Controversies in our understanding of extreme hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient neonates.

Despite declarations that kernicterus should be a "never-event", the condition continues to occur, glucose-6-phosphate dehydrogenase (G6PD)-deficiency being a leading cause. In this paper, we address some controversies regarding the pathophysiology and the potential for extreme hyperbilirubinemia associated with G6PD-deficiency. We present evidence to demonstrate that G6PD-deficiency-associated neonatal hyperbilirubinemia is no longer limited to countries and geographic regions to which the condition was indigenous, but is also encountered in North America and other Western countries with a low inherent G6PD-deficiency frequency. Pathophysiologically, while a diminished bilirubin conjugative component is undoubtedly present, we present evidence that there is a component of increased hemolysis as well, contributing to the extreme, exponential hyperbilirubinemia associated with G6PD-deficiency. Extreme hyperbilirubinemia in G6PD heterozygotes, while less frequent than in male hemizygotes or female deficient homozygotes, has been reported, suggesting previous underestimation of the risks of heterozygosity. Universal neonatal screening for G6PD-deficiency, while not expected to prevent acute, episodic hyperbilirubinemia, should increase awareness, thereby facilitating earlier referral for treatment, prior to the onset of bilirubin encephalopathy. Finally, we speculate as to what the future looks like for babies with G6PD-deficiency, potential therapeutic stratagems, and the effect of G6PD-deficiency on medical conditions beyond the realm of neonatal hyperbilirubinemia. IMPACT STATEMENTS: G6PD-deficiency is encountered in North America and Western countries previously thought to have a low frequency of the condition. Extreme, sudden neonatal hyperbilirubinemia is due, in the main, to increased hemolysis, an independent risk factor for neurotoxicity. Extreme hyperbilirubinemia may follow apparently resolved neonatal hyperbilirubinemia which had been treated by phototherapy. Female G6PD heterozygotes, previously thought to be unaffected clinically by G6PD-deficiency, while at low risk, may, nevertheless, develop extreme hyperbilirubinemia. Universal neonatal G6PD screening should be aimed towards increasing caretaker awareness and facilitating referral for treatment prior to the onset of bilirubin encephalopathy.