Background

Arias first described breast milk jaundice (BMJ) in 1963. Breast milk jaundice is a type of
neonatal jaundice associated with breastfeeding. It is characterized by indirect
hyperbilirubinemia in a breastfed newborn that develops after the first 4-7 days of life,
persists longer than physiologic jaundice, and has no other identifiable cause. It should be
differentiated from breastfeeding jaundice, which manifests in the first 3 days of life and is
caused by insufficient production or intake of breast milk.
Pathophysiology

Breast milk jaundice is a common cause of indirect hyperbilirubinemia. The etiology of

breast milk jaundice is not clearly understood, but the following factors have been
suggested to play a role:

An unusual metabolite of progesterone (pregnane-3-alpha 20 beta-diol),

a substance in the breast milk that inhibits uridine diphosphoglucuronic
acid (UDPGA) glucuronyl transferase

Increased concentrations of nonesterified free fatty acids that inhibit

hepatic glucuronyl transferase

Increased enterohepatic circulation of bilirubin due to (1) increased

content of beta glucuronidase activity in breast milk and, therefore, the
intestines of the breastfed neonate and (2) delayed establishment of
enteric flora in breastfed infants

Defects in uridine diphosphate-glucuronyl transferase ( UGT1A1) activity

in infants who are homozygous or heterozygous for variants of the
Gilbert syndrome promoter and coding region polymorphism.

Reduced hepatic uptake of unconjugated bilirubin due to a mutation in

the solute carrier organic anion transporter protein SLCO1B1.

Inflammatory cytokines in human milk, especially interleukin (IL)-1 beta

and IL-6, are increased in individuals with breast milk jaundice and are
known to be cholestatic and reduce the uptake, metabolism, and
excretion of bilirubin. [1]

High epidermal growth factor (EGF) levels in breast milk may be

responsible for jaundice in these neonates. EGF is responsible for growth,
proliferation, and maturation of the GI tract in newborns and is vital for is
adaptation after birth. Higher EGF serum and breast milk levels were
noted in patients with breast milk jaundice. [2] The reduced GI motility

and increased bilirubin absorption and uptake are thought to be the

mechanisms.

Serum alpha feto-protein levels were found to be higher in infants with

breast milk jaundice. [3] The exact significance of this finding is unknown.

Breast milk is an important source of bacteria in establishing infantile gut

flora. A recent study demonstrated that Bifidobacterium species in
breast milk may protect against breast milk jaundice. The exact
significance of this finding is unknown. [4]

Please see Neonatal Jaundice for an in-depth review of the pathophysiology of

hyperbilirubinemia.
Epidemiology
Frequency
United States

Jaundice occurs in 50-70% of newborns. Moderate jaundice (bilirubin level >12 mg/dL)
develops in 4% of bottle-fed newborns, compared to 14% of breastfed newborns. Severe
jaundice (bilirubin level >15 mg/dL) occurs in 0.3% of bottle-fed newborns, compared to
2% of breastfed newborns. A strong familial predisposition is also suggested by the
recurrence of breast milk jaundice in siblings. In the exclusively breast fed infant, the
incidence during the first 2-3 weeks has been reported to be 36%.[5]
International

International frequency is not extensively reported but is thought to be similar to that in the
United States.
Mortality/Morbidity

The prognosis is excellent, although jaundice in breastfed infants may persist for as long as
12 weeks.
Breast milk jaundice in otherwise healthy full-term infants rarely causes kernicterus
(bilirubin encephalopathy). Case reports suggest that some breastfed infants who suffer
from prolonged periods of inadequate breast milk intake and whose bilirubin levels
exceeded 25 mg/dL may be at risk of kernicterus. Kernicterus (bilirubin encephalopathy) is
a preventable cause of cerebral palsy. Another group of breastfed infants who may be at risk
of complications is late preterm infants who are nursing poorly.

Bilirubin encephalopathy (kernicterus) may occur in exclusively breastfed infants in the

absence of hemolysis or other specific pathologic conditions. Distinguishing between
breastfeeding jaundice and breast milk jaundice is important, because bilirubin-induced
encephalopathy occurs more commonly in breastfeeding jaundice. Near-term infants are
more likely to manifest breastfeeding jaundice because of difficulty achieving adequate
nursing, greater weight loss, and hepatic immaturity.
Race

Whether racial differences are observed in breast milk jaundice is unclear, although an
increased prevalence of physiologic jaundice is observed in babies of Chinese, Japanese,
Korean, and Native American descent.
Sex

No sex predilection is known.

Age

Breast milk jaundice manifests after the first 4-7 days of life and can persist for 3-12 weeks.

