In the absence of risk factors for neurotoxicity, we observed no cases of ABE below a TSB level of 31.8 mg/dL and no evidence of BE at discharge despite TSB levels of >30 mg/dL in 25 infants. Longer-term outcome studies by Newman et al10,11
also indicate that healthy term infants have a greater tolerance for severe hyperbilirubinemia. Physicians treating an asymptomatic infant with no risk factors and a TSB level in the range of 25 to ≥30 mg/dL are faced with a dilemma of whether to use intensive phototherapy or perform the more risky exchange transfusion, as currently recommended. In some environments, the risk of exchange transfusion19–21
may exceed the risk of BE in this group of patients.
The AAP guidelines do not rank the risk of hemolytic disease according to etiology or severity, but logistic regression indicated that ABO with associated anemia (the direct antiglobulin test was unreliable) had far less influence on outcome than Rh incompatibility. The TSB threshold for severe disease was higher in ABO (33.7 mg/dL) than in Rh incompatibility (25.4 mg/dL), again indicating that the magnitude of risk for BE in hemolytic disease depends more on the etiology of hemolysis than on the severity of hyperbilirubinemia. On occasion, ABO hemolytic disease can present as overt erythroblastosis fetalis with severe hemolysis. This was not documented in our patients but might lower the TSB threshold for neurotoxicity.
Infants with sepsis or Rh hemolytic disease had a low group threshold for disease, but above 25 mg/dL, up to 43 mg/dL, the TSB value had no apparent relationship to outcome (). This surprising observation suggests that the threshold of 25 mg/dL is permissive of neurotoxicity, but above this threshold, the major determinants of neurotoxicity involve unidentified plasma and/or host defense variables that are altered by neurotoxicity risk factors. The sample size precluded determining specific thresholds for intervention in infants with and without risk factors, and the study entry level of TSB ≥25 likely concealed the true threshold for infants with sepsis and Rh hemolytic disease.22
The reason for the variation in susceptibility of infants to a given TSB level is unknown. Erythroblastosis fetalis will produce a more rapid rate of rise in TSB with a higher rate of bilirubin production that might alter distribution of bilirubin between plasma and alternative body compartments, including the brain. Similar intolerance to a rapid load of bilirubin has been observed in hemolytic crises from glucose-6-phosphate dehydrogenase deficiency.23
Low serum albumin levels, lower serum binding affinity for bilirubin, immaturity or alteration of the blood–brain barrier, and decreased cellular defense systems may also modify risk in severe hemolytic disease.8,24–27
Although plasma binding of bilirubin has not been systematically evaluated in term/near-term infants or in patients with Rh isoimmune disease, there is good evidence that sick newborns with acidosis or sepsis, especially premature infants, have both poor binding and an increased risk for kernicterus.24,25
Equally intriguing in this study is the observation that several infants with very high TSB levels were free of disease. Although free bilirubin levels were not measured, the high level of TSB in these infants would most probably require bilirubin binding to sites other than the primary site on albumin, implying that free bilirubin will be high and that resistance or susceptibility to neurotoxicity is not solely controlled by plasma factors.26,27
This study has several important limitations. Birth histories were not available, and documentation of birth weight and gestational age was rarely available for the population studied. Separating the effects of gestational age and fetal growth retardation was usually impossible. The diagnosis of hemolytic disease was compromised by an unreliable direct antiglobulin test, and we did not routinely screen for glucose-6-phosphate dehydrogenase deficiency. Thresholds for neurotoxicity in patients with Rh incompatibility and suspected sepsis were at or only slightly higher than the subject entry criterion of 25 mg/dL. The delay in evaluating blood types and other risk factors after admission precluded stratifying TSB entry criteria. Bilirubin/albumin ratios were not measured, and the roles of free bilirubin and plasma binding as mediators of risk factors (eg, in sepsis, Rh hemolytic disease) or as independent risk factors were not studied. We did not evaluate auditory pathway toxicity as an adverse outcome. Alterations in brainstem auditory evoked potentials are common and may be the only manifestation of bilirubin-induced brain injury.28,29
These changes may resolve as transient expressions of mild ABE or progress to severe neurosensory hearing loss or auditory neuropathy/auditory dysynchrony.8,28,29
Longer term follow-up might reveal more subtle expressions of BE or resolution of neurologic signs persisting at discharge.
Strengths of the current study include a short time frame to achieve targeted recruitment, consistency in treatment protocol using a single institution, consistent neurologic assessment because a single investigator (Dr Aboraya) performed BIND evaluations in the majority of patients, and consistency in TSB assays performed at a single hospital laboratory. In contrast to problems encountered in multicenter outcome studies required in countries having a low incidence of severe hyperbilirubinemia,30,31
we were able to conduct a large systematic evaluation of neurotoxicity in patients with extremely high TSB levels within a single referral institution. With >250 newborns with severe hyperbilirubinemia admitted for care each year, Cairo University Children's Hospital provides a unique venue to evaluate variables that place jaundiced infants at risk for BE.