COMMENTARY
What’s in a Name? Physiologic and Pathologic
Jaundice: The Conundrum of Defining Normal
Bilirubin Levels in the Newborn
M. Jeffrey Maisels, MB, BCh
Department of Pediatrics, William Beaumont Hospital, Royal Oak, Michigan
The author has indicated he has no financial relationships relevant to this article to disclose.
B ECAUSE at some point during the first week after
birth almost every newborn has a total serum bili-
rubin (TSB) level that exceeds 1 mg/dL (17 ␮mol/L), the
upper limit of normal for an adult, and ⬃2 of every 3
newborns are jaundiced to the clinician’s eye, this type
of transient bilirubinemia has been called “physiologic
jaundice.” When TSB levels exceed a certain value, the
infant is often described as having “pathologic jaundice.”
I would like to argue that these terms have limited utility
and are often used incorrectly, with potentially damag-
ing consequences. They should be abandoned.
PHYSIOLOGIC JAUNDICE AND “NORMAL” BILIRUBIN LEVELS
The physiology of the newborn differs from that of older
children and adults in many ways. Newborns breathe 40
to 60 times per minute, and their hearts beat 120 to 160
times per minute. Their hematocrit levels are frequently
⬎60%. In time, all of these values return to normal
levels, as does their bilirubin level. However, we don’t
talk about physiologic tachypnea, tachycardia, or poly-
cythemia, so why pick on jaundice?
Some like the term “physiologic jaundice” because it
has a reassuring sound for parents and physicians. Pre-
sumably, physiologic jaundice should apply to newborns
whose TSB levels fall within a certain range, but what is
that range? Because very few (if any) newborns have
peak TSB levels ⬍2 mg/dL, should an infant with a peak
TSB of 1.5 mg/dL be considered abnormal or hypobil-
irubinemic? Unlike serum sodium levels, the range of
normal TSB levels varies widely depending on the racial
composition of the population, the incidence of breast-
feeding, and other genetic and epidemiologic factors.1
There are also significant variations between different
laboratories in their measurements of serum bilirubin.2
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Term, healthy, North American, formula-fed infants
have mean peak TSB levels between 5 and 6 mg/dL (86
and 103 ␮mol/L),3,4 whereas Japanese breastfed new-
borns have levels more than twice as high.5 Data from
the Collaborative Perinatal Project,6 conducted from
1955 to 1961 (when 30% or fewer mothers breastfed
their infants), indicated that ⬃95% of infants had a TSB
concentration that did not exceed 12.9 mg/dL (221
␮mol/L), and this (95th percentile) became a commonly
accepted upper limit of physiologic jaundice. It is inter-
esting that in our hospital’s predominately white (73%)
and breastfed (80%– 85%) population, the 95th percen-
tile at age 96 hours is 13.1 mg/dL (224 ␮mol/L),7
whereas studies of infants in Philadelphia, Pennsylva-
nia,8 and Northern California9 show the 95th percentile
to be 17.5 mg/dL (299 ␮mol/L). In a mixed population of
infants from the United States, Hong Kong, Japan, and
Israel,10 the 95th percentile was 15.5 mg/dL (265 ␮mol/
L). Thus, unlike the serum sodium or many other bio-
chemical and hematologic measurements, defining a
normal serum bilirubin level in the newborn is a prob-
lem.
Even if we accept that one, or an average, of these
values represents the true 95th percentile (as if values
Abbreviation: TSB, total serum bilirubin
Opinions expressed in these commentaries are those of the authors and not necessarily
those of the American Academy of Pediatrics or its Committees.