History
Aspects of history may include the following:

Physiologic jaundice usually manifests after the first 24 hours of life. This can be
accentuated by breastfeeding, which, in the first few days of life, may be associated
with suboptimal milk and suboptimal caloric intake, especially if milk production is
delayed. This is known as breastfeeding jaundice. Jaundice that manifests before the
first 24 hours of life should always be considered pathologic until proven otherwise.
In this situation, a full diagnostic workup with emphasis on infection and hemolysis
should be undertaken.

True breast milk jaundice (BMJ) manifests after the first 4-7 days of life. A second
peak in serum bilirubin level is noted by age 14 days.

In clinical practice, differentiating between physiologic jaundice from breast milk

jaundice is important so that the duration of hyperbilirubinemia can be predicted.
Identifying the infants who become dehydrated secondary to inadequate
breastfeeding is also important. These babies need to be identified early and given
breastfeeding support and formula supplementation as necessary. Depending on
serum bilirubin concentration, neonates with hyperbilirubinemia may become
sleepy and feed poorly.

Physical
The following physical findings may be noted:

Clinical jaundice is usually first noticed in the sclera and the face. Then it
progresses caudally to reach the abdomen and extremities. Gentle pressure on the
skin helps to reveal the extent of jaundice, especially in darker-skinned babies;
however, clinical observation is not an accurate measure of the severity of the
hyperbilirubinemia.

A rough correlation is observed between blood levels and the extent of jaundice
(face, approximately 5 mg/dL; mid abdomen, approximately 15 mg/dL; soles, 20
mg/dL). Therefore, clinical decisions should always be based on serum levels of
bilirubin. Skin should have normal perfusion and turgor and show no petechiae.

Neurologic examination, including neonatal reflexes, should be normal, although

the infant may be sleepy. Muscle tone and reflexes (eg, Moro reflex, grasp, rooting)
should be normal.

Evaluate hydration status by an assessment of the percentage of birth weight that

may have been lost, observation of mucous membranes, fontanelle, and skin turgor.

Causes
The following causes may be noted:

Supplementation of breastfeeding with dextrose 5% in water (D5W) can actually

increase the prevalence or degree of jaundice.

Delayed milk production and poor feeding lead to decreased caloric intake,
dehydration, and increased enterohepatic circulation, resulting in higher serum
bilirubin concentration.

The biochemical cause of breast milk jaundice remains under investigation. Some
research reported that lipoprotein lipase, found in some breast milk, produces
nonesterified long-chain fatty acids, which competitively inhibit glucuronyl
transferase conjugating activity.

Glucuronidase has also been found in some breast milk, which results in jaundice.

Decreased uridine diphosphate-glucuronyl transferase (UGT1A1) activity may be

associated with prolonged hyperbilirubinemia in breast milk jaundice.[6] This may be

comparable to what is observed in patients with Gilbert syndrome.[7] Genetic

polymorphisms of the UGT1A1 promoter, specifically the T-3279G and the
thymidine-adenine (TA)7 dinucleotide repeat TATAA box variants, were found to be
commonly inherited in whites with high allele frequency. These variant promoters
reduce the transcriptional UGT1A1 activity. Similarly, mutations in the coding
region of the UGT1A1 (eg, G211A, C686A, C1091T, T1456G) have been described
in East Asian populations; these mutations reduce the activity of the enzyme and are
a cause of Gilbert syndrome.[8]

The G211A mutation in exon 1 (Gly71Arg) is most common, with an allele

frequency of 13%. Coexpression of these polymorphism in the promoter and in the
coding region are common and further impair the enzyme activity.[9]

A 2011 study has shown that neonates with nucleotide 211GA or AA variation in
UGT1A1 genotypes had higher peak serum bilirubin levels than those with GG.
This effect was more pronounced in the exclusively breast fed infants compared
with exclusively or partially formula fed neonates.[10]

The organic anion transporters (OATPs) are a family of multispecific pumps that
mediate the Na- independent uptake of bile salts and broad range of organic
compounds. In humans, 3 liver-specific OATPs have been identified: OATP-A,
OATP-2, and OATP-8. Unconjugated bilirubin is transported in the liver by OATP2. A genetic polymorphism for OATP-2 (also known as OATP-C) at nucleotide 388
has been shown to correlate with 3-fold increased risk for development of neonatal
jaundice (peak serum bilirubin level of 20 mg/dL) when adjusted for covariates.[11, 12]
When the combination of the OATP-2 gene polymorphism with the variant
UGT1A1 gene at nucleotide 211 further increased the risk to 22-fold (95% CI, 5.588). When these genetic variants were combined with breast milk feeding, the risk
for marked neonatal hyperbilirubinemia increased further to 88-fold (95%CI, 12.5642.5).

