Background

The term kernicterus literally means "yellow kern," with kern indicating the most commonly
afflicted region of the brain (ie, the nuclear region). Historically, the term refers to an
anatomic diagnosis made at autopsy based on a characteristic pattern of staining found in
babies who had marked hyperbilirubinemia before they died.
Hervieux first described the condition in 1847, and Schmorl first used the term kernicterus as
early as 1903. Regions most commonly affected include the basal ganglia; hippocampus;
geniculate bodies; and cranial nerve nuclei, such as the oculomotor, vestibular, and cochlear.
The cerebellum can also be affected. Bilirubin-induced neurologic dysfunction (BIND) refers
to the clinical signs associated with bilirubin toxicity (ie, hypotonia followed by hypertonia
and/or opisthotonus or retrocollis) and is typically divided into acute and chronic phases. The
2 terms are commonly used interchangeably, but this use is not technically accurate because
one refers to clinical manifestations and the other to an anatomic diagnosis.
Conventional wisdom characterizes kernicterus as prevalent in the 1950s and 1960s, virtually
eradicated in the 1970s and 1980s, only to reappear during the 1990s. It was speculated that
early discharge of term infants (before their serum bilirubin concentration peaks) could be a
factor in the reemergence of this devastating neurologic affliction, and medical research
focused on developing surveillance and treatment paradigms to eliminate the condition.
Whereas it is undeniable that kernicterus remains a cause of major neurologic morbidity in
the infant population, population studies of children born in California between 1988 and
1997 suggest the prevalence of kernicterus has remained virtually unchanged since 1980.[1]
Much of the traditional teaching regarding hyperbilirubinemia is now being questioned as
more is learned about bilirubin metabolism and neurologic injury. Kernicterus is now
recognized in the premature infant and, very rarely, in the term infant in the absence of
profound hyperbilirubinemia[2] ; however, other problems (eg, acidosis or infection) are
present in term infants without profound hyperbilirubinemia. Conversely, physiologic
jaundice (sometimes to levels previously thought to be universally dangerous) has been
recognized to be within the reference range in the first week of life in healthy term babies,
particularly those who are breastfed. Jaundice of this type usually spontaneously resolves
without sequelae.
Despite the lack of a clear-cut cause-and-effect relationship between kernicterus and the
degree of hyperbilirubinemia, laboratory investigations have demonstrated that bilirubin is
neurotoxic at a cellular level. Other in vitro studies have shown bilirubin to have more
antioxidant capability than vitamin E, which is commonly assumed to be the most potent
antioxidant in the human system.[3] This possible role of bilirubin in early protection against
oxidative injury, coupled with identification of multiple neonatal mechanisms to preserve and
potentiate bilirubin production, has led to speculation about an as-yet-unrecognized beneficial
role for bilirubin in the human neonate.

Pathophysiology
Bilirubin staining can be noted on autopsy of fresh specimens in the regions of the basal
ganglia, hippocampus, substantia nigra, and brainstem nuclei. Such staining can occur in the

absence of severe hyperbilirubinemia; in this situation, factors influencing permeability of the

blood-brain barrier (eg, acidosis, infection) and the amount of unbound (versus albuminbound) bilirubin may play a role.
Characteristic patterns of neuronal necrosis leading to the clinical findings consistent with
chronic bilirubin encephalopathy are also essential in the pathophysiology of this entity.
Bilirubin staining of the brain without accompanying neuronal necrosis can be observed in
babies who did not demonstrate clinical signs of bilirubin encephalopathy but who
succumbed from other causes. This staining is thought to be a secondary phenomenon,
dissimilar from the staining associated with kernicterus.
Improved brain imaging modalities, such as MRI and ultrasonography, may be emerging as
instrumental tools to help clarify the complex picture of kernicterus in contrast with
asymptomatic bilirubin staining of brain tissues. Bilirubin staining has been suggested to be
visualized on MRI as an increased signal in the posteromedial aspect of the globus pallidus.
Despite its theoretical value, however, efforts to use cranial imaging in the clinical setting
have remained unsatisfying. A 2008 case series by Gkoltsiou et al reported the inexplicable
conclusion that, while all children with severe cerebral palsy and a history of
hyperbilirubinemia had abnormal central grey matter on later scans, the characteristic central
grey matter MRI features of kernicterus were not seen in early scans.[4]

