J.

Arab Neonatal Forum 2005; 2: 12-24

Kernicterus: A Preventable Neonatal Brain Injury

1
Vinod K. Bhutani, and 2Lois Johnson
1
Department of Neonatal-Developmental Medicine, Department of Pediatrics, Lucile Packard Children’s Hospital,
Stanford University, Stanford, CA; 2Department of Pediatrics, Pennsylvania Hospital, University of Pennsylvania School
of Medicine, Philadelphia, PA

Key Words: kernicterus, bilirubin induced neurologic dysfunction, neonatal hyperbilirubinemia, newborn jaundice

Summary
Kernicterus, one of the most easily preventable causes of brain injury from severe neonatal jaundice, has re-emerged in
the United States and other nations with well developed healthcare systems as a public and societal health concern.
Kernicterus, in its usually recognized form, causes devastating disabilities including athetoid cerebral palsy (CP) and
speech and hearing impairment. It represents the severe manifestation of bilirubin induced neurologic dysfunction
(BIND) syndrome. This condition not only ranks amongst the highest cost per new case (according to the Center of
Disease Control’s Financial Burden of Disability study in 1992), but also results in profound and uncompromising grief
for the family and loss to siblings of healthy, talkative playmates. And for the child with kernicterus (usually remarkably
intelligent, but trapped in an uncontrollable body), grief and frustration are enormous. In 2001 national healthcare
organizations, including Centers for Disease Control (CDC), the Joint Commission for the Accreditation of Healthcare
Organizations (JACHO) and the American Academy of Pediatrics (AAP) issued alerts to all accredited hospitals and
public health professionals in the United States and affiliated organizations that all healthy infants are at potential risk of
kernicterus if their newborn jaundice is unmonitored and inadequately treated. Evidentiary analysis of 125 cases, from an
informal Pilot Kernicterus Registry, documents that unmonitored or inadequately treated severe hyperbilirubinemia
results in kernicterus in otherwise healthy term and near term infants. On the basis of this empirical evidence, the lapses
in care and root causes have been associated with the occurrence of kernicterus in these infants. The re-emergence of
kernicterus in the United States is the result of interacting phenomena including a) early hospital discharge (before extent
of jaundice is known and signs of impending brain damage have appeared); b) lack of adequate concern for the risks of
severe jaundice in healthy term and near term newborns; c) an increase in breast feeding without adequate instruction,
monitoring and support; d) medical care cost constraints leading to early discharge with loss of supervision; e) paucity
of educational materials to enable parents to participate in safeguarding their newborns; and f) limitations within the
healthcare systems to provide continuity of care. 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 with excessive hyperbilirubinemia. 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.

Introduction Furthermore, adherence by clinicians to the guidelines

Kernicterus incidence has not been measured as a clinical
or public health index even though it has long been
recognized as the pathologic sequela of severe
hyperbilirubinemia. Although the condition is uncommon,
the consequences are tragic, especially when it affects
otherwise healthy term and near term infants.1-3
Kernicterus has become uncommon because of effective
screening for and prevention of Rh incompatibility, a
historically important cause, and the accessibility of
phototherapy to treat hyperbilirubinemia due to increased
production and/or decreased elimination of bilirubin.
___________________________________
Contact Address: Vinod K Bhutani, MD. , 750 Welch
Rd. #315, Stanford, California, 94305-5731 Voice: (650)
723-5711Fax: (650) 725-8351,
Email: bhutani@stanford.edu
from the American Academy of Pediatrics (AAP)
concerning management of neonatal jaundice was
expected to eliminate severe hyperbilirubinemia and
prevent kernicterus.4 Little contemporary information is
available on the incidence or prevalence of kernicterus or
its consequences. However, anecdotal cases continued to
be seen by practicing pediatricians and neurologists and
cumulative occurrence is not recorded as a matter of
public record or medical literature. That kernicterus
occurs in otherwise healthy infants is evident from 125
cases of infants who had been discharged as healthy from
their birthing hospitals and who were voluntarily reported
to the Pilot Kernicterus Registry from 1992 to 2002.5,6
However, no cases of kernicterus in infants with cerebral
palsy were found in the retrospective database of the
Northern California Kaiser Permanente Medical Care
Program (KPMCP) during a similar time period (1991 to

