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Jaundice and kernicterus jaundice

About 60% to 80% of newborn Infants in the United States
are jaundiced, that is they look yellow. Jaundice is yellow
coloring of the skin and other tissues. Jaundice can often be
seen in the sclera, the “whites” of the eyes, which look
yellow. Although many babies look jaundiced, but they are
not deeply jaundiced, not jaundiced below the abdomen, and
they act OK – they nurse, they aren’t too sleepy, they have
normal muscle tone, their cry is normal, and they don’t arch
their backs.

Jaundice and Kernicterus

Jaundice

Most newborn Infants are temporarily jaundiced in the first week or two of life. That is, 60 to 80% of newborns have visible jaundice in the first week or two of life.

Jaundice is yellow coloring of the skin and other tissues because of a high level of bilirubin in the blood (hyperbilirubinemia[1]). Bilirubin is a normal breakdown product of red blood cell hemoglobin. Babies are normally born with a large part of their blood composed of red blood cells, about 60%, that is, about 60% is red blood cells, and 40% is plasma. The red cell volume of the blood, actually called the hematocrit, is higher in the newborn than any other time of life.[2]

Red blood cells are made constantly at all ages. Mature red blood cells survive for about 2 months in newborns and about 3 months in older children and adults and therefore must be replaced. When red cells breakdown, the hemoglobin which gives blood its red color, is released and broken down into bilirubin. This bilirubin is unconjugated bilirubin or also called indirect bilirubin.

Bilirubin. The unconjugated bilirubin (UCB) cannot dissolve in water, that is to say it is not soluble in water or in blood. If it is free to move out of the blood into tissue, UCB can be toxic to specific parts of the brain. However, in blood UCB binds tightly to albumin and other proteins, and this keeps it from moving out of blood into tissue. The albumin-bound UCB then goes to the liver where a sugar molecule (called a glucuronide) is attached or conjugated onto it forming conjugated bilirubin (also called direct bilirubin). This conjugated bilirubin is soluble in blood and water, it is non-toxic, and it is excreted into the gut where it is eliminated with the stool.

Why is there bilirubin and why is it temporarily high in newborn infants?

Bilirubin has some important beneficial biological effects. First, it is a natural endogenous (inside the body) antioxidant. It is the most potent natural antioxidant and is thought topas newborn babies, and it is thought that unconjugated bilirubin levels (UCB) rises to levels in the blood higher than in older children and adults to eliminatesome of the toxic oxidant compounds from mild birth asphyxia. Second, individuals with a very common genetic condition called Gilbert’s _____Syndrome_____ which causes very mild lifelong hyperbilirubinemia have a lower incidence of heart attacks and strokes and ?diabetes. So, a little bit of bilirubin is good for babies and adults.

BUT . . . .

Like everything, too much of a good thing can be a bad thing. Extremely high levels of unconjugated bilirubin (UCG) can become neurotoxicity, i.e., damage the brain. This occurs rarely, almost exclusively in newborns in the first weeks of life, and can usually be predicted in time to treat the baby to prevent it from reaching toxic levels.

When does bilirubin become toxic to the brain, i.e., when does bilirubin neurotoxicity occur?

The simple answer is that bilirubin become neurotoxic when it: 1) exceeds the capacity of the blood to hold it inside the blood vessels and it escapes into the tissue, and 2) exceeds the capacity of the tissue (i.e., the brain) to get rid of it. The more complex answer is that bilirubin (or UCB) is held in the blood bound to protein, especially albumin in the blood, and when it exceed the capacity of albumin to bind it, it can escape into tissue. When this happens varies for different babies, depending on their maturity (gestational age), size, health (or sickness), amount of blood albumin, amount of feeding and stooling.