Epidemiology
Frequency
United States
The exact incidence of kernicterus is unknown. A pilot kernicterus registry monitoring the
cases of babies with kernicterus in the United States who have been voluntarily reported
shows 125 babies with chronic kernicterus enrolled in the registry from 1984-2002.[5, 6] All but
4 babies reported in the registry had been discharged from the hospital fewer than 72 hours
after birth (97%). Five babies were born at home (4%). No sequelae were identified in 9 of
115 infants, and 1 was lost to follow-up.
International
In Denmark, 8 cases of kernicterus were reported from 1994-2002[7] , whereas no cases had
been reported for the preceding 20 years[8] . Following this report, from 2002-2005, a more
vigilant approach was taken to the management of newborn jaundice, and no more cases have
been reported in Denmark.[9] These combined data result in an overall incidence of kernicterus
in Denmark of 1.1 in 100,000 live births from 1994-2005.
In June 2003, The Quarterly Bulletin of the Royal College of Paediatrics and Child Health
announced the commencement of a surveillance program of cases of severe neonatal
hyperbilirubinemia following anecdotal reports throughout Britain and Ireland of increasing
observation of kernicterus.[10] A 2004 UK surveillance study has reported kernicterus
occurring at a rate of 1 in 100,000 live births.

A Canadian survey published in 2004 assessed the frequency of extreme hyperbilirubinemia

(serum bilirubin >427 mol/L or >25 mg/dL) as 1:2,840 live births, of which 13 (2 in
100,000) had abnormal neurological outcomes at the time of discharge.[11]
Using these data, the risk of developing kernicterus in infants manifesting extreme
hyperbilirubinemia (>25 mg/dL) can be estimated across populations. In Canada, this risk
calculates to 1 in 17.6 infants, whereas in Denmark, the population risk is estimated as 1 in
16.2.[12] When the threshold of extreme hyperbilirubinemia is increased to >30 mg/dL (>513
mol/L), the risk of developing kernicterus increases to 1 in 5.5-7 live births, depending on
the reports. It should be noted that kernicterus also occurs in infants in whom bilirubin levels
remained < 25 mg/dL, and the population risk of this occurrence remains unknown.
Hispanic and Asian populations appear to have a greater propensity to develop
hyperbilirubinemia, although the underlying explanation for this observation remains elusive.
Genetic variants, such as Gilbert disease or G6PD deficiency that occur in sequestered
populations, result in geographic and/or ethnic differences in the risk and frequency of
kernicterus.

Mortality/Morbidity
Classic kernicterus has been defined in the term infant. Increasing experience with premature
babies indicates that the clinical presentation in premature infants may be somewhat different.
Identifying kernicterus as the specific cause of death in either the term or preterm infant may
be difficult because of concomitant ongoing pathologic conditions. Neurologic sequelae due
to bilirubin encephalopathy vary, and correctly attributing some of the long-term neurologic
deficits frequently associated with prematurity alone to kernicterus may be problematic.
Review of the 125 cases reported to the Pilot Registry by August 2004 revealed 26 patients
with underlying G-6-PD deficiency, 25 with hemolytic disorders, 18 with birth trauma
contributing to their hyperbilirubinemia, and 53 with idiopathic hyperbilirubinemia. Of these
patients, 30 were born at 35 to less than 37 weeks estimated gestational age (EGA), 24 at 37
weeks EGA, and 71 at greater than 37 weeks EGA.[13] (See the Gestational Age from
Estimated Date of Delivery calculator.) Gamaleldin et al, in an attempt to better predict the
development of bilirubin encephalopathy based serum total bilirubin levels, reviewed 249
newborns admitted to Cairo University Children's Hospital in a 12-month period with total
serum bilirubin levels greater than or equal to 25 mg/dL. Although the correlation between
total serum bilirubin and encephalopathy was poor, patients with hyperbilirubinemia resulting
from Rh incompatibilitydeveloped BIND at an odds ratio of 48.6 and those with sepsis an
odds ratio of 20.6 as compared with other etiologies.[14]
In the kernicterus registry mentioned above, 6 of 125 patients (4.8%) died.[13] Additional risk
factors for mortality included late prematurity, G6PD deficiency, and sepsis. The number of
patients who died from kernicterus without being reported to the registry is unknown, as is
the experience in countries other than the United States, especially those with a high
prevalence of hereditary hemolytic disorders. Of patients reported to the kernicterus registry,
111 of 119 survivors (93%) had severe sequelae due to BIND; 8 of 119 babies (6.7%) had no
discernible sequelae after age 1 year; one baby was lost to follow-up prior to 3 months of age.

