Breast Milk Jaundice

Background

Arias first described breast milk jaundice (BMJ) in 1963.^{[1, 2]} This condition is a type of neonatal jaundice associated with breastfeeding that is characterized by indirect hyperbilirubinemia in an otherwise healthy breastfed newborn that develops after the first 4-7 days of life, persists longer than physiologic jaundice, and has no other identifiable cause.^{[3, 4, 5]}

Breast milk jaundice should be differentiated from breastfeeding jaundice, which manifests in the first 3 days of life, peaks by 5-15 days of life, disappears by week 3 of life, and is caused by insufficient production or intake of breast milk.^[4]  In contrast to babies with breast milk jaundice, infants suffering from breastfeeding jaundice generally exhibit mild dehydration and weight loss in the first few days of life.^[5]

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Pathophysiology

Breast milk jaundice is a common cause of indirect hyperbilirubinemia. The etiology of breast milk jaundice is not clearly understood, but a combination of genetic and environmental factors may play a role.^[5] The following factors may contribute:

• 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^[5]
• Increased concentrations of nonesterified free fatty acids that inhibit hepatic glucuronyl transferase^[5]
• 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^[6]
• 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^[7]
• Reduced hepatic uptake of unconjugated bilirubin due to a mutation in the solute carrier organic anion transporter protein SLCO1B1
• Increased levels of inflammatory cytokines in human milk, especially interleukin (IL)-1 beta and IL-6,  in individuals with breast milk jaundice; these are known to be cholestatic and reduce the uptake, metabolism, and excretion of bilirubin^[8]

Epidermal growth factor (EGF) is responsible for growth, proliferation, and maturation of the gastrointestinal tract in newborns, and it is vital for adaptation after birth. Higher EGF serum and breast milk levels have been noted in patients with breast milk jaundice.^[9]  Reduced gastrointestinal motility and increased bilirubin absorption and uptake are thought to be the mechanisms.

Serum alpha fetoprotein levels have been found to be higher in infants with breast milk jaundice.^[10] The exact significance of this finding is unknown.

Breast milk is an important source of bacteria in establishing infantile gut flora. Tuzun et al demonstrated that Bifidobacterium species in breast milk may protect against breast milk jaundice.^[11]  The exact significance of this finding is unknown. A phase I trial that evaluated the safety and tolerability of Bifidobacterium longus subspecies infantis EVC001 supplementation in 34 healthy term breastfed infants compared to 34 who received lactation support alone found no differences between the groups in mean gestational age at birth, weight at postnatal months 1 and 2, and breast milk intake.^[12]  B infantis supplementation was safe and well tolerated, and infants receiving this supplementation had fewer and better formed stools than those in the lactation support–only group.

Please see the Medscape Drugs and Diseases article Neonatal Jaundice for an in-depth review of the pathophysiology of hyperbilirubinemia.

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Etiology

Replacement of  breastfeeding with oral glucose solution does not appear to decrease the prevalence or degree of jaundice.^[13]

Note the following causes of breast milk 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.^[14]  This may be comparable to what is observed in patients with Gilbert syndrome.^[15]  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 white individuals 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.^[16]
• 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.^[17]
• A study showed 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 to exclusively or partially formula fed neonates.^[18]
• The organic anion transporters (OATPs) are a family of multispecific pumps that mediate the sodium independent uptake of bile salts and broad range of organic compounds. In humans, three liver-specific OATPs have been identified: OATP-A, OATP-2, and OATP-8. Unconjugated bilirubin is transported in the liver by OATP-2. A genetic polymorphism for OATP-2 (also known as OATP-C) at nucleotide 388 has been shown to correlate with three-fold increased risk for development of neonatal jaundice (peak serum bilirubin level of 20 mg/dL) when adjusted for covariates.^{[19, 20]}  The combination of the OATP-2 gene polymorphism with the variant UGT1A1 gene at nucleotide 211 further increased the risk to 22-fold (95% confidence interval [CI], 5.5-88). When these genetic variants were combined with breast milk feeding, the risk for marked neonatal hyperbilirubinemia increased further to 88-fold (95% CI, 12.5-642.5).
• Bilirubin is a known antioxidant.^[21] It has been suggested that there is a homeostasis maintained by external sources such as breast milk and internal production of antioxidants such as bilirubin in the body. In a study by Uras et al, the breast milk of mothers of newborns with prolonged jaundice was found to have increased oxidative stress, whereas there was a reduction in the protective antioxidant capacity.^[22] The exact clinical significance of this finding is not known.
• Breastfeeding women in populations with a high prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid consumption of fava beans as well as ingestion of quinine-containing sodas.^[23] The presence of these pro-oxidant items in breast milk may induce G6PD crises in the breastfed children, leading to jaundice and/or hemolytic anemia.^[23]