When UCB starts to leave the blood and go into brain tissue, it starts to cause neurological signs and symptoms. Early on it’s hard to tell – increased sleepiness – but then lethargy, abnormal increased ± decreased muscle tone, abnormal high-pitched (high-sounding cry), backward arching of the trunk and spine (opisthotonus), download deviation of the eyes (sun-setting sign), and even worse – seizures and cardiovascular collapse. I’ve described the worst case scenario, a progression of worsening signs and symptoms that progresses to become a neurological emergency requiring immediate treatment. But, we’ll talk more about that later on (see Acute Bilirubin Encephalopathy and Kernicterus)

Back to hyperbilirubinemia and jaundice cause by an high levels of bilirubin in the blood. Jaundice can be seen in 60-80% of babies, and can sometimes be seen in the sclera, the “whites” of the eyes, which look yellow. Although many babies look jaundiced, they are not deeply jaundiced, i.e., not jaundiced below their abdomen, and they act normal – they nurse, they are not too sleepy, they have normal muscle tone, their cry is normal, and they don’t arch their backs or have any of the worst-case-scenerio signs I’ve mentioned above. Importantly, they continue to nurse, gain weight, and wake up easily and normally from sleep (i.e. they are not lethargic).

Jaundice and levels of bilirubin

Most pediatricians and physicians and nurses who take care of babies can recognize jaundice when the level of bilirubin in the blood reaches about 6 milligrams per deciliter (6 mg/dL[3]). Most guidelines to prevent brain damage and kernicterus recommend treating hyperbilirubinemia in an infant 5 days of age or older at a level of about 21 mg/dL in a healthy, term infant without risk factors, 18 mg/dL in an infant at medium risk, and 15 mg/dL at high risk. But, there is no way to know the difference between a “safe” level of bilirubin and one that is high enough to be treated without measuring it.

To be clear, once the baby becomes jaundiced, it is hard to tell the difference between a level that is concerning versus not to worry about without measuring, even for experienced professionals. There, many pediatricians and so-called “bilirubinologists” believe in hour-specific universal screening of infants to predict those that will rise to a level at which treatment will be recommended.

How to determine bilirubin levels?

That’s easy – there are two ways: 1) a blood bilirubin level, usually a total bilirubin (TB) which is almost always equal to the toxic form, UCB, in newborns, or 2) a transcutaneous bilirubin level. The blood level takes a drop of blood, usually from a “heel stick” and is the gold standard. Transcutaneous bilirubin (TcB) is done with an instrument that has a light that is pressed on the skin, shines a light on the skin and reads the color of the light that is reflected back from the tissue, and calculates the bilirubin. The TcB correlates very well with the total and unconjugated bilirubin up to a level of about 15 mg/dL, and over that will read ≥ 15 mg/dL and require a blood level. This is important to do because it could be much higher than 15 mg/dL.

The blood or TcB can be plotted on an hour-specific nomogram (e.g., the Bhutani nomogram) or via an app (e.g., Bili-Tool) that predicts how likely the bilirubin will rise to a level that might need to be treated (17 mg/dL), (not whether there is brain damage). Note for some high-risk babies with Rh or ABO bloodtype mismatches, G6PD deficiency, or other rare causes of hemolysis (conditions which lead to abnormal breakdown of red blood cells) this nomogram should not be used because this babies may have bilirubin levels that rise faster than the nomogram predicts. More on Rh, ABO, G6PD and other causes of hemolysis later.


[1] hyperbilirubinemia: hyper•bilirubin•emia means high level (hyper•) of bilirubin in the blood (•emia). Neonatal hyperbilirubinemia means a high level of bilirubin in the blood of a newborn infant.

[2] Normal hematocrit values  for newborns is 53-69%; for adult females 36-46%, and for adult males 40-54% (https://emedicine.medscape.com/article/2054320-overview?src=ppc_google_rlsa-traf_mscp_emed_t1-neuro_us)

[3] Most of the world except the USA uses International Units for bilirubin, where 1 mg/dL = 17.1 micromolar (17.1 µM), so 6 mg/dL = 103 µM, 17 mg/dL= 301 µM, and 25 mg/dL = 427 µM.

