Screening for Severe Neonatal Hyperbilirubinemia

Vinod K. Bhutani


Pediatr Health. 2009;3(4):369-379. 

In This Article

Abstract and Introduction


Screening for severe neonatal hyperbilirubinemia is integral to newborn care. Predischarge risk assessment relies on documentation of visual jaundice: age at onset and progression; identification of clinical risk such as late prematurity and bruising; with determination of total bilirubin (blood or transcutaneous assay) adjusted for age in hours. Along with promotion of breastfeeding, coordination between birthing hospital and medically supervised outpatient follow-up, a systems approach allows for a safer and effective means to prevent adverse effects of extreme hyperbilirubinemia.


Postnatal hyperbilirubinemia is universal and manifests as newborn jaundice in over 60% of all newborns in the USA. Unmonitored and untreated hyperbilirubinemia may progress to excessive levels that can be associated with evident bilirubin neurotoxicity. Jaundice is the most common clinical diagnosis in neonatal medicine and is due to elevated unconjugated (indirect) and/or conjugated (direct) bilirubin levels. Confirmation is by a total serum (plasma) blood test for bilirubin (TB) or transcutaneous bilirubin (TcB). Bilirubin is a known antioxidant at low levels (in vitro) and a potent neurotoxin at high levels (in vivo). Elevated bilirubin concentrations may occur due to increased bilirubin production (breakdown of heme moiety of hemoglobin) and/or delayed bilirubin elimination (hepatic and intestinal) as well as by a unique neonatal phenomenon of enterohepatic reabsorption of bilirubin. Bilirubin and carbon monoxide are the major degradation products of heme. The nonwater-soluble unconjugated bilirubin (bound to albumin) is processed in the hepatocyte to the excretable water-soluble conjugated bilirubin by the enzyme uridine-di-phospho-glucuronosyl-transferase (UGT). With decreased gastrointestinal activity and/or starvation in the immediate postnatal period, some of this conjugated is reconverted to unconjugated bilirubin in the gut and reabsorbed in the circulation (enterohepatic recirculation). The neurotoxic effect of bilirubin does not correlate well with total serum bilirubin (TSB) levels because it is influenced by the ability of unconjugated bilirubin (mg/dl) to bind with albumin (g/dl) - a ratio of approximately 8:1. Bilirubin binding to albumin is influenced by acidosis, hypoalbuminemia, lower gestational age, postnatal age (age <3 days) and interference by drugs such as sulfa and some cephalosporins.[1]

Most frequent clinical and contributory risk factors for extreme hyperbilirubinemia and kernicterus are late prematurity, undiagnosed hemolytic disease, genetic abnormalities (such as glucose-6-phosphate dehydrogenase [G6PD] deficiency, congenital spherocytosis, galactosemia, Crigler-Najjar syndrome and others that are undiagnosed) and concurrent complications of dehydration, sepsis, or acidosis, hypoalbuminemia or poor feeding.[1,2,3] Neonatal jaundice and hyperbilirubinemia occur more commonly and are more prolonged among late preterm infants than full-term infants.[4,5,6] Late preterm infants have delayed maturation and a lower concentration of uridine diphosphoglucuronate glucuronosyltransferas, immature gastrointestinal function, and exhibit feeding difficulties that predispose them to dehydration, increased enterohepatic circulation, decreased stool frequency and hyperbilirubinemia. G6PD deficiency is also associated with a high incidence of neonatal hyperbilirubinemia and risk of kernicterus. Both increased bilirubin production (that may or may not have been exacerbated by a hemolytic process) and concurrent diminished bilirubin conjugation are the likely basis for severe hyperbilirubinemia.[6,7] Exacerbation with coexpression of genetic mutations involved with bilirubin conjugation and elimination and/or a triggered increase in bilirubin production (such as exposure to oxidants, infections and drugs) may lead to progressive or hazardous hyperbilirubinemia.[8,9]

Kernicterus, a preventable form of neonatal bilirubin-related brain injury, is currently prevalent in the USA and is a matter of public and societal concern.[3] Acute bilirubin encephalopathy and/or chronic kernicterus, in its usually recognized form, occurs and results in neonatal death or multisystem disabilities, including irreversible athetoid cerebral palsy with speech, and ocular and hearing impairments. A range of TB levels, rather than a specific level, is a threshold for the onset of neurotoxicity in otherwise healthy term infants.[10] Bilirubin neurotoxicity is likely to occur when bilirubin moves from the circulation into the brain. Of the several distinct forms of circulating bilirubin, those not bound to albumin, red blood cells or lipoproteins, concentrations of free or unbound bilirubin is considered to be a better predictor of neurotoxicity.[11] The risk of neurotoxicity may be interdependent on levels of free bilirubin and/or TSB. It is in this context, that universal predischarge screening combined with assessment of gestational age is most predictive of subsequent severe hyperbilirubinemia at age over 72 h and during the first week after birth such that timely intervention should be implemented efficiently because of a narrow safety margin.[1,12]

Case reports of kernicterus are unusual and rarely identified in healthy infants when TB levels were less than 25 mg per 100 ml (427 μmol/l) and none have been reported for infants with known peak TB levels less than 20 mg per 100 ml (342 μmol/l). In one report, infants with acute bilirubin encephalopathy who presented with TB levels more than 35 mg per 100 ml (598 mol/l) sustained some degree of posticteric sequelae regardless of treatment.[3] On the other hand, not all infants with TB levels greater than 30 mg per 100 ml (513 μmol/l) manifest classic kernicterus.[13,14,15] Vulnerability to chronic sequelae, in infants with TB levels between 20 and 35 mg per 100 ml, is influenced by postnatal age, rate of TB rise, duration of extreme hyperbilirubinemia, late prematurity (<37 weeks), gender (male), being large for gestational age, dehydration (>15% weight loss over birthweight) and infection that is often associated with genetic abnormalities.[3] In an analogy to aviation safety standards, acute kernicterus events are akin to airline crashes.

A family-centered, system-based approach that builds constructive parent/healthcare partnerships aimed at the prevention of a spectrum of bilirubin toxicity and related disabilities are incorporated in the 2004 American Academy of Pediatrics guidelines[1] and made available through the CDC website.[101] Strategies to implement and institutionalize the evidence-based and consensus-driven guidelines for safer management of newborn jaundice are needed and should be complemented with practice-based surveillance use of phototherapy and incidence of near-miss events.[16]


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