 dB nHL. If no repeatable wave V was present, the
intensity was increased by 10 dB nHL steps until a repeatable wave V was
detectable or until 105 dB nHL, the maximum output of the machine. If
a repeatable response appeared at 80 dB nHL, the intensity was reduced
to 40 dB nHL, and if no response occurred at 40 dB nHL, the intensity was
increased by 10 dB nHL steps until a repeatable wave V was acquired. As
a hearing screening tool, 40 dB nHL is the lowest intensity used in this
study.

Criteria of Abnormal Brainstem

Auditory Evoked Potential
The hearing threshold; latencies of wave I, III, and V; and interpeak laten-

We recruited Chinese full-term infants with hyperbilirubinemia born in the

cies of IIII, IIIV, and IV were analyzed. On the basis of the results, the

Queen Mary Hospital of The University of Hong Kong from 1995 to 2000.

subjects were classified as (1) normal or (2) abnormal with conductive or

In our center, all full-term neonates with a total serum bilirubin level

sensorineural hearing impairment:

> 255 mol/L (or 15 mg/dL) receive phototherapy after all investigations looking for the underlying cause have been performed, and exchange transfu-

1. Normal: a repeatable wave V detectable at 40 dB nHL and latencies and

sion is performed if the total serum bilirubin level is > 340 mol/L (or

interpeak latencies within 2 SD of normal for appropriate age groups

20 mg/dL) or if there is a rapid increase in the bilirubin level within 24 hours

in the authors laboratory

for those with hemolytic causes. For those with hemolytic hyperbiliru-

2. Abnormal brainstem auditory evoked potential: conductive type: the hear-

binemia with a rapid increase in serum bilirubin level, double photother-

ing threshold is above 40 dB nHL. Latencies of waves I, III, and V are

apy will be given at a serum bilirubin level lower than 340 mol/L (or

increased > 2 SD of the age-matched normal value, and interpeak laten-

20 mg/dL), pending exchange transfusion. All neonates with a total serum

cies of IIII, IIIV, and IV are normal. Sensorineural type: the hearing

bilirubin level > 340 mol/L (or 20 mg/dL) have the brainstem auditory evoked

threshold is above 40 dB nHL, and latencies and interpeak latencies are

potential performed after discharge.

normal, or increased intensities of wave V and/or III and increased

Inclusion criteria were as follows:

interpeak latencies I-V, III-V.

1. Chinese full-term neonates (birthweight 2500 g and gestational age

37 weeks)
2. Absence of any congenital or metabolic anomalies or any syndromal disorders
3. Absence of asphyxia, sepsis, meningitis, intracranial hemorrhage, or other
brain anomalies
The etiology of hemolytic hyperbilirubinemia is due to isoimmunization diseases (ABO or Rh incompatibility) or glucose-6-phosphate dehy-

Time of the Brainstem Auditory Evoked Potential Test

All 29 children in the hemolytic group had the brainstem auditory evoked potential performed after discharge at a mean age of 3.2 months. Serial brainstem
auditory evoked potentials were performed in three children with an initial
abnormal brainstem auditory evoked potential until 2 years of age (two with
two brainstem auditory evoked potentials and one with five brainstem auditory evoked potentials).

drogenase deficiency. ABO incompatibility is defined as blood group A or

All 99 children in the nonhemolytic group had the brainstem auditory

B babies with blood group O mothers with or without a positive direct

evoked potential performed after discharge at a mean age of 3.1 months.

Coombs test.

Serial brainstem auditory evoked potential studies were performed until 2

years of age in 18 children (61 tests), of whom 9 had an abnormal initial brain-

Subjects

stem auditory evoked potential.

One hundred twenty-eight neonates were recruited, and they were divided
into two groups:

Neurodevelopmental Outcome

1. Hemolytic group (n = 29): mean maximum total serum bilirubin level

All infants recruited had regular physical, neurologic, visual, and auditory

of 352.6 mol/L (20.6 mg/dL) (range 218637 mol/L or 12.837.3 mg/dL)

evaluations conducted by a neurodevelopmental pediatrician (V.C.N.W.) and

2. Nonhemolytic group (n = 99): mean maximum total serum bilirubin of

a child neurologist (V.C.N.W.) until 3 years of age.

