Bilirubin can be a toxin, crossing the blood-brain barrier
and causing brain injury. The blood-brain barrier is very protective,
maintaining a huge wall between the bloodstream and the cerebral spinal fluid.
When all is working well, nothing can cross that barrier without an invitation.
In newborns, however, that barrier is leaky.
(I feel as if every time I wrote about something related to
breastfeeding, I am writing about something leaky!)
The leaky newborn blood-brain barrier can let bilirubin through, and at
some level that we have not discovered, can cause injury. That injury is called
bilirubin encephalopathy or kernicterus.
Kernicterus is awful, permanent, devastating and completely preventable
with current therapies. (On a potentially powerful side note, “completely
preventable” means if it occurs, in addition to the horrors of the injury, it is
also a likely lawsuit.)
Medicine was introduced to kernicterus in the early 1900s,
when researchers noticed yellow discoloration of the basal ganglia (a part of
the brain) during autopsies of babies who most likely had a problem called Rh
Isoimmunization. The need to urgently
identify and treat Rh Isoimmunization peaked in the 1950s-1970s. The Rh factor is a protein on the surface
of a red blood cell. Most people
have the protein, so they are Rh positive (Rh+).
Those that don’t are Rh negative (Rh-).
In Rh isoimmunization, an Rh- mother has a baby who is Rh+ and she makes
antibodies against that Rh protein.
That first baby is just fine, but mom keeps those antibodies against the Rh
factor protein. The problem comes
with the next baby. If that baby is
Rh+, those antibodies mom made against the Rh protein start attacking the new
baby’s Rh+ red blood cells. We know
that bilirubin is created when red blood cells are destroyed. Because the baby’s
red cells are being attacked, lots of bilirubin is produced.
And bilirubin can cross the blood brain barrier.
The researchers noted that a bilirubin level of about 20 mg/dl was the
threshold for the yellow coloring in the brain to appear.
When the medication Rhogam was invented, Rh isoimmunization was
essentially wiped out and we started to relax a little about hyperbilirubinemia
in newborns. But, from then on, bilirubin became a toxin and 20 became a
In the 1980s, researchers noted that breastfed babies were
more likely to become jaundiced and the search started for the jaundice-causing
mystery ingredient in breastmilk; because, bilirubin is a toxin, remember? What
they did not know, or maybe they did, is that breastfeeding is normal, and what
happens in breastfed kids is normal and physiologic.
Maybe jaundice in healthy, term infants is actually normal. Maybe
bilirubin is not always a toxin. But in the 1980s, we are just coming off of
years where breastfeeding was hardly the cultural norm, so maybe it was too soon
for that kind of thinking.
In 2004, the AAP suggests that all babies should be assessed
before discharge for the risk of severe hyperbilirubinemia.
that statement, “exclusive breastfeeding, especially if not nursing well and
excessive weight loss” is a major risk factor for hyperbilirubinemia.
I find it hard to get my head around physiology being a risk factor. I
get the “not nursing well” and you know my take on “excessive
weight loss” but exclusive breastfeeding is normal.
Maybe hyperbilirubinemia is normal.
The timing was still probably premature for this type of thinking.
This same statement also gives us an algorithm for checking
the nomogram onto which we plot the bilirubin.
I’ll give you a few minutes to find the part where it says “assess
breastfeeding.” Nah, don’t bother.
It’s not there. (Hence, the inclusion of this algorithm in a nearly
So, now we have something to measure, total serum bilirubin
(TSB) and know what to do with that number.
But the nomogram on which we are supposed to plot the baby’s TSB and make
any future management decisions was created based on a sample where less than
60% of the babies were breastfed.
So, the nomogram is not based on normal. Maybe it was still too early to
question if we were doing the right thing.
In 2009, a
commentary by experts in the field of neonatal jaundice suggested that all
babies should have their bilirubin checked, regardless of risk factors, at the
time of discharge and when any signs of jaundice appear.
Then we plot that measured bilirubin on our nomogram and proceed with
appropriate therapy. Interestingly, they
admit that kernicterus can occur without elevated bilirubin, and that they do
not know the incidence of kernicterus in the US. They also say that they do not
know if their suggested interventions are cost-effective or if they even
prevent kernicterus. Now I am
confused. Really confused. We do
not know what causes kernicterus, if we are doing the right thing, or if it is
even helpful…but check every baby anyway.
But, you may say, it is really a simple thing to do, what’s
the harm? Well, as mothers, we
remember that number. This
study, done in 1989 when we were still using risk factors to screen babies,
says just by checking the total serum bilirubin,
just by checking, an otherwise healthy infant, with or without treatment,
can lead to adverse psychological and behavioral consequences.
Mothers of babies who were checked were less likely to leave their child
with anyone, more likely to seek medical attention, and more likely to stop
breastfeeding. There is your harm.
Bilirubin as an antioxidant: an alternative theory where
bilirubin is not bad
Normally, a baby adapts to the low oxygen concentration of
the womb (the babies are breathing through the placenta- not perfect) by
creating more red blood cells. At
birth, the baby does not need as many of those red blood cells and the extras
are destroyed. As we have talked
about, the inside of the red blood cell contains the yellow pigment, bilirubin.