Information for Parents: Jaundice in Newborns and its Treatment

Kernicterus is a form of brain damage caused by excessive jaundice. The substance which causes jaundice, bilirubin, is so high that it moves out of the blood into brain tissue. When babies begin to be affected by excessive jaundice, when they begin to have brain damage, they become excessively lethargic. They are too sleepy, and they are difficult to arouse – either they don’t wake up from sleep easily like a normal baby, or they don’t wake up fully, or they can’t be kept awake. They can develop a high-pitched cry and decreased muscle tone (become hypotonic or floppy), sometimes with episodes of increased (hypertonic) muscle tone and may have episodes of backwards arching of the head and neck. They may have sun-setting sign, downward deviation of the eyes so that you can see the “white’s of their eyes under the top eyelid, and the pupil and iris (colored part) of the eye is force downward, so it looks like a setting sun. As the damage continues, may arch their head and neck backward into a very contorted position known as opisthotonus or retrocollis, and may develop fever and seizures

Yellow coloring in jaundiced babies starts at the head and progresses down the body toward the toes. Severely jaundiced babies may show symptoms of distress such as: difficulty nursing, being unusually sleepy and difficult to arouse (also called lethargic), with abnormal muscle tone becoming hypotonic or floppy with episodes of increased muscle tone (hypertonic), a high pitched cry, and arching of the back into a very contorted position known as opisthotonus or retrocollis, they may develop fever, and they may even develop seizures (convulsions). Infants who show one or more of these signs while jaundiced may be suffering from acute bilirubin encephalopathy (or acute kernicterus) and should be seen for treatment as soon as possible.

Yellow coloring in jaundiced babies starts at the head and progresses down the body toward the toes. As the bilirubin goes higher, the bilirubin can no longer be held inside the blood vessels and out of the brain. Then, severely jaundiced babies may show signs and symptoms of distress cause by bilirubin getting into the brain, known as acute bilirubin encephalopathy (ABE).

Acute Bilirubin Encephalopathy (ABE)

This means that more bilirubin has entered the brain than the baby’s brain can handle, and it starts to cause abnormal brain function. These signs of ABE may be subtle and mild at first, progressing to become more severe from #1 to #5 below:

  1. Difficulty nursing, being unusually sleepy and difficult to arouse (also called lethargic),
  2. Abnormal muscle low tone (called floppy or hypotonic) with episodes of high muscle tone (hypertonic),
  3. A high pitched cry (? link to sound file), and
  4. Arching of the back into a contorted position known as opisthotonus or retrocollis  (link to picture),
  5. Setting sun sign – the eyes . . . . . . (link to picture)

These often occur in a progression from mild to severe, from lethargic to abnormal tone, a high-pitched cry, and arching of the back as the effect on bilirubin on the brain progresses.

Finally, in the most severe cases:

  • they may develop fever and even seizures (convulsions), and heart, blood pressure and breathing problems.

Kernicterus

Kernicterus is a form of brain damage caused by excessive
jaundice. The substance which causes jaundice, bilirubin, is
so high that it can move out of the blood into brain tissue.
When babies begin to be affected by excessive jaundice,
when they begin to have brain damage, they become
excessively lethargic. They are too sleepy, and they are difficult to arouse – either they don’t wake up from sleep
easily like a normal baby, or they don’t wake up fully, or they
can’t be kept awake. They may have a high-pitched cry, and
decreased muscle tone, becoming hypotonic or floppy with
episodes of increased muscle tone (hypertonic) and arching
of the head and back backwards. As the damage continues
they may arch their heads back into a very contorted position
known as opisthotonus or retrocollis, they may develop fever,
and they may even develop seizures (convulsions).
Kernicterus is from the Greek “kern” or kernel plus “icterus”
or yellow. Kernicterus refers to the yellow staining of the
deep nuclei (i.e., the kernel) of the brain namely, the basal
ganglia. Kernicterus involves a specific part of the basal
ganglia, the globus pallidus. It also includes lesions (damage)
to brainstem nuclei in auditory (hearing), oculomotor (eye
movement), and vestibular (balance) systems and the
cerebellum (coordination). Abnormalities of the globus
pallidus can be seen on MRI scan of infants with kernicterus.
Clinically, classic kernicterus involves:
• Specific movement disorders of abnormal tone and involuntary movements
• Auditory processing disturbance with or without hearing loss or deafness
• Impairment of eye movements especially upward gaze
• Abnormal staining of the enamel of baby teeth