Race

Among infants reported in the US kernicterus registry, 58% were white.[6] Asian and Hispanic
babies born either in their native countries or in the United States and Native American and
Eskimo infants have higher production levels of bilirubin than white infants. Black infants
have lower production levels (see image below). The reasons for these racial differences have
not been fully elucidated.

Typical patterns of total serum bilirubin levels in neonates of

different racial origins. Used with the permission of the Academy of Pediatrics.

Sex
Male infants have consistently higher levels of serum bilirubin than do female infants.
Among infants reported in the US kernicterus registry, 67% of the patients were male.[6]

Age
Acute bilirubin toxicity appears to occur in the first few days of life of the term infant.
Preterm infants may be at risk of toxicity for slightly longer than a few days. If injury has
occurred, the first phase of acute bilirubin encephalopathy appears within the first week of
life.
The pilot kernicterus registry data show that, of 122 infants (all >35 weeks' gestational age at
birth), symptoms became apparent in 13 babies (10.6%) aged 3.5 days or younger and in 66
babies (54%) aged 4-7 days.[13] In 36 babies (29.5%), symptoms did not appear until after the
first week of life. Most of these babies (76%) were term infants (at least 37 completed weeks'
gestation), and no infant was younger than 35 weeks' estimated gestational age. (See the
Gestational Age from Estimated Date of Delivery calculator.)

History
When assessing possible kernicterus, remember that a history of risk for hemolytic disease
can be an important clue to a neonate's increased risk of pathologic hyperbilirubinemia,
particularly Rh antigen incompatibility between mother and baby[14] . ABO incompatibility
and a family history of RBC abnormalities (ie, glucose-6-phosphate dehydrogenase
deficiency, hereditary spherocytosis) are also concerning. A review of neonatal readmissions
in Canada showed that, of 258 infants readmitted for severe hyperbilirubinemia from 20022004, 87 (34%) demonstrated one of these hematologic abnormalities.[15]
Certain cultural postnatal practices may also contribute to significant hyperbilirubinemia and
should be inquired about if culturally relevant. In the Middle East, Peker et al reported in
2010 a case series of 10 severely hypernatremic babies who also presented with kernicterus, 2
of whom died.[16] Of 112 postpartum women surveyed in Jordan Hospital, Amman, Jordan,
almost 50% of them admitted to "salting" their newborns as is the common custom. Women
doing this practice broadly represented all socioeconomic and educational strata.[17]
Conversely, if the baby is breastfeeding well and appears healthy and vigorous, this can be
reassuring. The mother may have breastfed previous babies who also developed significant
jaundice. If so, she may be one of the approximately 20-40% of women who have aboveaverage levels of beta-glucuronidase in their breast milk, which potentiates and prolongs
hyperbilirubinemia in their breastfed babies.

Physical
Bilirubin-induced neurologic dysfunction (BIND) is the term applied to the spectrum of
neurologic abnormalities associated with hyperbilirubinemia. It can be further divided into
characteristic signs and symptoms that appear in the early stages (acute) and those that evolve
over a prolonged period (chronic).

