Pediatric Clinics of North America
Volume 48 • Number 2 • April 2001
Copyright © 2001 W. B. Saunders Company
PART 2: THE MANAGEMENT OF
BREASTFEEDING
JAUNDICE AND BREASTFEEDING
Lawrence M. Gartner 1 2 4 MD
Marguerite Herschel 1 3 MD
Departments of Pediatrics (LMG, MH)
Obstetrics and Gynecology (LMG)
3 General Care Nursery (MH), The University of Chicago, Chicago
4 Provisional Section on Breastfeeding, American Academy of Pediatrics (LMG), Elk
Grove Village, Illinois
1
2
Address reprint requests to
Lawrence M. Gartner, MD
MedWord
28398 Alamar Road
Valley Center, CA 92082-6452
e-mail: gart@midway.uchicago.edu
Jaundice is a common clinical manifestation in most newborn infants and usually
is called physiologic jaundice of the newborn. In most breastfed infants, the
duration of physiologic jaundice is increased. This condition is known as breast
milk jaundice, a normal physiologic response to the ingestion of human milk. In
addition, inadequate breastfeeding, particularly in the first week of life, can
increase the intensity of jaundice. This condition is known as breastfeeding
jaundice. The cause of jaundice in infants is often multifactorial; thus, breastfed
infants may develop exaggerated jaundice caused by various pathologic
conditions in addition to, or unrelated to, breastfeeding.
Preventing toxicity from excessive jaundice and protecting and ensuring
successful breastfeeding require an understanding of the normal and abnormal
patterns and mechanisms of jaundice in the newborn period, particularly the
mechanisms related to breastfeeding and human milk ingestion. Exaggerated
jaundice can be a warning sign that breastfeeding is not going well for the infant
and for entire populations of newborns. Optimal breastfeeding minimizes these
exaggerations.
This article first examines the normal patterns and mechanisms of physiologic
jaundice in artificially fed and breastfed infants, limiting the discussion to fullterm infants. With that understanding, the abnormal situations are then
examined. Finally, this article looks at tools for the prediction and diagnosis of
jaundice and schemes for the management of various clinical situations, all
oriented to protecting breastfeeding and minimizing the risk for bilirubin
toxicity.
PHYSIOLOGIC JAUNDICE AND BREAST MILK JAUNDICE
At birth, newborns have a cord total serum bilirubin concentration of approximately
1.5 mg/dL (25.5 mumol/L). This concentration increases during the early days to
reach a mean peak of approximately 5.5 mg/dL (93.5 mumol/L) by the third day in
white and black infants and approximately 10 mg/dL (170 mumol/L) in infants of
Asian origin[15] [24] (Fig. 1) . Following an initially rapid decrease over the next several
days in breastfed and artificially fed infants, there is then a more gradual decrease in
artificially fed infants to reach the adult normal value of approximately 1.0 mg/dL by
the end of the second week of life. This pattern usually is designated as physiologic
jaundice of the newborn.
Figure 1. Three typical patterns of total serum bilirubin during neonatal jaundice in the early
weeks of life are illustrated. Square = full-term, healthy, artificially fed newborns; triangle = fullterm, healthy, breastfed infants; X = full-term, healthy infants of Asian origin.
In breastfed infants, the pattern of hyperbilirubinemia generally is altered so that the
decrease is much more gradual, or the bilirubin concentration increases to reach a
second peak at around the 10th day of life.[5] [22] [39] Elevated bilirubin levels persist in
more than two thirds of breastfed infants into the third week of life, during which time
half of them are clinically jaundiced and have bilirubin concentrations that exceed 5
mg/dL (85 mumol/L), the level at which clinical jaundice usually can be perceived in
newborns.[1] In contrast to artificially fed infants, at least two thirds of all breastfed
infants have serum bilirubin concentrations that exceed the adult normal level of 1.5
mg/dL (25.5 mumol/L) during the third week of life. Jaundice may persist in
breastfed infants for many weeks, and hyperbilirubinemia, for as many as 3 months.
In most breastfed infants, clinical jaundice resolves by the beginning of the second
month of life. These serum bilirubin concentrations are predominantly of the
unconjugated (indirect) type, with no more than 10% direct reacting or conjugated.
Most infants with breast milk jaundice have serum bilirubin concentrations that do
not exceed 10 to 12 mg/dL (170-204 mumol/L), but higher values can be observed
and rarely infants with breast milk jaundice may reach 22 to 24 mg/dL (375-410
mumol/L). Breastfed infants with this pattern of prolonged exaggerated
hyperbilirubinemia who are healthy and thriving are considered to have breast milk
jaundice. Prolonged jaundice, defined as a serum total bilirubin concentration of
more than 5.9 mg/dL (100 mumol/L) at day 28 also has been shown to be associated
with the genotype for the benign inherited condition, Gilbert's syndrome, in some
breastfed infants.[35] One or both parents may be found to have slightly elevated
unconjugated bilirubin concentrations.
