Kernicterus or bilirubin encephalopathy, a preventable cause of handicap, still occurs in our community. The crash cart approach to babies with severe hyperbilirubinemia and rapid intervention with intensive phototherapy and exchange transfusion is the only known measures to prevent the occurrence of bilirubin-induced neurological damage [8, 9].
Measurements of albumin concentration and bilirubin/albumin (B/A) ratio may provide much more insight into the likelihood of BIND. The B/A ratio is considered a surrogate parameter for free bilirubin and an interesting additional parameter in the management of hyperbilirubinemia .
The current study included 100 newborn infants and was conducted as a prospective cohort study on neonates with hyperbilirubinemia reached critical level of phototherapy or exchange transfusion according to the American Academy of Pediatrics admitted to the NICU department, at Abuelrish pediatric Hospital, over a period of 6 months from January 2016 to June 2016.
In our study, we found that the male to female ratio was 1.2:1. The male predominance was also noted in the group of patients with neurological manifestation with a ratio of 1.2:1.
This correlates well with the study done by [7, 22].
This also correlates well with the study done by Iskander et al.  who reported 68% for males and 31.4% for females, (male/female ratio = 1.16:1).
 suggested that this increased susceptibility to bilirubin-induced injury in male neonates may be due to an impact of gonadotropin surge during late embryonic and early postnatal life on CNS development or innate gender-based neuronal differences independent of circulating sex steroids.
In the present study, the mean age of onset of jaundice was 2.36 ± 1.04 days and the mean age of neonatal ICU admission of the babies was 4.97 ± 2.46. In a Turkish study,  studied neonates > 35 weeks and documented that the day the family noticed jaundice was 2.9 days (± 1.7 SD) and the postnatal age at admission was of 4.6 ± 2.3 days. Iskander et al.  related this late presentation to early discharge from maternity units (< 24 h) often with no neonatal clinical examination prior to discharge, no evaluation for the risk of developing jaundice, or any instructions for follow-up, lack of available or affordable phototherapy, and false sense of security regarding the potential consequences of severe jaundice by both physicians and parents.
Signs of acute bilirubin encephalopathy (ABE) were studied in the group of patients with neurological manifestations who were representing 50% of the studied neonates on admission. The BIND score was used to assess the severity of acute bilirubin encephalopathy through examining mental state, muscle tone, and cry. Subtle ABE was found in 25 patients (50%) with BIND score (1–4), 18 patients (36%) had signs suggestive of moderate ABE with BIND score (5–6) while only 7 patients (14%) showed signs suggestive of advanced ABE with BIND score (> 7).
In a 2-year British study by , they reported an incidence of ABE of 12% which correlates well with our results.
On the other hand, a higher percentage was found by , who reported 40% of their cases suffered from ABE on admission and 14% still had evidence of BE at discharge. This higher incidence of ABE on admission could be explained by their inclusion criteria which required a higher admission TSB (> 25 mg/dl) compared with our study.
Severe neonatal hyperbilirubinemia due to hemolytic causes represented 34% of our cases of which 50% and 17.64% of the cases were due to ABO incompatibility and Rh incompatibility respectively, while undiagnosed hemolytic causes represented 26.47% of the total number of cases. The latter could be attributed to minor blood group incompatibilities which are not routinely tested for. On the other hand, non-hemolytic jaundice occurred in 66% of our cases. A study by  documented that 21.8% of neonates with hyperbilirubinemia above 20 mg/dl had ABO incompatibility, and 2.9% had Rh incompatibility in their study. The incidence of Rh incompatibility in our country is still high compared with the developed world. This is due to the defective antenatal Rh screening for mothers and timely provision of anti-D antibody which is an essential component of primary prevention of Rh disease and its consequences.
