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Factors that influence hyperbilirubinaemia and kernicterus

aminoglycoside antibiotics were excluded. Screening for hearing loss was done using brain-
stem-evoked response on the day of discharge. The outcome assessors were blinded to
treatment and serum bilirubin levels. Altogether 35% of the babies had hyperbilirubinaemia
(defined as serum bilirubin levels ≥ 340 micromol/litre); hearing loss was detected in 22% of
the babies. Although there was a higher percentage of babies with hearing loss among those
with hyperbilirubinaemia compared with babies with serum bilirubin levels below
40 micromol/litre, the difference was not statistically significant (33% versus 16%; P = 0.11).
After controlling for various confounding factors in a logistic regression analysis, variables
statistically significantly associated with hearing loss were jaundice that required exchange
transfusion and an earlier onset of hyperbilirubinaemia. [EL II]
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Another retrospective multicentre study from the USA assessed the association between peak
serum bilirubin levels and neurodevelopmental outcomes in extremely low birthweight babies
(birthweight range 401–1000 g) born during a 4 year period who survived to 14 days of age.
Trained and certified personnel performed a comprehensive history, physical examination and
neurodevelopmental assessment at 18–22 months age. Blinding was not reported. The variables
indicative of abnormal neurodevelopment included Psychomotor Developmental Index (PDI)
< 70, Mental Developmental Index (MDI) < 70, moderate or severe cerebral palsy, hearing
impairment (needing hearing aids), and a composite category designated as
neurodevelopmental impairment (NDI). Of 3167 babies eligible for the study, 2575 (81%) were
followed up. Regression analysis showed various demographic and clinical variables to be
associated with poor neurodevelopmental outcomes. However, after adjustment for these risk
factors, statistically significant associations were found only between peak serum bilirubin levels
and death or NDI (OR 1.07, 95% CI 1.03 to 1.11), PDI < 70 (OR 1.06, 95% CI 1.00 to 1.12),
and hearing impairment requiring hearing aids (OR 1.14, 95% CI 1.00 to 1.30). There was no
statistically significant association between peak serum bilirubin levels and cerebral palsy, MDI
< 70 or NDI in extremely low birthweight babies. [EL II]

Evidence summary
There is a lack of good-quality evidence on the association between hyperbilirubinaemia and
kernicterus or other adverse sequelae.

One small cohort study reported a history of birth asphyxia, higher serum bilirubin levels and
free bilirubin levels as statistically significant risk factors for kernicterus in term babies. A poor-
quality retrospective study found no statistically significant difference between babies diagnosed
with kernicterus at autopsy and those without. In a third study, a higher proportion of late
preterm babies developed kernicterus and post-icteric sequelae compared with term babies, but
the difference was not statistically significant.
Three studies evaluated the association of high serum bilirubin levels (> 340 micromol/litre)
with adverse sequelae: two studies were in term babies and one in babies with birthweight less
than 1000 g. One study in term babies found no statistically significant association between
hyperbilirubinaemia and IQ, abnormal neurological examination or sensorineural hearing loss.
Another study reported severe jaundice requiring exchange transfusion and early onset of
jaundice as statistically significant risk factors for hearing loss. The third study found a weak
association between high serum bilirubin levels and neurodevelopmental impairment, hearing
impairment and psychomotor impairment in babies with birthweight less than 1000 g.
GDG translation from evidence

No good-quality studies identified risk factors for kernicterus.
Poor-quality studies have shown a link between kernicterus and both high serum bilirubin levels
and free bilirubin levels in all babies.
Severe jaundice requiring exchange transfusion (criterion was bilirubin > 340 micromol/litre)
and early onset of jaundice (within 24 hours) are statistically significant risk factors for hearing
loss. Deafness is a clinical manifestation of kernicterus. Haemolytic disorders such as G6PD
deficiency and ABO incompatibility may cause a rapid increase in bilirubin level, and these
disorders have been over-represented in international kernicterus registries and population
studies of significant hyperbilirubinaemia (see Chapter 6 on formal assessment). A study of low-

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