Acute bilirubin encephalopathy

The clinical features of this diagnosis have been well described and can be divided into 3
stages. Of babies with BIND, approximately 55-65% present with these features, 20-30%
may display some neurologic abnormalities, and approximately 15% have no neurologic
signs.

Phase 1 (first few days of life): Decreased alertness, hypotonia, and poor feeding are
the typical signs. Obviously, these are quite nonspecific and could easily be indicative
of a multitude of neonatal abnormalities. A high index of suspicion of possible BIND
at this stage that leads to prompt intervention can halt the progression of the illness,
significantly minimizing long-term sequelae. Of note, seizure is not typically
associated with acute bilirubin encephalopathy. Among infants reported in the US
kernicterus registry, the mean birth weight was 3281 g.[6]

Phase 2 (variable onset and duration): Hypertonia of the extensor muscles is a typical
sign. Patients present clinically with retrocollis (backward arching of the neck),
opisthotonus (backward arching of the back), or both. Infants who progress to this
phase develop long-term neurologic deficits.

Phase 3 (infants aged >1 wk): Hypotonia is a typical sign.

Chronic bilirubin encephalopathy

The clinical features of chronic bilirubin encephalopathy evolve slowly over the first several
years of life in the affected infant. The clinical features can be divided into phases; the first
phase occurs in the first year of life and consists of hypotonia, hyperreflexia, and delayed
acquisition of motor milestones. The tonic neck reflex can also be observed. In children older
than 1 year, the more familiar clinical features develop, which include abnormalities in the
extrapyramidal, visual, and auditory systems. Minor intellectual deficits can also occur.

Extrapyramidal abnormalities: Athetosis is the most common movement disorder

associated with chronic bilirubin encephalopathy, although chorea can also occur. The
upper extremities are usually more affected than the lower ones; bulbar functions can
also be impacted. The abnormalities result from damage to the basal ganglia, the
characteristic feature of chronic bilirubin encephalopathy.

Visual abnormalities: Ocular movements are affected, most commonly resulting in

upward gaze, although horizontal gaze abnormalities and gaze palsies can also be
observed. These deficits result from damage to the corresponding cranial nerve nuclei
in the brain stem.

Auditory abnormalities: Hearing abnormalities are the most consistent feature of

chronic bilirubin encephalopathy and can develop in patients who show none of the
other characteristic features. The most common abnormality is high-frequency
hearing loss, which can range from mild to severe. These deficits can result from
damage both to the cochlear nuclei in the brain stem and to the auditory nerve, which
appear to be exquisitely sensitive to the toxic effects of bilirubin, even at relatively
low levels. Clinically, this deficit can manifest as delayed language acquisition.
Hence, auditory function must be assessed early in any baby at risk for chronic
bilirubin encephalopathy.

Cognitive deficits: Cognitive function is relatively spared in chronic bilirubin

encephalopathy. However, individuals with chronic bilirubin encephalopathy are often
mistakenly considered to have mental retardation because of their choreoathetoid
movement disorders and hearing deficits. The clinician must emphasize that
intellectual functioning is not typically severely affected.

Abnormalities of dentition: Some degree of dental enamel hypoplasia can be observed

in about three quarters of patients with chronic bilirubin encephalopathy. A smaller
number of individuals develop green-stained teeth.

Causes
Familiarity with bilirubin metabolism leads to an understanding of the factors leading to an
increased risk of kernicterus (see image below). Bilirubin is produced during the catabolism
of the heme component of RBCs. Red cell destruction is usually increased in the immediate
neonatal period; it can be pathologically elevated in the presence of immune-mediated or
nonimmune-mediated hemolytic disease. The first enzyme in the catabolic cascade leading to

bilirubin is heme oxygenase. A constitutive form and an inducible form are recognized and
are induced by physiologic stressors. The creation of bilirubin, a potentially toxic waterinsoluble compound, from biliverdin, a nontoxic water-soluble substance, consumes energy.

