The Clinical Syndrome of

Bilirubin-Induced Neurologic Dysfunction

Lois Johnson, MD, FAAP,* and Vinod K. Bhutani, MD, FAAP†

We believe that the syndrome of bilirubin-induced neurologic dysfunction [BIND] repre-

sents a spectrum of neurologic manifestations among vulnerable infants who have expe-
rienced an exposure to bilirubin of lesser degree than generally described in previous
publications. Clinical neuro-motor manifestations extend to a range of subtle processing
disorders with objective disturbances of visual-motor, auditory, speech, cognition, and
language among infants with a previous history of moderate-to-severe hyperbilirubinemia
of varied duration. Confounding effects include prematurity, hemolysis, perinatal-neonatal
complications, altered bilirubin-albumin binding, severity and duration of bilirubin expo-
sure, and the individual vulnerability of the infant related to genetic, family, social, and
educational predilection, regardless of the cause of neonatal jaundice. Tools to better
assess BIND specific domains of multisensory processing disorders, identified by pyscho-
metric, audiologic, speech, language and visual-motor, and neuromotor examination would
allow for prospective surveillance of infants at risk for the syndrome.
Semin Perinatol 35:101-113 © 2011 Published by Elsevier Inc.

KEYWORDS kernicterus, bilirubin induced neurologic dysfunction, jaundice, hyperbiliru-

binemia, bilirubin encephalopathy, newborn jaundice

U nconjugated bilirubin is a known and well-established

neurotoxin. At excessively high concentrations, it
causes permanent neural damage in newborn infants, ie,
“chronic bilirubin encephalopathy” or kernicterus.1-4 Listed
in Table 1 are the definitions we use to categorize severity of
hyperbilirubinemia as low risk (mild), significant (moder-
ate), severe (high), extreme (excessive), and hazardous, qual-
ified by their total serum bilirubin (TSB) percentiles for post-
natal age in hours in term healthy infants.5 Studies in term
infants with hyperbilirubinemia attributable to hemolysis6
from rhesus (Rh) blood type incompatibility have shown that
kernicterus occurred in more than 50% of infants with TSB
levels ⬎30 mg/dL (513 ␮mol/L) but rarely occurred at levels
⬍20 mg/dL (427 ␮mol/L). More recently, term infants with
TSB levels ⬎35 mg/dL (599 ␮mol/L), regardless of etiology,
rapidity of intervention or clinical assessment of severity of
acute bilirubin toxicity (encephalopathy), either before or
*Pennsylvania Center for Kernicterus, Philadelphia, PA.
†Division of Neonatal-Developmental Medicine, Department of Pediatrics,
Stanford University School of Medicine and Lucile Packard Children’s
Hospital, Stanford, CA.
Address reprint requests to Vinod K. Bhutani, MD, FAAP, Stanford Univer-
sity School of Medicine, Lucile Packard Children’s Hospital, Department
of Pediatrics, Division of Neonatal and Developmental Medicine, 750
Welch Ave #315, Stanford, CA 94304. E-mail: bhutani@stanford.edu
after treatment, have been observed to develop some degree
of irreversible sequelae.7
As assessed in the usual clinical setting, the diagnosis of acute
bilirubin encephalopathy (ABE) may be a poor predictor of ir-
reversible sequelae. Especially in the preterm infant, its clinical
signs are often subtle and indistinct.8 The precise threshold at
which bilirubin may be neurotoxic in a given infant is unknown.
A better understanding of the patho-physiology as it is related to
the rate of hemolysis and bilirubin-albumin binding along with
the expedited development of their respective assays will help
resolve this uncertainty.9 The importance and possibility of
identifying individual differences in ability to destroy bilirubin
in the brain and expedite or delay its neuronal exit, also needs to
be addressed.
Concerns regarding subtle manifestations of acute or chronic
bilirubin-induced neurologic dysfunction (BIND), either be-
cause of hyperbilirubinemia that is not generally considered
severe enough to need treatment or to prolonged exposure to
lesser degrees of hyperbilirubinemia in a vulnerable infant, have
yet be validated in prospective studies.10-13 Recent reports of the
consequences of early bilirubin exposure of developing neurons
in cell culture leading to neuritic atrophy, cell death, decreased
neuronal arborization, arrested neuritic growth, and neuritic
hypoplasia14 suggest an incompletely defined spectrum of
BIND. Neurodevelopmental maturation may be impacted by

0146-0005/11/$-see front matter © 2011 Published by Elsevier Inc. 101

doi:10.1053/j.semperi.2011.02.003
102 L. Johnson and V.K. Bhutani

Table 1 Standard Definitions for Severity of Neonatal Hyperbilirubinemia at Age >72 Hours5
Adjective TSB Level (at Age >72 Hours) TSB Percentile
Low-risk (mild) <14 mg/dL (239 ␮mol/L) <40th percentile
Significant (moderate) >17 mg/dL < 20 (291 ␮mol/L) >95th percentile
Severe >20 mg/dL < 25 (342 ␮mol/L) >98th percentile
Extreme (excessive) >25 mg/dL < 30 (427 ␮mol/L) >99.9th percentile
Hazardous (fulminant) >30 mg/dL (513 ␮mol/L) >99.99th percentile