12

1998).7 In addition, among 111,009 infants in the KPMCP
database, 11 (0.01%) developed total serum bilirubin
(TSB) levels ≥30mg/dL (when measured), and none
apparently developed kernicterus.8 On the other hand, a
Danish population-based study reports 6 cases of
kernicterus over a duration of 5 years for an estimated
incidence of 1:38,000 well-babies cared for in Danish
nurseries.9
Pediatricians who have managed babies with neonatal
hyperbilirubinemia that progress to acute or chronic
bilirubin encephalopathy often feel stigmatized and are
disinclined to report, discuss, review or publish their
experience. Thus, the scope of the true incidences of overt
kernicterus as well as possible “subtle” neurological
deficits cannot be ascertained without an innovative and
non-adversarial investigative approach. There is a societal
expectation to provide a universally available safe
birthing experience that includes a safe experience with
newborn jaundice. Thus, kernicterus (or a TSB level >30
mg/dL) is now considered a “never-event” by the public
health community.10-14
This review focuses on the clinical definitions of BIND,
its relationship with hyperbilirubinemia, bilirubin/albumin
ratio and with a specific focus on G6PD deficiency-
related neonatal hyperbilirubinemia. In addition, the
article briefly addresses the role of a systems strategy for
a safer experience with newborn jaundice and the
potential role of chemoprevention.
A. Bilirubin Induced Neurologic Dysfunction
1. Determinants of Neuronal Injury by Bilirubin
The risk of neuronal injury by bilirubin is primarily
determined by the concentration of unbound or “free”
unconjugated bilirubin (Bf) and hydrogen ion (pH) in
blood. Bf can be measured indirectly or estimated by
calculating the molar ratio of total serum bilirubin (TSB)
to albumin. Bilirubin enters brain tissue as Bf when the
blood binding capacity is exceeded, or when other
displacing substances, such as sulphonamides, compete
for bilirubin binding sites on albumin.15 Other important
risk factors for kernicterus relate to neuronal
susceptibility, including gestational age, infection or
sepsis, and hemolysis, especially Rh disease. Sepsis or
other neonatal inflammatory conditions and prematurity
may decrease the bilirubin binding affinity of albumin.
Even though a "safe" level of bilirubin has not yet been
determined, most of the circulatory bilirubin is bound to
albumin which acts as a “neuro-protective”. The blood-
brain-barrier has long been considered to play a role in
protection of the brain from bilirubin toxicity, and its
disruption produces diffuse yellow staining but not the
specific pattern of kernicterus.16 Whether the blood brain
Kernicterus: A Preventable Neonatal Brain Injury
barrier acts as a pump through ATP-dependent export by
transporter molecules to remove Bf from the brain and
maintain the concentration gradient of bilirubin from
plasma to CSF has yet to be determined, though ATP-
dependent export by transporter molecules has been
suggested.17-19
Another important determinant of toxicity is neuronal
susceptibility. Shapiro et al examined cerebella of
jaundiced Gunn rats made toxic at various developmental
ages and found that neurons undergoing differentiation at
the time of exposure were the most susceptible to cell
death, while those that were slightly more or less mature
showed only transient changes or seemed to be much less
sensitive.19 This supported the presence of a critical or
sensitive period when elevated bilirubin could be most
toxic to neuronal development.
Bilirubin can cause neuronal necrosis, and there is now
good evidence in vitro that it induces apoptosis, which
supports in vivo observations in older literature showing
neuroanatomical changes consistent with apoptosis.
Evidence also suggests that bilirubin interferes with
intracellular calcium homeostasis by altering function and
expression of calcium/calmodulin kinase II, by selectively
decreasing calcium binding proteins in susceptible
brainstem areas and increasing intracellular calcium in
cultured neurons, and by sensitizing the cell to other
injuries or triggering apoptosis. Bilirubin may also kill
cells by causing neuronal hyperexcitability perhaps via
excitatory amino acid neurotoxicity, or it may have other
membrane of neurotransmitter effects. Finally, it may act
by interfering with mitochondrial respiration and energy
production, perhaps as an oxidant injury.20-23
Overall, it is hypothesized that bilirubin damages brain
tissue cells via necrosis and apoptosis, either alone or in
combination, in a neuro-anatomical distribution
dependant on the amount, duration, and the
developmental timing of exposure of sensitive brain tissue
to free bilirubin. With this perspective, the neuro-
anatomical and clinical expression of injury is likely to be
complex with different patterns of damage and a range of
clinical expression. Different patterns of expression may
relate to 1) the amount of, and duration of exposure to
free bilirubin (high level, short duration exposure not
necessarily the same as lower level, long duration
exposure), 2) the susceptibility of the developing CNS, 3)
the relative amount of necrosis vs. apoptosis produced,
and 4) whether surviving neurons will be functionally
normal or more susceptible to other stressors either at the
time of hyperbilirubinemia or afterwards.
2. Neuropathology of Kernicterus
Kernicterus causes selective yellow staining in the basal
13
J. Arab Neonatal Forum 2005; 2: 12-24