Overview of bilirubin metabolism.

Because of its lipophilic nature, bilirubin must be bound to albumin to travel through the
blood stream. In this state, it is not free to cross the blood-brain barrier and cause kernicterus.
The albumin-bilirubin complex is carried to the liver, where bilirubin enters the hepatocyte
for further metabolism. Once in the liver, bilirubin is conjugated via the action of uridine
diphosphate glucuronyl transferase (UDPGT), an enzyme not fully functional until 3-4
months of life.
Conjugated bilirubin is excreted into the intestinal tract via the biliary system. Betaglucuronidase, present in the intestinal lumen of human neonates, deconjugates the
conjugated bilirubin, allowing it to be reabsorbed across the intestinal lipid cell membranes
back into the blood stream where it must be re-bound to albumin to repeat the cycle. This
process, called enterohepatic recirculation, is a unique neonatal phenomenon and contributes
significantly to physiologic jaundice. Feeding and excretion of meconium and stool interrupt
the enterohepatic recirculation.
Among infants reported in the US kernicterus registry, 56% had abnormalities known to
increase the bilirubin concentration in the blood.[13] Severe hemolytic processes were
identified in 25 of 122 babies (20.5%); glucose-6-phosphate dehydrogenase deficiency was
diagnosed in 26 babies (21.3%), birth trauma identified in 18 patients (15%), and other
causes such as galactosemia, Crigler-Najjar syndrome, and sepsis were diagnosed in 8 babies
(7%). In 53 of 122 infants (43.4%), no etiology for the severe hyperbilirubinemia was
discovered.

Increased Bilirubin Production

Most of the circulating bilirubin in the neonate arises from destruction of circulating RBCs.
Neonates produce bilirubin at more than double the daily rate of the average adult, primarily
because of the larger circulating volume of RBCs and their shorter life span. Any event
resulting in increased serum bilirubin load puts the infant at risk for hyperbilirubinemia.

Polycythemia
Prenatal factors, such as maternal smoking, maternal illness, placental insufficiency, and
gestation at high altitude, can result in neonatal polycythemia. Obstetric factors, such as

delayed clamping of the cord, stripping the cord, or holding the baby below the level of the
introitus for a prolonged period, can result in increased RBC mass in the baby. This is
particularly true for babies born in the absence of a trained birth attendant.

Hemolysis
Immune hemolytic disease, most often Rh isoimmunization (erythroblastosis fetalis), is the
prototype etiology for kernicterus.
ABO isoimmunization, as well as minor blood group antigens, can also cause hemolytic
disease in the newborn, usually of moderate severity. Infants born to mothers of blood type O
negative are at greatest risk, with one series of 249 infants with severe hyperbilirubinemia
reporting an odds ratio of 48.6 for infants with Rh incompatibility.[14]
Abnormalities of the red cell itself can also predispose to hemolysis. These can be grouped
into membrane defects, such as hereditary spherocytosis and elliptocytosis; enzyme defects,
such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and
hemoglobinopathies, such as alpha and beta thalassemias.
Sickle cell disease does not typically cause hemolytic disease in the neonatal period.

Extravasated blood
Significant areas of bruising, such as severe cephalohematoma, subgaleal hemorrhage or
peripheral ecchymoses from birth trauma, can result in an increased bilirubin load in the
serum as the blood collection resolves. Internal areas of hemorrhage, such as pulmonary or
intraventricular bleeds, can also be a significant occult source of serum bilirubin.

Enzyme induction
As mentioned above, heme-oxygenase-one (HO-1) is the inducible form of the first enzyme
involved in the creation of bilirubin. This enzyme is activated by physiologic stressors, such
as hypothermia, acidosis, hypoxia, and infection (odds ratio 20.6 in sepsis).[14]

Epidemiologic factors
East Asian and Native American babies produce bilirubin at higher rates than do white
infants; black infants have lower production rates than do infants of other racial groups. Male
infants have higher serum bilirubin levels than females. Hyperbilirubinemia also runs in
families; the etiology is unclear but may relate to genetically increased levels of betaglucuronidase in the infant, in the mother's breast milk, or both (if the infant is breastfed).