Therefore normal babies will have higher levels of bilirubin because normal
newborn mechanisms produce those higher levels.
The normal, healthy term newborn gets rid of bilirubin when
the liver changes it into a water-soluble form which can be then transported
into bile. Once water-soluble bilirubin gets into the small intestine, many
things can happen to it, like sneaking back into the bloodstream through a
enterohepatic circulation. We could talk more about bilirubin metabolism,
but I have decided to skip it, since I imagine
that it would be pretty boring. (I actually know it is boring.) But
in the end, the bilirubin comes out in the stool. And what helps stooling?
Efficient transfer of breastmilk into that newborn gut.
That means, if we notice jaundice, we need to know how
breastfeeding is going. One of the
most common ingredients in breastmilk are oligosaccharides. They are
non-digestible sugars that help develop the infant’s immune system by preventing
inflammation. Because they are non-digestible, they come out in stool.
Therefore, the more breastmilk the baby gets, the more oligosaccharides
the baby gets, the more poop we get.
The more poop we have, the more bilirubin that is excreted, and the less we need
to worry about that jaundice we noticed. When we assess a healthy, term newborn,
we need to know about poop. Effective breastfeeding causes greater stool
output. Less effective breastfeeding causes less stool output.
Fixing ineffective breastfeeding is one way we can help with bilirubin
excretion. We need to work on "look at the baby" before we intervene with
something other than human milk.
Then let’s look at the normal pattern of jaundice:
should not normally be present in the first 24 hours, peaks at days 4-6 and then
drops off with time, sometimes several weeks. Many species do not
make bilirubin. They stop at the creation of biliverdin, another pigment
produced by the breakdown of red blood cells, except this one is green and is
easily excreted. Humans continue to the production of bilirubin, but the
conversion of biliverdin to bilirubin takes energy, and anything that takes
energy in a newborn should serve some great purpose. Hopefully, when we
convert green to yellow, it serves a purpose.
You know that it would serve some great purpose, right?
Biliverdin (green) is converted to bilirubin (yellow) by an enzyme (biliverdin
reductase) in a reaction that requires energy. I have written before about
the importance of avoiding inflammation in the
newborn gut, so it should come as no surprise that bilirubin and biliverdin
have a role in protecting the newborn from inflammation. Biliverdin has
properties and bilirubin
is an anti-oxidant like vitamin E. Even the enzyme that converts green
to yellow has a role; bilverdin reductase is another regulator of the immune
system response to inflammation.
Having a good supply of anti-inflammatory agents and
anti-oxidants around makes sense.
The conversion of biliverdin to bilirubin, and the resulting increase in
bilirubin production in most healthy, term newborns is more likely an expected
and valued part of the transition to being born than a really dangerous brain
toxin. The process of creating extra
bilirubin serves as an elegant anti-oxidant, anti-inflammatory bridge
from the womb to the outside world, and does not waste the product of the normal
breakdown of unneeded red blood cells. Cool
Having increased bilirubin, and therefore jaundice, is a
smart way to transition a newborn to living life outside the womb.
But some children have been injured from too much bilirubin. How did that
The concept of free bilirubin
When we check the bilirubin level on a baby we are using a
total serum bilirubin (TSB) which is the total bilirubin the bloodstream, or a
transcutaneous bilirubin meter, where we put a little probe thingy on the baby’s
forehead and get a measurement from the skin. Both of these measurements give us
That may be a little harsh, but well, it is true. Total serum
consistently been shown to be a poor risk indicator for kernicterus (I
linked to it, but since the study is a good one and well worth the read: here it
http://pediatrics.aappublications.org/content/117/2/474.short. Make sure to
check out Figure 1: “Outcome
of newborns who were readmitted with severe hyperbilirubinemia, illustrating the
low specificity of TSB in predicting bilirubin neurotoxicity” because it is a
very powerful illustration of how much we are relying on a test that does not
work very well.)
What makes more sense is the concept of free bilirubin. Lots
of things in the body, like thyroid hormone or testosterone, exist either bound
and stuck in the blood stream without any effectiveness, or free and
biologically active. It is the free
part that does the work.
Studies now show that bilirubin exists in a
free and bound
state and the free part is the one that sneaks across the blood-brain
barrier and does the damage. So we
really should be measuring free bilirubin levels if we are worried.
But we can’t. No good tests
have been developed yet.
If we are worried about free bilirubin, which I think we
ought to be, then we need to be aware of which states create a situation where
the bilirubin breaks from its binding like sepsis, acidosis, and hypoxia.
Infants with those conditions are usually very sick, and ones who might
not be breastfeeding well. We also
need to worry about conditions where there is too much bilirubin to bind because
too much is being made. The most
important of those conditions is called
hemolysis and it happens, frequently but not always, when mom and baby have
different blood types.
The United States Preventive Services Task Force: not
enough information to recommend all this screening
In order to have a good screening test, it should be able to
correctly predict that
a patient with
a positive test result has the disease (sensitivity) and that a patient with a
negative test result does not have the disease (specificity).