Breast milk jaundice is a normal prolongation of physiologic jaundice caused by a
factor in human milk. It has been suggested that this prolongation of physiologic
jaundice in breastfed infants may provide protective effects for newborns by the
antioxidant effects of bilirubin, compensating for the relative deficiency of
endogenous antioxidants in newborns.[7] [20] [40] Despite the attractiveness and
intuitiveness of this theory, there is insufficient evidence to prove that
hyperbilirubinemia protects infants against tissue injury or disease. Breast milk
jaundice occurs in infants of all racial and ethnic groups, including those of Asian
origin, having a similar presentation worldwide.
MECHANISM OF PHYSIOLOGIC AND BREAST MILK JAUNDICE
Increased bilirubin synthesis caused by a shortened erythrocyte life span, increased
blood volume, higher hemoglobin concentrations, and increased turnover of
nonhemoglobin heme proteins (e.g., cytochromes or myoglobin), combined with
specific deficiencies in hepatic uptake and conjugation of bilirubin, result in retention
of unconjugated bilirubin in the circulation and in tissues throughout the body,
including skin[36] (Fig. 2) . Heme oxygenase in reticuloendothelial cells in all tissues,
but predominantly in spleen and liver, converts heme to the water-soluble, green
pigment biliverdin, with release of iron. In addition, each molecule of heme degraded
yields one molecule of carbon monoxide, which is excreted in expired air.[6] A second
enzyme, biliverdin reductase, immediately reduces biliverdin to the water-insoluble,
unconjugated bilirubin. Transport of bilirubin to the liver, the primary site of its
disposal, requires binding to a transport protein, preferentially albumin, or to another
vehicle, such as the erythrocyte.[11] Reduction in affinity and capacity of albumin to
bind bilirubin in newborns may be a factor that increases the risk for bilirubin
encephalopathy (kernicterus). [12] [14] [30] Uptake of bilirubin by the liver cell is limited in
newborns because of a reduction in the concentration of ligandin, a bilirubin-binding
protein within the liver cell.[29] Hepatic conjugation of bilirubin is reduced because of a
deficiency of the enzyme glucuronyl transferase, which converts insoluble
unconjugated bilirubin to bilirubin glucuronide, the water-soluble conjugated
bilirubin. Conjugation is an essential step for the excretion of bilirubin from the liver
cell into bile. Not only is bilirubin poorly conjugated in newborns but also newborns
attach only one glucuronide molecule to each bilirubin molecule, whereas in adults,
two glucuronide molecules attach to each bilirubin.[10] The mono- and the
diglucuronide are equally soluble and readily excreted, but the monoglucuronide is
less stable and more readily hydrolyzed back to unconjugated bilirubin in the
intestine.[28] This occurrence is of importance because unconjugated bilirubin is readily
absorbed across the intestinal mucosa to return to the liver and general circulation by
the portal circulation, known as the enterohepatic circulation of bilirubin. This
increase in hydrolysis of bilirubin glucuronide is further promoted by the 10-fold
greater concentration of the enzyme beta-glucuronidase in the mucosa and lumen of
the intestine in newborns compared with that of adults.[13] The increased enterohepatic
circulation of bilirubin, combined with the increased synthesis of bilirubin, exceeds
the capacity of the hepatic uptake and conjugation mechanisms, resulting in retention
of unconjugated bilirubin and the manifestation known as physiologic jaundice of the
newborn.[24]
Figure 2. Bilirubin metabolism and transport. The synthesis of bilirubin from heme occurs in the
reticuloendothelial cells. Synthesis of new bilirubin and bilirubin returning from the intestine by
way of the enterohepatic circulation constitute the load of bilirubin presented to the liver for
uptake. Bilirubin that has entered the liver is conjugated to form the water soluble conjugated bilirubin
that then can be excreted into the bile duct, flowing into the duodenum of the small intestine.
Hydrolysis of conjugated bilirubin returns some of the bilirubin to the unconjugated form, allowing its
reabsorption across the intestinal mucosa to enter the portal circulation for return to the liver: the
enterohepatic circulation of bilirubin.