Children with kernicterus have a “dystonic” or “athetoid”
form of cerebral palsy. The “athetoid” form of cerebral palsy
is classic and athetosis refers to the slow, writhing involuntary movements that occur. Dystonia, or abnormal
muscle tone and position, is more common, and may occur
with or without athetosis.
Some children with kernicterus are deaf, some have normal
hearing, and some with or without deafness have an auditory
processing problem called auditory neuropathy, auditory dys-
synchrony or by it’s new name, auditory neuropathy
spectrum disorder (ANSD). Auditory brainstem responses,
ABRs also known as BAEPs, BAERs or BSERs are often
abnormal, whereas other “hearing” tests, such as otoacoustic
emissions (OAEs) and cochlear microphonic responses are
normal. An abnormal ABR with a normal cochlear
microphonic response is the “gold standard” way to diagnose
ANSD, and requires recording electrical activity (brain waves)
from a few electrodes pasted on the scalp in response to
sounds played through insert earphones, usually when the
child is asleep or sedated
Kernicterus is fortunately a very rare occurrence. Other
forms of more subtle bilirubin-induced neurological damage
may exist, including auditory processing problems, one form
of which is ANSD, and other problems of sensorimotor
integration. 

Caveats

The opinions in this article are solely mine except where I’ve

cited others. I am a child neurologist and medical researcher.
I’ve been studying brain damage due to jaundice since 1982.
I care very deeply about preventing brain damage, and
kernicterus is a preventable form of brain damage that
occurs in newborn infants. There are many well established
scientific facts known about how bilirubin toxicity damages
the brain, but unfortunately, there is much that is not known.
Usually conservative in my clinical practice, in a baby with
excessive hyperbilirubinemia I would err on the side of
treatment that is more aggressive. For example, if there is a
possibility that subtle cognitive processing problems are
caused by levels of bilirubin lower than are usually treated,
and if it will take time for new studies to resolve this concern,
then I’d err on the side of over- treating while there is still
uncertainty because the cost of treating is a few days or so of
a very safe treatment, whereas the cost of not treating might
be a lifetime of a neurological problem.

About 60% to 80% of newborn infants in the United States
are jaundiced, that is they look yellow. Excessive jaundice in
newborn infants may cause brain damage. Jaundice is caused
by a high level of bilirubin in the blood (hyperbilirubinemia)
and tissues. When bilirubin in the blood (hyperbilirubinemia)
gets too high, babies can be treated to lower the bilirubin
level. Norms exist for bilirubin in term and near-term
premature babies based on their age in hours after birth.
Other factors, such as prematurity, blood group
incompatibilities between infant and mother including Rh and
ABO blood types, and bruising, especially cephalohematomas
and caputs (bleeding under the skin of the scalp), can increase bilirubin production and lead to excessive jaundice
and hyperbilirubinemia.
Babies with high bilirubin levels can be effectively treated.
Phototherapy (treatment with light) is usually very effective.
It is the blue color in visible light that alters the bilirubin from
a toxic form to a water soluble, non-toxic form that can be
eliminated. At higher, more dangerous levels of bilirubin, or
in certain situations where the bilirubin is expected to rise
very rapidly, such as Rh disease or other hemolytic diseases
of the newborn, a more extreme treatment may be used,
such as a blood exchange transfusion to rapidly remove toxic
bilirubin from the blood. 

The jaundiced baby with signs of acute
kernicterus: a medical emergency

When signs of acute kernicterus occur in a jaundiced baby,
brain damage is starting to occur. Immediate treatment
should be done to prevent further damage or the damage
may become permanent, because at the earliest times some
of the damage may be reversible.
Treatment should be immediate triple-bank phototherapy
lights put as close as possible to the baby. A STAT
measurement of blood bilirubin should be sent, but the
phototherapy should be started before the bilirubin results
come back. The baby should be hydrated with fluids and if the baby is not too sick should probably be given an elemental infant formula via a tube from the nose or mouth
into the stomach. The baby should be blood typed for a
possible exchange transfusion, which should be done as soon
as possible unless there is a large drop in the
hyperbilirubinemia and the baby improves before the blood is
ready for an exchange transfusion. 

The jaundiced baby with a high bilirubin and NO signs of acute kernicterus

For babies who are term (37 to 42 weeks gestation) or near-term (premature but greater than 35 weeks gestation) and without any other known risk factors, the bilirubin should be plotted on a nomogram (graph) such as the hour-specific “Bhutani nomogram” to see what percentile it is in (Figure 1) or entered into a convenient app such as the BiliTool. This nomogram predicts the likelihood that the baby’s bilirubin will reach a level of 17 mg/dL, a level that should be treated according to the AAP 2004 Guidelines.

