How common is hyperbilirubinemia and how often does it entail the subsequent development of encephalopathy?

It is very hard to obtain meaningful numbers, since the literature can be quite confusing. The incidences of hyperbilirubinemia reported may be based on different criteria used to define (severe) hyperbilirubinemia, and distinctions are not always made between acute and chronic encephalopathies. In addition, the number of cases of bilirubin encephalopathy is extremely small, making statistical conclusions next to impossible.

However it appears that:

65 – 80% of infants develop neonatal (physiological) jaundice,
4 – 8% exceed the guidelines for phototherapy,
2% develop TSB >20mg/dL
0.15% develop TSB >25mg/dL
Around 7 cases per 100,000 births develop bilirubin levels above 30mg/dL

For the US, the data is quite patchy and mostly consists of reviews of case reports that document fewer than 200 cases of kernicterus over several decades. This data does not allow for a reliable estimate of the incidence of bilirubin encephalopathy. Additionally, since the incidence of hyperbilirubinemia without kernicterus is also not well documented, the frequency of progression of hyperbilirubinemia to bilirubin encephalopathy cannot be estimated reliably. Many cases of severe hyperbilirubinemia, ABE and chronic kernicterus may simply not be reported in medical literature.

A prospective study from the UK that identified 108 infants with TSB greater than 30mg/dl found 14 cases of ABE. This is equivalent to an incidence of 0.9/100,000 live births and indicated a 1 in 7 ratio of ABE to hyperbilirubinemia. A Canadian study identified 258 cases over two years with TSB > 25mg/dL (39/100,000) of which 32 had neurological abnormalities, suggesting an incidence of 4.8/100,000 and a 1 to 8 ratio of ABE to hyperbilirubinemia. These results need to be treated with a degree of caution. In the UK study, some cases of ABE may have been excluded because they occurred at TSB levels below 30mg/dL and even the Canadian study may have missed cases. Both studies only looked for cases of ABE associated with TSB levels above 30 or 25mg/dl respectively. It has been claimed, however, that 8 – 9% of kernicterus cases have followed lower TSB levels, between 20 and 25mg/dL (which may reflect the lack of total correlation between TSB and free bilirubin). Nevertheless, it is clear that bilirubin encephalopathy is a rare event in developed countries.

The progression from ABE to CBE and kernicterus is not inevitable. In the UK study, 3 of 11 surviving cases of were normal after one year and several other studies from different countries have found eventual normalization in a significant number of cases. However, the possible presence of more subtle deficiencies in neurological function is beginning to be recognized.

Preterm infants with a very low birth weight may be especially at risk of suffering kernicterus at serum bilirubin levels well below those considered dangerous for normal infants, and so may not be associated with classical symptoms of ABE. This may account for some of the cases of kernicterus reported following lower values of TSB.

Since aggressive treatment with phototherapy and the availability of exchange perfusion often prevents the rise in bilirubin levels to dangerous levels, the incidence of severe hyperbilirubinemia and its progression to ABE and/or CBE is as much a reflection of the overall health care system in place and the particular circumstances of any individual case as it is a consequence of the underlying biology. Thus, one factor that might be contributing to a resurgence of kernicterus is the modern practice of discharging infants less than 48 hours after birth. This means that the infant is no longer under medical supervision just when the increase in TSB is beginning, and a pathologically rapid rise is likely to be missed. The evidence suggests that prolonged exposure to high TSB values usually precedes the development of kernicterus but that once the symptoms of Acute Bilirubin Encephalopathy (ABE) are apparent, there is a small window of opportunity during which effective treatment can prevent the development of CBE and kernicterus. Delay in recognizing the symptoms of ABE and readmission of the infant increase the danger of kernicterus.

It has been suggested that if proper systematic procedures for identifying and treating hyperbilirubinemia were in place, the incidence of kernicterus could be kept to fewer than 10 cases per year in the United States.


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