In the only controlled clinical trial conducted on the treatment of hemolytic disease of the newborn, Mollison and Walker (153) demonstrated beyond reasonable doubt that exchange transfusion in these infants improved their chance of survival and decreased the risk of fatal kernicterus. The results of these studies, combined with subsequent uncontrolled observations, established exchange transfusion as the standard treatment for preventing
kernicterus in infants with erythroblastosis fetalis and showed that kernicterus was unlikely to occur if TSB levels were kept below 20 mg/dL (342 μmol/L), an observation that has been amply confirmed by subsequent experience with the treatment of hemolytic disease (142,143). It is interesting to recall, however, that these studies were performed on infants born in the late 1940s and early 1950s. These infants were commonly asphyxiated and seriously ill, and many were delivered prematurely to prevent stillbirth. Streptomycin, an ototoxic drug was frequently administered to those who received exchange transfusions.

Hsia and associates (142) reported that the incidence of kernicterus in their infants was 8% for those with TSB levels of 19 to 24 mg/dL (325 to 410 μmol/L), 33% for TSB levels of 25 to 29 mg/dL (428 to 496 μmol/L), and 73% for those with bilirubin levels higher than 30 mg/dL (513 μmol/L). Later experience with Rh hemolytic disease was far more encouraging. Johnston and associates (126) studied 129 infants born between 1957 and 1958, all of whom had indirect-reacting serum bilirubin levels higher than 20 mg/dL (342 μmol/L). Ninety-two infants with Rh hemolytic disease were followed to age 5 to 6 years and evaluated with detailed psychometric, neurologic, and audiologic evaluations. One of 92 infants had a minimal sensorineural hearing loss (and a normal IQ) and 1 infant had mild athetosis, moderate sensorineural hearing loss, and a normal IQ. Thus, the risk of bilirubin encephalopathy in infants with Rh disease born from 1957 to 1958 with indirect-reacting bilirubin levels higher than 20 mg/dL (342 μmol/L) was 2 of 92 or approximately 2% (126).

In a study of full-term Turkish infants (154), those who had Coombs-positive ABO incompatibility or Rh immunization had a greater risk (vs. infants without hemolytic disease) of neurologic abnormalities and lower IQ scores when their indirect-reacting bilirubin levels exceeded 20 mg/ dL (342 μmol/L). These data reinforce the belief that hemolysis is an important risk factor in bilirubin-dependent brain damage. The risk of neurologic abnormalities also was associated with the duration of indirect-reacting hyperbilirubinemia higher than 20 mg/dL (342 μmol/L). In those exposed to these bilirubin levels for less than 6 hours, the incidence of neurologic abnormalities was 2.3%. This increased to 18.7% if the exposure lasted 6 to 11 hours and to 26% with 12 or more hours of exposure (154). These data support earlier observations suggesting that the duration of hyperbilirubinemia is related to the risk of long-term neurodevelopmental outcome (155). It is difficult to define the risk of abnormal outcomes in infants with hemolysis from causes such as red cell membrane defects and glucose-6-phosphate dehydrogenase (G6PD) deficiency, although the risk of bilirubin encephalopathy in G6PD deficiency appears to be similar to that of Rh hemolytic disease (156).

Two issues in neonatal medicine that consistently generate controversy are the relationship between hyperbilirubinemia and adverse developmental outcome in nonhemolyzing newborns and the indications for treating these infants. These issues are addressed in multiple studies and the reader is referred to extensive reviews for details of the individual studies (124,139,140,144,152). When carefully analyzed, the data tend to demonstrate that, in otherwise healthy neonates without hemolytic disease, TSB levels that do not exceed approximately 25 mg/dL (428 μmol/L) are very unlikely to place these infants at risk of adverse neurodevelopmental consequences. Specifically, in many large studies there has been no convincing demonstration of any adverse effect of such serum bilirubin levels on IQs, definite neurologic abnormalities, or sensorineural hearing loss (124,139,140,144,152).

