Breast Milk Jaundice

Etiology

The exact etiology of breast milk jaundice has not been determined. Most of the proposed etiologies involve the factors present in the human breast milk itself. Other hypotheses suggest potential genetic mutations present in the affected neonates.

Some human breast milk factors that may be related to breast milk jaundice's etiology include pregnane-3a,20ß-diol, interleukin IL1ß, ß-glucuronidase, epidermal growth factor, and alpha-fetoprotein.[5] The presence of pregnane-3a,20ß-diol, is thought to inhibit bilirubin's conjugation, which in turn impedes bilirubin excretion. ß-glucuronidase is an enzyme naturally present in the body that deconjugates bilirubin in the intestinal brush border, leading to increased serum reabsorption instead of excretion.[2] Studies have shown that this enzyme's activity within formula milk is negligible, but it is considerable in human breast milk.[6] Interleukine IL1ß is thought to have a cholestatic effect that leads to hyperbilirubinemia.[5] The epidermal growth factor is present in higher concentrations in human breast milk and strictly breastfed infants' serum. The reason is that this substance enhances intestinal resorption of bilirubin and reduces intestinal motility in the neonatal period, leading to increased unconjugated bilirubin levels.[2]The serum of babies with breast milk jaundice often has elevated levels of alpha-fetoprotein. The mechanism underlying this is not yet understood.

Several studies have shown that mutations in the coding region of the UGT1A1 gene increase the risk of developing breast milk jaundice. Mutations in this gene's regulatory region are known to cause Crigler-Najjar and Gilbert syndrome, two syndromes known to cause persistent hyperbilirubinemia[7].

Epidemiology

The frequency of breast milk jaundice within the United States is about 20 to 30% of neonates who are mostly breastfed.[8] About 30-40% of breastfed infants are expected to have bilirubin levels greater than or equal to 5 mg/dL, with about 2 to 4% of exclusively breastfed infants having bilirubin levels above 10 mg/dL in week 3 of life.[1] International studies in countries such as Turkey and Taiwan found that 20 to 28% of neonates had breast milk jaundice present at four weeks. Total serum bilirubin levels were also noted to be greater than or equal to 5 mg/dL.[7] The international frequency of breast milk jaundice is not extensively reported but is thought to be similar to the United States frequency. No reports exist demonstrating a sex-related higher incidence.

Pathophysiology

Before discussing the mechanism for breast milk jaundice, it is crucial to understand neonatal bilirubin metabolism and why neonates, in general, are affected by hyperbilirubinemia. Newborns have markedly increased bilirubin production compared to their adult counterparts, secondary to a higher blood volume and hemoglobin concentration, a shorter red blood cell lifespan, and liver enzymes' physiological immaturity. These factors combined result in relatively high production of unconjugated form, which is not water-soluble. To excrete bilirubin from the body, there is the conversion of the unconjugated form to the conjugated (water-soluble) form is required. The conjugation process occurs within the hepatocyte by bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme. UGT1A1 gene codes this enzyme production. Therefore those with genetic mutations in this gene are unable to conjugate bilirubin adequately. This enzyme is also significantly less active in neonates than in adults, leading to less efficient conjugation. After conjugation and excretion from hepatocytes, the bilirubin passes to the small intestine, where it gets converted to stercobilin by gut flora and subsequently excreted via the stool. 

Infants have a decreased concentration of gut flora needed for this process than adults, leading to a higher concentration of bilirubin remaining within the intestinal tract. The enzyme ß-glucuronidase will deconjugate bilirubin remaining within the intestine. After this process, it is returned to the liver for re-conjugation via portal circulation. This process is known as "enterohepatic circulation." Neonates have significantly higher activity of the enzyme ß-glucuronidase and a more permeable gut wall, leading to overall higher concentrations of unconjugated bilirubin and increased enterohepatic circulation.[2] 

Basic and clinical studies were conducted and are still ongoing to investigate breast milk jaundice's pathophysiology by studying breast milk's effect on the processes discussed above.[9][10] A visual summary of bilirubin metabolism and suggested mechanisms of breast milk jaundice is shown in figure 1.

History and Physical

Breast milk jaundice typically presents within the first two weeks of life in an otherwise healthy infant who is predominantly breastfed. These infants exhibit normal weight gain with adequate production of urine and stools.[2]. A total serum bilirubin level above 1.5 mg/dL is considered elevated at this time, but most infants will not appear jaundiced unless the level is above 5 mg/dL. If the infant does appear jaundiced, this yellowish discoloration of their skin and/or sclera is typically first noted in the face and then proceeds to the trunk and extremities.

Evaluation

The evaluation of a patient presenting with hyperbilirubinemia must include a work-up to rule out pathological causes of hyperbilirubinemia before making the breast milk jaundice diagnosis. First, both unconjugated and conjugated bilirubin levels must be measured. Conjugated bilirubin levels higher than 1 mg/dL or 20% of the total bilirubin level indicate conjugated hyperbilirubinemia (also known as cholestasis or direct hyperbilirubinemia). Once cholestasis is suspected, disorders such as biliary atresia, neonatal hepatitis, and other bilirubin excretion disorders. Both breast milk jaundice and hemolytic anemias cause elevated unconjugated bilirubin levels. Hemolytic causes for hyperbilirubinemia include ABO incompatibility, G6PD deficiency, hereditary spherocytosis, and other antibody-mediated hemolysis. Hemolysis assessment should consist of direct Coombs’ testing, measurement of hemoglobin, hematocrit, and reticulocyte count, a peripheral blood smear, and genetic testing.

The clinician should consider other non-hemolytic causes of prolonged hyperbilirubinemia, such as Crigler-Najjar or Gilbert syndrome but need not investigate them unless jaundice persists longer than what is expected for breast milk jaundice. Galactosemia and hypothyroidism can also cause unconjugated hyperbilirubinemia, hence should be ruled out.[2][11]

Treatment / Management

Treatment is not necessary for breast milk jaundice unless the infant's total serum bilirubin level is greater than the phototherapy guidelines recommended by the American Academy of Pediatrics (AAP).[12] The first step of management is phototherapy. It works by using light to convert bilirubin molecules into water-soluble isomers that the body can excrete. If the total serum bilirubin level remains below 12 mg/dL, the recommendation is to continue breastfeeding. If the total serum bilirubin level is higher than 12 mg/dL but below the phototherapy level, and further investigation shows no hemolysis evidence, the recommendations are also to continue breastfeeding.[2] When the bilirubin is greater than 20, a brief 24-hour cessation of breastfeeding may be beneficial. (A1)

Differential Diagnosis

Differential diagnosis of breast milk jaundice include:

• Physiological jaundice of newborns
• Hemolysis associated hyperbilirubinemia ( ABO, G6PD, hereditary spherocytosis, others)
• Breastfeeding jaundice ( inadequate milk intake and dehydration)
• Genetic causes ( Crigler-Najjar, pyruvate kinase deficiency, and Gilbert syndromes)
• Cholestasis (Biliary atresia, neonatal hepatitis, choledochal cyst, and disorders of bilirubin excretion)

Prognosis

Overall, infants' prognosis with breast milk jaundice is excellent as it is a self-limited condition that usually resolves around 12 weeks of age.

Complications

The most feared complication of all neonatal hyperbilirubinemia, including breast milk jaundice, is acute bilirubin encephalopathy acutely and kernicterus (chronic bilirubin encephalopathy) in the long term. This concern is due to its potential for permanent neurodevelopmental delay. It is a rare complication of breast milk jaundice and occurs in less than 2% of breastfed term infants who have no evidence of hemolytic anemia.[13]