the ability of bilirubin to promote alterations in neurogenesis,
neuritogenesis, and synaptogenesis, especially in the premature
infant. Therefore, the possible deleterious role of unconjugated
bilirubin in neuronal differentiation, development, and plastic-
ity needs further investigation.
In this work, we review the clinical observations that con-
tribute to our hypothesis of an expanded syndrome of BIND.
We believe that BIND is a disorder characterized by impair-
ment of audiologic, speech, and language processing as well
as disturbances in visual-motor and cognitive functions asso-
ciated with failure of fine neuromotor control (usually ex-
trapyramidal signs) that are apparent among infants with a
previous exposure of moderate-to-severe hyperbilirubinemia
with varying duration and altered bilirubin-albumin binding,
and who have at familial, social, or genetic predilection.
Review of the
Clinical Spectrum of BIND
The hallmark sign of extreme bilirubin neurotoxicity is irre-
versible severe posticteric sequelae, usually confirmed at au-
topsy, as the icteric (yellow) staining and microscopic evi-
dence of cellular damage in basal ganglia nuclei, specifically
the globus pallidus. In surviving infants this damage can now
often be observed at that location, and in the subthalamus, as
an increased signal on magnetic resonance imaging. Cellular
injury occurs when the total bilirubin (TSB) level exceeds the
infant’s neuroprotective defenses. Neurotoxicity is seen pri-
marily in the basal ganglia, central and peripheral auditory
pathways, hippocampus, diencephalon, subthalamic nuclei,
midbrain, and pontine nuclei for respiratory, neurohumoral
and electrolyte control, brain stem nuclei for oculomotor and
auditory function, and in the cerebellum, most prominently
in the vermis.2,14 Clinical signs of ABE include progressive
changes in an infant’s mental (behavioral) status and muscle
tone, crying with varying degrees of drowsiness, poor feed-
ing, hypotonia, and alternating tone followed by increasing
hypertonia, especially of extensor muscles, with intermittent
and then more severe and constant retrocollis and opisthot-
onos. Paralysis of upward gaze and a mask like “kernicteric
facies” in severe ABE is also described.2,14-16
Acute-stage mortality (about 7%-10%) is caused by respi-
ratory failure and progressive coma or intractable seizures.
Rate of progression of clinical signs depends on the rate of
bilirubin increase, duration of hyperbilirubinemia, host-sus-
ceptibility, and the presence of co-morbidities.2,7 The term
kernicterus is now usually reserved for the irreversible classic
sequelae in infants who survive severe ABE. Classic ker-
nicterus is diagnosed primarily as generalized dystonia, ath-
etoid cerebral palsy, paralysis of upward gaze, and sensori-
neural hearing loss of varying degrees of severity. Cognition
is usually spared to a striking degree, even in severely hand-
icapped children. This preservation of intellectual capacity is
most easily recognized if consistently adequate nutrition is
achieved, prevention of regurgitation of food into the lungs
is prevented and early physical, occupational and speech
therapy, as well as appropriate hearing aids and cochlear
implants, if indicated, have been provided.
BIND refers to a wider spectrum of disorders that empha-
sizes the increasing clinical and technological evidence of
damage confined to more narrow neural pathways. For ex-
ample, damage to the auditory system may not result in se-
vere hearing loss (deafness) but in isolated, less severe forms
of auditory neuropathy (auditory dyssynchrony) defined by
characteristic clinical criteria and distinctive findings on the
auditory brainstem-evoked response (ABR) with normal co-
chlear function (normal cochlear microphonics and otoa-
coustic emissions) without severe hearing loss. Similar audi-
tory neuropathy associated with minimal fine and/or gross
motor disability also occurs.16
Before the development of now widely available ABR technol-
ogies, audiologists and educators, notably M. Vernon, J. Rosen
and H. Mykjlebus in the 1950s and 1960s, anticipated these
findings (see below, BIND). These investigators described the
auditory disorder of survivors of Rh disease as more similar to
those of aphasic brain-damaged children than to otherwise-
healthy deaf children. Rh disease survivors seemed to be unable
to use what residual hearing they had, as if there was a disorder
of perceptual integration and an inability to listen. Although not
yet proven, some experts believe there are also subtle neurolog-
ical manifestations of BIND with only signs of awkwardness,
minimal fine and gross motor incoordination and gait abnor-
malities, fine tremors, exaggerated extrapyramidal reflexes as
shown in Table 2 and reported in a review by Newman and
Klebanoff,17 and perhaps associated attention, learning, and be-
havioral problems.
In a recent study from the Netherlands,10 researchers de-
scribed disorders of movement in 20 infants with neonatal TSB
levels between 13.7 (233 ␮mol/L) and 26 mg/dL (355 ␮mol/L)
compared with 20 clinically nonjaundiced infants, born during
the same time (November 1, 1997, and June 30, 1998) and
closely matched for gestational age, gender, breastfeeding, and
social class. Dysfunctional movements were still present at age 3
and 12 months with a strong dose response correlation to sever-
ity of hyperbilirubinemia among the infants exposed to “mod-
erate” hyperbilirubinemia range of 13.7-26 mg/dL (233 ␮mol/L
BIND syndrome 103