www.pediatrics.org/cgi/doi/10.1542/peds.2006-0675
doi:10.1542/peds.2006-0675
Accepted for publication Mar 8, 2006
Address correspondence to M. Jeffrey Maisels, MB, BCh, Department of Pediatrics, William Beaumont
Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073. E-mail: jmaisels@beaumont.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2006 by the
American Academy of Pediatrics
PEDIATRICS Volume 118, Number 2, August 2006 805
⬎95th percentile are, by definition, abnormal; they are
not), it is not uncommon to see a discharge diagnosis for
an infant with a bilirubin level of 21 mg/dL (359
␮mol/L) listed as “exaggerated physiologic jaundice.” If
the jaundice is physiologic, one wonders why a battery
of blood tests is performed and why the infant is in the
hospital receiving phototherapy. Others call this TSB
level pathologic jaundice, but more often than not, the
battery of tests yields no identifiable pathology.11,12
Finally, we have an additional problem that is unique
to bilirubin levels: they change almost every hour for ⬃1
week or more, so meaningful interpretation of TSB lev-
els can only be made in relationship to the infant’s age in
hours.13
DEFINING A NORMAL VALUE
How do we define the term “normal?” This question is
elegantly discussed by Sackett et al14 in their text on
clinical epidemiology, and the definition depends on
why we are asking the question.
Gaussian or Percentiles
Perhaps the most commonly used definitions of normal
in medicine are based on the mean ⫾ 2 SDs (assuming a
normal or Gaussian distribution). When the distribution
is not Gaussian, percentiles have been used. If we know
the characteristics and ranges of values in the population
being studied, then percentile values can help to identify
infants who need additional investigation for the cause
of their jaundice or more careful follow-up because they
are at risk for severe hyperbilirubinemia.15 The general
use of either the Gaussian or percentile definitions of
normal, however, is open to criticism. As noted by Sack-
ett et al,14 if the highest and lowest 2.5% of diagnostic
tests are called abnormal (if we use the mean ⫾ 2 SDs)
or if those above the 95th percentile or below the 5th
percentile are called abnormal, then all diseases have the
same frequency— clearly an illogical conclusion. Al-
though it does not represent the natural history of neo-
natal bilirubinemia, the nomogram developed by Bhu-
tani et al8 has given us a very useful tool for identifying
infants who need additional evaluation and more careful
follow-up. This nomogram also reemphasizes a long
known but oft-forgotten fact: the TSB is changing con-
tinually and can only (logically) be interpreted in rela-
tionship to the infant’s age in hours and not days.
Diagnostic
There are other ways of defining normal. A diagnostic
definition of normal implies that if a result falls outside
of a defined range, then there is a known probability of
a specific disease being present.14 For jaundiced new-
borns, this definition does not work well at all. In infants
who are readmitted to the hospital with TSB levels of 18
to 20 mg/dL (308 –342 ␮mol/L), the likelihood of finding
a specific etiology for the hyperbilirubinemia (other than
806 MAISELS
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an association with breastfeeding) is very small.15,16
Hour-specific TSB levels can be informative, however; a
TSB level of 10 mg/dL (171 ␮mol/L) at age 12 hours is
almost certainly caused by a hemolytic process, although
the precise cause of the hemolysis might not be known.
Risk Factor
Normal can also be defined using the risk-factor ap-
proach.14 Here a normal range includes levels that carry
no additional risk of morbidity or mortality. In jaundiced
newborns this would be based on the relationship be-
tween TSB levels and subsequent cognitive and neuro-
logic outcome. There are 2 problems with this definition:
(1) in the term infant, we have been unable, thus far, to
associate a specific risk of damage with a particular bil-
irubin level, and (2) at the other end of the spectrum,
kernicterus has been described in extremely premature
infants at very low TSB levels.17,18
Therapeutic
For bilirubin levels, a useful definition of normal is the
therapeutic definition.14 Here the normal range defines a
level beyond which a specific therapy will likely do more
good than harm. The recommendations of the American
Academy of Pediatrics13 for the use of phototherapy and
exchange transfusion in term and near-term newborns
are examples of the application of this principle. For
example, the American Academy of Pediatrics recom-
mends using phototherapy in a well term infant if the
TSB level is ⬃15 mg/dL (257 ␮mol/L) at age 48 hours.
