What is the morbidity and mortality associated with bilirubin encephalopathy in hemolytic disease of the newborn (HDN)?

Updated: Dec 28, 2017
  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Muhammad Aslam, MD  more...
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  • Before the advent of exchange transfusion, kernicterus affected 15% of infants born with erythroblastosis. Approximately 75% of these neonates died within 1 week of life, and a small remainder died during the first year of life. Survivors had permanent neurologic sequelae and were thought to have accounted for 10% of all patients with cerebral palsy (CP).

  • The mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. Bilirubin enters the brain as lipophilic free bilirubin unbound to albumin, as supersaturated bilirubin acid that precipitates on lipid membrane in low pH, or as a bilirubin-albumin complex that transfers bilirubin to tissue by direct contact with cellular surface. The blood-brain barrier is comprised of ATP-dependent transport proteins and pumps free bilirubin from the brain back into plasma and maintains the concentration gradient of unconjugated bilirubin. A damaged blood-brain barrier enhances the entry and fails to remove all forms of bilirubin into the brain, which is especially important in preterm neonates with respiratory acidosis and vascular injury.

  • Bilirubin has been postulated to cause neurotoxicity via 4 distinct mechanisms [43] : (1) interruption of normal neurotransmission (inhibits phosphorylation of enzymes critical in release of neurotransmitters), (2) mitochondrial dysfunction, (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and precipitates on phospholipid membranes of mitochondria), and (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes).

  • The pathologic findings include characteristic staining and neuronal necrosis in basal ganglia (especially the globus pallidus and subthalamic nucleus), hippocampal cortex (especially the CA2 sector), brainstem nuclei (especially the auditory, vestibular, and oculomotor), and cerebellum (especially Purkinje cells). The cerebral cortex is generally spared. About half of these neonates also have extraneuronal lesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic cells.

  • Clinical signs of bilirubin encephalopathy typically evolve in 3 phases. Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and hypertonia are observed in phase 2, and, at times, the condition progresses to opisthotonus. Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor feeding, and athetosis.

  • Long-term sequelae include choreoathetoid CP, upward gaze palsy, sensorineural hearing loss, dental enamel hypoplasia of the deciduous teeth, and, less often, mental retardation. The abnormal or reduced auditory brainstem response of wave I (auditory nerve) and wave II and V (auditory brainstem nuclei), depicted as decreased amplitudes, and increased interval I-III and I-V characterize phase I of early, but reversible, encephalopathy. Subtle bilirubin encephalopathy that consists of either cognitive dysfunction, isolated hearing loss, or movement disorder has been described in absence of kernicterus and better correlates with free bilirubin levels.

  • Currently, the mortality rate stands at 50% in term newborns, but mortality is nearly universal in the preterm population who may simply appear ill without signs specific for kernicterus. Research has indicated that bilirubin production rates may be the critical piece of information identifying jaundiced infants at risk of neurotoxicity. A high bilirubin production rate is thought to result in rapid transfer of bilirubin to tissue, causing high tissue load, in which case any small further increase has great potential to enter the brain. Because the total serum bilirubin represents not only bilirubin production but also distribution and elimination, it is not an absolute indicator of risk of kernicterus. Techniques have been developed to measure the bilirubin production rates accurately and noninvasively using end-tidal carbon monoxide measurement and percutaneous measurement of carboxyhemoglobin.

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