ganglia, especially the globus pallidus and subthalamic Table I: Root Causes for Reemergence of Kernicterus
[adapted from JCAHO Sentinel Alert (11) and Johnson et al (5)]
nucleus. Brainstem nuclei, especially the auditory
(cochlear nucleus, inferior colliculus, superior olivary System Failure Major Root Causes for Reemergence of
complex), oculomotor and vestibular nuclei are especially Kernicterus
vulnerable. Other vulnerable areas include the cerebellum, Institutional Early hospital discharge (before extent of
Purkinje cells, and the hippocampus (especially the CA2 jaundice is known and signs of impending
brain damage have appeared)
sector). The basal ganglia are associated with the Structural limitations within the
movement disorders of dystonia, athetosis and healthcare systems to deal with continuity
choreoathetosis. Abnormalities of the auditory brainstem of mother-infant care after birthing.
nuclei are associated with deafness, hearing loss, and a Providers Lack of adequate concern for the risks of
severe jaundice in healthy term and near
recently described entity known as auditory neuropathy. term newborns
Abnormalities of the brainstem oculomotor nuclei are Medical care cost constraints with early
associated with strabismus and gaze palsies, especially discharge and limited access to healthcare
paresis of upgaze.1-3 In the auditory system, bilirubin does during the first week after birth
Family and Societal A lauded increase in breast feeding but
not appear to affect either inner or outer hair cells, but unsupported by optimal lactation
appears to be toxic to cell bodies of the auditory nerve in counseling to instruct, monitor and guide.
the spiral ganglia. Brainstem auditory nuclei and not the Paucity of educational materials to enable
pathways are particularly susceptible.24,25 The optimum parents to participate in safeguarding their
newborns
means of assessment is neuro-physiological since this
component of the auditory system cannot be imaged. Table II: Bilirubin-induced neurological dysfunction (BIND)
Neuro-physiological assessment involves the evaluation Score (adapted from Johnson et al (31)
of the mechanical structure of the inner ear by otoacoustic
emissions (OAE), and the outer hair cells (inner ear) by Severity Score Mental Date/ Date/ Date/
Status Time Time Time
cochlear microphonic responses (CM). In infants with None 0 Normal
kernicterus, these are both normal. Sensori-neural Mild 1 Sleepy, poor
assessment requires the testing of auditory brainstem feeding
response (ABR) or brainstem auditory evoked potential Moderate 2 Lethargic,
Irritable
(BAEP). In bilirubin-related injury, it is absent or
Severe 3 Semicoma,
abnormal and reflects damage to the auditory nerve (wave Seizures
I) as well as the auditory brainstem nuclei (waves III and Coma
V). Severity Score Muscle Tone
None 0 Normal
Mild 1 Neck
The basal ganglia lesions can be imaged with magnetic Stiffness,
resonance imaging (MRI), the signature of which is Mild hyper-
bilateral damage of the globus pallidus. The subthalamic /hypotonia
nuclei can sometimes be seen and are characteristically Moderate 2 Arching
neck,
affected. Disordered outputs from the basal ganglia are retrocolis,
possibly responsible for the dyskinetic movements. The Arching
MRI evidence of kernicterus is distinct from that of trunk
hypoxia-ischemia; in the latter, the thalamus, cortex and Severe 3 Bowing of
trunk
peri-ventricular white matter are involved; while, the Opisthotonus
caudate nuclei and putamen are not affected in Severity Score Cry pattern
kernicterus.26 None 0 Normal
Mild 1 High pitched
Moderate 2 Shrill
Severe 3 Inconsolable
3. Clinical Definitions of Bilirubin Induced Neurologic Total Bind Score
Dysfunction Nurse/MD signature

Kernicterus has usually referred to the post-mortem
evidence of icteric (yellow) staining of the basal ganglia
and lesions of the extra-pyramidal nervous system. The
Pilot Registry has offered formal clinical definitions of
BIND and Kernicterus (Table I). The spectrum of acute
and chronic manifestations of BIND varies from the acute
stage bilirubin encephalopathy to those of chronic
sequelae such as isolated auditory neuropathy ( a form of
Score of 7 to 9: represent severe acute bilirubin encephalopathy;
urgent interventions are recommended to possibly minimize further
brain injury.
Scores of 4 to 6: Represent moderate acute bilirubin encephalopathy
and is likely to be reversible with urgent bilirubin reduction.
Scores of 1 to 3: Represent mild acute bilirubin encephalopathy and
are usually reversible with urgent bilirubin reduction strategies. An
abnormal ABR or “referred” automated ABR would indicative of
BIND would be suggestive of moderate to severe ABE

14
 Kernicterus: A Preventable Neonatal Brain Injury

Table III: Clinical classification of Kernicterus (as proposed by Shapiro SM35)

Classification Clinical
Classic Kernicterus Have ? 3 classic signs of kernicterus including : 1) Auditory (AN, hearing loss), 2)Motor
(hyperkinetic dystonia or athetosis, choreoathetosis, “athetoid” CP, 3) oculomotor disorder
esp. impairment of upgaze, 4) dental enamel dysplasia.
Mixed kernicterus Auditory predominant: moderate of severe AN ± hearing loss with mild motor symptoms
or (hypotonia, mildly delayed walking, slightly abnormal muscle tone), normal or slightly
Location BIND abnormal GP (Signals) or MRI
Isolated Kernicterus Has signs and symptoms limited to only one system, either the auditory or motor system.
or BIND Most cases of isolated kernicterus have turned out to be not strictly isolated, but have findings
in another system on close examination

Auditory Symptoms Motor Symptoms

Mild Mild AN (ABR abnormal but present, may Mild dystonia ± athetosis; mild gross motor delays
normalize) eg. Walking; ambulates well, speech intelligible

Moderate AN with absent or persistent abnormal ABR, Moderate hyperkinetic dystonia/ “athetoid”
Severity Mild/moderate hearing loss, may fluctuate; CP; ambulates with or without assistance with
speech delayed or absent athetoid/ choreoathetoid gait
Severe AN with absent ABR, severe-to-profound Severe dystonia/hyperkinetic CP; unable to
hearing loss/ deafness ambulate, feed self, sign, speak; often with episodic
severe hyper-tonial/spasticity, cramps