Although a level of 15 mg/dL poses no imminent threat
to the infant’s well-being, at that age it is certainly well
above the 95th percentile8 and, if left untreated, might
increase to a level that is dangerous for the infant. The
suggested intervention, phototherapy, is safe and effec-
tive and, under these circumstances, is much more likely
to do good than harm.
Thus, with the exception of an early or rapidly rising
bilirubin level that suggests hemolysis, the diagnostic
definition of normal for indirect hyperbilirubinemia is of
limited value, and the risk-factor definition is unhelpful.
Currently, the most practical way of describing normal
bilirubin levels in term and near-term newborns is to use
percentiles. A therapeutic definition of normal values
can also be helpful in some circumstances.
PRETERM INFANTS
If untreated, low birth weight infants have exaggerated
and prolonged hyperbilirubinemia. Although this could
be considered physiologic because it occurs in all pre-
term infants, in very low birth weight infants, TSB levels
well within the “physiologic range” are potentially haz-
ardous17,18 and are treated with phototherapy. Thus, to-
day, the natural history of hyperbilirubinemia in the
very low birth weight infant is never observed, and
defining certain bilirubin levels as physiologic in this
population is misleading and potentially dangerous. A
TSB level of 10 mg/dL on day 4 in a 750-g neonate
requires no investigation to identify a cause for the
jaundice. Nevertheless, almost all neonatologists would
treat this infant with phototherapy, implying that this
value exceeds the therapeutic definition of normal (ie,
treatment is much more likely to do good than harm).
CONCLUSIONS
Jaundice is an important clinical sign seen in most
healthy newborns. But, just like tachypnea, tachycardia,
and polycythemia, it is a transient event. In sick ex-
tremely low birth weight infants, perfectly normal TSB
levels can be dangerous. Apparently healthy, term new-
borns, with TSB levels ⬎20 mg/dL (342 ␮mol/L) do not
have physiologic jaundice. They have hyperbiliru-
binemia, for which we often cannot find a cause. In
time, and with better techniques such as measurements
of end-tidal carbon monoxide19 or genetic testing,20 we
might identify the cause of the jaundice in more of these
infants. We should abandon the terms physiologic and
pathologic jaundice and substitute the term “newborn
jaundice” or, better, “neonatal bilirubinemia,” which
simply means what it says. If we can agree on this
terminology we can, presumably, agree on other de-
scriptors for different TSB levels in term and near-term
newborns. I suggest that hyperbilirubinemia is the ap-
propriate term for a TSB level that exceeds the 95th
percentile for the infant’s age in hours in that popula-
tion. TSB levels ⬎20 mg/dL (340 ␮mol/L) might be
called severe hyperbilirubinemia, and those ⬎25 or 30
mg/dL (428 or 513 ␮mol/L), extreme hyperbiliru-
binemia. In the low birth weight population we cannot
use population-based norms. In these infants, the ther-
apeutic definition of normal (treatment more likely to
help than harm) is probably most useful.
Application of the definitions discussed above should
help us in our management of jaundiced infants. If we
can also agree on a common terminology, we at least will
know what everyone is talking about. Calling jaundice
physiologic or pathologic does not achieve these goals.
ACKNOWLEDGMENTS
I thank Drs Tony McDonagh, Michael Kaplan, Tom
Newman, and Jon Watchko for helpful comments. Tony
McDonagh suggested the quote in the title; “What’s in a
name?” comes from Romeo and Juliet, act 2, line 43.
REFERENCES
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Co; 2005:768 – 846
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PEDIATRICS Volume 118, Number 2, August 2006 807
 What's in a Name? Physiologic and Pathologic Jaundice: The Conundrum of
Defining Normal Bilirubin Levels in the Newborn
M. Jeffrey Maisels
Pediatrics 2006;118;805
DOI: 10.1542/peds.2006-0675

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What's in a Name? Physiologic and Pathologic Jaundice: The Conundrum of
Defining Normal Bilirubin Levels in the Newborn
M. Jeffrey Maisels
Pediatrics 2006;118;805
DOI: 10.1542/peds.2006-0675

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/118/2/805

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