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 week of life and is caused by insufficient production or intake of breast milk.
Pathophysiology
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.
Please see Jaundice, Neonatal 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.
International
International frequency is not extensively reported but is thought to be similar to that in the United States.
Mortality/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. Another group of breastfed infants who may be at risk of complications are borderline premature infants who are poorly nursing.
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.
Zanardo V, Golin R, Amato M, Trevisanuto D, Favaro F, Faggian D. Cytokines in human colostrum and neonatal jaundice. Pediatr Res. Aug 2007;62(2):191-4. [Medline].
Kumral A, Ozkan H, Duman N, Yesilirmak DC, Islekel H, Ozalp Y. Breast milk jaundice correlates with high levels of epidermal growth factor. Pediatr Res. Aug 2009;66(2):218-21. [Medline].
Rosa Manganaro, Lucia Marseglia, Carmelo Mami, Giuseppe Saitta, Romana Gargano, Marina Gernellie. Serum alpha-fetoprotein (AFP) levels in breastfed infants with prolonged indirect hyperbilirubinemia. Early Human Development. 2008;84:487-490.
Maruo Y, Nishizawa K, Sato H, Sawa H, Shimada M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene. Pediatrics. Nov 2000;106(5):E59. [Medline]. [Full Text].
Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, Salemi I. Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr. Apr 1999;134(4):441-6. [Medline].
Huang CS, Chang PF, Huang MJ, Chen ES, Hung KL, Tsou KI. Relationship between bilirubin UDP-glucuronosyl transferase 1A1 gene and neonatal hyperbilirubinemia. Pediatr Res. Oct 2002;52(4):601-5. [Medline].
Lin Z, Fontaine J, Watchko JF. Coexpression of gene polymorphisms involved in bilirubin production and metabolism. Pediatrics. Jul 2008;122(1):e156-62. [Medline].
Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res. Nov 2004;56(5):682-9. [Medline].
Watchko JF. Genetics and the risk of neonatal hyperbilirubinemia: commentary on the article by Huang et al. on page 682. Pediatr Res. Nov 2004;56(5):677-8. [Medline].
[Guideline] American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. Jul 2004;114(1):297-316. [Medline].
van Dommelen P, van Wouwe JP, Breuning-Boers JM, van Buuren S, Verkerk PH. Reference chart for relative weight change to detect hypernatraemic dehydration. Arch Dis Child. Jun 2007;92(6):490-4. [Medline].
Stark AR, Lannon CM. Systems changes to prevent severe hyperbilirubinemia and promote breastfeeding: pilot approaches. J Perinatol. Feb 2009;29 Suppl 1:S53-7. [Medline].
[Best Evidence] Gourley GR, Li Z, Kreamer BL. A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice Among Breastfed Newborns. Pediatrics. 116:385 - 391. [Medline].
Maisels MJ. Transcutaneous bilirubinometry. Neoreviews. 2006;7(5):e217-e225.
Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics. Jan 2008;121(1):e170-9. [Medline].
Maisels MJ, Deridder JM, Kring EA, Balasubramaniam M. Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol. Sep 2009;29(9):612-7. [Medline].
Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications. Pediatrics. Oct 2009;124(4):1193-8. [Medline].
Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. Jan 1999;103(1):6-14. [Medline].
Fontaine P. The first month of life. In: Handbook of Pregnancy and Perinatal Care in Family Practice. Hanley & Belfus; 1995:396-429.
Gartner LM, Herschel M. Jaundice and breastfeeding. Pediatr Clin North Am. Apr 2001;48(2):389-99. [Medline].
Grunebaum E, Amir J, Merlob P, et al. Breast mild jaundice: natural history, familial incidence and late neurodevelopmental outcome of the infant. Eur J Pediatr. Feb 1991;150(4):267-70. [Medline].
Hamosh M, Bitman J. Human milk in disease: lipid composition. Lipids. Nov 1992;27(11):848-57. [Medline].
Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res. Nov 2004;56(5):682-9. [Medline].
Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr. Apr 2002;140(4):396-403. [Medline].
Lovejoy FH Jr, Robertson WO, Woolf AD. Poison centers, poison prevention, and the pediatrician. Pediatrics. Aug 1994;94(2 Pt 1):220-4. [Medline].
Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics. Oct 1995;96(4 Pt 1):730-3. [Medline].
Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics. Feb 1993;91(2):470-3. [Medline].
Schneider AP 2nd. Breast milk jaundice in the newborn. A real entity. JAMA. Jun 20 1986;255(23):3270-4. [Medline].
Yamauchi Y, Yamanouchi I. Breast-feeding frequency during the first 24 hours after birth in full-term neonates. Pediatrics. Aug 1990;86(2):171-5. [Medline].