Decreased Elimination
Even with normal bilirubin production, abnormalities in transport, excretion, or both can
result in an increased level of free bilirubin in the serum.

Albumin binding

Because of its lipophilic nature, bilirubin must be bound to carrier protein to be transported in
the aqueous environment of the serum. Albumin has one primary high-affinity binding site
for bilirubin and two lower-affinity sites. At physiologic pH, the amount of free bilirubin (eg,
bilirubin not bound to albumin) is very low. This is important because only free bilirubin is
available to cross the blood-brain barrier and cause neurotoxicity. Decreased albumin binding
capacity, decreased albumin binding affinity, or both can serve to increase the amount of free
serum bilirubin. Binding affinity is lower in neonates than in older infants and is lower still in
premature and sick infants than in healthy term ones.
Some authors advocate including measures of unbound (ie, free) bilirubin when assessing the
risk of bilirubin neurotoxicity,[18] in part because some studies have shown a closer association
between the unbound bilirubin concentration and auditory abnormalities than those seen with
total serum bilirubin, although identifying the neurotoxic unbound bilirubin concentration
threshold remains elusive.[19]
Decreased binding capacity can occur in hypoalbuminemia or if the binding sites are filled
with other anions. Whether parenterally administered lipid can displace bilirubin from its
albumin-binding site is controversial. If faced with dangerously high levels of serum
bilirubin, restricting lipid administration to less than maximal levels may be prudent. Drugs,
such as sulfisoxazole and ceftriaxone, can also compete for bilirubin-binding sites on the
albumin molecule and must be used with caution or avoided in the neonatal period.

Hepatic uptake and conjugation

Albumin carries bilirubin to the liver, where it is incorporated into the hepatocyte by an
acceptor protein called ligandin. Hepatic levels of ligandin do not reach adult values until
around age 5 days, but they can be induced by administration of phenobarbital.
Once inside the hepatocyte, bilirubin is conjugated to a sugar moiety, glucuronic acid, via the
enzyme UDPGT. Inherent neonatal deficiency of this enzyme is the principal etiology of
physiologic jaundice. For the first 10 days of life, UDPGT is present at levels about 0.1% of
adult values, and hyperbilirubinemia appears to be the primary stimulus to enzyme
production.
Beyond physiologic jaundice, congenital inherited defects in UDPGT cause pathologic
hyperbilirubinemia of varying severity. Crigler-Najjar syndrome type I is the virtual absence
of UDPGT and is characterized by profound refractory hyperbilirubinemia with the ongoing
risk of kernicterus at any point during an individual's lifespan. Currently, liver transplantation
is the only definitive therapy, although experimental therapies are under investigation.
Patients with Crigler-Najjar syndrome type II (ie, Arias syndrome) have a similar clinical
presentation as patients with type I. However, patients with type II dramatically respond to
therapy with phenobarbital, which is how the diagnosis is made.
Gilbert syndrome is characterized by a benign chronic indirect hyperbilirubinemia without
evidence of liver disease or abnormality. The genetic basis for this syndrome has recently
been identified as an amplified triplet repeat in the coding gene for UDPGT, and
investigations are continuing to clarify the possible role of Gilbert syndrome in infants with
neonatal hyperbilirubinemia.