359.7 mol/L (21 mg/dL) (range 301500 mol/L or 17.629.2 mg/dL)

Statistical Analysis
Brainstem Auditory Evoked Potential

Students t-test was used to compare the demographic data between the

The brainstem auditory evoked potential was performed with a Nicolet Viking

hemolytic and nonhemolytic groups. The chi-square test was used to com-

IIIP machine (Nicolet Biomedical, Inc., Madison State, WI) in our neuro-

pare outcomes of the brainstem auditory evoked potential, neurodevelop-

physiology laboratory. It was recorded in a quiet room 2 hours after feed-

mental status, and treatment method between the hemolytic and

ing, with sedation using chloral hydrate (50 mg/kg) if the neonate could not

nonhemolytic groups. All data were calculated using SPSS, version 11.5.1

remain still for the whole procedure. Silver chloride electrodes filled with

(SPSS Inc, Chicago, IL). A P value of < .05 was regarded as significant.

conducting paste were applied to the scalp at the vertex (Cz) and the ipsilateral mastoids (A1/A2) in response to rarefaction click stimuli presented

RESULTS

monaurally at a rate of 1.1 Hz. The bandpass was 150 to 3000 Hz, with a speed
duration of 10 milliseconds. Impedance was maintained below 5 kohms. Two
averages, each consisting of 2000 sweeps, were performed. At least two
repeatable waveforms were obtained.

Demographic Data
There was no significant difference between both groups except
the rate of treatment with exchange transfusion, which was sig-

476

Journal of Child Neurology / Volume 21, Number 6, June 2006

Table 1. Demographic Data of the Children

N

Gender
(M/F)

Group

Gestation
(wk)

Birthweight
(g)

Maximum
TSB (mol/L)

BAEP
Test (mo)

Treatment
(PT/PT + ET)

Mean SD

Mean SD

Mean SD

Mean SD

Mean SD

352.6 71.0
20.6 4.2*
359.7 37.4
21.0 2.2*
> .05

3.2 2.2

25/4

3.1 1.8

96/3

> .05

< .05

Hemolytic

29

15/14

39.0 1.20

3270.6 504.3

Nonhemolytic

99

60/39

38.71 1.38

3171.2 393.2

> .05

> .05

> .05

P value

BAEP = brainstem auditory evoked potential; ET = exchange transfusion; PT = phototherapy; TSB = total serum bilirubin
*mg/dL.

nificantly higher in the hemolytic group than in the nonhemolytic

group (Table 1).
Outcome of Brainstem Auditory Evoked Potential
The initial brainstem auditory evoked potential recorded at a mean
age of 3.2 months (range 112 months) in the hemolytic group (Figure 1) showed that three children (10.4%) had abnormalities, but
all returned to normal after 2 years except one (3.5%) with a slightly
increased hearing threshold (60 dB nHL).
The initial brainstem auditory evoked potential in the nonhemolytic group was recorded at a mean age of 3.1 months (range
19 months) (Figure 2) and showed that nine children (9.1%) had
abnormalities, but all returned to normal after 2 years except two
(2%) with a slightly increased hearing threshold (50 dB nHL).
The comparison of the brainstem auditory evoked potentials
of the hemolytic and nonhemolytic groups (Table 2) showed that
there were no significant differences in the rate of abnormal brainstem auditory evoked potentials between both groups.
Outcome of Neurodevelopmental Status
For the hemolytic group, all had normal neurodevelopmental status at 3 years except three children (10.4%) with mild motor delay
and hypotonia noted at 3 months, which returned to normal at 6,
11, and 24 months (see Table 2). None had features of the choreoathetoid type of cerebral palsy.

