Prolonged Unconjugated Hyperbiliriubinemia in Breast-fed Male Infants with a Mutation of Uridine Diphosphate-Glucuronosyl Transferase

doi:10.1016/j.jpeds.2009.05.034

The Journal of Pediatrics

Volume 155, Issue 6, December 2009, Pages 860-863

https://doi.org/10.1016/j.jpeds.2009.05.034 Get rights and content

Objective

To test the hypothesis that a mutation in uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) gene of breast-fed infants is a contributory factor to prolonged unconjugated hyperbilirubinemia.

Study design

Of 125 breast-fed term infants, 35 infants had prolonged unconjugated hyperbilirubinemia; another 90 breast-fed neonates without prolonged jaundice were control infants. The polymerase chain reaction–restriction fragment length polymorphism method was used to detect the known variant sites (promoter area, nucleotides 211, 686, 1091, and 1456) of the UGT1A1 gene.

Results

Of 35 breast-fed infants with prolonged unconjugated hyperbilirubinemia, 29 had at least 1 mutation of the UGT1A1 gene. Variation at nucleotide 211 was most common. The percentages of the neonates carrying the variant nucleotide 211 were significantly different between the prolonged hyperbilirubinemia group and control neonates. Male breast-fed infants had a higher risk than female infants for prolonged hyperbilirubinemia.

Conclusions

Male breast-fed neonates with a variant nucleotide 211 in UGT1A1 have a high risk for developing prolonged hyperbilirubinemia.

Section snippets

Methods

From April 1, 2006, to January 31, 2008, all term (≥37weeks' gestation) infants with breast milk feeding were recruited. Umbilical cord blood samples were collected for neonatal screening at Far Eastern Memorial Hospital. Those breast-fed neonates with risk factors for neonatal hyperbilirubinemia, such as ABO incompatibility, hemolytic anemia, hypoxia/asphyxia, dehydration/vomiting, cephalohematoma, sepsis, liver dysfunction, hypothyroidism, and small for gestational age babies, were excluded.

Results

Birth weight, gestational age, and G6PD deficiency were not significantly different between the prolonged hyperbilirubinemia and control groups. Sex, however, was significantly different between the study and the control groups (Table I). The serum bilirubin levels of the study group were 164 ± 54 μmol/L (9.6 ± 3.2 mg/dL) at 30 days old.

The normal UGT1A1 gene, variation in promoter [(A(TA)₆TAA/A(TA)₇AA (6/7) and A(TA)₇TAA/A(TA)₇TAA), variation at nucleotide 211 (G to A, heterozygous and

Discussion

Breast milk feeding may be involved in the development of prolonged neonatal unconjugated hyperbilirubinemia. The etiology of hyperbilirubinemia in breast-fed infants is not clearly understood. Some components in the breast milk such as 5β-pregnane-3α, 20β-diol, nonesterified fatty acids, and glucuronidase inhibit uridine diphosphoglucuronic acid glucuronyl transferase, the enzymes responsible for conjugation and subsequent excretion of bilirubin. These factors may contribute to jaundice in

References (16)

G. Monaghan et al.
Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn
J Pediatr
(1999)
C.S. Huang et al.
Glucose-6-phosphate dehydrogenase deficiency, the UDP-glucuronosyltransferase 1A1 gene, and neonatal hyperbilirubinemia
Gastroenterology
(2002)
G.R. Gourley
Breast-feeding, neonatal jaundice and kernicterus
Semin Neonatol
(2002)
J.D. Bancroft et al.
Gilbert's syndrome accelerates development of neonatal jaundice
J Pediatr
(1998)
A. Iolascon et al.
UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis
Blood
(1998)
K. Yamamoto et al.
Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler-Najjar syndrome type II
Biochim Biophys Acta
(1998)
Y. Maruo et al.
Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene
Pediatrics
(2000)
C.S. Huang et al.
Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1A1 gene in healthy Taiwanese
Pharmacogenetics
(2000)

There are more references available in the full text version of this article.

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A prospective study was conducted to investigate the effects of birth body weight, sex, mode of delivery, glucose-6-phosphate dehydrogenase (G6PD) deficiency, variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on hyperbilirubinemia in neonates who were breast-fed. Hyperbilirubinemia was diagnosed when a full term neonate had a bilirubin level ≧15.0 mg/dL (256.5 μM) in serum at 3 days old. The polymerase chain reaction-restriction fragment length polymorphism method was used as a means of detecting the known variant sites in the UGT1A1 and SLCO1B1 gene.
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: Supported by grants from Far Eastern Memorial Hospital (FEMH-96-C-022).

: The authors declare no conflicts of interest.

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Original ArticleProlonged Unconjugated Hyperbiliriubinemia in Breast-fed Male Infants with a Mutation of Uridine Diphosphate-Glucuronosyl Transferase

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

J Pediatr

Gastroenterology

Semin Neonatol

J Pediatr

Blood

Biochim Biophys Acta

Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene

Pediatrics

Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1A1 gene in healthy Taiwanese

Pharmacogenetics

Original Article
Prolonged Unconjugated Hyperbiliriubinemia in Breast-fed Male Infants with a Mutation of Uridine Diphosphate-Glucuronosyl Transferase