Mini Review

Hyperbilirubinemia is a common situation in neonates, and measurements of bilirubin are key to the management of neonatal jaundice [1]. Bilirubin production is increased 2- to 3-times in term neonates in comparison with adults mainly due to a neonate’s shortened red blood cell (RBC) lifespan. Premature infants have proportionally increased bilirubin production rates as a consequence of an even shorter RBC lifespan [2]. Depending upon the balance between a neonate’s ability to produce and excrete bilirubin, i.e., either increased RBC breakdown and/or decreased bilirubin excretion may cause the severity of the hyperbilirubinemia, and thus increase the risk for developing neurologic dysfunction [2]. Drugs are commonly administered for treatment of diseases in neonates. Although most drugs are considered harmless, rarely drug-associated hyperbilirubinemia may occur [3]. Kernicterus or bilirubin neurotoxicity may appear following free bilirubin penetrates the blood brain barrier (BBB), and occurrence of this situation is subject to the ratio of unconjugated bilirubin concentration to reserve albumin concentration. The ratio increases whenever part of the albumin is occupied by a drug with apparent displacement of bilirubin, [4] prompting early measurement of serum bilirubin level in susceptible neonates.

As free (unbound) bilirubin, the portion of albumin-unbound bilirubin, is able to penetrate the BBB and is more closely correlated with bilirubin neurotoxicity, [5] and hence free bilirubin has a better specificity and sensitivity than total serum bilirubin (TSB) level and forecasts the risk of bilirubin neurotoxicity more precisely [6]. Free bilirubin and TSB respond individually. These two indices correspond well before phototherapy, yet TSB tends toward a reduction following treatment, free bilirubin does not [7]. However, monitoring free bilirubin is not widely available in clinical practice. TSB level, despite poorly correlating with bilirubin neurotoxicity and not being useful as a sensitive and specific predictor of neurological outcomes [5], is currently commonly used to guide treatment post phototherapy for neonatal hyperbilirubinemia. In the hospital, TSB is monitored daily or less frequently to reveal risk for neurological dysfunction at which to initiate or stop phototherapy management or when to start exchange transfusions in unresponsive cases. The risk for developing neurologic dysfunction relies on the concentration of unconjugated bilirubin, along with affinity of serum albumin to bind bilirubin, and the total amount of albumin [8]. Bilirubin displacement capability has been regarded as an essential factor for a drug to displace bilirubin from its albumin binding site, and subsequently lead to an elevation of plasma bilirubin, which crosses the BBB and causes neurologic dysfunction in a neonate [9], in addition to factors such as genetic variations and certain pathologic conditions, [8,10] suggesting that the use of a drug with apparent displacing ability may influence bilirubin binding to albumin. As a result, free bilirubin will rise, increasing an infant’s risk for developing neurologic dysfunction [8].

While protein binding is a fundamental reason, yet this may not be the only mechanism for a drug’s impact on elevated TSB levels in infants. With high protein bindings of 99% and 91% to 99%, and low daily doses of 0.2 mg/kg/day and 1mg/kg/day respectively (ref: Micromedex database), indomethacin and furosemide have never been considered increasing bilirubin levels in neonates. Daily dosage of a drug may play a vital role: Sulfisoxazole or ceftriaxone with each drug’s daily dosage 75-150 mg/ kg/day and 50 mg/kg/ day, and protein binding 85% and 85% to 95% (ref: Micromedex) respectively, causing significant elevation of bilirubin levels and should be avoided in infants with hyperbilirubinemia [11,12]. Disorders of bilirubin binding to albumin may be connected with the occurrence of neurological injury associated with the lower bilirubin levels observed in premature infants, leading to acute bilirubin encephalopathy in these infants without pronounced hyperbilirubinemia, [8] and VLBW (very low birth weight; <1.5kg) neonates have relatively higher risk of Kernicterus or brain injury due to hyperbilirubinaemia [13] i.e. premature infants or VLBW neonates are comparatively vulnerable and have the highest bilirubin toxicity index mainly due to the lowest reserve albumin levels [14]. As bilirubin is associated with the balance between prooxidant and antioxidant agents which are especially important for a neonate, [15] and aggressive phototherapy could increase mortality in certain extremely low birth weight infants, [2] the lower the better is not an option. Prior to the wide use of free bilirubin measurement, a new drug with high daily dosage and high protein binding ability trying to be administered in premature infants and/ or VLBW infants with severe hyperbilirubinemia should be carefully followed TSB level and evaluated potential bilirubin neurotoxicity.