Timing
Acute First few days or weeks of life, at the time of
Time unconjugated bilirubin neurotoxicity,
usually with excessive hyperbilirubinaemia
but may have low bilirubin with displacers.
Rarely may occur in older children and
adults, eg with Crigler-Najjar syndrome or
severe hepatic failure, but always with acute
unconjugated bilirubin neurotoxicity.
Subacute In the days or weeks after bilirubin
neurotoxicity, eg after treatment with
exchange transfusion or phototherapy the
natural decline in bilirubin
Chronic Months, years, decades
Symptoms
In infants: lethargy, variable hypotonia ±
hypertonia, high pitched cry, arching,
retrocollis- opisthotonus, impaired upgaze,
fever, seizures, death
Similar to acute, but also may have feeding
and sleep disorders
Classical clinical kernicterus (movement
Disorder, auditory, oculomotor, dental) or
Subtle kernicterus/BIND

Table IV: Clinical definitions of Kernicterus severity

Signs Neuromotor Oculomotor Dental ABR MRI

Abnormal [with onset Sensori-neural Abnormal [if

Severe Abnormal Abnormal of dentition] hearing loss available]

All four abnormal signs are present and /or abnormal MRI
Moderate Abnormal Any two of three of these abnormal are present If unavailable

Mild Any two of these four signs are abnormal If unavailable

sensorineural hearing loss), and chronic bilirubin
encephalopathy of both neuromotor and auditory damage
(kernicterus). Though not yet proven, some experts
believe that there may be more neurological
manifestations of BIND including subtle basal ganglia
and central processing disorders.27-29 The effect of even
moderate increases in TSB levels on early development
remains a source of controversy, especially because some
clinical manifestations are reversible upon reduction of
the TSB concentration.
a. Acute Bilirubin Encephalopathy (ABE)
The actual incidence of ABE is not known because (a)
there have been no longitudinal surveillance studies of the
condition, (b) there is limited awareness and recognition
of this diagnosis in healthy babies and (c) the diagnosis is
usually not coded on discharge summaries (Table II).
However, recent case reports and registries suggest that
kernicterus has re-emerged as a public health problem
after years of near extinction.6,11-14 The introduction in the
1960’s of Rhogam to prevent Rh sensitization and
Figure 1: The Magnetic resonance image shows post-icteric
bilateral and increased T-2 weighted signals from the globus

15
J. Arab Neonatal Forum 2005; 2: 12-24
pallidus in an year old infant who previously manifested acute
bilirubin encephalopathy
erythroblastosis, and exchange transfusion and
phototherapy to treat hyperbilirubinemia, virtually
eradicated kernicterus, which had accounted for 6% of all
cases of cerebral palsy seen in large clinics in the early
1950’s. Thus, for the 20 years prior to 1991, there were no
published reports of kernicterus in healthy full term
infants. The recent cases, during the early and mid 1990s,
coincided with trends towards earlier post-partum
discharge (before jaundice is clinically evident or reaches
its peak) and decreased concern about the toxic potential
of bilirubin. The most troubling feature of these reports
was that, contrary to popular belief, many of the affected
infants had been otherwise well, term newborns without
evidence of hemolytic disease.6,30
Clinical Signs
The classic signs of acute bilirubin encephalopathy in the
severely hyperbilirubinemic term infants include
increasing hypertonia, especially of extensor muscles,
with retrocolis, opisthotonus, in association with varying
degrees of drowsiness, poor feeding, hypotonia, and
alternating tone. The early presenting signs and symptoms
of ABE can be described in terms of the infant’s mental
status, muscle tone, and cry; these progress as the injury
worsens (Table III). Because an accurate and reliable
scoring system is needed to characterize the phases and
progression of ABE and to determine prognosis, this
schema for grading the severity of ABE has been
developed as a clinical tool (Table IV).31
The presenting signs of ABE are subtle, non-specific and
should be elicited by direct questioning from parent of a
severely hyperbilirubinemic neonate. During this phase
early and prompt interventions can prevent chronic
kernicteric sequelae.32 BIND abnormalities with
progression to scores between 4 and 6 are often reversible
with timely interventions. These signs include early
hypertonia and retrocolis, which increase in severity and
are usually accompanied by a shrill cry, an unexplained
irritability alternate with increasing lethargy. Advanced
signs are marked by 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. Acute stage
mortality is due to respiratory failure and progressive
coma or intractable seizures. Rate of progression of
clinical signs depends on the rate of bilirubin rise,
duration of hyperbilirubinemia, host-susceptibility and
presence of co-morbidities.
b. Post-Icteric Sequelae: Chronic Bilirubin
Encephalopathy
Chronic, irreversible bilirubin encephalopathy has
variable presentations and may include extra-pyramidal
movement disorders (dystonia and athetosis), gaze
abnormalities (especially upward gaze-figure 1), auditory
disturbances (especially sensori-neural hearing loss with
central processing disorders and / or auditory neuropathy),
and enamel dysplasia of the deciduous teeth.1-3 Cognitive
deficits are unusual but described as being occasionally
present and in the retarded range in earlier reports. Such
estimates probably reflected, for the most part, an
inability to accurately assess intelligence in children with
hearing, communication and coordination problems. The
neuromotor manifestations of extra-pyramidal damage are
present in almost all cases, but occasionally are apparent
only with repeated attempts at skilled movements.
B. Relationship of Total Serum Bilirubin Level to
Occurrence of ABE
There are no randomized clinical trials that demonstrate a
specific bilirubin level will or will not cause neuro-toxic
damage. The critical TSB level in any healthy baby is
likely to be influenced by postnatal age, maturity within
the range of term gestational age, duration of
hyperbilirubinemia and rate-of-TSB rise. Presence of co-
morbidities such as near-term gestation (35 to <38 weeks
gestation), hypoalbuminemia, disruption of the blood-
brain barrier (asphyxia or trauma), hemolysis
(intravascular or extravascular), factors that interfere with
albumin binding of bilirubin, infection, and hypoglycemia
predispose a newborn to BIND at lower TSB values. A
number of investigators, as noted by Poland, have
presented evidence that unbound or “free bilirubin” is an
appropriate predictor of neurotoxicity.33 At present there
are no commercial assays for albumin binding reserve or
unbound bilirubin in the US. Preliminary US and
Japanese studies have suggested that levels >0.86
microg/dL of unbound bilirubin are associated with an
increasing risk of BIND.34-36
16

