Hyperbilirubinemia and Neurodevelopmental Outcome of Very Low Birthweight Infants: Results from the LIFT Cohort

Abstract

BackgroundBilirubin-related neurotoxicity is an important clinical issue in very low birthweight (VLBW) infants, and the existing literature is inconsistent.ObjectiveTo analyze the relationship between maximal serum unconjugated bilirubin levels (SBL) and neurodevelopmental outcome at 2-year corrected age in VLBW infants.MethodsPhototherapy was initiated in all infants born before 33 weeks of gestation, according to Maisels' recommendations. Neurodevelopmental assessment at 2-year corrected age was performed in all infants that survived. SBLs collected during the first week of life were used to define three tertiles of max-SBL. The first tertile corresponded to infants with the lowest max-SBL.Results and ConclusionsA total of 724 infants were included in the study, and among them, 631 (87%) were evaluated at two years old. The infants of the first tertile were younger and smaller than the infants of the other two tertiles, in accordance with Maisels' recommendations for very small infants. No difference in the risk of impaired functional outcome among the three groups was observed. However, among infants weighing less than 1001 g, those in the third tertile had a poorer neurodevelopmental prognosis as compared to those in the second tertile (adjusted odds ratio = 6.8, 95% CI: 1.2–36.7, p = 0.03). Considering the results obtained, we propose 196 µmol/L (11.5 mg/dL) when birthweight varies between 1001 and 1500 g, and 170 µmol/L (9.9 mg/dL) when birthweight is less than 1001 g, as recommended max-SBLs (defined as maximal levels of 95th percentile curves of SBLs in infants with an optimal outcome). When Maisels' recommendations were applied, max SBLs were higher in 8% of infants weighing 1001–1500 g and in 15% of infants weighing less than 1001 g. Our data seems to validate Maisels' recommendations in the overall population of infants born before 33 weeks of gestation, but not in infants weighing less than 1001 g.

Evaluation of Treatment Thresholds for Unconjugated Hyperbilirubinemia in Preterm Infants: Effects on Serum Bilirubin and on Hearing Loss?

“…Yet, auditory impairment in preterm infants may also occur at TSB levels below applied treatment thresholds, and - despite the rather low TSB levels- similar TSB levels have contributed to profound neurological impairment including sensoneurinal hearing loss in extreme or very low birth weight infants [4], [18]–[20]…”

Impact of bilirubin-induced neurologic dysfunction on neurodevelopmental outcomes

“…The authors do not explain these apparently conflicting findings, though it is notable there were only 348 subjects in the severe hyperbilirubinemia group, which may have affected statistical power. More recently, a study of 631 neonates with two year follow-up also reported a partial relationship between neonatal hyperbilirubinemia and outcomes [8]. Subjects were divided into tertiles based upon peak TB.…”

An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation

“…[13][14][15] In past decades, autopsy proven kernicterus was reported in sick, very low birth weight infants who were exposed to low TSB levels (the so-called 'low bilirubin kernicterus') 16,17 and recent case series document that this remains a clinical risk. [18][19][20][21] In a recent study from the Netherlands, 18 5 sick, preterm infants (25 to 29 weeks gestation) with peak TSB levels ranging from 8.7 to 11.9 mg dl À1 (148 to 204 mmol l À1 ) developed the classical MRI findings of kernicterus. Serum albumin levels in these infants were strikingly low, ranging from 1.4 to 2.1 g dl À1 .…”

“…21,22 In a retrospective analysis of ELBW infants born between 1994 and 1997, peak TSB levels, generally in the 5 to 12 mg dl À1 (85 to 204 mmol l À1 ) range were directly correlated with the risk of (i) death or NDI (odds ratio (OR): 1.068; 95% confidence interval (CI): 1.03 to 1.11), (ii) hearing impairment (OR: 1.138; CI 1.00 to 1.30) and (iii) a psychomotor development index <70 (OR: 1.057; CI 1.00 to 1.12) 22 although the effect size of each association was very small and barely significant. Nevertheless, other studies suggest that moderate hyperbilirubinemia in these infants poses no risk of neurotoxicity.…”