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Epidemiology

United States data

Jaundice occurs in 50-70% of newborns. Excess physiologic jaundice (bilirubin level >12 mg/dL) develops in 4% of bottle-fed newborns, compared to 14% of breastfed newborns. Exaggerated physiologic jaundice (bilirubin level >15 mg/dL) occurs in 0.3% of bottle-fed newborns, compared to 2% of breastfed newborns.^[24]

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 20-30%,^[25]  although a more recent review indicates about 2-4% of exclusively breastfed infants have jaundice with bilirubin levels above 10 mg/dL in week 3 of life.^[4]

International

The international frequency of breast milk jaundice is not extensively reported but is thought to be similar to that in the United States.

Race-, sex-, and age-related demographic

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.

No sex predilection is known.

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

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Prognosis

The prognosis is excellent, although jaundice in breastfed infants may persist for as long as 12 weeks.

Morbidity

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.^[37] Note that kernicterus 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.

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 their difficulty in achieving adequate nursing, greater weight loss, and hepatic immaturity.

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History

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 their serum bilirubin concentration, neonates with hyperbilirubinemia may become sleepy and feed poorly.

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Physical Examination

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 the 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 bilirubin levels. Skin should have normal perfusion and turgor and show no petechiae.

Neurologic examination findings, 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 the infant's hydration status by an assessment of the percentage of birth weight that may have been lost, as well as observation of the mucous membranes, fontanelle, and skin turgor.

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Laboratory Studies

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

• A 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 they should have regained their birth weight by the end of the second week of life or demonstrate a weight gain of 1 oz/day.
• Measure the total serum bilirubin concentration in neonates who have jaundice that has progressed from the face to the chest, as well as in neonates who are 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 µmol/L). A total serum bilirubin concentration that rises faster than 5 mg/dL/d (85 µmol/L/d) or jaundice before 24 hours of life suggests pathologic jaundice.

A level of conjugated bilirubin greater than 2 mg/dL (34 µmol/L) suggests cholestasis, biliary atresia, or sepsis (see Neonatal Jaundice).

A complete blood cell (CBC) count with reticulocyte count. Findings may include the following:

• Polycythemia (hematocrit level >65%)
• Anemia (hematocrit level <40%)
• Neutropenia, high neutrophil count, and/or a predominance of immature polymorphonuclear neutrophil forms to total neutrophil ratio above 0.2: These finding suggest sepsis

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

If hemolysis is suspected, consider the following tests:

• Blood type of mother and infant 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 (G6PD) screen, especially if the infant's ethnicity is consistent (eg, black persons, Southeast Asians)

Factors that suggest the 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 over 0.5 mg/dL/h
• Pallor, hepatosplenomegaly
• Rapid increase in serum bilirubin level after 24-48 hours (G6PD deficiency)
• Ethnicity suggestive of G6PD deficiency
• Failure of phototherapy to lower bilirubin levels
• History of Rh-negative mother who did not receive RhoGAM in previous pregnancies when indicated

If sepsis is suspected, consider the following tests:

• Blood culture
• White blood cell (WBC) differential
• Platelet count
• Urine analysis and culture
• Lumbar puncture

Clinical 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

During follow-up of the newborn state,screen for galactosemia and hypothyroidism.

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Approach Considerations

The American Academy of Pediatrics Safe and Healthy Begininngs Project was established to facilitate implementation of the 2004 guidelines for management of hyperbilirubinemia using a systems-based approach. The three 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.^[26]

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

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 µmol/L).