The only prospective study that has shown an
association between TSB levels and occurrence of ABE
is that reported by Mollison and Cutbush in a 1954
follow-up report of babies with hyperbilirubinemia and
hypoalbuminemia due to Rh hemolytic disease.37 These
data are from over four decades ago and the sample size
is small (n=60) and applicable to babies with severe
hemolytic disease. However, an incremental
relationship of kernicterus to increasing levels of TSB
>19 mg/dl is apparent. Currently most US nurseries
discharge babies without screening for hemolysis other
than Rh disease. Though hemolysis screening could be
helpful, babies with pre-discharge high-risk
hyperbilirubinemia (>75th percentile for age in hours)
are as likely to have impaired bilirubin clearance due to
confounding genetic polymorphisms in the glucuronyl
transferase gene and / or delayed maturation of the
otherwise normal glucuronyl transferase enzyme
system. In the Pilot Kernicterus Registry,5 the causes
for kernicterus were attributed to three equivalent
categories (one-third each): hemolytic disorders (mostly
ABO isoimmunization), G6PD deficiency (associated
with both hemolysis and impaired bilirubin
conjugation) and idiopathic causes (presumably due to
delayed or impaired function of the glucuronyl
transferase enzyme system) coupled with breast-feeding
and inadequate nutritional intake. In such newborns
with TSB levels >75th percentile a rate of TSB rise
>0.20 mg/dl/hr will exceed the peak rate of rise
observed at the 95th percentile track on the bilirubin
nomogram and increase the bilirubin load.38 At these
rates of rise, the bilirubin load will increase to severe
hyperbilirubinemia and risk for BIND.
C. Relationship of Bilirubin to Albumin and Risk of
ABE
Albumin concentration is a powerful neuro-protective
agent as well as a major determinant of both bilirubin
Figure 2: An infant with early onset hyperbilirubinemia that was progressive, unresponsive to intensive
phototherapy. Following an exchange transfusion, the infant has had a normal neurologic outcome. Serial TSB
levels are plotted on an hour-specific bilirubin nomogram (38)
C a s e : M a le I n f a n t w ith G -6 -P D D e fic ie n c y
E x c h a n ge T ra n s fu s io n
30
Serum Bilirubin (mg/dl)
J a un dic e n ot e d
20
10
In te n s ive p h o t o t h er ap y
Kernicterus: A Preventable Neonatal Brain Injury
toxicity and level of unbound bilirubin in excessively
jaundiced babies. The integrity of binding (below the
1:1 molar ratio) is compromised in a newborn because
newborn albumin has a poor binding ability compared
to adult albumin. It is further compromised if a)
albumin binding affinity is markedly decreased with
concurrent prematurity, sickness or acidosis; b) protein
bound drugs compete for albumin binding sites. It is
further compromised for postnatal age < 72 hours, and
if the serum albumin level is lower than expected. In
severely hyperbilirubinemic but otherwise healthy
newborns (TSB levels >95th percentile and over 72
hours age) the bilirubin to albumin ratio is a useful tool
to define one’s “worry” and potential risk for BIND.39,40
For practical purposes, the B: A ratio can be expressed
in terms of mg of bilirubin to grams of albumin. A
bilirubin to albumin ratio of 7.0 in mg to grams
corresponds to a bilirubin to albumin molar ratio of
0.80. Exposure to bilirubin/albumin ratios of >7.0 (mg
to gram) carry a clear risk of irreversible neurotoxicity,
especially if such exposure is prolonged. Available
clinical and experimental data suggests that B: A ratios
of >5.3 and <7.0 mg/g (molar ratios of bilirubin to
albumin >0.63 and <0.80) are generally associated with
reversible abnormalities of auditory brainstem
responses.41-45 In a term newborn with subtle signs of
BIND these B: A ratio values can be reassuring as long
as the bilirubin load is vigorously reduced and signs of
progression are closely monitored.
D. G-6-PD deficiency, Neonatal Hyperbilirubinemia
and Kernicterus
G-6-PD deficiency is one of the commonest enzyme
deficiencies in humans and can present with hemolytic
crises in children and adults (favism) who ingest fava
beans or have exposure to stress of oxidants, drugs,
9 5 t h pe rc e n ti le
7 5 th p e rc e n ti le
4 0 t h p e rc e nt il e
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J. Arab Neonatal Forum 2005; 2: 12-24
infections and other chemical triggers.46 G-6-PD
deficiency is also associated with neonatal
hyperbilirubinemia though favism is unusual in infants.
The association with severe neonatal
hyperbilirubinemia with its potentially devastating
complication of kernicterus was made in Greece soon
after recognition of G-6-PD deficiency as an entity and
has subsequently been reported from many geographic
areas in which G-6-PD deficiency is found.47 The
incidence of neonatal hyperbilirubinemia has repeatedly
been shown to be several-fold greater in G-6-PD
deficient populations than in the G-6-PD normal
population.48,49 However, this incidence is not constant
and varies in different communities and geographic