Table 2 Infants with Suspected-to-Abnormal Neurologic Signs guage development is unknown.19 An auditory nerve/auditory-
at Age 7 Years and their Correlation to Neonatal Hyperbili- processing syndrome has been described in some children with
rubinemia: Association of Suspicious Neurologic Signs With difficulty hearing and understanding speech and language.20-23
Stepwise Increment in Peak Serum Bilirubin Levels During To some extent, these auditory as well as visual processing mea-
Their Birth Hospitalization
sures may be generalized to include possible effects on other
TSB Stratification aspects of cortical function. For example, transient changes in
Characterization and and Correlation to neonatal social behavior have been noted in infants with biliru-
Outcomes Reported Outcomes bin levels below 20 mg/dL24,25 and an association with autism,
Total children examined at age 7 34,299 attention deficit disorder, and developmental delay in infants
years with bilirubin levels greater than 19 mg/dL has been sug-
Abnormal or suspicious 14.7% gested.26 Good and Hou27 have reported visual-motor changes
examination (n ⴝ 5035) in jaundiced infants. In addition, there are reports of increase in
Peak TSB: <10 mg/dL 14.9% low motor and mental Bayley scores at ages 8 months and 1 year
(n ⴝ 4346) after controlling for birth weight and gestational age among in-
Peak TSB: 10-14.9 mg/dL 16.9%
fants enrolled in the large Collaborative Study of Cerebral
(n ⴝ 472)
Peak TSB: 15-19.8 mg/dL 18.0%
Palsy.28 In smaller studies, infants with TSB levels between 10
(n ⴝ 157) and 20 mg/dL, in the absence of phototherapy or after control-
Peak TSB: >20 mg/dL (n ⴝ 60) 22.4% ling for its effects, have been shown to have adverse effects on cry
Odds ratio 1.12; 95% CI 1.06-1.20; characteristics.29
P < 0.001 Learning disabilities are characterized by unanticipated fail-
Details of suspicious signs Probability ures of an individual to acquire, retrieve, and use information
Gait abnormalities <0.001 competently and likely to affect children with average or above-
Awkwardness <0.001 average intellectual abilities. These typically manifest as a loss of
Failure at fine stereognosis 0.008 executive function with failure to acquire reading, writing, or
Questionable hypotonia 0.005-0.07 math skills at grade- and age-expected levels.30 Learning disabil-
Gaze abnormalities 0.001-0.05
ities may be intrinsic to the individual and may occur concom-
Vasomotor abnormalities 0.005
itantly with other disabilities (such as movement disorders,
Abnormal cremastric reflexes 0.008
Abnormal abdominal reflexes 0.001 muscle tone dysregulation, and processing disorders) or with
extrinsic influences, such as cultural and nurturing differences
Data from Collaborative Perinatal Project: 54,795 live-births from
the “prephototherapy” years of 1959-1966 were studied for their
or insufficient or inappropriate instruction.
bilirubin-related long-term outcome. Of these, 34,299 (83%) in- There are no studies that have causally linked learning
fants who met inclusion criteria were followed to age 7 years. disabilities to a previous history of hyperbilirubinemia.
During their neonatal period, 323 infants had peak TSB >20 Whether the spectrum of bilirubin neurotoxicity leads to loss
mg/dL (0.8%) and 53% of these infants were treated with ex- of integrity of multiple physiological and behavioral systems
change transfusion; 66 infants had peak TSB >25 mg/dL
(0.16%), and 85% of these were treated with exchange transfu-
that regulate sensation, perception, affect, reward, executive
sion.17 function, motor output, and learning has been a debatable
TSB, total serum bilirubin. topic. Clearly, however, there has been increasing concern
that shared genetic and environmental risk factors may dis-
rupt executive function and that the brain structural pheno-
to 26.0 [355 ␮mol/L]) after the authors controlled for con- type of an expanded spectrum of BIND disorders may over-
founding variables by logistic regression. The height of the peak lap with these genetic and environmental risk factors. In
bilirubin was closely related to neurologic condition at age 12 addition, there is a distinctive neuroanatomic predilection for
months but not at earlier ages. On the basis of published studies the hippocampus being affected by age-related morphologic
in which researchers used the same techniques to assess general changes. That loss in hippocampal volume and lowered gray
movements in infancy and the relation of movement disorders matter volumes within limbic-striato-thalamic circuitry are
to minor neurologic dysfunction, school achievement, attention common to autism spectrum disorders, and schizophrenia
deficit-hyperactivity disorder (ADHD), and aggressive behavior suggests a degree of overlap that may reflect shared but un-
at school age, the authors concluded that their results indicated proven etiologic mechanisms.
TSB levels greater than 335 ␮mol/L (19.6 mg/dL) should be
avoided. All infants were treated with phototherapy for a TSB of Review of Earlier
310 ␮mol/L at age 2 days or one of 340 ␮mol/L from age 3 days
onward. Bilirubin Neurotoxicity Outcome
Other reports of the wide spectrum of injury that appears to Studies in Full-Term Infants
occur because of central nervous system bilirubin exposure are
available. Abnormalities of the ABR have been shown in new- Is an Elevated TSB a
borns with elevated TSB levels, with return to normal as the Measure of Bilirubin Neurotoxicity?
bilirubin level was lowered.18 In the absence of long-term fol- Bilirubin thresholds used to initiate treatment in clinical
low-up, however, their possible effect on later hearing and lan- practice have influenced clinical studies on neonatal biliru-
104
bin neurotoxicity. In the decades before the introduction of
phototherapy, exchange transfusion was recommended for
term infants with hemolytic disease at serum bilirubin levels
of 20 mg/dL. However, exchange transfusion was not recom-
mended for idiopathic jaundice until levels of 25 mg/dL or
greater had been reached. These recommendations were
based on several small follow-up studies of jaundiced full-
term infants with peak serum bilirubin levels of 20 mg/dL or
greater. Three of these studies were conducted in Scandina-
via among infants born between 1956 and 196231-33 who did
not have Rh hemolytic disease. The 2 smaller studies did not
provide a follow-up beyond age 2 years. One included infants
with perinatal-neonatal complications31 and the other in-
cluded infants with Coombs positive hemolytic disease.32
Infants treated with exchange transfusion at TSB levels of
⬎20 mg/dL were compared with infants not treated at these
bilirubin levels and to healthy, untreated less-jaundiced in-
fants. No abnormalities were found at the 2-year follow-up in
either of these studies in relation to serum bilirubin levels.
The third study was the largest and most rigorous.33 It
considered only healthy term infants born after vaginal de-
livery in the absence of prolonged labor, difficult delivery, or
any other complications and included the healthy full-term
infants without ABO hemolytic disease from the study of
Killander et al.32 Follow-up, performed between ages 6 and
13 years, consisted of audiologic, neurologic, and psycho-
metric examinations and included 226 infants without iden-
tified hemolytic disease, 115 of whom had had no visible
jaundice, and 111 who had had serum bilirubin levels ⱖ20
mg/dL. The direct Coombs’ test was negative in all infants,
but in 45 there was blood group system (ABO) incompatibil-
ity between infant and mother. No difference in mean IQ
scores was found between jaundiced and nonjaundiced in-
fants. A significant psychologic disturbance (eg, distractibil-
ity, short attention span) was found in 3 of the nonjaundiced
and in 6 of the jaundiced infants, which is a nonsignificant
finding.
No cases with hearing loss or of neurologic or behavioral
abnormality suggestive of bilirubin toxicity were identified in
children from the nonjaundiced group. In contrast, 3 cases of
hearing loss were found in the jaundiced group without any
other identifiable cause by neonatal, family history, or child-
hood information. It is of note that 2 of these 3 hearing-
impaired children had been part of the earlier study of Kil-
lander et al32 and had passed as normal by physical and
neurologic examination, without pure tone audiometry, at
age 2 years. Their peak serum bilirubin levels, before ex-
change transfusion, had been 25.6 mg/dL (on day 4, with no
ABO incompatibility) and 33.2 mg/dL (on day 4, with
Coombs’ negative blood type OA incompatibility). The third
child, whose serum bilirubin peaked at 23.7 mg/dL on days 7
and 10, had Coombs’ negative OA incompatibility, reticulo-
cyte count of 7.2%, and a hemoglobin level of 24 g/dL, and
had not been treated with exchange transfusion. In these 3
children, hearing loss was the only abnormal finding.
In contrast to these children with isolated hearing loss, the
investigators described a fourth child in whom there was no
ABO incompatibility, a reticulocyte count of 8%, and a peak
L. Johnson and V.K. Bhutani
scrum bilirubin on day five of 33.2 mg/dL, at which time an
exchange transfusion was performed. This child had a nor-
mal pure tone audiogram. However, at ages 3 and 7 years, the
