Jaundice, also known as hyperbilirubinemia, is a frequently encountered clinical problem in neonates. Estimates are that between 60-80% of all term or late-term, healthy newborns exhibit idiopathic jaundice. The definition of neonatal hyperbilirubinemia has typically been total serum bilirubin (TSB) levels within the high-risk zone, or greater than the 95th percentile for age within the first six days of life. When total serum bilirubin levels rise, a yellowish discoloration of the infant’s skin and sclera occurs and is referred to as jaundice. Neonatal hyperbilirubinemia has a higher frequency in breastfed infants compared to formula-fed infants. The two common mechanisms for this are “breastfeeding jaundice” and “breast milk jaundice.”
Breast milk jaundice was first described in 1963 when it was noted that some breastfed infants had prolonged, unconjugated hyperbilirubinemia that persisted beyond the third week of life. Breast milk jaundice typically presents in the first or second week of life and usually spontaneously resolves even without discontinuation of breastfeeding. However, it can persist for 8-12 weeks of life before resolution. Infants with breast milk jaundice often have higher peaks of serum bilirubin and an overall slower decline than infants without it, leading to longer resolution time. Usually, pathologic causes of persistent, unconjugated hyperbilirubinemia are ruled out before a diagnosis of breast milk jaundice can be made.
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. Another area of investigation has been the potential genetic mutations present in the affected neonates.
Some factors in human breast milk that may be related to the etiology of breast milk jaundice include pregnane-3a,20ß-diol, interleukin IL1ß e IL6, ß-glucuronidase, epidermal growth factor, and alpha-fetoprotein. The presence of pregnane-3a,20ß-diol, is thought to inhibit the conjugation of bilirubin that allows for its excretion. ß-glucuronidase is an enzyme naturally present in the body that deconjugates bilirubin in the intestinal brush border, leading to increased unconjugated bilirubin levels. Studies have shown that the activity of this enzyme within formula milk is negligible, but it is considerable in human breast milk. Interleukin IL1ß e IL6 is thought to have a cholestatic effect that leads to hyperbilirubinemia. The epidermal growth factor is present in higher concentrations in human breast milk and the serum of strictly breastfed infants. 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.[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
The frequency of breast milk jaundice within the United States is thought to be 20-30% for neonates from 3 to 4 weeks of age whose feeding is predominantly via breastfeeding. About 30-40% of breastfed infants are expected to have bilirubin levels greater than or equal to 5 mg/dL, with about 2-4% of exclusively breastfed infants having bilirubin levels above 10 mg/dL in week 3 of life. International studies in countries such as Turkey and Taiwan found that 20-28% of neonates had breast milk jaundice present at four weeks of age. Total serum bilirubin levels were also noted to be greater than or equal to 5 mg/dL in these cases. The international frequency of breast milk jaundice is not extensively reported but is thought to be similar to the frequency in the United States. No reports exist demonstrating a sex predilection.
To understand the mechanism for breast milk jaundice, it is crucial to understand neonate bilirubin metabolism and why neonates, in general, are affected by hyperbilirubinemia. Newborns have markedly increased bilirubin production as compared to their adult counterparts secondary to a higher blood volume and hemoglobin concentration and a shorter red blood cell lifespan. This bilirubin production is in its unconjugated form, which is not water-soluble and must, therefore, be conjugated into its water-soluble form before excretion from the body in the stool. This process takes place within the liver and specifically within the hepatocyte itself by the hepatic enzyme, bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT). The UGT1A1 gene codes production of this enzyme, and therefore those with genetic mutations in this gene are unable to conjugate bilirubin properly. This enzyme is also significantly less active in neonates than adults, leading to less efficient conjugation. After conjugation and excretion from hepatocytes within bile, the bilirubin travels to the small intestine where it converts to stercobilin by gut flora and gets excreted via the stool.
Infants have a decreased concentration of gut flora needed for this process compared to 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 the portal circulation. This process is known as “enterohepatic circulation.” Neonates have significantly higher activity of the enzyme ß-glucuronidase as well as a more permeable gut wall, leading to overall higher concentrations of unconjugated bilirubin and increased enterohepatic circulation.
Identification of the substances within breast milk and the genetic mutations that may be causes or risk factors for breast milk jaundice interfere with the healthy metabolism and excretion of bilirubin at the various stages are covered above.
Breast milk jaundice typically presents in the first or second week of life with an unconjugated hyperbilirubinemia in an otherwise healthy infant whose nutritional intake is predominantly via breastfeeding. These infants exhibit normal weight gain with the normal production of urine and stools.. 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 of a patient presenting with hyperbilirubinemia suspicious for breast milk jaundice must include methods to rule out other pathologic causes of hyperbilirubinemia. First, both unconjugated and conjugated bilirubin levels must be measured. Conjugated bilirubin levels less than 1 mg/dL or 20% of the total bilirubin level are considered normal. Conjugated bilirubin levels in excess of this indicate other disorders such as biliary atresia, neonatal hepatitis, and disorders of bilirubin excretion. Both breast milk jaundice and hemolytic anemias cause elevated unconjugated bilirubin levels. Hemolytic causes for hyperbilirubinemia, such as ABO incompatibility, G6PD deficiency, and hereditary spherocytosis, must be ruled out. Assessment should include 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 for them unless jaundice does not resolve by 12 weeks of age. Galactosemia and hypothyroidism have also been identified as causes of unconjugated hyperbilirubinemia and should be ruled out via newborn screening tests.
Treatment is not necessary for breast milk jaundice unless the total serum bilirubin level of the infant is greater than 20 mg/dL. If this occurs, the recommendation is for phototherapy treatment. Phototherapy is the use of light to convert bilirubin molecules into water-soluble isomers that can be excreted by the body. If the total serum bilirubin level remains below 12 mg/dL, the recommendation is to continue breastfeeding of the infant and to expect the resolution of jaundice by 12 weeks of age. If the total serum bilirubin level is between 12-20 mg/dL, and further investigation shows no evidence of hemolysis, the recommendations are the same. When the bilirubin is greater than 20, a brief 24-hour cessation of breastfeeding often leads to a sharp decline in the bilirubin levels.
Biliary atresia, neonatal hepatitis, and disorders of bilirubin excretion are all causes of conjugated hyperbilirubinemia that present with jaundice. These, along with hemolytic causes of hyperbilirubinemia, must be ruled out before a definitive diagnosis of breast milk jaundice can be made. Some hemolytic causes to be considered are ABO incompatibility, G6PD deficiency, and hereditary spherocytosis. Breastfeeding jaundice due to caloric deprivation must also be ruled out. Crigler-Najjar and Gilbert syndromes are two genetic disorders that can also cause prolonged hyperbilirubinemia and should be considered part of the differential diagnosis for breast milk jaundice.
Overall, the prognosis of infants with breast milk jaundice is excellent as it is a self-limited condition that usually resolves around 12 weeks of age.
The most feared complication of all neonatal hyperbilirubinemia, including breast milk jaundice, is kernicterus or chronic bilirubin encephalopathy. This concern is due to its potential for permanent neurodevelopmental delay, and 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.
Although jaundice in breastfed infants is a common and usually a benign finding, it cannot be ignored. Close communication between all members of the health care team and the parents is necessary to rule out other causes of neonatal hyperbilirubinemia. Combined with routine newborn evaluations and indicated lab tests, kernicterus, the most severe complication of neonatal hyperbilirubinemia, is preventable, and the successful continuation of breastfeeding is possible.
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