areas and is related to numerous mutations. Functional
severe mutations may cause hemolysis in the absence of
stress. Different mutations are characteristic of Asian,
African, Southern Europe populations. Gourley linked
neonatal jaundice with Gilbert syndrome. Neonates
with the GS polymorphism have an increased rate of
TSB rise in the first two days after birth and a
predisposition to prolonged or severe neonatal
hyperbilirubinemia in infants with G-6-PD deficiency
or co-inherited with hematological abnormalities: a)
beta-thalassemia, b) hereditary spherocytosis and
certain forms of ABO incompatibility.50,51 Kaplan et al
have observed that infants with G-6-PD deficiency do
not have an increased incidence of hyperbilirubinemia
(compared to G-6-PD normals) unless they also carry
the UGT1A1 promoter polymorphism. Homozygotes
have significantly higher TSB levels than
hemizygotes.52
Two clinical manifestations of G-6-PD deficiency and
neonatal hyperbilirubinemia are described in clinical
practice: 1) severe jaundice resulting from acute
hemolysis, similar to favism; 2) jaundice and
hyperbilirubinemia of more gradual but progressive
onset. The frequency of either manifestation is not well
documented.
1. Acute and severe jaundice accompanied by sudden-
onset of hemolysis is unusual in neonates. In some
cases a known trigger of hemolysis can be identified
and results in rapidly rising serum total bilirubin (TSB)
levels. Maternal ingestion of fava beans can cause
severe intrauterine hemolysis presumably by
transplacental transmission of the fava metabolites. In
other cases transmission of metabolites to the nursing
infant via breast milk has been suggested. However,
severe hemolytic episodes can occur even when all
known offenders are scrupulously avoided. It is possible
that as yet unidentifiable chemical offenders may be
included in the vast array of cleaning or other
household materials available. Beutler has emphasized
infection as a possible inducer of hemolysis. These
severe hemolytic episodes [with clinical evidence of
hemolysis] can be unpredictable and there is frequently
no warning that acute hemolysis is about to occur. This
form of G-6-PD deficiency associated neonatal
hyperbilirubinemia may not be completely amenable to
prediction of hyperbilirubinemia or prevention of
kernicterus.53,54
2. Gradual onset jaundice with progressive neonatal
hyperbilirubinaemia. In contradistinction to the above,
significantly more G-6-PD deficient neonates develop
hyperbilirubinemia compared with controls. Gradual
onset jaundice with progressive neonatal
hyperbilirubinemia can be severe and is associated with
a slower increase in TSB concentrations than in those
with acute hemolysis. With intensive, modern day
phototherapy exchange transfusion is rarely necessary
with this variant of the hyperbilirubinemia. As these
babies are usually treated aggressively, the natural
history of the hyperbilirubinemia and consequently the
potential of extreme hyperbilirubinemia and the risk of
kernicterus are unknown in this subgroup. There is
some evidence that this form of jaundice has its origins
in utero: TSB values sampled immediately after birth
were higher than in controls and correlated with both
third day TSB values as well as with those who
subsequently developed hyperbilirubinemia, defined as
TSB value >15.0 mg/dL. Also, blood
carboxyhemoglobin and end tidal carbon monoxide and
representative of hemolysis, were higher in G-6-PD
deficient neonates than in controls shortly after birth.
The pathogenesis of hyperbilirubinemia in G-6-PD
deficient neonates appears to be different from G-6-PD
normal counterparts, greater emphasis being laid on the
role of bilirubin conjugation defects. Also important in
understanding of the pathogenesis hyperbilirubinemia is
the concept that the TSB at any point in time represents
bilirubin production on the one hand, and its
elimination from the body, on the other. As long as
equilibrium between these processes is maintained,
TSB concentrations should not exceed the physiologic
range. However, should bilirubin production exceed
the body’s capacity to eliminate it, hyperbilirubinemia
may develop. Severe hemolysis is not essential to the
mechanism of hyperbilirubinemia: moderately
increased heme catabolism in the face of diminished
bilirubin conjugation may be sufficient to tip the
balance. Because increased hemolysis does not appear
to play a major role in the patho-physiology of
hyperbilirubinemia, diminished bilirubin conjugation
has been emphasized by some as an important factor
[see Figure 2]. The current literature suggests that
insufficiency of bilirubin conjugation is the mechanism
of neonatal hyperbilirubinemia in infants with G-6-PD
deficiency.55-57
Pre-discharge hour-specific bilirubin screening can
identify many G-6-PD deficient neonates at high risk
for developing hyperbilirubinemia and facilitate
discharge and follow-up planning. Of those G-6-PD
deficient neonates with pre-discharge TSB value <50th
percentile on the hour-specific nomogram, the
incidence of developing a TSB >15.0 mg/dL was very
18