In the nonhemolytic group, all had normal neurodevelopmental status at 3 years except two children (2%), who had mild motor
delay and hypotonia at 3 months and returned to normal at 6 and
11 months (see Table 2). There was a higher rate of abnormal neurodevelopmental outcome in the hemolytic group than in the nonhemolytic group, although there was no significant difference.
None of those with abnormal neurodevelopmental status had
an abnormal initial brainstem auditory evoked potential.
Relationship Between the Cause of Hemolytic
Hyperbilirubinemia and Brainstem Auditory Evoked
Potential Outcome and Neurodevelopmental Status
In general, there is a higher rate of abnormal brainstem auditory
evoked potential and neurodevelopmental outcome for those with
ABO incompatibility than glucose-6-phosphate dehydrogenase
deficiency, although not to any statistical significance (Table 3).
DISCUSSION
Neonatal hyperbilirubinemia is extremely common in the Chinese,
and our university-based hospital followed a standardized protocol for phototherapy and exchange transfusion,20 especially for those
with a rapid rise in the total serum bilirubin level within the first
24 hours of life, for those blood group A or B babies with mothers
with blood group O known before delivery, or when the glucose-

Figure 1. Brainstem auditory evoked

potential (BAEP) outcome in the hemolytic
group, tested at a mean age of 3.2 months.

Neurodevelopment Outcome of Severe Neonatal Hemolytic Hyperbilirubinemia / Chen et al

477

Figure 2. Brainstem auditory evoked potential (BAEP) outcome in the nonhemolytic

group, tested at a mean age of 3.1 months.

6-phosphate dehydrogenase status was known within 24 hours

using cord blood screening. We make a close surveillance of the
serum total bilirubin level for these high-risk neonates. An aggressive intervention approach with phototherapy and even early
exchange transfusion is implemented. Thus, the rate of neurophysiologic (brainstem auditory evoked potential) abnormalities
and neurodevelopmental abnormalities is only transient, as shown
in this and another study of ours.21
Despite advances in the treatment of hyperbilirubinemia,
there is still an increase in the morbidities associated with rapidly
increasing unbound bilirubin in the brain. The exact bilirubin concentration associated with kernicterus in the term infant is unknown
and varies with ethnic groups, maturation, and the presence of
hemolytic diseases.22,23
A list of common risk factors for hyperbilirubinemic
encephalopathy has been identified.24,25 High-risk factors for
unbound bilirubin toxicity such as Rh or ABO incompatibility and
glucose-6-phosphate dehydrogenase deficiency could be monitored by serum or transcutaneous bilirubin level.26,27 Neonates
with hemolytic hyperbilirubinemia can be treated more aggressively
than those with nonhemolytic jaundice because they are more
vulnerable to bilirubin toxicity.25,28

Short-Term Effect of Neonatal Hemolytic

Hyperbilirubinemia on the Brainstem
Auditory Evoked Potential
In our cohort, there was no significant difference for the effect of
hyperbilirubinemia on the brainstem auditory evoked potential
between both groups because 10.4% in the hemolytic group compared with 9.1% in the nonhemolytic hyperbilirubinemia group had
abnormalities on the initial brainstem auditory evoked potential.
Yilmaz et al reported the short-term effect of hyperbilirubinemia on the brainstem auditory evoked potential and found that
2 of 22 subjects (9%) had abnormalities within 6 months of followup, although only 17 of 22 subjects had hemolytic hyperbilirubinemia owing to Rh or ABO incompatibility.29
Long-Term Effect of Neonatal Hemolytic
Hyperbilirubinemia on the Brainstem
Auditory Evoked Potential
There were also no significant differences in serial brainstem auditory evoked potential outcome between the hemolytic and nonhemolytic groups in our cohort at 2 years. Only 3.5% in the hemolytic
group and 2% in the nonhemolytic group had abnormal brainstem
auditory evoked potentials.

