In this prospective observational trial, we found that BIND scores on admission, TSB, and B/A ratio were significantly higher in kernicteric infants compared to other jaundiced infants with normal neurological outcome at 3 months of age. A B/A ratio of 9.6 had sensitivity of 100% and specificity of 91% for predicting poor neurologic outcome at 3 months of age. B/A ratio was more specific than TSB in the prediction of poor neurologic outcome.
Regardless of the cause for jaundice, there is a risk of neonatal bilirubin neurotoxic sequelae that ranges from irreversible permanent injury to subtle multisensory and learning impairments during infancy. Confounding effects of prematurity, hemolysis, altered bilirubin-albumin binding, severity of bilirubin exposure, and the individual vulnerability of the infant contribute to the spectrum of clinical manifestations to be designated as syndrome of BIND [2].
Jaundice due to hemolysis is usually severe and appears within the first 24 h. Sgro et al. considered presentation within the first 48 h of age a strong predictor of abnormal neurological outcome in infants with severe neonatal hyperbilirubinemia [16]. On the contrary, we did not find any significant difference between ages of onset of jaundice among kernicteric infants compared with those having normal neurologic outcome.
In the current study, we reported ABE in 13% of our studied population. Nearly all infants who had residual neurologic deficits at 3 months follow up had BIND scores ≥ 4 on admission. Although babies with BIND score 0–1 should be completely normal at follow up [2], in the present study all but one baby were normal. This specific case had a BIND score of 1 on admission and a BIND score of 2 on discharge and had persistent neurologic affection on the 3 month follow up. He was diagnosed as Rh incompatibility, had serum bilirubin level of 41 mg/dl, and had the highest B/A (13.6) ratio among the kernicteric patients. Gamaleldin et a [17]. reported 40% of their cases suffered from ABE on admission; higher percentage than our results. This higher incidence of ABE could be explained by their inclusion criteria which required a higher admission TSB (> 25 mg/dl).
The lowest TSB level at which kernicterus occurred in our study was 31 mg/dl. Consistent with our results, Iskander et al. [11] reported that asymptomatic term newborns without risk factors rarely develop kernicterus or auditory neuropathy at TSB < 31 mg% and/or B/A < 8.6 mg/g and recommended that given the risks of exchange transfusion [18] and intensive phototherapy and close monitoring may be a safer treatment option for those infants. Mukhopadhyay et al. [19] found that all kernicteric babies in their study had TSB > 30 mg/dl as well. Analysis of this cumulative evidence may be used to revise the guidelines as to whether the cut off level at which exchange transfusion should be performed can be higher than 25 mg/dl among healthy full term neonates.
Johnson et al. [6] suggested that any infant with TSB > 35 mg/dl had post icteric sequelae regardless of age and intervention. However in the present study, 9 babies had TSB > 35 mg/dl of whom 6 patients (66.6%) had kernicterus and three appeared normal at 3 months follow up. Shapiro [14] reported that subtle neurotoxicity may appear later or even at school age as learning disabilities. This could be the case with these three newborns making long term follow up a necessity. It is clear from the previous results that there exists a wide variation in the individual response to TSB which indicates that though serum bilirubin is sensitive yet it is not specific. This also indicates that the pathogenesis of BE involves critical plasma and/or host defense variables that have to be identified.
Oh et al. [20] found that higher Bf levels are associated with a higher risk of death or adverse neurodevelopmental outcome regardless of clinical status. In the absence of an available assay for Bf, the bilirubin/albumin ratio (B/A) might provide a better estimate of Bf because it contains two of the three factors determining Bf: TSB, albumin, and the albumin-binding affinity [21]. However, due to the presence of drugs that interfere with bilirubin binding to albumin, and variations in the intrinsic affinity of albumin binding to bilirubin, Bf may be much higher than suggested by the calculated B/A ratio [22].