child showed a coordination disturbance of the ataxia-athe-
tosis type, a moderate speech disorder with incorrect word
construction and a defective pronunciation, perceptual ab-
normalities, slight behavioral problems, (not severe enough
to be classified as a psychologic disturbance), and an IQ of
91. In light of these findings at long term follow-up (age 6-13
years) among the 210 infants without apparent hemolytic
disease, the investigators concluded that despite the absence
of statistical power at the P ⬍ 0.05 level, the finding of defi-
cits typical of bilirubin-related brain damage in 4 of the jaun-
diced children and in none of the control patients made it
highly likely that the deficits were caused by hyperbiliru-
binemia.
In infants with possible ABO isoimmunization, despite a
negative direct Coombs’ test, the authors made the tenta-
tive recommendation that the bilirubin level not be al-
lowed to exceed 20 mg/dL and that in full-term infants
without isoimmunization the bilirubin level should not be
allowed to exceed 25 mg/dL.33 These instances of biliru-
bin-related brain damage in a carefully done relatively
large study cannot be lightly dismissed. This position is
supported by the much larger Greek trial of the effect of
prenatal phenobarbital on neonatal hyperbilirubinemia.34
In this trial, a high incidence (9%) of sensori-neural hear-
ing loss was found among healthy term infants (some of
whom had ABO incompatibility and G6PD deficiency),
whose serum bilirubin levels exceeded 12 mg/dL. An in-
cidence of hearing loss of 1% was found among infants
whose peak serum bilirubin levels had remained below
this level (P ⬍ 0.001, n ⫽ 415). These studies have con-
tributed to the now general agreement that peak TSB is a
useful test, but relatively poor measure of the toxic poten-
tial of unconjugated bilirubin.35-39 Consideration must be
given to such other factors as duration of exposure, con-
comitant level of serum albumin, bilirubin-binding re-
serve. Level of “unbound” bilirubin and to the presence or
absence of acidosis, immaturity, compromise of the blood-
brain barrier40 and potentiation of bilirubin toxicity by
unexpected accomplices, such as benzyl alcohol or consti-
tutional/genetic factors as discussed previously.38,41-45
Does Bilirubin Neurotoxicity
Affect Intellectual Capacity?
A review of literature by Newman and Klebanoff17 and
Newman and Maisels46 before the 1994 American Acad-
emy of Pediatrics practice Parameters35 questioned the im-
portance of exposure to hyperbilirubinemia of “moderate”
severity given the costs, benefits, and risks of efforts to
prevent its occurrence with currently available diagnostic
and intervention technologies. It is tempting to be reas-
sured by these statistical and clinical overviews. With ref-
erence to the Collaborative Project,17 for example, they
note that a mere 0.14-point depression of the intelligence
quotient for white infants and a 0.28-IQ point depression
BIND syndrome
for African-American infants was demonstrated for each
mg/dL increase in bilirubin. That may not seem impres-
sive, although, over an increment of 30 mg/dL (5-35 mg/
dL) of serum bilirubin range, this would imply that some
children could have a 4 – to 8-IQ point depression related
to degree of hyperbilirubinemia.
A closer look at data from Collaborative Project reports is
revealing.17,46 IQ data, presented as the percentage of chil-
dren with scores less than 90 in relation to increasing biliru-
bin levels, are less reassuring than when transformed into the
point for point statistical format. The same is true for analysis
of the collaborative project results as reported by Broman et
al47 showing the mean IQ data for 4-year-olds by sex, race,
and socioeconomic class as related to low (⬍10 mg/dL),
moderate (10-19 mg/dL), or high (20-28 mg/dL) peak serum
bilirubin levels. Unfortunately, none of these data was con-
trolled for birth weight or gestational age. White female pa-
tients of all socioeconomic groups appeared to be at “unde-
tectable” risk, but white male patients in the middle
socioeconomic group showed a 4-point decrease in IQ be-
tween high and low bilirubin groups. In the middle socioeco-
nomic groups, black males showed a 5-point decrease,
whereas black females showed a 7.5-point decrease between
high and low bilirubin groups.
Considering all socioeconomic groups, there was a 6 to 10
point decrease for African-American infants between high
and low bilirubin groups for combined male and female gen-
der. These are mean IQ differences comparable with those
associated with “high” or “low” levels of lead exposure.48
Furthermore, unlike exposure to bilirubin, high lead expo-
sure was associated with a dearth of superior IQ scores
(⬎120) and an increase in inferior IQ scores (⬍70). In a
17-year retrospective study of 1948 Israeli military recruits,
Seidman et al49 reported on the effect of neonatal hyperbili-
rubinemia on long-term cognitive ability in full-term new-
borns with a negative Coombs test. On the basis of a logistic
regression analysis adjusted for the confounding effects of
gestational age, birth weight, Apgar score, ethnic origin, so-
cioeconomic class, paternal education, birth order, and the
administration of phototherapy and exchange transfusion,
no direct linear association was shown between peak neona-
tal bilirubin levels and IQ scores or school achievement at 17
years of age. However, the risk for low IQ scores (⬍85) was
significantly greater (P ⫽ 0.014) among full-term male sub-
jects with serum bilirubin levels greater than 20 mg/dL or
342 ␮mol/L (odds ratio [OR] 2.96; 95% confidence interval
[95% CI] 1.29-6.79).
Should the Presence or Absence
of Long-Term Bilirubin-Related
Brain Damage Be Assessed by IQ Data?
Mean IQ, which lends itself to meta-analysis, is often used as
a major criterion. In their overview of the literature refer-
enced above, Newman and Maisels46 transformed the mean
IQ data from several studies in addition to the large Collab-
orative Project, to a combined mean point IQ decrease per
mg/dL increase in peak serum bilirubin, collapsed over so-
105
cioeconomic groups, race, and country. This mode of statis-
tical analysis fails to address the nature of bilirubin injury.
Irreversible, as distinct from apparently reversible bilirubin
compromise of brain function seems to be a threshold phe-
nomenon, with different thresholds for different babies un-
der confounding pathophysiological conditions. Some in-
fants are damaged at bilirubin levels that cause no apparent
permanent damage to apparently comparable other infants,
and both hearing loss and choreoathetosis can be seen in
children with IQ scores well within the normal range. In
addition, minimal brain damage can occur in the absence of
motor deficit or high tone hearing loss. It is unlikely that the
effects of bilirubin neurotoxicity for babies on general can be
safely reduced to the uniformity implied by a point decrease
in IQ per mg/dL increase in the serum bilirubin if for no other
reason than that individuals have widely different innate in-
telligence, including that estimated by IQ testing. In those
individuals with a high innate intelligence, unapparent bili-
rubin brain damage could cause compromise to one or more
component of measured intelligence but is reflected only in a
lower score than would otherwise have been the case but one
that is still well with the “normal” range.
Bilirubin-related Toxicity on
Audiologic, Speech, Language,
and Visual-Motor Development
Subtle forms of bilirubin-associated brain damage would
represent the lower end of the spectrum of BIND. If they
exist, do they matter? Early studies before exchange transfu-
sion was used to treat jaundice caused by Rh sensitization
suggest they do. For example, Gerver and Day50 presented
evidence that damage caused by neonatal hyperbilirubinemia
ranges from obvious kernicteric sequelae to damage so min-
imal as to be difficult to define in any one child. They found
significantly greater IQ scores (P ⬍ 0.001) among first born
children of couples with Rh incompatibility who had not
been jaundiced compared with later born children who had
been jaundiced but were judged to have escaped damage
because they had shown no clinical signs of neurologic ab-
normality.
In a later study reported in 1954, Day and Haines51 found the
difference between similarly matched sibling pairs to have been
decreased, but not eliminated, by treatment with a single ex-
change transfusion, the need for more than 1 exchange in some
infants to maintain TSB levels below 20 mg/dL not yet having
been translated into practice. As shown in Figs. 1 and 2, Table 3
a Philadelphia study of babies born some 15 years later (1965-
1966) and exposed to serum bilirubin levels in the range of 20
mg/dL in the prephototherapy era demonstrated subtle deficits
on psychometric, neuro-motor and communication examina-
tions in apparently normal children without recognized icteric
sequelae.52-54 Deficits correlated with increasing degrees of bili-
rubin exposure (Fig. 2, Table 4), in particular with low biliru-
bin-albumin binding reserve.
Similarly, in the absence of sensori-neural hearing loss,
deficits in central auditory perception by determination of
106 L. Johnson and V.K. Bhutani