Table 2. Comparison of Brainstem Auditory Evoked Potential and Neurodevelopment Between the Hemolytic and Nonhemolytic Groups
BAEP (Short Term)*
Group
Hemolytic (n = 29)
Nonhemolytic (n = 99)
P value

Normal
26
90
> .05

Abnormal
3
9

BAEP (Long Term)

Normal

Abnormal

28
97
> .05

BAEP = brainstem auditory evoked potential.

*Tested at a mean age of 3.2 months in the hemolytic group and 3.1 months in the nonhemolytic group.

Tested until 2 years of age in both groups.

Mild motor delay and hypotonia at 3 months but normal at 6, 11, and 24 months.

Mild motor delay and hypotonia at 3 months but normal at 6 months and 11 months.

1
2

Neurodevelopment
Normal
26
97
> .05

Abnormal
3
2

478

Journal of Child Neurology / Volume 21, Number 6, June 2006

Table 3. Etiologic Distribution and the Outcome of Brainstem Auditory Evoked Potential on Neurodevelopment in the Hemolytic Group
Maximum TSB
(mol/L)
Etiology
ABO incompatibility (n = 19)
Rh incompatibility (n = 1)
G6PD deficiency (n = 8)
ABO incompatibility combined with
G6PD deficiency (n = 1)
Total (n = 29)

BAEP (Short Term)

Normal

Abnormal

BAEP (Long Term)

Neurodevelopment

Normal

Abnormal

Normal

Abnormal

345.3*
218
386.6*
355

16
1
8
1

3
0
0
0

18
1
8
1

1
0
0
0

17
1
7
1

2
0
1
0

351.3*

26

28

26

BAEP = brainstem auditory evoked potential; G6PD = glucose-6-phosphate dehydrogenase; TSB = total serum bilirubin.
*Mean.

Tested at a mean age of 3.2 months.

Tested until 2 years.

Ozmert et al evaluated 102 full-term infants with hyperbilirubinemia at 8 to 13 years, of whom 17 had a hemolytic etiology
(11 owing to Rh incompatibility, 6 owing to ABO incompatibility).19 There was no significant difference between the hemolytic
and nonhemolytic groups in the mean brainstem auditory evoked
potential latencies.
Neurodevelopmental Outcome
in Neonatal Hemolytic Hyperbilirubinemia
All children in our cohort had a normal neurodevelopmental outcome at 3 years except 10.4% of the hemolytic group (two with ABO
incompatibility, one with glucose-6-phosphate dehydrogenase deficiency) and 2% of the nonhemolytic group. None had features of
cerebral palsy, and all of these abnormalities were minor and transient, with mild motor delay or hypotonia. All children in our
cohort with a transient abnormal neurodevelopmental outcome,
however, had a normal initial brainstem auditory evoked potential,
suggesting that there is a lack of correlation of the initial brainstem
auditory evoked potential and later neurodevelopment outcome.
Unlike our excellent result, Ozmert et al reported that infants
with isoimmunization were affected dramatically because the IQs
of the children with a positive Coombs test were significantly
lower than those of infants without isoimmunization.19 Yilmaz et
al reported that neurologic abnormalities owing to bilirubin neurotoxicity could be seen in children with a normal brainstem auditory evoked potential, but children with an abnormal brainstem
auditory evoked potential might not have any neurologic dysfunction apart from speech retardation.29 However, another Turkish study reported that nine children with an abnormal brainstem
auditory evoked potential had prominent neurologic abnormalities.19
Etiology in Neonatal Hemolytic Hyperbilirubinemia
Rh incompatibility is extremely rare in the Chinese. Our only case
in this cohort had exchange transfusion performed at a relatively
low total serum bilirubin level of 218 mol/L (ie, 12.8 mg/dL), and
the final outcome was normal.
Glucose-6-phosphate dehydrogenase deficiency is common in
the Chinese, blacks (11 13%), and immigrants from Mediterranean
countries and Southeast Asia.30 There have been case reports with
kernicterus in the United States.31,32 Glucose-6-phosphate dehydrogenase deficiency is very common in Hong Kong. We had eight
neonates with hyperbilirubinemia (with a maximum bilirubin level
of 637 mol/L, ie, 37.3 mg/dL). All had a normal brainstem auditory
evoked potential or neurodevelopment outcome except one child
with transient hypotonia and motor delay. The good prognosis in

