Hyperbilirubinemia in Preterm Neonates

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Key points

  • •

    Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion.

  • •

    Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin.

  • •

    There are clinical approaches that minimize the risk of bilirubin neurotoxicity.

Natural bilirubin profile in preterm neonates

Previous studies suggest that preterm infants with modest TB levels can sustain long-term NDI at age 18 to 22 months,7, 15, 16, 17, 18 and infants with high TB levels can experience increased mortality and NDI associated with auditory neuropathic or visuomotor processing disorders (now characterized as BIND).7, 8, 9, 10 However, some preterm infants are resistant to relatively high bilirubin loads in the absence of increased production rates because of efficient elimination of bilirubin and

Clinical profile of subtle posticteric sequelae

As summarized by Johnson and Bhutani,8 pilot studies conducted in the pre-phototherapy era for neonates cared for in 1965 to 1966, identified altered pyschometric, audiologic, speech, language, and visuomotor disorders. Their reanalysis of 4-year and 7-year follow-up studies showed a consistent, significant correlation of low bilirubin binding reserve, with suspicious and abnormal ratings for the psychometric and audiologic examinations. An abnormal bilirubin-albumin molar ratio (BAMR) appeared

Beneficial role of bilirubin

Tissue injury from a biological, chemical, or traumatic insult usually results in a cascade of adaptive response to protect against further injury possibly through restoring vascular integrity that may include endogenously elevated TB (See Stevenson DK, Wong RJ, Arnold CC, et al. Phototherapy and the risk of photo-oxidative injury in extremely low birth weight (ELBW) infants, in this issue). Mildly elevated TB may be associated with lowered morbidity and related mortality, which could be

Bench evidence of bilirubin neurotoxicity in preterm neonates

In a recent review, Brites and Brito59 outlined the mechanisms of dysfunction and demise of neurons by unconjugated bilirubin (UCB) derived from excitotoxicity, oxidative stress, alterations in neuronal arborizations, synaptotoxicity, and apoptosis mediated by alterations in mitochondria dynamics and caspase activation, ultimately leading to cell demise. UCB decreases the expression of presynaptic proteins and was shown to cause presynaptic degeneration in the Gunn rat, an animal model of

Margins of clinical safety

Management of hyperbilirubinemia in preterm infants varies among institutions, with little evidentiary support for these differences in management.62 Because of the limited specificity of TB as a predictor for neurotoxicity, the margin of safety is narrow and unpredictable. Thus, interventions are primarily for prevention rather than for rescue. Interventions include the following: (1) alterations of preterm gut physiology and enterohepatic circulation by early initiation of feeds to alter

Timing of Interventions to Reduce Excessive Bilirubin Load

The timing of bilirubin reduction strategies impacts the outcome of preterm infants at risk for excessive hyperbilirubinemia. Early implementation of strategies to rapidly and effectively reduce the excessive bilirubin load before the onset of neurologic signs, in all likelihood, could prevent chronic posticteric sequelae or kernicterus. The initial evidence for this approach, using phototherapy, was demonstrated by a National Institute of Child Health and Development (NICHD) Neonatal Research

Follow-up of preterm infants at risk for bilirubin-induced neurologic dysfunction

Posticteric sequelae are often unrecognized, mislabeled, or misdiagnosed in preterm infants. These errors have led to prolonged diagnostic and health-seeking odysseys for families. Follow-up studies of infants enrolled in the NICHD trial of 1979 to 1985 demonstrated the challenges of follow-up in this population as well as the residual morbidities identified at late childhood and in adults. Oh and colleagues,16 through a retrospective observational analysis in infants with BW less than 1000 g,

Summary

Bilirubin, a powerful antioxidant, also can act as a powerful but silent neurotoxin at the most vulnerable stage of preterm life. The impact is long-lasting with both functional and structural neurologic injury that alters the processing of afferent input and leads to disordered efferent function. Moreover, these perturbations can potentially arrest or retard the natural neural maturation and/or lead to disordered clinical extrapyramidal function, sensory processing of hearing, visual

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