Breast milk jaundice is the prolongation of increased enterohepatic circulation of
bilirubin caused by a factor in human milk that promotes intestinal absorption. This
occurrence has been demonstrated in two studies in which human milk has been fed to
adult rats.[1] [23] The factor has not been identified, and the precise mechanism by which
it enhances absorption is unknown. Early studies of breast milk jaundice indicated
that human milk from mothers whose infants had high serum levels of bilirubin
contained high concentrations of pregnane,3(alpha)20(beta),diol, an abnormal
metabolite of progesterone.[5] This metabolite was shown to inhibit bilirubin
conjugation in vitro. In one study,[4] its administration to human newborns increased
serum bilirubin concentrations significantly. Subsequent studies have not confirmed
the role of human milk or this steroid metabolite in the cause of breast milk
jaundice.[1] It also has been postulated that human milk beta-glucuronidase contributes
to the development of breast milk jaundice by increasing the hydrolysis of bilirubin
glucuronide to bilirubin and its subsequent reabsorption in the intestine[25] ; however,
subsequent studies have not supported this hypothesis.[27] [43]
ABNORMAL PATTERNS OF JAUNDICE
Although prolongation of physiologic jaundice after 5 days of age is recognized as a
normal occurrence in most breastfed infants, some, but not all, studies also have
shown that serum bilirubin concentrations in breastfed infants in the first 5 days of life
also are increased compared with artificially fed infants. A meta-analysis of 25 studies
showed that 13% of breastfed infants had peak serum bilirubin concentrations of 12
mg/dL (204 mumol/L) or higher during the first 5 days of life compared with only 4%
of artificially fed infants.[38] Unfortunately, the meta-analysis and most of the original
articles failed to examine or report specific breastfeeding behaviors, such as time of
initiation, frequency, and water supplementation of the breastfeeding. Study of a
single, large, US population yielded similar results (9% of breastfed and 2.2% of
artificially fed >12.9 mg/dL) and showed a significantly greater average weight loss
of 6.9% in breastfed infants compared with 4.2% in the artificially fed infants.[32] This
finding suggests that milk volume and, therefore, caloric intake, was less in the
breastfed infants than in the artificially fed infants. In contrast, a study of similar
design from Italy found no significant difference in serum bilirubin concentrations in
the first 5 days (4.6%; 3.5%) and identical weight loss in both groups (4.2%).[37]
Breastfeeding has not always been found to be associated with increased weight loss,
and one study[21] found that greater weight loss in both breastfed and artificially fed
infants correlated with increased serum bilirubin concentrations. Studies in which
breastfed and artificially fed infants have similar and low serum bilirubin
concentrations in the first 5 days are characterized by breastfeeding behaviors that are
more optimal, including initiation of breastfeeding in the first hour of life, continuous
rooming-in with unlimited time at each breast, a breastfeeding frequency of 10 to 12
times per day starting on the first day, prompt responses to early hunger cues, and
absence of all supplementation. Reduced breastfeeding frequency and
supplementation with water or glucose water have been associated with increased
serum bilirubin concentrations in the first 5 days of life and development of
breastfeeding jaundice or what some investigators have suggested is a more
appropriate designation: breast-nonfeeding jaundice.[17] [18] [19]
Weight loss of greater than 5% to 7% in breastfed infants suggests that breastfeeding
may not be proceeding well. Early formal evaluation of the breastfeeding, followed by
correction of identified problems (see article by Wight, page 321) can minimize
excessive increases in serum bilirubin and subsequent need for either formula
supplementation, phototherapy, or exchange transfusion. Significant jaundice caused
by inadequate breast milk, especially when hospital readmission occurs, also can lead
to permanent loss of breastfeeding. Jaundice in breastfed infants is the leading reason
for hospital readmission of infants in the early weeks of life and often is associated
with excessive weight loss and poor breastfeeding.
Breastfeeding jaundice or inadequate intake of human milk is the neonatal equivalent
of the adult disorder known as starvation jaundice. [9] [41] [42] Twenty-four hours of no
caloric intake, despite adequate water, leads to a doubling of serum unconjugated
bilirubin concentrations in nearly all healthy adults. The same phenomenon is seen in
most nonhuman mammals and has been attributed to various mechanisms, including
an increase in intestinal absorption of unconjugated bilirubin. Rats who were denied
feed for 48 hours but had free access to water more than doubled their absorption of a
test dose of unconjugated bilirubin instilled into their duodenums.[23] Insufficient food
intake in newborns also may delay passage of meconium, which is rich in
unconjugated bilirubin, and lead to increased bilirubin absorption.[13] [16]
PREVENTION
Although low to moderate levels of jaundice and hyperbilirubinemia are normal for
all infants and especially for breastfed infants, excessive levels of hyperbilirubinemia
raise concern about the possible presence of pathologic conditions and the risk for
bilirubin toxicity (bilirubin encephalopathy; kernicterus). The excessive levels of
bilirubin seen in some breastfed infants are the result of inadequate intake of human
milk resulting from a problem in breastfeeding management or in maternal milk
production or infant suck and swallowing. There may be other contributory factors,
such as maternal diabetes or gestational age of less than 38 weeks.[33] For most infants,
initiation of breastfeeding in the first hour of life followed by 10 to 12 breastfeeds per
day with good positioning and latch-on results in adequate caloric intake and
minimization of the levels of bilirubin during the early days of life and in later weeks.