In order to calculate specificity and specificity, we need to know a few
things, such as the incidence of the disease, and how our screening test
compares to the gold standard test. I guess here the disease is kernicterus and
despite attempts to figure it out, we do not know the incidence of kernicterus.
We also need to know that by screening our population, in our case, checking
their total serum bilirubin, we can prevent the disease in a meaningful point in
time, but kernicterus can occur without elevated levels of bilirubin. To
universally screen a population, early intervention should be beneficial in
preventing the disease from occurring. Again, treating high levels of bilirubin
might not prevent kernicterus. We just do not know enough about the disease, how
it is caused and what we need to do to prevent it well enough to subject every
baby and family to this testing.
One of the authors of the 2009 commentary said this:
“Guideline committees tend to be dominated by academics and
subspecialists with special interest, expertise, and even emotional
investment in the diseases for which they are producing guidelines. Most
of us authors of the hyperbilirubinemia commentary are no exception.
Although interest and expertise are invaluable, the career focus on a
particular disease, with resulting close relationships with funders,
patients, advocacy groups, industry, and each other, may lead to a
narrow perspective in which heroic efforts at preventing or treating the
target disease feel justiﬁed, even when a favorable balance of beneﬁts
over risks and costs is uncertain.”
T. B. (2009). Universal Bilirubin Screening, Guidelines, and Evidence.
Pediatrics, 124(4), 1199-1202.)
I get being emotionally invested about the health and well-being of children
or I would not have written this and I love that the obvious biases are
acknowledged by the authors, but their passion, not their evidence, changed
practice. I think the efforts
and goals of breastfeeding mothers are truly undermined by their suggestion
of universal screening for hyperbilirubinemia.
So, what are other experts saying?
States Preventive Services Task Force (USPSTF), an independent body of
experts that “conducts
scientific evidence reviews of a broad range of clinical preventive health
care services (such as screening, counseling, and preventive medications)
and develops recommendations for primary care clinicians and health systems.
They say that:
there is adequate evidence that screening using risk factors and/or
hour-specific bilirubin measurement can identify infants at risk of developing
Not all children with chronic bilirubin encephalopathy
(kernicterus) have a history of
There is no known screening test that will reliably identify all infants who are
at risk of developing chronic bilirubin encephalopathy.
Early treatment can
decrease the number of infants with elevated serum bilirubin levels.
However, the USPSTF
found inadequate evidence that treating elevated bilirubin levels in term or
near-term infants to prevent severe hyperbilirubinemia resulted in the
prevention of chronic bilirubin encephalopathy.
They go on to
describe harms of screening:
interference with breastfeeding
pain caused by
heel stick or venipuncture
infant weight loss
infants that have elevated bilirubin levels
(the effect of labeling kids with jaundice has not been measured or
quantified, but they acknowledge this may be important.)
Because of the
lack of evidence, the potential harms and costs, the USPSTF concluded that
“the evidence is insufficient to recommend screening infants for
hyperbilirubinemia to prevent chronic bilirubin encephalopathy.”
We have conflicting opinions on what to do.
I wrote all of this to get us thinking,
again, about numbers in context.
Current practice is based on expert opinion but there is potential bias in
expert opinion. Total serum bilirubin stinks as a screening tool, but the
concept of free bilirubin makes sense.
If the concept of free bilirubin makes sense, then our risk factors and
any screening tests should change to reflect those things that produce more free
bilirubin. Breastfeeding is normal, but we do not have any norms or protocols
based solely on exclusively breastfed infants for us to follow. Our screening
algorithms do not us to consider how well breastfeeding is going.
Nearly 25% of our babies are being supplemented in the hospital, at least
partially due to this screening and despite the encouragement of the AAP to not
interrupt breastfeeding when treating hyperbilirubinemia.
Most of us are in a
place that asks us to universally screen babies with some type of measurement of
bilirubin. We can help mothers and
babies by watching how we explain jaundice.
So many of the families in my own practice are scared about the level of
bilirubin because they were told of very scary, very unlikely, consequences of
high bilirubin. In healthy, term newborn
without hemolysis, we could explain that higher levels of bilirubin are expected
and then watch a feeding to make sure we are helping breastfeeding.
Telling mothers that we are checking to make sure their baby does not get
brain damage is just not supported by the evidence.
We can also help
mothers continue important practices like skin-to-skin and rooming- in by using
technology that facilitates these practices.
I love this suggestion from the
Indiana University School of Medicine:
If you are in a place that simply will not do any of these
practices, like watching a feeding, understanding the reliability of the
screening test, considering rooming in and skin to skin while under
phototherapy, or considering the USPSTF recommendations and someone recommends
supplementation and we have no mother’s milk or donor milk with which to
supplement making formula is the only course of action, a protein hydrolysate
formula is the recommended choice. Protein
hydrolysate formulas taste really awful
and bring the bilirubin
levels down faster.
If you have made it all the way through this, cool.
The take home message: think about jaundice and what it means to that
newborn and the family before we act.