Figure 1 Outcome on the psychometric examination (%) at age 4 years and its association to duration of hyperbiliru-
binemia (TSB ⬎15 mg/dL). Concentrations of indirect serum bilirubin are corrected to the nearest 0.5 mg/100 mL. A
concentration of 15 mg/100 mL or more for ⬍8 hours is considered 0 days of exposure. For a concentration of 15
mg/100 mL or more of 8-31 hours is considered as 1 day of exposure, 32-56 hours as 2 days of exposure, and so on.
Data were compiled and collated by the use of Fig. 5 from Johnson and Boggs.52

pure tone thresholds for recognition of phonically balanced
kindergarten word lists and sequencing of nonsense syllables
with an increased incidence of suspicious to abnormal ratings
were found for overall communication skills and for central
receptive and expressive language (Table 5). Audiologic ex-
aminations for overall communication skills, central recep-
tive, and expressive language included central auditory per-
ceptual evaluation and ratings for immediate auditory
memory and retrieval, figure ground separation, hyperaccu-
sis, shift of auditory set, attention span, dyspraxia, dysdi-
odokokinesis, motor overflow, and sequencing. These defi-
cits were far more evident at age 7 than at age 4, as maturation
and use of hearing pathways progressed.
All deficits correlated more closely with measures of de-
creased bilirubin-albumin binding reserve than with mea-
sured peak serum bilirubin concentration. These findings are
consistent with current research in several laboratories work-
ing with improved, potentially clinical applicable methodol-

Figure 2 Outcome on psychometric examination (%) at age 4 years and its association to bilirubin, bilirubin to albumin
ratio, and bilirubin binding level in jaundiced infants (measured during the first week after birth). Both bilirubin to
albumin molar ratio and the HABA binding level predict outcome at age 4 years. In comparison, TSB (corrected to
nearest 1.0 mg/100 mL) is a poorer indicator of risk. Data were compiled and collated by the use of Fig. 7 from Johnson
and Boggs.52
BIND syndrome 107

Table 3 Outcome at Age 4 Years in Infants With Neonatal in infants with Rh disease and below approximately 25
Jaundice mg/dL in those with idiopathic jaundice. Any infant with
Clinical Testing Done Percent Identified signs of ABE, including subtle ones, was treated promptly
in Infants Enrolled as as Suspect to with exchange transfusion regardless of etiology of jaundice.
Neonates in 1965- Abnormal at Age Implementation of these goals was feasible only for inborn
1966 (n ⴝ 83) 4 Years (n ⴝ 83) babies born because outborn babies were often not trans-
Psychometric examination ferred until after TSB levels had exceeded these levels and/or
Overall psychometric 34.0 had signs of ABE. This study predated availability of surfac-
examination tant, rhogam, and neonatal ventilator technologies as well as
Visual perceptual motor 43.5 of phototherapy. Bilirubin binding was measured by the 2-4-
integration hydroxybenzene-azo-benzoic acid (HABA) method and run
Neurologic examination in the Pennsylvania Hospital newborn pediatrics (LJH) re-
Suspect neurologic 13.0
search laboratory with the Coleman Junior photometer, with
examination
a wide bandwidth, recrystallized 2-HABA and a reference
Abnormal neurologic 4.0
examination standard of pooled cord serum or comparable crystallized
Audiologic examination human albumin preparation. It was measured in all infants
Peripheral hearing 0 with sufficient sample size with minimal hemolysis.
disorders Of those who returned at age 4 and 7 years, binding levels
Data are presented and adapted from Table 3 of Johnson and were available in all but 9 infants, in 4 because of inadequate
Boggs.52 sample size and in 5 because direct reacting bilirubin ac-
counted for more than 25%-30% of the TSB, which results in
an unreliable, (excessively low) estimate of low binding re-
ogies for estimating unbound bilirubin, (or bilirubin binding serve. A high direct reacting bilirubin also compromises the
reserve) as the more sensitive marker of toxicity, especially in accuracy of currently available techniques for assay of un-
the presence of clinical conditions, such as infection, hemo- bound bilirubin and in the same direction, ie, an excessively
lytic disease and prematurity. It is of note in regard to subtle high estimate for level of unbound bilirubin.59 It is of note
audiologic findings, that animal and human studies have that HABA binding by this technique was also used in Dr
shown that up to 75% of auditory nerve fibers can be de- Audrey K. Brown’s research laboratory and reported as useful
stroyed without elevation of hearing threshold, that humans as a predictive index for acute stage kernicterus at autopsy.60
with acoustic neuromas have poor speech discrimination rel- Peak TSB was measured with the use of both diazo and
ative to the pure tone threshold; and that small numbers of spectrophotometric techniques to determine, as indicated, its
cochlear nerve fibers can conduct impulses of threshold mag- indirect and direct reacting fractions. The study population
nitude, but that a greater number is needed to conduct the which returned for follow-up at age 4 (n ⫽ 83) and 7 years
complex neural patterns of speech.55-58 (n ⫽ 64) included healthy term, late-preterm, and preterm
The aforementioned Philadelphia study was exploratory in (30-34 weeks’ gestational age) infants and also infants who
nature. It was designed to assess, by extensive long term had Rh and Coombs-positive ABO hemolytic disease or neo-
follow-up examinations at age 3, 4, and 7 years, the possibil- natal complications of varying degree.
ity of occurrence of persistent, subtle bilirubin-related brain Table 3 summarizes the neonatal outcome at age 4 years.
damage in apparently normal inborn children at Pennsylva- Perinatal and neonatal complications included prolonged la-
nia Hospital in 1965-1966 who developed jaundice or in- bor and/or difficult delivery without asphyxia or apparent
fants transferred to the Children’s Hospital of Philadelphia prenatal insult, respiratory distress syndrome, acidosis, hyp-
for management of hyperbilirubinemia during that time.52-54 oxia, infection/sepsis, feeding problems, and hypoglycemia.
Dr T. R. Boggs, an expert neonatologist and early investigator Data regarding clinical course, perinatal/neonatal complica-
of Rh hemolytic disease, cared for all infants. The manage- tion and treatment were collected and coded for subsequent
ment of jaundice included as many exchange transfusions as analysis. Three of the Rh-sensitized inborn infants had one or
necessary to keep bilirubin levels from exceeding 20 mg/dL more intrauterine transfusions. The range of peak measured

Table 4 Combined Neonatal Bilirubin Risk Factors: Relationship to Outcome of Age 4 Years
Neonatal Bilirubin Risk Components of Neonatal Bilirubin Risk Normal Suspected-to-Abnormal
Status Assessment Outcome Outcome
High risk (n ⴝ 47) High TSB: >15 mg/dL, low bilirubin binding 17 30*
Low risk (n ⴝ 14) Low TSB <15 mg/dL, high bilirubin binding 12 2
These data are adapted from Table 14 of Johnson L and Boggs.52 Low bilirubin binding defined by HABA <50% for >1 days; high bilirubin
binding designated by measured HABA >50%. Children were rated as “suspected to abnormal” if psychologic, audiologic or neurological
examination was not normal or if a pertinent group of subtests were rated as suspect (such as, tests for visual-motor integration).
HABA, 2-4-hydroxybenzene-azo-benzoic acid; TSB, total serum bilirubin.
*Comparison by Fischer’s exact test, 2-tailed analysis; P ⴝ 0.002 and by ␹2 test, 2-tailed analysis; P ⴝ 0.005.
108 L. Johnson and V.K. Bhutani

