Unbound Bilirubin and Prematurity

A recent prospective study (SB Amin, H Wang. J Pediatr 2018; 192: 47-52) indicates that premature infants have lower bilirubin binding affinity which could place them at risk for neurological complications.

Background: Very high levels of unconjugated bilirubin can lead to bilirubin-induced neurotoxicity/kenricterus.  There is increased susceptibility in newborns, particularly premature infants.  Unbound bilirubin (not bound to protein) can cross blood-brain barrier.  However, unbound bilirubin, rather than total serum bilirubin, is a better predictor of abnormal neurological outcomes.

Key findings:

  • Among 166 infants, peak unbound bilirubin significant correlated with bilirubin-albumin binding affinity (Ka) (r=-0.44, P=.001)
  • Gestational age was a significant modifier for the association between Ka and peak unbound bilirubin.
  • Peak unbound bilirubin was primarily associated with a decrease in binding affinity in infants ≤30 weeks gestational age

Implications of study: “Phototherapy as a sole intervention may be insufficient in preventing or reducing bilirubin-induced neurotoxicity”

My take: If there is low bilirubin binding affinity, among premature infants ≤30 weeks gestational age, some neurologic toxicity could occur even with bilirubin levels that have been considered safe previously.

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Lipid Emulsions and Unbound Bilirubin in Preterm Infants

Happy birthday Stan!

In previous work, it had been shown that free bilirubin (Bf) and unbound free fatty acids (FFAu) were increased in extremely low birth weight infants who received intralipid (soybean) at 3 g/kg/d.  A recent study (T Hegyi et al. J Pediatr 2017; 184: 45-50) showed that Bf and FFAu are increased with increasing intralipid dosage (1 to 3 g/kg/d) in all gestational ages (23-34 weeks).

The concern with Bf and FFAu is that elevated concentrations could have adverse neurologic effects; intralipids may act to displace bilirubin from binding to albumin. For most infants in this study, the levels “would not be expected to pose a neurotoxic risk” (per editorial pg 6-7).  Factors that enhance the generation of FFAu include infection, steroids, carnitine deficiency, and low albumin conditions. Phototherapy, in this study, reduced total serum bilirubin but not Bf in those receiving 2-3 g/kg/d of intralipid.

My take: This study does not provide any information regarding neurotoxicity.  It shows that potentially toxic levels of Bf & FFAu can occur in infants born <28 weeks who receive 2 g/k/day or more of intralipid.  While this is a concern, we also know that poor growth is associated with worsened neurocognitive outcomes (Nutrition Week: Downside of Lipid Reduction)