low, but increased progressively as pre-discharge TSB
values increased from the 50th to >90th percentile.
Additional population-based data are needed to better
describe and understand the predictive role of pre-
discharge hyperbilirubinemia as well as the natural
history of hyperbilirubinemia in both homozygous and
heterozygous neonates with G-6-PD deficiency.58
E. A systems-approach for a safer management of
newborn jaundice
The rationale to update “bilirubin guidelines” such as
the 1994 AAP guidelines59 are based on new data
related to newborn safety, that jaundice is an unreliable
indicator for severity of hyperbilirubinemia, the
predictive abilities of pre-discharge screening for
subsequent severe hyperbilirubinemia is weak and there
is a need for lowered bilirubin level thresholds for
interventions.60-62 These studies have provided an
opportunity for restructuring to a more physician
friendly instrument and enhancing its acceptance for
wider implementation. The purpose of the guidelines is
to ensure that clear criteria for patient safety, family
centeredness, and precise, practical, user-friendly,
preventive approaches and for timely interventions, are
met.63 Barriers to seamless transition from birth to home
have been recognized to compound the risk for
hyperbilirubinemia.64-66 Four clinical entities that add to
inefficient continuity of care include 1) early discharge
(<72 hours age) without timely follow-up, 2) inadequate
lactation support, 3) undue reliance on the visual
assessment of jaundice to initiate evaluation, and 4)
lack of data to define persistence of jaundice, including
the potential for unrecognized cholestatic jaundice.
1. Early discharge and multiple providers at multiple
sites (problems with “hand-off”). Early discharge
shifted the locus of care from the hospital to home and
created a need for post discharge observation, a change
in venue for patient and family education, and gaps in
communication. Furthermore, follow-up appointments
after hospital discharge are often scheduled after the
anticipated peak of serum bilirubin concentration.
Systems are limited to facilitate sharing of clinical data
among multiple clinical providers at multiple sites such
as between the birth hospital and the paediatric office.
New parents may have difficulty arranging for a
clinician to check their child after discharge. Flawed
interactions between many different parties perpetuate
the problems. To ensure a safe first week after birth for
all newborns requires broad changes in the processes of
care.
2. Inefficient lactation counseling. A clinical diagnosis
of jaundice may lead to disruption of breastfeeding
rather than implementation of steps that would enhance
breast milk intake. Although breast milk is the most
appropriate feeding for newborns, exclusive breast
feeding, especially if it is not going well, is a major risk
factor for hyperbilirubinemia. However, no quantitative
data are available to document either the incidence of
Kernicterus: A Preventable Neonatal Brain Injury
lactation failure leading to adverse hyperbilirubinemia
outcomes or the incidence of lactation disruption
associated with management of hyperbilirubinemia.
3. Undue reliance on visual assessment of jaundice.
The AAP guideline cautions on the reliance of visual
estimation of jaundice. However, the inaccuracy of
visual assessment of jaundice may not be widely
appreciated.
4. Persistent hyperbilirubinemia. The incidence of
persistent indirect hyperbilirubinemia (age >2 weeks),
especially in breastfed infants, and its possible sequelae
are not known. In addition, clinical distinction of benign
persistent jaundice from cholestasis is often difficult.
Cholestasis, which occurs in approximately 1:2500 live
births, can be a manifestation of more than 70 different
diseases, biliary atresia being the most common.67,68
Factors contributing to delayed referral of infants with
biliary atresia include lack of follow-up of neonatal
jaundice and misdiagnosis of breast milk jaundice.
Early diagnosis of biliary atresia is crucial for a
successful surgical outcome but has no linkage with
kernicterus. It is to be noted the 2004 AAP guidelines
strongly recommends that a clinician should not
subtract the direct bilirubin value from the total serum
bilirubin value for clinical decisions, especially for
administration of phototherapy or exchange
transfusion.69
Since clear evidence for a course of action has been
absent, we have recommended an approach that
guarantees patient safety pending the “gathering” of
evidence. Structural changes that would facilitate such a
system-based approach should include a) pre-discharge
bilirubin management; b) follow-up bilirubin
management; and, c) lactational support and nutritional
management. Currently there are two major pre-
discharge screening strategies that are amenable to a
system-based approach: i) pre-discharge total serum
bilirubin screening and ii) a scoring system based on
clinical risk factors. With either approach there should
be no room for error and a wide margin of safety to
prevent the need for a “crash cart” approach for babies
with excessive hyperbilirubinemia. On the basis of
available evidence, we should screen all babies for
hyperbilirubinemia for targeted follow-up that is based
on an hour-specific TSB measured for risk assessment.
In addition, we should provide focused universal
education with an emphasis on supporting adequate
lactational nutrition to decrease severe
hyperbilirubinemia and thus prevent kernicterus.70
F. Role of Chemoprevention
Chemoprevention of hyperbilirubinemia by
pharmacological agents to effectively reduce adverse
bilirubin loads has been studied for several years and
recently reviewed by Dennery.71 The proven available
options for pharmacotherapy include drug-induced
acceleration of bilirubin excretion (such as use of
19
J. Arab Neonatal Forum 2005; 2: 12-24