Table 5 Audiologic Speech and Language Examination for Pure Tone Thresholds and Sequencing Ability for Phonically Balanced
Kindergarten Words and Nonsense Syllables
Association of
Neonatal
Bilirubin-Binding At Age 4 Years At Age 7 Years
to Outcome in Suspected to Correlation to Low Suspected to Correlation to Low
Childhood Abnormal (%) Bilirubin Binding* Abnormal (%) Bilirubin Binding*
Communication skills 3 ns 21.3 0.004
Central language 3 ns 6.5 ns
Receptive language 1.6 ns 14.7 ns
Expressive language 9.8 ns 27.9 0.001
HABA, 2-4-hydroxybenzene-azo-benzoic acid.
Data are compiled and collated from Johnson.52-54 This table reports findings in paired children tested at both age 4 and 7 years. With rare
exceptions, more compromise in communication skills was noted at age 7. If deficits in subtests for central perceptual tasks, such as tests
of figure ground separation, auditory memory and retrieval, symbol constancy and sequencing, perseverance, dyspraxia, and dysdiodoko-
kinesis, was added to the suspicious to abnormal ratings in the table above the incidence of compromise in communication skills was 33%
at age 7 and 15% at age 4 years.
*Low bilirubin binding was defined by HABA <40% and nonsignificant (ns).

TSB levels was from 10 mg/dL to 36 mg/dL. Infants with TSB
of 36 mg/dL had cholestasis with a direct-reacting bilirubin of
18 mg/dL. Gestational age ranged between 30 and 41 weeks
(mean 37.5 and mean birth weight 2772 ⫾ 732 g).
Drs Thomas Atkins, psychologist, Richard Winchester, au-
diologist, and Samuel Tucker, neurologist, of the Philadel-
phia Children’s Hospital Department of Rehabilitation, pro-
vided follow-up examinations. They were unaware of
bilirubin and binding data or neonatal-course. Dr D.S Gold-
stein at University of Pennsylvania conducted the statistical
analyses. For analysis, the National Institutes of Health (NIH)
Collaborative Study psychometric norms and raw scores
were used for analysis. Data to describe environmental, edu-
cational, and family characteristics were also comparable
with those used in the NIH Collaborative Study.47 Unlike the
NIH Collaborative Study, all infants were from stable sup-
portive homes, of lower to middle socioeconomic status, and
parental educational at least through high school. Prelimi-
nary details of the 4-year follow-up have been published.54
Table 4 summarizes the impact of combined neonatal biliru-
bin risk factors (on the basis of peak TSB levels and bilirubin-
binding) on neonatal outcomes. Detailed results of the 7 year
follow-have been partially reported in abstract form and are
presented here in Table 6.53,54 Of those who returned at age 7
years, binding levels were available in all but 9 infants. In 4
infants, the sample was inadequate in the remainder 5 of the
9 infants, the direct reacting accounted for over 24% to 30%
of the TSB that may result in unreliable measurements.
A high incidence of deficit in perceptual, visual-motor, and
auditory speech and language functions were found despite
normal IQ scores and absence of sensori-hearing loss was
evident. An overview of the findings are included in this
review as early evidence that deficits in central processing can
occur in healthy, apparently neurologically normal children
despite normal sensori-neural hearing thresholds and IQ
scores within the normal range. Univariate analysis showed
consistent trends, sometimes reaching statistical significance,
for recorded exposure to TSB levels greater than18 mg/dL
(Table 7).
Of particular note, the same univariate analysis showed a
consistent, highly significant correlation of low bilirubin
binding reserve with suspicious and abnormal ratings for the
psychometric and audiologic examinations at age 4 and 7
years as well as with several individual sub tests (Tables 4, 5,
and 6). Level of significance was greatest if duration of expo-
sure to binding levels below 50%, 40%, and 30% were con-
sidered. The highly significant correlation of low binding
reserve for suspect and abnormal performance at follow-up
persisted after controlling for all documented and severity
coded risk factors, including prematurity, birth weight, peri-
natal/neonatal complications, family history of learning dis-
abilities, maternal education, socio-economic factors and
stress in the home.
As shown in Table 6, perinatal/neonatal complications and
a positive family history of learning disability also correlated
with suspect to abnormal findings at follow-up but to a lesser
degree than low binding reserve. Although not as useful as
binding reserve in indicating risk of bilirubin toxicity, TSB
measurements remain the most useful available indicator of
need for bilirubin reduction treatments. Table 7 demon-
strates the increased incidence of at least one suspected-to-
abnormal rating on important subtests in the psychometric
examinations (n ⫽ 22) of infants with peak bilirubin levels of
ⱖ18 mg/dL compared with those with peak levels below that
point. Fourteen infants had more 2 or more suspect rating for
these subtests, 9 had 3 or more, and 2 had suspect ratings in
all 4 of these most bilirubin pertinent tests. The greater the
number of suspect-to-abnormal ratings on these subtests, the
more likely it was for the overall rating on the psychometric
examination to be suspect or abnormal.
In an effort to clarify the importance of bilirubin levels,
binding reserve, illness risk factors and family history of
learning disabilities (as one aspect of genetic vulnerability)
for clinical management of neonatal hyperbilirubinemia, the
data were analyzed by the stepwise logistic regression tech-
nique. Considering only babies with complete data for all
predictors of outcome morbidity as well as all measures of
outcome morbidity, the sum of days exposure to a low bili-
 BIND syndrome
Table 6 Specific Psychometric Test for Jaundiced Infants With Suspected-to-Abnormal Findings at Age 7 Years as Related to Neonatal-Perinatal Events
Correlation (Univariate Analysis) of Measured (Raw) Scores for
a Spectrum of Psychometric Tests*
Association of Detailed Term and Score for Family
Psychometric Evaluation in Late Preterm Preterm (<34 wks Morbidity Score History of
Childhood to Neonatal Risk 35 to 41 wks GA) 30-34 wks for Neonatal Learning Low
Factors (n ⴝ 50) (n ⴝ 13) Illness Disabilities Bilirubin-Binding
Median TSB, mg/dL (range) 20 (10-31) 17.5 (15-24)
% use of exchange transfusion 80% 61.5%
for hemolytic hyperbilirubinemia 48% 38.5%
for idiopathic hyperbilirubinemia 32% 23.0%
Wechsler intelligence Scaling for 2% 0% 0.016 0.005 0.002
children (WISC): full-scale IQ
“Draw A Man” Concept Formation 18.0% 15.4% NS NS 0.007
test
Illinois Test of Psycholinguistic 6.0% 7.7% 0.002 0.015 0.002
Abilities
Finger agnosia: tactile finger 34.0% 53.8% 0.06 NS 0.02
recognition test
Slingerland dysarthria/ dyslalia 26.0% 30.7% NS NS 0.001
score
Halstead-Reitan aphasia screen 20.0% 30.7% NS 0.015 0.024
Bender-gestalt visual motor 16.0% 30.7% NS 0.055 0.039
perception
WRAT-Reading 0% 0.0% NS 0.001 0.042
WRAT-spelling 0% 0.0% 0.065 0.003 0.019
WRAT-arithmetic 0% 7.7% 0.009 0.013 0.001
Data are presented for 63 surviving infants born in 1965-1966, before the availability of phototherapy.52 Infants were treated according prevalent guidelines with exchange transfusion for TSB >18
mg/100 mL in preterm infants and >20 mg/100 mL in term and late preterm infants for hemolytic disease, >25 mg/100 mL for idiopathic jaundice. Study population includes infants with
hemolytic disease (Rh and ABO sensitization), neonatal illness of varying degrees, and prematurity, as well as completely healthy well term infants. None of these infants received ventilation
support. Range of TSB values in this cohort are all >95th percentile for age in hours. Morbidity score for composite ratings of neonatal complications, other than jaundice, included respiratory
distress, sepsis, dehydration, symptomatic hypoglycemia, prematurity and Apgar scores <6 at age 5 minutes. Score for family history of Learning Disabilities are based on a composite rating
of history of learning disability or mental retardation in primary or secondary family. Data are compiled and collated from Johnson et al.53,54
TSB, total serum bilirubin.
*P values are based on one tailed ␹2 analysis for this underpowered sample size.