If the percentile is high on the nomogram above, then recommendations for treatment are found  in the American Academy of Pedatrics 2004 Guidelines[1] determine if the baby needs treatment with either phototherapy or exchange transfusion. The AAP Guidelines tell when to treat a term or near-term baby with phototherapy (Figure 2) or with an exchange transfusion (Figure 3), taking into consideration whether the child is premature and has other risk factors.

The cause of the jaundice should be determined. Measures to increase feeding and hydration, e.g. lactation counseling and increased breast-feeding and/or temporary supplementation should be considered. Home phototherapy with a phototherapy blanket (“biliblanket”) might be prescribed, but levels must be closely followed since the amount of phototherapy delivered by home systems is relatively small.


[1] Management of Hyperbilrubinemia in the Newborn Infant. Pediatrics Vol. 114 No. 1 July 2004 pages 297-316. (Attached). This graph is reproduced from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999 Vol. 103 N. 1, pages 6-14.

All clinical practice guidelines from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

Plan: check AAP website for updates.

Jaundice and preventing brain damage

When infants have signs of brain dysfunction from bilirubin
toxicity, immediate treatment is needed to minimize
permanent brain damage. The signs of acute bilirubin toxicity
are:
• Abnormalities of tone, including increased tone
(hypertonia), decreased tone (hypotonia), or a variation in
tone from hypertonia to hypotonia.
• Lethargy, difficulty in arousing the baby.
• A high-pitched cry,
• Arching the back and spine (retrocollis or opisthotonus),
and fever.
Feeding or nursing is decreased, which makes matters worse
not only because of dehydration, but because bilirubin is
eliminated via the stool, and decreased feeding prevents
bilirubin from being eliminated from the body. Expert
neonatologists say that the most common cause of bilirubin
levels rising high enough after discharge from the hospital to
require readmission is inadequate feeding.
We and others have proposed a clinical scale called the BIND
scale, for Bilirubin-Induced Neurological Dysfunction. Babies
are scored from 0-3 on each of three characteristics, tone,
cry and mental status, with 0 being normal and 3 being the
worst. Overall, 0 is normal and 9 is the worst score. Degrees
of severity of mental status, for example, would include with
a normal awake baby or a sleeping baby who is easily roused (score 0), a lethargic baby who is difficult to rouse and falls
back to sleep (score 1), a comatose baby responsive to only
deep painful stimuli (score 2), and a comatose unresponsive
baby (score 3). In any event, jaundice with any of abnormal
signs such as lethargy, abnormal tone, arching, high-pitched
cry, or fever, is a cause for IMMEDIATE concern, and an
URGENT visit to a physician or hospital emergency room is
required.
Some physicians have asked me, when the signs occur, isn’t
it too late to treat? No! Although damage may have occurred,
when the infant is jaundiced and signs are occurring, damage
is continuing to occur. The sooner the bilirubin level in the
blood is reduced, the better, the less permanent brain
damage will occur. This is a true emergency. Delay will make
the damage worse.
With an excessively high bilirubin level, and with signs of
acute kernicterus, arrangements should immediately be
made for a double volume exchange transfusion. This may
take a few hours, even in the best of medical centers. In the
meantime, the baby should be given double or triple
phototherapy with the lights as close as possible to the baby
with maximal surface area exposed (and the eyes covered),
and the baby should be fed orally or by gavage tube with
Nutramigen or another elemental formula, to eliminate
bilirubin via the gut. Dehydration may be corrected by
intravenous infusion, but gastrointestinal feeding should not
be ignored unless the baby is having a seizure or severely ill.