our glucose-6-phosphate dehydrogenase deficiency cohort might

be due to our aggressive early-intervention protocol as well.
Many hospitals do not perform routine blood typing in the
infants of group O mothers, so the ABO status of the infant is often
unknown.33 However, we routinely perform blood grouping for all
neonates; thus, those babies with a mother with group O blood will
be monitored regularly, especially for the first 48 hours of life, for any
sudden increase in bilirubin level. The two children with ABO incompatibility had only transiently mild neurodevelopmental abnormality. The good prognosis in our hemolytic ABO incompatibility cohort
might be due to our aggressive early-intervention protocol as well.
We had one case with hyperbilirubinemia owing to ABO
incompatibility and glucose-6-phosphate dehydrogenase deficiency,
and the outcome was normal. Other studies also did not find an additive effect of ABO blood group incompatibility on glucose-6-phosphate dehydrogenase deficiency.33,34 Kaplan et al compared neonates
with combined ABO incompatibility with glucose-6-phosphate
dehydrogenase deficiency with those with either condition alone
and did not find an increased risk of hemolysis.35
We also noticed that with the massive influx of immigrants
from mainland China over the past 10 years to Hong Kong, we have
children referred to our center for assessment of possible special
educational needs whom we found to have a severe type of cerebral palsy or mild clumsiness with bilateral high-frequency sensorineural deafness that was not diagnosed while they were in
China. On retrospective questioning, some of these children came
from rural areas, where phototherapy was not available, and the
neonatal jaundice was left to follow its natural course. Some mothers were advised by health care workers to have their babies
exposed to sunlight or were even taking traditional Chinese medicine as folklore medicine, which might have caused the severe
hemolysis for those with glucose-6-phosphate dehydrogenase deficiency. Babies in China are not routinely screened for glucose-6phosphate dehydrogenase deficiency. Thus, bilirubin
encephalopathy was not detected in our center over the past 30
years with a regular surveillance program for all neonates with jaundice. In our university-based neonatal center with an aggressive
early-intervention program for neonatal hyperbilirubinemia, we had
not encountered even a subtle case of clumsiness or mild cerebral
palsy even in those with a serum bilirubin level as high as 637 mol/L
(ie, 37.3 mg/dL, as seen in this cohort). With the regular neurodevelopmental surveillance program using brainstem auditory evoked
potential monitoring and neurodevelopmental assessment at least
up to 3 years for our children with hemolytic hyperbilirubinemia,
we have proven that an aggressive early-intervention approach to

Neurodevelopment Outcome of Severe Neonatal Hemolytic Hyperbilirubinemia / Chen et al

all neonates with an underlying hemolytic mechanism for hyperbilirubinemia can prevent kernicterus.
CONCLUSION
We found that the toxic effect of bilirubin on the auditory brainstem pathway and abnormal neurodevelopmental outcome in
Chinese term neonates with hemolytic hyperbilirubinemia is transient and mild, except for a slightly raised brainstem auditory
evoked potential threshold. We do not think that such a brainstem
auditory evoked potential threshold of 50 to 60 dB nHL will affect
the functional outcome of these children. The excellent prognosis in our cohort with hemolytic hyperbilirubinemia (ABO incompatibility or glucose-6-phosphate dehydrogenase deficiency) might
be due to our aggressive early-intervention approach within the
first 24 to 48 hours after delivery once the risk of ABO incompatibility or glucose-6-phosphate dehydrogenase deficiency status is known. Thus, although the brainstem auditory evoked
potential is a useful neurophysiologic tool for monitoring for possible neurologic complications, it is not a useful tool for predicting the final neurologic outcome. Although we do not have
untreated cases as a control group for ethical reasons, we found
that adopting an aggressive early-intervention approach to neonates
with hemolytic hyperbilirubinemia can prevent kernicterus.
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