Jaundice is a common condition that requires medical attention in newborns worldwide. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In many infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. In some cases, however, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns, and lifelong neurologic sequelae in infants who survive—including hearing loss (Christensen and Yaish, 2015).
This issue of CSI examined the prevalence of neonatal jaundice in Nigeria, where it is a major cause of hearing loss for a long period of time. Audiological data collected from the International Hearing Center (the Center) over a period of 15 years shows that 265 patients with different degree of hearing loss were affected by neonatal jaundice
Biochemically, hyperbilirubinamia is the major cause of neonatal jaundice, but it could be mitigated by the use of some drugs (phenobarbitols, dexamethasone, and clofibrates) that causes the production of uridine diphospate glucoronyl transferase (UDPGT), an enzyme that helps to convert the bilirubin to water soluble bilirubin (conjugated bilirubin). This is because if unconjugated bilirubin is not converted, it could pass through the brain barrier membrane and cause neurotoxicity which results in auditory nerve damage thereby giving rise to hearing loss. Instead of these drugs, patients are normally given antibiotics that have little or no action on the enzyme UDPGT conversion of unconjugated bilirubin to conjugated water soluble bilirubin.
Jaundice in infants is caused by the accumulation of unconjugated bilirubin. This normally reflects as the yellow coloration of the skin and sclera in newborns. Unconjugated bilirubin is neurotoxic and can lead to death in newborns or lifelong neurologic sequelae. Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena:
Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.
Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).
Bilirubin is the reduced product of biliverdin. Heme is normally broken down into water soluble biliverdin through the action of oxido-reductase enzymes releasing iron and carbon-monoxide. The oxidation reaction is catalyzed by Heme oxygenase. Due to its hydrophobic nature; bilirubin is transported tightly bound to albumin in the plasma (Fujiwara, 2015).
The degree or extent, after birth, at which bilirubin binds to albumin depends on age. In most cases, it is low in infants especially during illness.
However, competition by exogenous and endogenous compounds can decrease the binding affinity of albumin for bilirubin in the presence of UDPGT (uridine diphosphoglucoronyltransferase), a catalyst that catalyzes the conjugation of bilirubin to water soluble form before it is excreted into the small intestine through the bile can reduce the concentration of bilirubin, and help reduce its health complications.
However, drugs like phenobarbitals would help to increase the concentration of UDPGT, thereby helping to reduce the concentration of harmful water insoluble bilirubin that leads to neurotoxicity, which sometimes causes hearing loss. Conjugated bilirubin can be deconjugated by beta-glucoronidase located in the brush border of the proximal area of the small intestine. This action helps to increase the concentration of unconjugated bilirubin in the plasma. The action is extensive in neonates because nutrients intake is limited in the first few days of life.
Neonatal Jaundice and Hearing Loss
Hearing loss in infants and children can be traced to unnecessary build up of bilirubin in their systems. The inability to clear out unconjugated bilirubin through the formation of glucoronides as a result of reduced action of uridine diphosphate glucoronyltransferase enzyme, leads to the crossing of unconjugated bilirubin into the brain barrier. This causes neurotoxicity that affects the auditory nerves leading to hearing loss (Ebbsen, 2005). An estimated 50 percent of term and 80 percent of preterm infants develop jaundice, typically two to four days after birth. Nearly all newborns develop an unconjugated serum bilirubin level more than 30 µmol/L (1.8 mg/dL) during the first week of life.
The incidence and degree of neonatal jaundice varies from country to country. For example, in 1986, Maisels and Gifford reported 6.1 percent of infants with serum bilirubin levels of more than 220 µmol/L (12.9 mg/dL). In another study in 2003 in the United States, 4.3 percent of 47,801 infants had total serum bilirubin levels in a range in which phototherapy was recommended by the 1994 American Academy of Pediatrics (AAP) guidelines, and 2.9 percent had values in a range in which the 1994 AAP guidelines suggested considering phototherapy (Atkinson et al, 2003; Woodgate and Jardine, 2015). However, in some LMICs (low middle-income countries), the incidence of severe neonatal jaundice may be as much as 100 times higher than in higher-income countries.