Excretion

Once conjugated, water-soluble bilirubin is excreted in an energy-dependent manner into the

bile canaliculi for ultimate delivery into the small intestine. Disruption in this system or
obstruction in the biliary system results in accumulation of conjugated bilirubin in the serum,
identified by an elevation in the direct fraction of total bilirubin. Direct hyperbilirubinemia in
the neonate (defined as a direct fraction greater than one third of total bilirubin) is always
pathologic, and an etiology must be pursued.
In the small intestine, conjugated bilirubin cannot be reabsorbed. Intestinal florae convert it
into urobilinogen, which is excreted. In the neonate, the paucity of colonic bacteria impedes
this conversion. Furthermore, the neonatal gut (but not that of the adult) produces betaglucuronidase, an enzyme that acts upon conjugated bilirubin, releasing free bilirubin for
potential absorption across the intestinal cell lipid membrane into the blood stream. Breast
milk also contains beta-glucuronidase, and breast milk feedings increase the level of this
enzyme in the neonatal intestine. Combined with slow intestinal motility in the first few days
of life, the above factors result in what is called enterohepatic recirculation of bilirubin back
into the blood stream.

Systemic Factors
Various systemic conditions increase the risk of hyperbilirubinemia and the risk of
kernicterus without severe hyperbilirubinemia.

Galactosemia
Patients with this rare inborn error of metabolism may primarily present with
hyperbilirubinemia, although the direct fraction typically increases during the second week of
life. The baby may manifest other characteristic signs, such as hepatomegaly, poor feeding, or
lethargy. Urine for reducing substances, but not glucose, is diagnostic. Many state newborn
metabolic screens include a test for this disorder.

Hypothyroidism
Although the etiology is unclear, prolonged indirect hyperbilirubinemia is one of the typical
features of congenital hypothyroidism, and this diagnosis must be ruled out in any baby with
hyperbilirubinemia persisting after age 2-3 weeks. Most state metabolic screens include an
assay of thyroid function, although false-negative results and delayed receipt of results may
necessitate individual testing in symptomatic infants.

Drugs
Maternal administration of oxytocin, diazepam, or promethazine may result in increased
serum bilirubin in the infant. Similarly, neonatal administration of pancuronium and chloral
hydrate increases bilirubin levels. Additionally, some drugs, such as sulfonamides and some
penicillins, can displace bilirubin from its albumin-binding site, effectively increasing the
serum concentration of free bilirubin available to cross the blood-brain barrier.

Acidosis

Systemic acidosis decreases the binding affinity of albumin for bilirubin, resulting in
increased levels of free bilirubin in the blood stream. Ready availability of protons promotes
the formation of bilirubin acid (free bilirubin anion plus 2 hydrogen ions); that moiety
demonstrates increased binding and transport into neural cell membranes.

Disrupted blood-brain barrier

The neonatal blood-brain barrier is more permeable to substances than is the adult's.
Administration of hyperosmolar substances, hypercarbia, asphyxia, infection (particularly
meningitis), and impaired autoregulation with variations in blood pressure all may weaken
capillary tight junctions, increasing capillary permeability. This, in turn, might lower the
concentration at which bilirubin is toxic to the CNS.

Breast milk feedings

The well-described physiologic jaundice observed in the first few days of life, particularly in
the breastfed infant, is called breastfeeding jaundice. Breastfeeding jaundice is thought to
result from multiple mechanisms, described above, which promote production and inhibit
excretion of bilirubin, as well as from insufficient milk intake because of reduced mammary
gland milk production in the first few days postpartum. Breastfeeding jaundice should be
distinguished from breast milk jaundice.
Some breastfed infants, although clinically thriving, continue to manifest an indirect
hyperbilirubinemia of unidentifiable etiology for several months. If this is witnessed in a
breastfed infant, the exclusion diagnosis of breast milk jaundice may be made. Such
hyperbilirubinemia is thought to be caused by persistently high levels of as-yet-unidentified
components in some women's breast milk, which result in persistence of the infant's
hyperbilirubinemia. One clue may be a history of similar hyperbilirubinemia in other
breastfed siblings. This entity is benign.

Differential Diagnoses

Fetal Alcohol Syndrome

Head Trauma

Hearing Impairment

Herpes Simplex Virus Infection

Hyperammonemia

Hypothyroidism

Meningitis, Bacterial

Neonatal Sepsis

Periventricular Leukomalacia