In a 2012 study, researchers measured antioxidant properties of breast milk.

Bilirubin is a known antioxidant in vitro. It is suggested that there is a homeostasis
maintained by the external sources such as breast milk and internal production of
antioxidants like bilirubin in the body. In this study, in the breast milk of mothers of
newborns with prolonged jaundice, oxidative stress was found to be increased and
the protective antioxidant capacity was found to be decreased. The exact clinical
significance of this finding is not known.[13]

Diagnostic Considerations
Important considerations

Differentiate breast milk jaundice (BMJ) from pathologic jaundice.

Appropriately treat elevated bilirubin levels in a timely manner
Identify and treat inadequate breastfeeding; avoid dehydration.
Treat preterm infants (estimated gestational age < 38 wk at birth) with phototherapy at
lower bilirubin levels (see Neonatal Jaundice).
Other problems to be considered
The following conditions should also be considered in patients with suspected breast milk
jaundice:

Hemolytic anemia (RBC membrane defects: spherocytosis, acanthocytosis,

ovalocytosis; RBC enzyme defects, hemoglobinopathies)

Blood type incompatibility (ABO and minor group antigens)

Large cephalhematoma

Hypothyroidism

Urinary tract infections

Sepsis

Gilbert syndrome

Early galactosemia

Differential Diagnoses

Anemia, Acute

Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)

Hemolytic Disease of Newborn

Hypothyroidism

Neonatal Jaundice

Neonatal Sepsis

Polycythemia

Polycythemia of the Newborn

Laboratory Studies
Breast milk jaundice (BMJ) is a diagnosis of exclusion. Note the following:

Detailed history and physical examination showing that the infant is thriving and
that lactation is well established are key elements to diagnosis. Breastfed babies
should have 3-4 transitional stools and 6-7 wet diapers per day and should have
regained birth weight by the end of the second week of life or demonstrate a weight
gain of 1 oz/d.

Measure total serum bilirubin concentration in neonates who have jaundice that has
progressed from the face to the chest and in neonates at risk for hemolytic disease of
the newborn.

Consider obtaining the tests discussed below if serum bilirubin levels are greater than 12
mg/dL (170 mol/L). A total serum bilirubin concentration that rises faster than 5 mg/dL/d
(85 mol/L/d) or jaundice before 24 hours of life suggests pathologic jaundice.
A level of conjugated bilirubin greater than 2 mg/dL (34 mol/L) suggests cholestasis,
biliary atresia, or sepsis (see Neonatal Jaundice).
CBC count with reticulocyte count findings are as follows:

Polycythemia (hematocrit level, >65%)

Anemia (hematocrit level, < 40%)

Sepsis (WBC count, < 5 K/mL or >20 K/mL) with immature to total neutrophil ratio
greater than 0.2

Urine specific gravity can be useful in the assessment of hydration status.

If hemolysis is suspected, consider the following tests:

Blood type to evaluate for ABO, Rh or other blood group incompatibility

Coombs test, as well as an elution test for antibodies against A or B, to evaluate for
immune mediated hemolysis

Peripheral smear to look for abnormally shaped RBCs (ovalocytes, acanthocytes,

spherocytes, schistocytes)

Glucose-6-phosphate dehydrogenase (G-6-PD) screen, especially if ethnicity

consistent

Factors that suggest possibility of hemolytic disease include the following:

Family history of hemolytic disease

Onset of jaundice before 24 hours of life

Rise in serum bilirubin levels of more than 0.5 mg/dL/h

Pallor, hepatosplenomegaly

Rapid increase in serum bilirubin level after 24-48 hours (G-6-PD deficiency)

Ethnicity suggestive of G-6-PD deficiency

Failure of phototherapy to lower bilirubin level

If sepsis is suspected, consider the following tests:

Blood culture

WBC differential

Platelet count

Urine analysis and culture

Factors that suggest the possibility of sepsis include the following:

Poor feeding

Vomiting

Lethargy

Temperature instability

Apnea

Tachypnea

Signs of cholestatic jaundice that suggest the need to rule out biliary atresia or other causes
of cholestasis include the following:

Dark urine or urine positive for bilirubin

Light-colored stools

Persistent jaundice for more than 3 weeks

The follow-up includes the state newborn screen for galactosemia and hypothyroidism.

