Short- and Long-Term Outcome of Severe Neonatal Nonhemolytic Hyperbilirubinemia

Virginia Wong MBBS, FHKAM, FHKC Paed, FRCPCH, FRCP (London, Edinburgh), DCH (London, Glasgow); Wen-Xiong Chen MD; Kar-Yin Wong MBBS, FHKAM, FHKC Paed, MRCP (UK)

Disclosures

J Child Neurol. 2006;21(4):309-315. 

In This Article

Abstract and Introduction

We studied the effects of hyperbilirubinemia on brainstem auditory pathways and neurodevelopmental status in 99 full-term neonates with severe nonhemolytic hyperbilirubinemia (total serum bilirubin level = 301 to 500 µmol/L) born between 1995 and 2000. These were divided into three groups: group 1, moderate hyperbilirubinemia (n = 30; mean maximum total serum bilirubin = 320.7 µmol/L or 18.9 mg%); group 2, severe hyperbilirubinemia (n = 63; mean maximum total serum bilirubin = 369.0 µmol/L or 21.7 mg%); and group 3, super hyperbilirubinemia (n = 6; mean maximum total serum bilirubin = 457.2 µmol/L or 26.9 mg%). All received phototherapy, and three neonates also had exchange transfusion. Initial brainstem auditory evoked potentials were recorded in all at the mean age of 3.1 months (range 19 months). At initial assessment, only nine neonates (9.1%) had abnormal brainstem auditory evoked potentials. All except two returned to normal at 2 years. These two children had a hearing threshold at 50 nHL. We then compared serial brainstem auditory evoked potentials until 2 years for these nine cases with initial abnormal brainstem auditory evoked potentials, and nine cases with initial normal brainstem auditory evoked potentials were recruited for comparison. All 99 children had regular physical, neurologic, visual, and auditory assessments every 3 to 6 months until the age of 3 years. There was no significant correlation between demographic factors (gender, gestational age, or birthweight), maximum total serum bilirubin, and total serum bilirubin at discharge with an abnormal brainstem auditory evoked potential. There was no significant difference in the rate of brainstem auditory evoked potential abnormalities between the three groups: moderate (10%), severe (7.9%), and super (16.7%). All had normal neurodevelopmental status at 3 years. Only two children had transient mild motor delay and hypotonia, and both had normal brainstem auditory evoked potentials. There was no relationship between the abnormalities of the brainstem auditory evoked potentials and neurodevelopmental status. None of the three children receiving exchange transfusion had abnormal brainstem auditory evoked potentials or neurodevelopmental outcome. With the neurophysiologic and clinical outcomes in our cohort with severe nonhemolytic hyperbilirubinemia, we propose that the toxic effect of hyperbilirubinemia on auditory brainstem pathways might be transient provided that prompt treatment is initiated.

Neonatal jaundice is common in neonates, especially in Orientals. The prevalence of neonatal jaundice is 50% to 60% in term and 80% in preterm neonates.[1] Neonatal hyperbilirubinemia can lead to sensorineural hearing impairment, cerebral palsy, psychologic impairment, disturbances in visual perception, or gaze paralysis.[2,3,4,5]

There is no objective method to evaluate the toxic cerebral effects of hyperbilirubinemia during the acute management of hyperbilirubinemia. Evoked potentials are noninvasive tools to evaluate the integrity and functional maturation of the afferent pathways of the central and peripheral nervous systems. The brainstem auditory evoked potential has been demonstrated to be a useful tool in detecting the acute neurotoxicity of bilirubin in the peripheral and central auditory pathways.[6,7,8,9,10,11]

Studies published in the 1980s were mainly explorative in the use of the brainstem auditory evoked potentials in neonatal hyperbilirubinemia during the acute phase, with serial brainstem auditory evoked potential assessments recorded just before and after treatment by either phototherapy and/or exchange transfusion.[12,13,14,15,16,17] These studies showed that the abnormalities of the brainstem auditory evoked potentials in premature or term neonates with hyperbilirubinemia improved after phototherapy and/or exchange transfusion.

However, short-term outcome studies published in the 1990s remained controversial in the final outcome.[18,19,20,21,22,23,24,25,26,27] The geographic distribution of these studies was as follows: three in India,[18,19,20] two in Italy,[21,26] two in Japan,[22,23] and one each in Korea,[24] Turkey,[25] and Hungary.[27] Most short-term studies evaluated the short-term effect within 6[18,19,20,21,22,24,25] to 12 months.[23,26,27] There were a few long-term studies: one in Italy,[28] and two in Turkey.[29,30,31] Serial brainstem auditory evoked potentials were performed at different ages: 15 to 80 months,[28] 2 to 6 years,[30,31] and 8 to 13 years.[29]

The possibility of delayed effects on growth and development,[32,33,34,35,36] vision,[37] and skin abnormalities,[38,39] had been reported for phototherapy. However, a recent multicenter randomized controlled study concluded that phototherapy can effectively control neonatal hyperbilirubinemia without adverse outcome at 6 years.[40]

The criterion of a total or even an unbound serum bilirubin level considered neurotoxic can be different for different ethnic groups. The reasons for ethnic differences at risk of kernicterus are not clear.[41] The different etiologies for different ethnic origins might be contributory; for example, glucose-6-phosphate dehydrogenase deficiency is common in Orientals, whereas rhesus incompatibility is rare.

In this pilot study, we aimed to evaluate the effects of hyperbilirubinemia on auditory brainstem pathways and neurodevelopmental status in Chinese children with severe nonhemolytic neonatal hyperbilirubinemia.

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