Provide gravidas with excellent breastfeeding education. Refer them to a lactation consultant or La Leche League. For patient education resources, see the Pregnancy Center, as well as Breastfeeding.

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Medical Care

Medication is not currently a component of care for breast milk jaundice (BMJ).

Treatment recommendations in this section apply only to healthy term infants with no signs of pathologic jaundice and are based on the severity of the hyperbilirubinemia. In preterm, anemic, or ill infants and those with early (25 mg/dL or 430 µmol/L), different treatment protocols should be pursued (see the Medscape Drugs and Diseases article Neonatal Jaundice).^[27]

For healthy term infants with breast milk or breastfeeding jaundice who have bilirubin levels of 12 mg/dL (170 µmol/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. Reassure the mother about the relatively benign nature of breast milk jaundice . 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 then 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 µmol/L).^[28]

For infants with serum bilirubin levels in the range of 17-25 mg/dL (294-430 µmol/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.^[29]

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.

View Image

The graph represents indications for phototherapy and exchange transfusion in infants (with a birthweight of 3500 g) in 108 neonatal ICUs. The left pa....

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 below 15 mg/dL (260 µmol/L).
• The average bilirubin level rebound has been shown to be less than 1 mg/dL (17 µmol/L); therefore, rechecking the level after discontinuation of phototherapy is not necessary unless the hyperbilirubinemia is due to a hemolytic process.^[30]

For an in-depth discussion of phototherapy, see the Medscape Drugs and Diseases article Neonatal Jaundice.

If the infant has not been discharged with the parent, it is important to monitor the baby's daily weights and serum bilirubin concentration for the need for phototherapy as well as assess the caloric intake. Once the serum bilirubin concentration is determined to be within a safe range (

Weight monitoring is very important in breastfed infants to avoid prolonged and severe jaundice, as well as to avoid hypernatremic dehydration. The general standard indicates that the loss of 10% of the birth weight is considered to be significant.

van Dommelen proposed a reference chart for relative weight change to detect hypernatremic dehydration.^[31]

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Consultations

The following consultations may be indicated:

• Consider consultation with a neonatologist when serum bilirubin levels approach 20 mg/dL (430 µmol/L) or when signs and symptoms suggest pathologic jaundice and the rate of rise in the serum bilirubin level is over 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.

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Diet and Activity

Diet

Continue breastfeeding, if possible, and increase the 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 activity 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.

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Prevention

Keys to deterrence and prevention of breast milk jaundice (BMJ) include the following:

• Poor caloric intake associated with insufficient breastfeeding contributes to the development of severe breast milk jaundice. 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 are nursed more than 8 times during the first 24 hours have earlier meconium passage, reduced maximum weight loss, increased breast milk intake on days 3 and 5, lower serum bilirubin levels and, thus, a significantly lower incidence of severe hyperbilirubinemia (>15 mg/dL) on day 6.
• Gourley et al demonstrated that beta-glucuronidase inhibition with L-aspartic acid and enzymatically hydrolyzed casein in exclusively breastfed babies resulted in a reduction in the peak serum bilirubin level by 70% in first week of life.^[32]
• According to the American Academy of Pediatrics 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; thus, all infants should be evaluated for the risk of subsequent hyperbilirubinemia by plotting their discharge serum bilirubin levels on an hour-specific nomogram.^[29]
• Transcutaneous bilirubinometry is a measurement of yellow color of the blanched skin and subcutaneous tissue, and it can be used as a screening tool. This tool has been shown to be fairly reliable, with good correlation between total serum bilirubin (TSB) and transcutaneous bilirubin (TcB) levels obtained using instruments available in the United States. The TcB measurement tends to underestimate the TSB at higher levels.^[33]  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.
• Studies have suggested that combining clinical risk factors with predischarge measurement of TSB or TcB levels improves the accuracy of risk assessment for subsequent hyperbilirubinemia.^[34]  The factors most predictive included predischarge TSB or TcB levels above the 75th percentile, lower gestational age, and exclusive breastfeeding.^[35]
• 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 high-intermediate range and newborns who were born at less than 38 weeks' gestation should undergo repeat TcB and TSB measurements within 24 hours of discharge, or they should receive follow-up within 2 days.^[36]

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