In Nigeria, neonatal jaundice is a major cause of hearing loss in infants and children. Data surveyed from the center between 2001 and 2015 show that infants between the ages of one to three years old have a high percentage (51.6 percent) of hearing loss due to neonatal jaundice. However, the data also show that neonatal jaundice is low among infants that are less than one year old (10.1 percent). In total, 318 cases of hearing loss caused by neonatal jaundice has been recorded over a period of 16 years. This amounts to 23 cases per annum. It is my belief that if data from other centers were collated and analyzed, the rate of hearing loss caused by neonatal jaundice in infants would move health policy makers to action in Nigeria.
Conclusion and Recommendations
In conclusion, neonatal jaundice is basically caused by the presence of abnormal concentration of bilirubin which, in most cases, is transported to different parts of the body. The passage of bilirubin to the brain barrier region of the body causes neurotoxicity which sometimes involves the damage of the auditory nerve giving rise to hearing loss. In most cases, the antibiotics given to infants do not help because they do not increase the enzymes needed to clear or solubilize the unconjugated bilirubin by conjugating it into a water soluble form that can be excreted from the body. Drugs like phenobarbitols, dexamethasone, or clofibrates are more preferable since they boost the enzymatic system (Moore et al, 1984).
In conclusion, medical specialists should be aware of these findings and should be careful about the drugs they prescribe to patients with neonatal jaundice in order not to compound their problems through wrong diagnosis and prescriptions.
I am very grateful to International Hearing Center for all their support throughout this research work.
Atkinson LR, Escobar GJ, Takyama JI, Newman TB. (2003) Phototherapy use in jaundiced newborns in a large managed care organization: do clinicians adhere to the guideline? Pediatrics 111:e555.
Christensen RD, Yaish HM. (2015) Hemolytic disorders causing severe neonatal hyperbilirubinemia. Clin Perinatol 42 (3):515–27.
Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR. (2005) Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta Paediatr 94(1):59–64.
Fujiwara R, Maruo Y, Chen S, Tukey RH. (2015) Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol 289 (1):124–32.
Hua L, Shi D, Bishop PR, Gosche J, May WL, Nowicki MJ. (2005) The role of UGT1A1*28 mutation in jaundiced infants with hypertrophic pyloric stenosis. Pediatr Res 58(5):881–4.
Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. (2004) Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 56(5):682–9.
Kumral A, Ozkan H, Duman N, Yesilirmak DC, Islekel H, Ozalp Y. (2009) Breast milk jaundice correlates with high levels of epidermal growth factor. Pediatr Res 66(2):218–21.
Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. (1985) Epidemiology of neonatal hyperbilirubinemia. Pediatrics 75(4):770–4.
Macias RI, Marin JJ, Serrano MA. (2009) Excretion of biliary compounds during intrauterine life. World J Gastroenterol Feb 21. 15(7):817–28.
Maisels MJ, Gifford K. (1986) Normal serum bilirubin levels in the newborn and the effect of breast- feeding. Pediatrics 78(5):837–43.
Maisels MJ, Newman TB. (2012) The epidemiology of neonatal hyperbilirubinemia. Stevenson DK, Maisels MJ, Watchko JF. Care of the jaundiced neonate. New York: McGraw-Hill. 97–113.
Memon N, Weinberger BI, Hegyi T, Aleksunes LM. (2015) Inherited disorders of bilirubin clearance. Pediatr Res Nov 23.
Moore LG, Newberry MA, Freeby GM, Crnic LS. (1984) Increased incidence of neonatal hyperbilirubinemia at 3,100 m in Colorado. Am J Dis Child 138(2):157–61.
Sarici SU, Serdar MA, Korkmaz A, et al. (2004) Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns. Pediatrics 113:775–80.
Slusher TM, Olusaniya BO. Neonatal jaundice in low- and middle-income countries.
Stevenson DK, Maisels MJ, Watchko JF, Lin Z.(2012) Care of the Jaundiced Neonate. New York: McGraw-Hill. 263–73.
Woodgate P, Jardine LA. (2015) Neonatal jaundice: phototherapy. BMJ Clin Evid May 22, 2015.
Yamamoto A, Nishio H, Waku S, Yokoyama N, Yonetani M, Uetani Y. (2002) Gly71Arg mutation of the bilirubin UDP-glucuronosyltransferase 1A1 gene is associated with neonatal hyperbilirubinemia in the Japanese population. Kobe J Med Sci 48(3-4):73–7.
Yusoff S, Van Rostenberghe H, Yusoff NM, et al. (2006) Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population. Biol Neonate 89(3):171–6.