Review
Neonatal hemolysis and risk of bilirubin-induced neurologic dysfunction

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Summary

The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Several immune and non-immune conditions have been found to cause severe hemolysis, and these are often exacerbated in those infants with perinatal sepsis and genetic predispositions. Therefore, identification of these infants, with novel technologies, is paramount in reducing the incidence of BIND and the long-term neurologic sequelae for these at-risk infants.

Introduction

Neonatal jaundice is a benign condition occurring in 65–85% of all healthy term and late preterm infants. It is a result of a combination of naturally occurring factors in an infant's first week of life [1]. First, newborn infants have an increased red blood cell (RBC) turnover rate, which is up to two to three times that of a normal adult [2], [3]. Second, newborns have an impaired hepatic ability in the uptake and conjugation of bilirubin. This transitional imbalance of production and elimination is normal, but can be upset in several conditions, which are often associated with increased bilirubin production, such as prematurity, bruising (e.g., cephalhematoma), infants of diabetic mothers (IDM), ethnicity, cholestasis, and hemolysis. All these may further increase an infant's bilirubin load to cause severe unconjugated hyperbilirubinemia, especially in those infants with perinatal sepsis in countries with high neonatal mortality rates and among those with genetic predispositions where the rate of sepsis has been more efficiently managed [4]. Recent epidemiologic data show that there is an increased risk for bilirubin-induced neurotoxicity in infants with hemolytic disease regardless of its etiology [5]. Therefore, if these at-risk infants are unidentified or left untreated, bilirubin-induced neurological dysfunction (BIND) may develop and lead to long-term neurologic sequelae, and even kernicterus [4], [6], [7]. Therefore, developing novel technologies that can identify these at-risk infants may play a key role in reducing the incidence of BIND.

Section snippets

Causes of hemolysis

The American Academy of Pediatrics (AAP) in its 2004 guideline considers hemolysis as a major risk factor in the development of severe hyperbilirubinemia [8]. In fact, the guideline recommends administering phototherapy or performing exchange transfusions in neonates with hemolytic conditions at lower total serum/plasma bilirubin (TB) levels compared to those that are non-hemolysing, healthy newborns. Hemolysis in newborn infants can originate from a number of different conditions, which are

Genetic predispositions

Superimposed on this physiology is an infant's genetic predisposition, which can further impact rates of bilirubin production and elimination. Individuals can possess genetic variants that can affect bilirubin production or its elimination alone; or in some combination, thereby affecting both bilirubin production and elimination.

Assessment of hemolysis

Regrettably, there are no clinical tests or point-of-care devices currently available that can reliably detect ongoing hemolysis. Existing technologies can identify only those infants at high risk [36], [37]. These include blood bank screening of cord blood for ABO incompatibilities and blood collection, which are invasive, used for determinations of Rh type, TB, and direct antiglobulin test (DAT) or Coombs positivity.

Risk of BIND associated with neonates with hemolytic disease

It is now well recognized that an increased bilirubin production rate is a major cause of severe hyperbilirubinemia. Because all neonates have a transiently impaired elimination of bilirubin, disorders in hepatic uptake, conjugation, and enterohepatic circulation can exacerbate the transitional neonatal jaundice and lead to severe hyperbilirubinemia. Infants are at more risk for injury because of their absolute bilirubin level, binding capacity, and clinical circumstances that might alter their

Summary

Although severe hyperbilirubinemia can be best understood with regards to complications related to the uptake and conjugation of bilirubin, the hyperbilirubinemia requiring treatment in newborn infants most frequently observed by the pediatrician is associated with increased bilirubin production, and most likely due to hemolysis, which is often further exacerbated by environmental or genetic factors. Thus, early identification of these infants combined with a therapeutic approach aimed at

Conflict of interest statement

None declared.

Acknowledgments

We would like to thank the Mary L. Johnson Research Fund, Christopher Hess Research Fund, and the HML for their generous support of our work throughout the years.

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    Portions of this review were presented at the Bilirubin Club held at the Pediatric Academic Societies 2013 Annual Meeting in Washington, DC, on May 4, 2013.

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