The development of elevated levels of unconjugated bilirubin in the first week of life
because of inadequate intake or pathologic conditions tends to increase the levels of
bilirubin during the later weeks when breast milk jaundice manifests. Because breast
milk jaundice is caused by recycling of bilirubin through the enterohepatic
circulation, infants with a high early serum bilirubin level and, therefore, a larger total
body bilirubin pool, have a much greater increase in bilirubin pool size in the later
weeks of the first month because of greater availability of bilirubin for reabsorption
across the intestinal mucosa. Early optimal breastfeeding management that results in
lower early levels also minimizes the later levels and prevents second- and third-week
serum bilirubin concentrations that require diagnostic workup and specific therapy.
An additional preventive measure to ensure optimal human milk intake and to
minimize serum bilirubin concentrations includes avoidance of supplementation with
water or glucose water. Supplementation reduces breastfeeding frequency and milk
production, causing decreased caloric intake or starvation. Newborn infants receive
adequate water in human milk to meet their metabolic needs, which are minimal
because of their relatively large water volume at birth. If an infant has adequate renal
function as indicated by having had an appropriate volume of amniotic fluid in utero,
it is not necessary to monitor urine output in the first days of life. Undue concern over
perceived inadequate volume of urine output often leads to water supplementation of
the healthy newborn and increasing jaundice. Excessive hyperbilirubinemia causes
lethargy and poor feeding in some infants, further reducing breastfeeding frequency,
duration, and milk production. This vicious cycle ultimately can lead to termination of
breastfeeding or to severe inanition.
DIAGNOSIS AND MANAGEMENT
Early discharge at less than 72 hours of life of infants from hospital has raised
concerns about the ability to evaluate breastfeeding and the opportunity to evaluate
infants for jaundice.[33] Increased surveillance of both has been suggested. Formal
observation of breastfeeding with evaluation of effectiveness of breastfeeding and
milk transfer at regular intervals throughout the first days of life can identify
breastfeeding problems sufficiently early to ensure correction of problems.[3]
Identification of infants who are truly failing to obtain adequate milk intake despite
such measures may indicate the need to use other means to feed pumped maternal
milk or artificial milk by cup, supplementer, spoon, or bottle. With good breastfeeding
policies and support, the need for supplementation is rare. A strong recommendation
has been made that all breastfed infants be evaluated by a trained observer within 2 or
3 days after discharge from the hospital.[3] Clinical evaluation of jaundice and
observation of breastfeeding, together with weighing and physical examination,
identify infants with breastfeeding problems leading to inadequate intake and
exaggeration of jaundice. Correction of the feeding problem and, in some cases,
laboratory examination may be required. Early postdischarge visits are advocated for
artificially fed infants to identify problems with hyperbilirubinemia sufficiently early
to intervene before the development of bilirubin encephalopathy.
The ability of various individuals to evaluate the severity of clinical jaundice varies
widely and is influenced by lighting intensity and color and the experience of the
observer. Daylight on a clear day provides the best lighting for evaluation of
jaundice. Infants with minimal hyperbilirubinemia typically have jaundice of the
face and upper thorax. More severe degrees of jaundice are associated with caudal
progression.[26] Jaundice involving the lower body and extremities indicates need for
laboratory confirmation. Despite such clinical correlations, even experienced
clinicians remain uncertain about their ability to estimate serum bilirubin levels. A
recommendation has been made to screen all infants for total serum bilirubin level
before hospital discharge to identify infants at greater risk for hyperbilirubinemia who
must have close follow-up.[8] One noninvasive tool for transcutaneous measurement of
bilirubin (BilivChek, Respironics, Marietta, GA) is a reliable screening method for
identifying infants who need additional workup and close follow-up for diagnosis and
management of an elevated bilirubin level. This device has clinically proven accuracy
in all races, at 32 to 42 weeks' gestation to 8 days of age, in the bilirubin range of 0 to
20 mg/dL (0-340 mumol/L). It is less accurate and should not be used after an infant
has been exposed to phototherapy or exchange transfusion.