References

1. Hulzebos CV, Libor Vitek, Carlos D Coda Zabetta, Aleš Dvořák, Paul Schenk, et al. (2021) Diagnostic methods for neonatal hyperbilirubinemia: Benefits, limitations, requirements, and novel developments. Pediatr Res 90(2): 277-283.
2. Lizhong Du, Xiaolu Ma, Xiaoxia Shen, Yinying Bao, Lihua Chen, et al. (2021) Neonatal hyperbilirubinemia management: Clinical assessment of bilirubin production. Semin Perinatol 45(1): 151351.
3. Walker PC (1987) Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement. Clin Pharmacokinet 13(1): 26-50.
4. Brodersen, R, B Friis-Hansen, L Stern (1983) Drug-induced displacement of bilirubin from albumin in the newborn. Dev Pharmacol Ther 6(4): 217-229.
5. Letamendia-Richard E, Rafik Ben Ammar, Ascanio Tridente, Daniele De Luca (2016) Relationship between transcutaneous bilirubin and circulating unbound bilirubin in jaundiced neonates. Early Hum Dev 103: 235-239.
6. Hegyi T, A Kleinfeld (2021) Neonatal hyperbilirubinemia and the role of unbound bilirubin. J Matern Fetal Neonatal Med, p. 1-7.
7. Hegyi T, Alan Kleinfeld, Andrew Huber, Barry Weinberger, Naureen Memon, et al. (2020) Unbound bilirubin levels in phototherapy-treated preterm infants receiving soy-based lipid emulsion. Pediatr Int 62(12): 1357-1363.
8. Morioka I, Sota Iwatani, Tsubasa Koda, Kazumoto Iijima, Hajime Nakamura (2015) Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction. Semin Fetal Neonatal Med 20(1): 31-36.
9. Thyagarajan B, SS Deshpande (2014) Cotrimoxazole and neonatal kernicterus: A review. Drug Chem Toxicol 37(2): 121.
10. Ah YM, Young-Mi Kim, Min-Jung Kim, Young Hee Choi, Kyoung-Ho Park, et al. (2008) Drug-induced hyperbilirubinemia and the clinical influencing factors. Drug Metab Rev 40(4): 511-537.
11. Ahlfors CE (2000) Unbound bilirubin associated with kernicterus: A historical approach. J Pediatr 137(4): 540-544.
12. Monte SV, William Allan Prescott, Kristin K Johnson, Lori Kuhman, Joseph A Paladino (2008) Safety of ceftriaxone sodium at extremes of age. Expert Opin Drug Saf 7(5): 515-523.
13. Romagnoli C, P De Turris, A A Zuppa, V Currò, M P De Carolis, et al. (1983) Physiologic hyperbilirubinemia in low-birth-weight newborn infants: Relation to gestational age, neonatal weight and intra-uterine growth. Pediatr Med Chir 5(5): 299-303.
14. Hulzebos CV, PH Dijk (2014) Bilirubin-albumin binding, bilirubin/albumin ratios, and free bilirubin levels: Where do we stand? Semin Perinatol 38(7): 412-421.
15. Dani C, C Poggi, S Pratesi (2019) Bilirubin and oxidative stress in term and preterm infants. Free Radic Res 53(1): 2-7.

ABSTRACT

Hyperbilirubinemia is a common situation in neonates, and measurements of bilirubin are key to the management of neonatal jaundice [1]. Bilirubin production is increased 2- to 3-times in term neonates in comparison with adults mainly due to a neonate’s shortened red blood cell (RBC) lifespan. Premature infants have proportionally increased bilirubin production rates as a consequence of an even shorter RBC lifespan [2]. Depending upon the balance between a neonate’s ability to produce and excrete bilirubin, i.e., either increased RBC breakdown and/or decreased bilirubin excretion may cause the severity of the hyperbilirubinemia, and thus increase the risk for developing neurologic dysfunction [2]. Drugs are commonly administered for treatment of diseases in neonates. Although most drugs are considered harmless, rarely drug-associated hyperbilirubinemia may occur [3]. Kernicterus or bilirubin neurotoxicity may appear following free bilirubin penetrates the blood brain barrier (BBB), and occurrence of this situation is subject to the ratio of unconjugated bilirubin concentration to reserve albumin concentration. The ratio increases whenever part of the albumin is occupied by a drug with apparent displacement of bilirubin, [4] prompting early measurement of serum bilirubin level in susceptible neonates.