Medical Care
Treatment recommendations in this section apply only to healthy term infants with no signs
of pathologic jaundice and are based on the severity of hyperbilirubinemia. In preterm,
anemic, or ill infants and those with early (< 24 h) or severe jaundice (>25 mg/dL or 430
mol/L), different treatment protocols should be pursued (see Neonatal Jaundice).
For healthy term infants with breast milk or breastfeeding jaundice and with bilirubin levels
of 12 mg/dL (170 mol/L) to 17 mg/dL, the following options are acceptable:

Increase breastfeeding to 8-12 times per day and recheck the serum bilirubin level
in 12-24 hours. The mother should be reassured about the relatively benign nature
of breast milk jaundice (BMJ). This recommendation assumes that effective
breastfeeding is occurring, including milk production, effective latching, and
effective sucking with resultant letdown of milk. Breastfeeding can also be
supported with manual or electric pumps and the pumped milk given as a
supplement to the baby.

Continue breastfeeding and supplement with formula.

Temporary interruption of breastfeeding is rarely needed and is not recommended

unless serum bilirubin levels reach 20 mg/dL (340 mol/L).

For infants with serum bilirubin levels from 17-25 mg/dL (294-430 mol/L), add
phototherapy to any of the previously stated treatment options. The reader is referred to the

American Academy of Pediatrics' practice parameter on the management of

hyperbilirubinemia in healthy full-term newborn infants.[14]
The most rapid way to reduce the bilirubin level is to interrupt breastfeeding for 24 hours,
feed with formula, and use phototherapy; however, in most infants, interrupting
breastfeeding is not necessary or advisable.
Phototherapy can be administered with standard phototherapy units and fiberoptic blankets.
See the image below.

The graph represents indications for phototherapy and

exchange transfusion in infants (with a birthweight of 3500 g) in 108 neonatal ICUs. The
left panel shows the range of indications for phototherapy, whereas the right panel shows
the indications for exchange transfusion. Numbers on the vertical axes are serum bilirubin
concentrations in mg/dL (lateral) and mmol/L (middle). In the left panel, the solid line
refers to the current recommendation of the American Academy of Pediatrics (AAP) for
low-risk infants, the line consisting of long dashes (- - - - -) represents the level at which the
AAP recommends phototherapy for infants at intermediate risk, and the line with short
dashes (-----) represents the suggested intervention level for infants at high risk. In the right
panel, the dotted line (......) represents the AAP suggested intervention level for exchange
transfusion in infants considered at low risk, the line consisting of dash-dot-dash (-.-.-.-.)
represents the suggested intervention level for exchange transfusion in infants at
intermediate risk, and the line consisting of dash-dot-dot-dash (-..-..-..-) represents the
suggested intervention level for infants at high risk. Intensive phototherapy is always
recommended while preparations for exchange transfusion are in progress. The box-andwhisker plots show the following values: lower error bar = 10th percentile; lower box
margin = 25th percentile; line transecting box = median; upper box margin = 75th
percentile; upper error bar = 90th percentile; and lower and upper diamonds = 5th and 95th
percentiles, respectively.
Note the following:

Fiberoptic phototherapy can often be safely administered at home, which may allow
for improved infant-maternal bonding.

Although sunlight provides sufficient irradiance in the 425-nm to 475-nm band to

provide phototherapy, practical difficulties involved in safely exposing a naked
newborn to sunlight, either indoors or outdoors (and avoiding sunburn), preclude
the use of sunlight as a reliable phototherapy tool; therefore, it is not recommended.

Phototherapy can be discontinued when serum bilirubin levels drop to less than 15
mg/dL (260 mol/L).

Average bilirubin level rebound has been shown to be less than 1 mg/dL (17
mol/L); therefore, rechecking the level after discontinuation of phototherapy is not
necessary unless hyperbilirubinemia is due to a hemolytic process.

For an in-depth discussion of phototherapy, see Neonatal Jaundice.

Consultations
The following consultations may be indicated:

Consider consultation with a neonatologist when serum bilirubin level approaches

20 mg/dL (430 mol/L) or when signs and symptoms suggest pathological jaundice
and the rate of rise in the serum bilirubin level is more than 0.5 mg/dL/h.

A consultation with a lactation specialist is recommended in any breastfed baby who

has jaundice. The expertise of lactation consultants can be extremely helpful,
especially in situations in which inadequate breastfeeding is contributing to the
jaundice.

Diet
Continue breastfeeding, if possible, and increase frequency of feeding to 8-12 times per
day. Depending on maternal preference, breastfeeding can be supplemented or replaced by
formula at the same frequency. Supplementation with dextrose solution is not
recommended because it may decrease caloric intake and milk production and may
consequently delay the drop in serum bilirubin concentration. Breastfeeding can also be
supplemented by pumped breast milk.