Phenobarbital) and alteration of bilirubin production by
synthetic heme analogues that act as competitive
inhibitors for heme catabolism (such as tin
mesoporphyrin). In view of patient safety concerns
from unmonitored adverse effects related to severe
hyperbilirubinemia, the role of chemoprevention in
infants at risk for severe hyperbilirubinemia is being
investigated. Phenobarbital increases hepatic clearance
and excretion, and may be administered prenatally.71,72
It is effective when administered 1 week prior to
delivery and when given to newborn infants. However,
this intervention has limited or no clinical effect when
administered to infants <32 weeks of gestation and has
now been shown to be ineffective when given prior to
12 hours of age. The adverse effects of this therapy are
of concern. These are sedation, risk of hemorrhagic
disease, and potential for addiction. This drug has a
slow onset of effect (usually several days) and a long
duration of action (one to two weeks) after its
discontinuation. In addition, its confounding effects on
other hormones and concerns of drug safety have
limited the clinical value of phenobarbital as a
chemopreventive agent for newborn jaundice.
Newer chemopreventive strategies have included
investigations of a number of synthetic heme analogues
that are protoporphyrin derivatives of tin, zinc,
manganese, chromium, and cobalt.73 Overall,
metalloporphyrins (MePs) reduce bilirubin production,
can be phototoxic and may increase transcription of
HO-1, the inducible HO isozyme. Effective
development of this class of compounds has been in the
direction of products that are less phototoxic and are
stronger inhibitors of heme oxygenase. A number of
MePs have been evaluated experimentally with
variations of the pertinent metal (such as tin, zinc,
chromium) and porphyrin (protoporphyrin,
mesoporphyrin, bisglycol porphyrin, etc). Our
understanding of the molecular basis of heme
oxygenase inhibition is evolving as new heme
oxygenase isoenzymes are characterized in different
organs. The significance of prolonged and potent, long-
lasting inhibition of heme oxygenase needs to be
differentiated from a single, acute and transient
inhibition. The inherent appeal of naturally occurring
molecules, such as zinc, has been questioned by the
finding of deleterious effects on rabbit bone marrow
erythroid and myeloid cells and by lethal consequences
of chromium mesoporphyrin injection in animals. Thus
far, the stannic porphyrins, in particular tin
protoporphyrin and tin mesoporphyrin have been
extensively investigated and found to be safe and
effective in preclinical studies. With the successful
completion of nearly two decades of extensive clinical
pharmacological and toxicological studies, as recently
summarized by Kappas,74 stannate, an effective MeP,
has demonstrated its therapeutic ability to safely reduce
bilirubin production through competitive inhibition of
heme-oxygenase, the rate-limiting enzyme in heme
catabolic sequence. Its chemopreventive role is being
investigated and evaluated in infants at risk for severe
hyperbilirubinemia.
Other strategies that warrant further investigations and
clinical trials are use of agents that interrupt the entero-
hepatic circulation and bilirubin accumulation from the
continued action of beta-glucuronidase.
Chemoprevention with use of casein supplements75 or
other agents such as L-aspartic acid could decrease
intestinal reabsorption of bilirubin and may have a
potential clinical role.76
G. Global Perspective of Jaundice and Kernicterus.
Kernicterus is still thought of by many as a condition
that occurs primarily in underdeveloped countries. As
the JCAHO root cause list suggests, the safety net
protecting newborns has significant deficits. Most
families learn about potential problems related to
newborn care during childbirth education classes.
Unfortunately, the lack of concern about jaundice
among health care providers has led to a major lacuna
in childbirth education curricula.77 The teaching and
discussion of jaundice, impact of early discharge, and
breast-feeding have been minimal or non-existent. The
role of family and community in prevention of BIND
and Kernicterus is an integral component of any public
health strategy.78 Since this condition is not yet a
“notifiable” disease, there is an urgent need for a
tightening of the “safety net” and reaching all families
and health-care workers to supplement existing
information and expedite change in current practices for
assessing and effectively treating hyperbilirubinemia.
Kernicterus is frequent and less preventable in countries
with poor access to healthcare (for example: South
Asia, and Africa), those with high-risk populations
(Middle-East, as well as North African and South
African nations) and countries who are rapidly
improving their healthcare systems to contemporary
standards (Eastern Europe and Latin America).
In conclusion, Kernicterus ranks as a major cause for
infant mortality and morbidity in developing countries
but not considered as serious as birth asphyxia, sepsis,
malnutrition and prematurity. However, it is the only
neonatal condition for which safe, inexpensive and
effective clinical strategies are easily available. Cost-
effective bilirubin reduction strategies such as
promotion of breast feeding, universal availability of
safe and effective phototherapy as well as
chemoprevention need to be targeted to infants at risk
while ensuring patient safety and universal access.
Global eradication of kernicterus, through a national
public health agenda, is feasible and practical. It is
essential to a society that aspires for every family and
their newborn to have a safer experience with newborn
jaundice.
Acknowledgement: Preliminary paper presented at the
“Hot Topics in Newborn Care”, Jeddah, Saudi Arabia,
February, 2005 (Convener: Dr. Mai-Seoud).
20

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23