109
110 L. Johnson and V.K. Bhutani

Table 7 Spectrum of Psychometric Tests Conducted on Children at Age 7 years with Neonatal History of Hyperbilirubinemia
(Term and Preterm Infants Enrolled Within the First Week After Birth, in 1965-66)
TSB > 18 mg/dL TSB <18 mg/dL Total
(n ⴝ 42) (n ⴝ 21) (n ⴝ 63)
Infants with at least 1 of the 4 tests rated 22* 5 27
as suspect to abnormal (n ⴝ 27)
Infants with all 4 tests are rated as 20 16 36
normal (n ⴝ 36)
Pertinent psychometric tests that were rated and included are “Draw-A-Man” Concept Formation, Slingerland Dysarthria/dyslalia, Bender-
Gestalt Visual-motor, and Halstead-Reitan Aphasia evaluations. Data are compiled and collated from Johnson et al.52-54
TSB, total serum bilirubin.
*The primary outcome of this study was to investigate the possibility of unrecognized morbidity in infants, cared for by then accepted clinical
management routine, who seemed to have escaped kernicteric sequelae by nursery findings at discharge. Comparison of low versus higher
TSB levels on outcome is a post-hoc analysis of an expected impact: two-tailed analysis Fischer Exact analysis: levels of significance, P ⴝ
0.0354. Odds ratio 3.52; 95% confidence interval 1.08-11.37.

rubin binding reserve was always entered into the equation
first and in itself, accounted for 40% of variance in outcome
morbidity.
The only other predictors selected for entrance at the P ⫽
0.05 level of significance were family history of speech and
learning disability and parental education level, in that order.
These 3 variables accounted for 60% of outcome morbidity
variance. In contrast, if bilirubin binding reserve was not
made available for the analysis, only 40% of outcome mor-
bidity was accounted for and perinatal/neonatal complica-
tions was the first predictor variable selected, followed, fam-
ily history of speech and learning disability, parent education
and days bilirubin to total protein ratio ⬎3, 3.5, or bilirubin
to albumin ratio 6.0, 6.5, and 7.0 in that order. In the infants
in this study who had a worrisome degree of hyperbiliru-
binemia, the increased potential for bilirubin toxicity associ-
ated with concurrent perinatal/neonatal complications and
illness seems to have been entirely included in the binding
reserve estimate.
The Philadelphia study provides strong evidence that an
estimate of bilirubin binding reserve would help clinicians in
their management of neonatal hyperbilirubinemia52-54 and
emphasize the need for expedited development of reliable,
cost-effective, clinically available assays of unbound bilirubin
and/or binding reserve. Such assays reflect the increased tox-
icity of bilirubin in association with illness, prematurity and a
high bilirubin-to-albumin ratio and therefore indicate the
need for timely, effective individualized bilirubin reduction
measures in a particular baby. It is of note in this regard, that
2 of the children examined at age 4 and 7 years in the Phila-
delphia study had definitive signs of late mid to early severe
stage ABE with complete resolution before nursery discharge.
One, a boy born at term who had severe Rh disease and
incipient hydrops, was treated with 8 exchange transfusions.
The second, also a male born at term was transferred for
treatment at age 16 days with severe jaundice, (no blood
group incompatibility) and antibiotic-sensitive Escherichia
coli sepsis and meningitis. He was treated with 2 exchange
transfusions (the first one albumin fortified). These infants
had no abnormal or suspicious findings at the 7-year fol-
low-up except for an abnormal tactile finger recognition test
in the baby with E. coli sepsis.
In a subsequent study conducted after phototherapy had
become available in United States, an inborn population of
infants at Pennsylvania Hospital in 1971-1972 was managed
on an anticipatory, preventive protocol to prevent TSB from
increasing to greater than 20 mg/dL in term and 18 mg/dL in
preterm infants. As in the prephototherapy study, this cohort
included infants with hemolytic disease as well as other peri-
natal/neonatal complications. The same laboratory, clinical,
family and environmental risk factors, as with the previous
cohort, were measured and recorded. A comparison of 4-year
follow-up results for this study with those of the earlier pre-
phototherapy cohort is presented in Table 8. A much lower
overall neurologic morbidity outcome score was found in the
second study in association with predictive management of
hyperbilirubinemia with phototherapy as well as lowered use
of exchange transfusions. Infants considered unlikely to de-
velop TSB levels of 18-20 mg/dL received no treatment for
hyperbilirubinemia. The peak TSB level in the second cohort
was 18.5 mg/dL for a term baby with Rh sensitization. The
second highest was 18.0 mg/dL in an infant with Coombs-
positive ABO hemolytic disease. In treated infants, the peak
TSB was 20 mg/dL in a baby with idiopathic jaundice who
received a single exchange transfusion in addition to photo-
therapy. There was no correlation of degree of hyperbiliru-
binemia, or binding reserve with the outcome morbidity
score in the 1971-72 cohort of babies. The total outcome
variance accounted for by logistic regression analysis consid-
ering all predictor variables was 19% in contrast to 60% in
the first cohort of prephototherapy study. These data suggest
that the degree of bilirubin exposure for babies in the second
cohort resulted in no currently recognizable pathology.
Is There a Risk of Autism
Among Infants With BIND?
The authors of the aforementioned exploratory studies de-
scribed did not assess for risk of autism. A more recent pro-
spective population-based study from Nova Scotia reported
no cases of kernicterus in 61,238 infants born between 1994
and 2000 after the implementation of treatment guidelines
for hyperbilirubinemia in term and late preterm infants.26
BIND syndrome 111