When bilirubin is very high do not make or let your child’s
physicians make any of the following mistakes in care:
• Not believing the bilirubin level from the lab, and delaying
treatment while it is repeated. There is no problem in
repeating the test, but don’t delay treatment for an instant
while waiting for the repeat. You have nothing to lose by
treating with a huge dose of phototherapy, gavage feeding,
hydrating, ordering a type and cross match and blood for a
possible exchange transfusion. If the bilirubin drops rapidly
to a relatively safe level, and the child is asymptomatic (no
symptoms), the exchange transfusion can be cancelled.
• Delaying treatment or interrupting phototherapy for
diagnostic testing to determine the risk of an exchange. If a
sepsis workup or lumbar puncture (LP, a.k.a. spinal tap) or
an echocardiogram (ultrasound study of the heart) etc. is
needed, do it under the lights. If it’s not possible, keep the
lights on every possible minute. If the baby needs to go for
a test out of the unit, the lights go with him or her.
• Not examining the baby for signs of acute kernicterus.
• Using the indirect (or unconjugated) bilirubin level instead
of the total bilirubin level to make treatment decisions. Experts agree, use the total bilirubin.
• Allowing the bilirubin to reach potentially dangerous levels.
Obtaining a transcutaneous bilirubin level or measuring
blood bilirubin is very easy to do. It is much easier to
prevent bilirubin from rising too high than to treat it when
it does.

• Measuring the bilirubin and not comparing it to hour-
specific norms. This is very important. A bilirubin level in a
one-day-old may be normal or dangerously high depending
on whether the baby is 24 or 47 hours old. A level of 8.5
mg/dL would be in a high-risk zone (95th percentile) in a
24h old baby, and in a low risk zone (40th percentile) in a
47h old baby. Most use the Bilirubin Nomogram (see
Figure), which is used in the American Academy of
Pediatrics (AAP) guidelines (see References) although some
may use their own normal values. The nomogram predicts
the risk of the baby’s bilirubin rising to a level of 17 mg/dL,
a level at which a term infant should be treated in
phototherapy to prevent the bilirubin from rising higher.

Patients benefit from having access to a collaborative
approach to care that includes specialists in pediatric
genetics, neurosurgery, neuromuscular and movement
disorders specialists, physical medicine rehabilitation,
audiology; otolaryngology; speech, physical, and
occupational therapy, gait analysis, and neuropsychology.

Pharmacological Treatments (Medications)

Non-pharmacological treatments which might include
referrals to speech, physical and/or occupational therapy,
rehab and/or assistive technology, educational
recommendations, botulinum toxin injections, baclofen
pumps, cochlear implants, or deep brain stimulators.

Additional information and support for parents
 
PICK, Parents of Infants and Children with Kernicterus
One excellent source of information for parents (or
grandparents, other relatives, friends, or older people who
have neurological problems that might be related to
hyperbilirubinemia) is PICK, Parents of Infants and Children
with Kernicterus, a parent’s organization dedicated to
preventing and treating kernicterus. I have known many of
the parents in this organization and served on its medical
advisory board since its inception in the year 2000. Their
website is www.pic-k.org. 

Kernicterus Research Fund

Kernicterus, hyperbilirubinemia and BIND do not appear to
be current funding priorities of the major sources of funding
for medical research, such as the NIH (National Institutes of
Health).


We welcome donations to our Kernicterus Research Fund. If you (or your friends or relatives) care to make a charitable contribution to support research on kernicterus and the neurological effects of
newborn jaundice and hyperbilirubinemia, please consider a gift to our Kernicterus Research Fund to support research on
kernicterus, hyperbilirubinemia and Kernicterus Spectrum Disorders. Any amount is welcome. The Kernicterus Research Fund supporting
clinical and basic science research to detect, prevent and
treat kernicterus and bilirubin-induced neurological disorders is currently administered by Dr. Shapiro in conjunction with PICK, a non-profit 501(c)3. Please use the link at this website

Contact information

If you have any questions or comments, please feel free to
contact me via email:
Dr. Steven M. Shapiro MD, MSHA
stevenmshapiro@gmail.com
Please put “kernicterus” or “newborn jaundice” in the subject line.

Bilirubin Nomogram

This widely used nomogram, first published in 1999 in an
article by Drs. Vinod Bhutani, Lois Johnson, and Emedio Sivieri
in the medical journal Pediatrics, volume 103, issue #1,
pages 6 to 14, and was printed in “Management of
hyperbilirubinemia in the newborn infant 35 or more weeks
of gestation”, the current guideline for the management
endorsed by the American Academy of Pediatrics, published
in Pediatrics in 2004, volume 114, issue 1, pages 297 to 316. We plan to attach copies of these articles.