The major diagnostic challenge in infants with increased serum bilirubin is to identify
hemolysis because this condition usually indicates a greater likelihood of a steeper
increase and increased risk for kernicterus. Serum bilirubin concentrations in excess
of 5 mg/dL (85 mumol/L) during the first 24 hours of life or more than 12 mg/dL (204
mumol/L) at 48 hours or less usually suggest the need for additional laboratory
studies. Maternal and infant major blood group and Rh type, direct Coombs' test,
hematocrit or hemoglobin, and examination of erythrocyte morphology are usually
adequate for the initial laboratory evaluation. A reticulocyte count may not be helpful
because it may be elevated because of stress and hypoxia or may not increase even
with significant hemolysis, at least initially. Another new, noninvasive, commercially
available technique to assist in the identification of significant hemolysis is the
portable expired carbon monoxide breath analyzer (CO-Stat End Tidal Breath
Analyzer, Natus Medical, San Carlos, CA). One molecule of carbon monoxide (CO)
is formed for every molecule of bilirubin produced by the degradation of heme.
Exhaled CO provides an accurate measure of bilirubin production.[6] The CO level is
expressed in parts per million, corrected for ambient air, and is measured simply and
rapidly by a small catheter placed a maximum of 7 mm into the infant's nose. This
technique, coupled with use of transcutaneous bilirubin evaluation, is a new approach
to the early evaluation and diagnosis of jaundice in infants. It provides an opportunity
to evaluate jaundice in the breastfed infant more accurately and to specifically
differentiate most causes of exaggerated jaundice caused by pathologic conditions
from the normally occurring increases caused by breastfeeding later in the newborn
period. It also provides a means for differentiation of early exaggerated jaundice
caused by poor caloric intake from that caused by hemolysis. Although breast milk
feeding is associated normally with prolonged jaundice, the clinician must be sure
that the infant does not have hypothyroidism or other pathologic condition if the
infant is jaundiced beyond 2 weeks. Jaundice that persists beyond 3 weeks is an
indication for a fractionated serum bilirubin level to assess the level of conjugated
bilirubin.[31]
BILIRUBIN ENCEPHALOPATHY
Bilirubin encephalopathy (kernicterus) has been observed in breastfed infants in the
absence of hemolysis or other specific pathologic conditions.[34] Case reports suggest
that these infants usually were suffering from a prolonged period of inadequate intake
and were not observed by a knowledgeable physician or other health care provider.
Severe and prolonged starvation can increase serum unconjugated bilirubin
concentrations to levels in excess of 25 mg/dL (425-510 mumol/L). At these levels,
kernicterus can occur and exceed levels that have been observed in breast milk
jaundice in thriving infants. Early and competent evaluation of breastfeeding can
prevent such risks in breastfed infants.
Another group of breastfed infants who seem to be at risk for kernicterus are
borderline premature infants (born at 36-37 weeks' gestational age) who are not
nursing adequately and are therefore at greater risk for breastfeeding jaundice.
Premature infants have less mature hepatic mechanisms for disposal of bilirubin and
increased risk for kernicterus at levels that may be safe for more mature infants.
Elevations of total serum bilirubin in excess of 20 mg/dL (340 mumol/L) may
indicate the need for aggressive therapy, including exchange transfusion, in this group
of infants.
Healthy, full-term infants (born at or beyond 38 weeks' gestational age) whose serum
bilirubin levels increase but remain at less than 20 mg/dL (340 mumol/L) at 72 hours
and beyond do not require phototherapy or other specific therapy other than careful
evaluation of feeding and milk intake followed by corrective action to ensure
adequate intake. In these infants, the use of phototherapy or supplementation of
breastfeeding at levels of less than 20 mg/dL (340 mumol/L) has not been shown to
be useful and may interfere with the establishment of good breastfeeding by
separating mother and infant and by interfering with the infant's development of good
breastfeeding practices. The reader is referred to the American Academy of Pediatrics'
Practice Parameter on the Management of Hyperbilirubinemia in healthy, full-term
newborn infants.[2]
SUMMARY
Optimal management of breastfeeding does not eliminate neonatal jaundice and
elevated serum bilirubin concentrations. Rather, it leads to a pattern of
hyperbilirubinemia that is normal and, possibly, beneficial to infants. Excessive
frequency of exaggerated jaundice in a hospital or community population of
breastfed infants may be a warning that breastfeeding policies and support are not
ideal for the establishment of good breastfeeding practices. The challenge to clinicians
is to differentiate normal patterns of jaundice and hyperbilirubinemia from those that
indicate an abnormality or place an infant at risk.
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