Table 8 Comparison of Outcome at Age 4 Years for Jaundiced Infants With Varying Duration of Hyperbilirubinemia for 2 Study
Population of Newborns Enrolled in the Prephototherapy Era (1965-1966) and After Introduction of Phototherapy (1971-1972)
Mean
Mean Birth Peak Days with TSB Days with Low IQ Score at Neurologic
Year weight, TSB mg/ >15, 18, 25 Bilirubin Age 4 Morbidity
Enrolled n g dL mg/dL* Binding† Years Score‡
1965-66§ 83 2772 ⴞ 732 18.1 ⴞ 3.9¶ 4.41 ⴞ 3.5d 2.96 ⴞ 3.0d 110 ⴞ 17 5.55 ⴞ 10.8
1971-72§ 88 2847 ⴞ 695 13.3 ⴞ 3.5储 0.39 ⴞ 0.9d 0.46 ⴞ 1.2d 116 ⴞ 19 1.53 ⴞ 12.0
TSB, total serum bilirubin.
*Duration of hyperbilirubinemia was calculated as sum of mean days TSB >15, 18, 25 mg/dL.
†Days of low bilirubin binding was calculated as sum of mean days HABA <50%, 40%, 30%.
‡Neurologic morbidity score is based on composite rating for abnormal psychometric as well as audiologic, speech and language examinations
at age 4 years.
§NIH-sponsored studies: NB-05138, NB-04828 (Data are compiled and collated from Johnson).53,54
¶Infants were either inborn or out-born and enrolled in the prephototherapy era. They were treated with exchange transfusion(s) only.
储Infants were inborn and prospectively treated with phototherapy if needed to prevent TSB reaching mg/dL. Infants who were not treated with
phototherapy (55/88, 62.5%) had peak TSB <18.5 mg/dL. Of the 33 infants prospectively with phototherapy, exchange transfusion used as
an adjunct in 13 (30%) infants as per prevalent guidelines (see text).

There were no differences in the overall neurologic compos-
ite outcome (cerebral palsy, developmental delay, hearing
and vision abnormalities, attention-deficit disorder, and au-
tism) in infants with “moderate” hyperbilirubinemia (TSB
ⱖ230 ␮mol/L [13.5 mg/dL] and ⬍325 ␮mol/L [⬍19 mg/
dL]) and those with “severe” hyperbilirubinemia (TSB levels
⬎325 ␮mol/L or 19 mg/dL) in comparison with infants with-
out visible neonatal hyperbilirubinemia. Of the 56,019 in-
fants with linked data for analysis, associations with develop-
mental delay, attention-deficit disorder, and autism were
observed in the ⬎325 ␮mol/L (⬎19 mg/dL) group.
By contrast, on the basis of their case-control study nested
within the cohort of singleton term infants born between
1995 and 1998 at a northern California Kaiser Permanente
Hospital, of 338 subjects with an autism spectrum disorder
diagnosis and 1817 control subjects without the diagnosis, of
whom 28% received ⱖ1 bilirubin test in the first 30 days
of life, Croen et al61 found no case-control increased risk of
autism, after adjustment for gender, birth facility, maternal
age, maternal race/ethnicity, maternal education, and gesta-
tional age. They concluded that neonatal hyperbilirubinemia
was not a risk factor for autism spectrum disorder. For a
similar time (late 1990s), a Danish, population-based, case-
control study of 1216 case subjects with autistic disorders
and 6080 control subjects were matched with respect to gen-
der, birth year, and birth hospital.62 Neonatal hypoglycemia,
respiratory distress, and neonatal jaundice were associated
with increased risk of autistic disorders for term but not
preterm infants.
Maimburg et al,63 in series of population based studies,
found that infants transferred to a neonatal ward after deliv-
ery had an almost 2-fold increased risk of being diagnosed
with infantile autism later in childhood despite extensive
controlling of obstetrical risk factors. To specifically test for
neonatal hyperbilirubinemia and neurological abnormalities,
they first conducted a population-based matched case-con-
trol study of 473 children with autism and 473 matched
controls born from 1990 to 1999 in Denmark. They reported
an almost 4-fold risk for infantile autism in infants who had
hyperbilirubinemia after birth (odds ratio [OR] 3.7; 95%
confidence interval [CI] 1.3-10.5). No associations were
found between infantile autism and low Apgar scores, acido-
sis, or hypoglycemia. In a much larger national, population-
based cohort, the authors of a follow-up study of all 733,826
children born alive in Denmark between 1994 and 2004
tracked data collected from 4 national registers. Exposure to
jaundice in neonates was associated with increased risk of
disorders of psychological development for children born at
term. The excess risk of developing a disorder in the spec-
trum of psychological development disorders after exposure
to jaundice as a neonate was between 56% (OR 1.56; 95% CI
1.05-2.30) and 88% (OR 1.88; 95% CI 1.17-3.02). The ex-
cess risk of infantile autism was 67% (OR 1.67; 95% CI
1.03-2.71). Maternal parity and season of birth also seemed
to play important roles. Neither of the Danish studies defined
newborn jaundice by severity of hyperbilirubinemia or the
TSB thresholds for interventions. Though curious, these data
are not suggestive or conclusive of a causal association be-
tween newborn jaundice and autism.
Conclusions
Our review supports the hypothesis that regardless of the
cause for jaundice, there is a risk of neonatal bilirubin neu-
rotoxic sequelae that ranges from irreversible permanent in-
jury to subtle multisensory and learning impairments during
infancy and childhood. Confounding effects of prematurity,
hemolysis, altered bilirubin-albumin binding, severity of bil-
irubin exposure and the individual vulnerability of the infant
contribute to the spectrum of clinical manifestations to be
designated as a syndrome of BIND. The cumulative evidence
thus far of moderate hyperbilirubinemia and its relationship
to subtle processing disorders and specifically, learning dis-
abilities, autism spectrum disorder, ADHD, and nonprogres-
sive developmental delay, is circumspect but of significant
concern. Prospective studies are needed to better understand
the unique vulnerability of an infant to mild or moderate
hyperbilirubinemia and track the long-term childhood out-
112
come of these specific neonatal environmental experiences.
Because the irreversible neonatal injury is preventable but
not treatable, the clinical focus remains rooted to a preventive
approach. The 2004 American Academy of Pediatrics Guide-
lines and its recent update have addressed the management
of moderate hyperbilirubinemia by providing specific biliru-
bin thresholds for interventions. Prospective identification of
biological risk factors for the syndrome of BIND, with use of
diagnostic prenatal and neonatal technologies, would permit
more target-specific prevention or treatment approaches.
Acknowledgments
The work for this research was supported by NIH grants
NB-05138, NB-04828, McR-420022, the Hartford Foun-
dation, the Pennsylvania Hospital Kernicterus Fund and
by the Sandy Eglin Fund which supported initiation of the
Pilot Kernicterus Registry at Pennsylvania Hospital, Phil-
adelphia, PA.
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