Considering the occurrence of bilirubin encephalopathy in preterm infants with low TSB levels, the risk of developing bilirubin neurotoxicity is not determined by TSB alone [23]. Only free bilirubin and perhaps the B/A ratio are more closely associated with BIND. Authors conclude that the pathophysiological role of low serum albumin levels must be considered in BIND especially when acidosis and jaundice are present in preterm infants [24]. Severe hemolytic disease and capillary leak from a variety of conditions can result in plasma albumin depletion. In such infants, the risk for kernicterus may occur at TSB levels well below AAP-recommended intervention levels for sick infants, but the B/A cutoff would be breeched [25].
Several experts in the field of bilirubin research advocate the additional use of B/A ratio in jaundiced infants especially when TSB level is close to that at which exchange transfusion is recommended; that is next to but not instead of TSB, on which to base the management of hyperbilirubinemia [26, 27].
Ardakani et al. [28] reported a mean B/A ratio of 10 ± 1.6 among his studied neonates presenting with BE. He identified B/A of 8 to predict acute BIND (AUC 0.957) with sensitivity of 100% and specificity of 66%, whereas a TSB cut off value of 25 mg/dl showed sensitivity of 100% and specificity of 57%; hence, agreeing with our results that B/A ratio was more specific than TSB in the prediction of poor neurologic outcome.
In their randomized controlled study, Hulzbos et al. [10] concluded that they did not find any significant effect of the additional use of B/A ratio compared to TSB-based treatment on the motor development in preterm babies at 2 years of life; however, they reported significantly higher B/A ratios in their non survivors. They speculated that the additional use of B/A ratio is a valuable parameter in the management of hyperbilirubinemia in preterm infants when the bilirubin is more harmful and the infant brain is more vulnerable to bilirubin neurotoxicity.
In their cohort of 193 term infants, Iskander et al. [11] reported that moderate to severe bilirubin encephalopathy occurred only when the molar concentration of bilirubin approached or surpassed the concentration of albumin at B/A ratio of 8.8 mg/dl. As TSB exceeds this binding capacity, free bilirubin increases dramatically and the final deposition is governed by the availability of alternative plasma binding loci and ultimately by the low solubility of free bilirubin. In the present study, all babies with B/A ratio > 13 mg/g developed kernicterus. However, we observed one baby with normal outcome at B/A ratio of 12.7 mg/g. This suggests that additional bilirubin binding sites other than albumin must exist in plasma. They partly agreed with our results that B/A ratio at cut off 11.5 is a strong predictor for residual bilirubin neurotoxicity with 100% sensitivity but they stated that B/A offers no additional advantage over TSB alone.
Despite the fact that no definite cut off value at which TSB or B/A ratio are neurotoxic is yet known, we therefore agree with Johnson and Bhutani [2] that it is very important to study and identify the individual variations in the ability to buffer bilirubin the brain and the factors that expedite or delay its neuronal exit which may render the baby more prone to neurological insults thus preventing kernicterus.
ElTatawy and colleagues [29] confirmed that a cut off TSB ≥ 27.5 mg/dl was found to detect kernicterus and auditory impairment at 1 year of age (100% sensitive, 76% specific). They found that poor neurodevelopmental outcome as well as auditory impairment was positively correlated to high TSB, high BIND score, and longer duration of exposure to severe hyperbilirubinemia. They reported that 41% of the studied population had unfavorable outcomes at 3 months of age and further reduced to 13.6% at 1 year of age since most of them improved with time. These numbers were much higher than our results in which only 6% of enrolled neonates presented with kernicterus at 3 months follow up. We attributed this difference to different methods of neurological evaluation at follow up visits.
Limitations of this study include absence of risk stratification, gestational age, and cause of jaundice was not clear in some included neonates. Serial BIND score assessment and serial measurement of TSB and albumin could not be done. Sometimes, there was some delay in performing exchange transfusion because of unavailability of needed blood group. Subtle neurological deficits could have been missed; MRI and auditory brain stem response were done only to babies having abnormal motor examination; they should have been done to all babies attending the 3 months follow up visits. Long-term follow up is needed since some neurological insults may present in school age. Further randomized controlled trials are needed to emphasize know on evidence basis whether the concurrent use of B/A ratio with TSB in the management of hyperbilirubinemia is of value or not needed.
