Outcomes in Kernicterus Cases

Summarizing case reports of kernicterus from different investigators in different countries from different time periods is problematic. First, definitions used in these reports varied greatly. They included gross yellow staining of the brain, microscopic neuronal degeneration, acute clinical neuromotor impairment, neuro-auditory impairment and chronic neuromotor impairment. In some cases, the diagnoses were not established until months or years after birth. Second, case reports without controls makes interpretation difficult, especially in infants with comorbid factors, and could very well lead to misinterpretation of the role of bilirubin in neurodevelopmental outcomes. Third, different reports used different outcome measures. “Normal at follow-up” may be based on parental reporting, physician assessment, or formal neuropsychological testing. Fourth, time of reported follow up ranged from days to years. Fifth, cases were reported from different countries at different time periods and with different milieu (some have high prevalence of G6PD and some use naphthalene moth balls routinely in their dressers) and varying standards of practice concerning hyperbilirubinemia. The effect of the differences on outcomes cannot be known for certain. Finally, it is difficult to infer from case reports the true incidence of this uncommon disorder. Nevertheless, one can conclude from these data that high levels of serum bilirubin are strongly associated with kernicterus. The distribution of bilirubin levels in reported cases of kernicterus is substantially skewed compared to the population-based distribution of neonatal bilirubin levels described by Newman, Escobar, Gonzales et al. (1999). (See Figure 4.1.)

Figure

Figure 4.1 Peak total serum bilirubin (TSB) values (mg/dl) obtained from case reports of 35 otherwise healthy infants with kernicterus suprimposed on the distribution of peak TSB values from a birth cohort of 50,000 infants born in 11 California hospitals (more...)

Based on our summary of multiple case reports that spanned more than 30 years, we conclude that kernicterus, although infrequent, has significant mortality (at least 10 percent) and long-term morbidity (at least 70 percent). It is evident that the preponderance of kernicterus cases occurred in infants with high bilirubin (>20mg/dl). This summary affirms the role of elevated bilirubin level in kernicterus but does not provide incontrovertible proof of causality in this association.

Five of 26 (19 percent) term or near-term infants with kernicterus and reported follow-up data survived without sequelae, while only three of 63 (5 percent) infants with kernicterus and comorbid factors were reported to be normal at follow up. This suggests the importance of comorbid factors in determining long-term outcome in infants initially diagnosed with kernicterus.

Outcomes of Hyperbilirubinemia

Only a few prospective controlled studies looked specifically at behavioral and neurodevelopmental outcomes in healthy term infants with hyperbilirubinemia. Most of these studies have a small number of subjects. Two very short-term studies with well-defined measurement of newborn behavioral organization and physiologic measurement of cry are of high quality methodology (Escher-Graub and Fricker, 1986; Rapisardi, Vohr, Cashore et al., 1989). But the significance of long term abnormalities in newborn behavior scales and variations in cry formant frequencies are unknown. There remains very little information on the long-term effects of hyperbilirubinemia in healthy term infants.

Among the mixed studies (combined term and preterm; non-hemolytic and hemolytic; non-diseased and diseased) and studies with subjects from racial backgrounds other than black and white infants, the following observations can be made:

• Excluding the Collaborative Perinatal Project (CPP) study and the studies looking at IQ, out of nine studies looking primarily at behavioral and neurodevelopmental outcomes, only three studies were of high methodologic quality. One very short-term study showed a correlation between bilirubin level and decreased scores on newborn behavioral measurements (Vohr, Lester, Rapisardi et al., 1989). One found no difference in prevalence of CNS abnormalities at age 4 years when bilirubin was below 20 mg/dl, but infants with bilirubin above 20 mg/dl had a higher prevalence of CNS abnormalities (Hyman, Keaster, Hanson et al, 1969). Another study that followed infants with bilirubin greater than 16 mg/dl found no relationship between bilirubin and neuro-visual-motor testing at 61 to 82 months of age (Valaes, Kipouros, Petmezaki et al., 1980). Although data reported in the rest of the studies are not of the highest caliber, there is a suggestion of abnormalities in neurodevelopmental screening tests in infants with bilirubin > 20 mg/dl, at least by the Denver Developmental Screening Test (DDST), when followed up at one year of age. It appears that bilirubin > 20 mg/dl may have short-term (up to one year of age) adverse effects at least by DDST, but there is no strong evidence to suggest neurologic abnormalities in children with neonatal bilirubin > 20 mg/dl when followed up to 7 years of age.
• Nine of 15 studies (excluding the CPP) addressing neuro-auditory development and bilirubin level were of high quality. Six of them showed BAER abnormalities correlate with high bilirubin levels. The majority reported resolution with treatment. Three studies reported hearing impairment associated with elevated bilirubin (> 16 mg/dl to > 20 mg/dl). We conclude that high bilirubin level does have an adverse effect on neuro-auditory development, but the adverse effect on BAER is reversible.
• Again, excluding the CPP, of the eight studies reporting intelligence outcomes in subjects with hyperbilirubinemia, four studies were considered high quality. These four studies reported no association between IQ and bilirubin level with follow up ranging from 6.5 years to 17 years. Seidman, Paz, Stevenson, et al. (1991) also reported no direct linear association between bilirubin levels and IQ scores. However, the risk for IQ score < 85 at age 17 years was found to be significantly higher among full-term Coombs-negative male subjects with serum bilirubin > 20 mg/dl. We conclude that there is no evidence to suggest a linear association of bilirubin level and IQ.
• The Collaborative Perinatal Project (CPP), with 54,795 live births between 1959 and 1966 from 12 centers in the U.S. has, by far, the largest database for the study of hyperbilirubinemia. Newman and Klebanoff (1993), focusing only on black and white infants with birthweight ≥ 2500 grams, did a comprehensive analysis of 7-year outcome in 33,272 subjects. All causes of jaundice were included in the analysis. The study found no consistent association between peak bilirubin level and IQ. Sensorineural hearing loss was not related to bilirubin level. Only the frequency of abnormal or suspicious neurologic examinations was associated with bilirubin level.

A large prospective study comprised of healthy infants ≥ 34-week gestation with hyperbilirubinemia, specifically looking at long-term neurodevelopmental outcomes, has yet to be done. The report of Newman and Klebanoff (1993) came closest to that ideal because of the large number of subjects and the study analytic approach. However, a population born from 1959 to 1966 may no longer be relevant to present day newborns. There are more infants born to non-black and non-white mothers. More infants are breastfed. Phototherapy for hyperbilirubinemia has become standard therapy. Hospital stays are shorter. All these and other factors may have unknown long-term developmental effects on present day newborns with hyperbilirubinemia.

Short-term studies reviewed in this section, while in general having good methodologic quality, use tools that have unknown long-term predictive abilities. Long-term studies suffer from high attrition rates of the study population and a non-uniform approach to defining “normal neurodevelopmental outcomes.” The total bilirubin levels reported in all the above studies were measured anywhere from first day of life to more than two weeks of life. Definitions of significant hyperbilirubinemia ranged from 12 mg/dl to 20 mg/dl.

Given the diversity of conclusions reported, except in cases of kernicterus with sequelae, it is evident that the use of a single total serum bilirubin level (within the range described in the reviewed studies) to predict long-term behavioral or neurodevelopmental outcomes is inadequate and will lead to conflicting results.