No studies have looked specifically at infants who are 35 to 37 weeks of gestation, although the data analyzed by Ip and associates includes infants of of 34 weeks and older (139,140). In the very large CPP, the study population included all infants with birth weights ≥2,500 g (145,152, 157). Presumably some of these infants were in the 34- to 37-weeks’ gestational age category. There are insufficient followup data on infants who had TSB levels of 25 to 30 mg/dL (292 to 513 μmol/L) to draw firm conclusions about this group. Nevertheless, a 21-month followup of 26 Coombs-negative, healthy, term infants with TSB levels of 26.2 to 46.3 mg/dL (446 to 788 μmol/L) revealed no neurodevelopmental abnormalities and no hearing loss (158). Newman identified 11 infants out of 111,009 infants born between 1995 and 1998 with TSB levels ≥30 mg/dL (513 μmol/L); 5 were 35 to 37 weeks’ gestation and 5 were 38 to 39 weeks’ gestation. They were followed for 1.5 to 5 years and none had neurologic or developmental problems (159).

When they combined both abnormal and suspicious neurologic examination results, Newman and Klebanoff (160), in their analysis of the CPP, did demonstrate a significant increase in abnormalities associated with increasing bilirubin levels. The “suspicious” abnormalities included nonspecific gait abnormalities, awkwardness, an equivocal Babinski reflex, abnormal cremasteric reflex, abnormal abdominal reflex, failure of stereognosis, questionable hypotonia, and gaze abnormalities. The most frequent abnormal findings were awkwardness and abnormal cremasteric reflexes. When the abnormal and suspiciously abnormal children were combined, the risk of abnormalities increased from 14.9% for those whose TSB levels were less than 10.0 mg/dL (171 μmol/L) to 22.4% for those whose TSB levels exceeded 20 mg/dL (340 μmol/L). Because 41,324 infants were enrolled in this study, these differences were statistically highly significant, but this finding should be kept in perspective. Even if the relationship between these findings is causal, we have no evidence that the use of a bilirubin-lowering intervention, such as phototherapy, at these low bilirubin levels would affect the outcome. Finally, as Newman and Klebanoff (160) point out, even if bilirubin levels had been prevented from exceeding 10 mg/dL (171 μmol/L) in every infant, the expected rate of abnormal or suspicious neurologic examination results would only decline from 15.13% to 14.85%.

Less-reassuring information is provided by a study of a group of Israeli army draftees (n = 1,948) in which their preinduction psychological and physical examinations at age 17 years were matched with their newborn bilirubin levels. Seidman and associates (161) found an association between the risk of an IQ below 85 and a TSB level higher than 20 mg/dL (342 μmol/L) in full-term boys (but not with girls) with a negative Coombs test (p = 0.01). On the other hand, no association was found between bilirubin levels and mean IQ score, the risk of physical or neurologic abnormality, or hearing loss. In a subsequent analysis of a similar population, Seidman and colleagues (162) found no increase in the risk of an IQ less than 85 with TSB levels higher than 20 mg/dL (342 μmol/L).

Two studies raised concerns regarding “soft signs” of neurologic dysfunction in infants exposed to moderate levels of bilirubin (163,164). In a study performed in the Netherlands, the investigators prospectively evaluated 20 jaundiced infants whose TSB levels ranged from 13.6 to 26 mg/dL (233 to 444 μmol/L) and compared them with a control group of 20, healthy, nonjaundiced infants matched for sex and gestational age (164). At age 1 year, 5 of 8 (63%) infants with TSB levels between 19.6 and 26 mg/dL (335 and 444 μmol/L) demonstrated minor abnormalities in muscle tone and posture compared with 0 of 20 control infants (p<0.001). In a German study, children at 7 years of age whose neonatal TSB levels had exceeded 20 mg/dL (342 μmol/L) scored significantly worse on a scale designed to measure choreiform and athetoid movements. In that study 8 of 16 (50%) children in the hyperbilirubinemia group versus 3 of 18 (17%) in the control group had abnormal scores (data not found in the original paper but kindly provided by the authors) (141,163). The sample sizes in both the Dutch and German studies were small, but the effect sizes were large. Nevertheless, the outcome measurements are subjective and the blinding was not rigorous.

In a much earlier study, Johnson and Boggs followed 83 infants for 4 years and found abnormal neurologic examinations in 14 of 68 (21%) children whose indirect-reacting bilirubin levels were ≥15 mg/dL (257 μmol/L) versus 0 of 15 in those with TSB levels less than 15 mg/dL (155) (1 tail p = 0.047). Of the 14 children, 11 had “minimal cerebral dysfunction” and 3 had other abnormal signs, including fine and gross motor delay, athetoid movements, and mild mental retardation (it is not stated how many of the 3 infants had some or all of these findings). In that study, however, 53% of the infants had hemolytic disease and 33% were premature, and there is no mention of whether or not the followup evaluations were performed in a blinded fashion (155).