Activity
No restrictions are necessary. Encourage parents to remove the child from the warmer or
infant crib for feeding and bonding. Fiberoptic blankets allow holding and breastfeeding
without interruption in treatment.

Further Inpatient Care

If the patient has not been discharged with the parent, monitoring daily weights and serum
bilirubin concentration for the need for phototherapy as well as assessment of caloric intake
are important. Once serum bilirubin concentration is determined to be within a safe range

(< 20 mg/dL) and is not rapidly rising, home phototherapy is an option to consider as long
as thorough outpatient follow-up (home visiting nursing assessment or office check-up and
bilirubin level monitoring) are feasible.
Weight monitoring is very important in breastfed infants to avoid prolonged and severe
jaundice, as well as to avoid hypernatremic dehydration. The general standard states that
loss of 10% of birth weight is considered to be significant.
A reference chart for relative weight change to detect hypernatremic dehydration has been
proposed.[15]

Further Outpatient Care

The American Academy of Pediatrics Safe and Healthy Begininngs Project has been
established to facilitate implementation of the 2004 guidelines for management of
hyperbilirubinemia using a systems-based approach. The 3 key aspects of this project
include (1) assessment of risk for severe hyperbilirubinemia before hospital discharge, (2)
breastfeeding support, and (3) care coordination between the nursery and primary care.[16]
If the infant is treated on an outpatient basis, measure serum bilirubin levels either daily in
the clinic or in the home with home-health nurses until the bilirubin level is less than 15
mg/dL (260 mol/L).

Transfer
Transfer infants with pathologic jaundice or bilirubin levels greater than 20 mg/dL to a
center capable of performing exchange transfusions.

Deterrence/Prevention
Keys to deterrence and prevention include the following:

Poor caloric intake associated with insufficient breastfeeding contributes to the

development of severe breast milk jaundice (BMJ). The first step toward successful
breastfeeding is to make sure that mothers nurse their infants at least 8-12 times per
day for the first several days starting from the first hour of life. The whey portion of
human milk contains a feedback inhibitory peptide of lactogenesis; hence, effective
emptying of the breast with each feeding results in successful lactation.

Infants who nursed more than 8 times during the first 24 hours had earlier
meconium passage, reduced maximum weight loss, increased breast milk intake on
days 3 and 5, and lower serum bilirubin levels and significantly lower incidence of
severe hyperbilirubinemia (>15 mg/dL) on day 6.

In a recent double-blind controlled study, beta-glucuronidase inhibition with Laspartic acid and enzymatically hydrolyzed casein in exclusively breastfed babies
resulted in reduction in peak serum bilirubin level by 70% in first week of life.[17]

According to the latest clinical practice guidelines for the management of

hyperbilirubinemia in the newborn aged 35 or more weeks' gestation, exclusive
breastfeeding is a major risk factor for severe hyperbilirubinemia and all infants
should be evaluated for the risk of subsequent hyperbilirubinemia by plotting their
discharge serum bilirubin levels on an hour-specific nomogram.[14] .

Transcutaneous bilirubinometry is a measurement of yellow color of the blanched

skin and subcutaneous tissue and can be used as a screening tool. It has been shown
to be fairly reliable, with good correlation between total serum bilirubin (TSB) and
transcutaneous bilirubin (TcB) levels obtained using instruments currently available
in the United States (eg, Draeger Air-Shields Jaundice Meter JM-103, Respironics
BiliChek meter by Philips). The TcB measurement tends to underestimate the TSB
at higher levels.[18] Confirmation with TSB measurement is indicated in all patients
with TcB levels above the 75th percentile and in those in whom therapeutic
intervention is considered.

Recent studies suggest that combining clinical risk factors with predischarge
measurement of TSB or TcB levels improves the accuracy of risk assessment for
subsequent hyperbilirubinemia.[19] The factors most predictive included predischarge
TSB or TcB levels above 75th percentile, lower gestational age, and exclusive
breastfeeding.[20]

Newborns who are exclusively breastfed and who have elevated predischarge TcB
or TSB levels do not qualify for discharge before 48 hours and should be evaluated
for phototherapy in 24 hours. Newborns with TcB and TSB levels in the highintermediate range and newborns who were born at less than 38 weeks' gestation
should undergo repeat TSB and TcB measurement within 24 hours of discharge or
should receive follow-up within 2 days.[21]

Patient Education
Provide excellent breastfeeding education. Refer to a lactation consultant or La Leche
League.
For patient education resources, see the Pregnancy and Reproduction Center, as well as
Breastfeeding.