In our study, 10 of 14 infants with Rh incompatibility (71.4%) developed BE but only one (7.1%) developed chronic bilirubin encephalopathy, 22 of 46 (47.8%) infants with ABO hemolytic disease developed BE but only 2 (4.3%) developed kernicterus. On the other hand, 21 of 66 (31.8%) infants with non-hemolytic jaundice developed BE but only 3of 66 (4.5 %) developed kernicterus.
This suggests that hemolysis is a risk factor for the occurrence of acute bilirubin encephalopathy and that timely intervention may stop the progression to chronic bilirubin encephalopathy and is in agreement with the risk factors defined by the AAP guidelines in 2004 . also reported that kernicterus was more common in neonates with blood group incompatibility compared with other causes of jaundice.
In our study, the risk factors in cases in order were prematurity in 24 newborns (24%), ABO incompatibility in 46 newborns (46%), RH incompatibility in 14 newborns (14%), infants of diabetic mothers in 2 newborns (2%), and history of neonatal jaundice in previous babies in 15 newborns (15%).
In a study by Zabeen et al.,  on 60 jaundiced newborn infants in a tertiary hospital to detect different risk factors for neonatal jaundice, they found that prematurity, IDM, septicemia, and ABO incompatibility were observed in 44 (73.3%), 21 (35%), 16 (26.6%), and 8 (13.3%) cases respectively. G6PD deficiency was found in only one (1.7%) case. They agree with our study in that prematurity was the risk for neonatal jaundice in most cases and G6PD deficiency was the least risk factor.
In the present study, the mean peak TSB level in all cases was 26.14 ± 7.36 mg/dl. A statistically significant difference was found between the mean peak TSB level in the patients with neurological manifestations (29.24 ± 7.78 mg/dl) and the mean peak TSB level in the patients without neurological manifestations was (23.04 ± 5.41 mg/dl).
The total serum bilirubin level in patients on admission without neurological manifestations on admission (22.8 mg/dl) was lower than the median TSB level for patients with neurological manifestations which was 30 mg/dl.
Although the TSB was higher in the group 2, higher bilirubin levels were recorded in those with moderate ABE than those with severe ABE. This question whether TSB can be relied upon as an independent prognostic factor for poor neurological outcome.
Gamaleldin study 2011 reported that out of 106 infants who were disease free, 26% had a TSB level of > 31.5 mg/dl and the lowest bilirubin level at which kernicterus occurred was 25 m/dl . also showed that all kernicteric babies in their study had TSB levels > 30 mg/dl. These findings prompt us to agree with  that in the absence of risk factors i.e. in healthy full-term neonates, such levels are detected (serum bilirubin less than 30 mg%).
 reported that subtle neurotoxicity may appear later or even at school age as learning disabilities. This could be important in 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 in many cases. This also indicates that the pathogenesis of BE involves critical plasma and/or host defense variables that have yet to be identified.
Free bilirubin and not TSB is the principal determinant of bilirubin neurotoxicity. There is presently no method available for measuring free bilirubin concentrations accurately in plasma or serum so the bilirubin albumin ratio (B/A) is considered as a surrogate parameter for free bilirubin and an additional parameter in the prediction of BE .
The mean B/A ratio among the neonates with neurological manifestations was (8.38 ± 2.34), whereas among the jaundiced neonates without neurological manifestations was (6.46 ± 1.84) and this difference was statistically significant.
 reported that the mean B/A ratio among patients with BE was (10 ± 1.6), whereas among other jaundiced neonates was (6.1 ± 2.4). They also reported that neurotoxicity does not occur until the molar concentration of bilirubin approached the concentration of albumin (B/A ratio = 8.8). 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.
All babies with B/A ratio > 13.1 developed BIND. However, we observed one baby with normal outcomes at B/A ratio of 12.5 mg/g. This suggests that additional bilirubin binding sites other than albumin must exist in plasma.
Receiver operating characteristics (ROC) analysis identified B/A ratio cutoff value for predicting bilirubin-induced neurological dysfunction was 6.68 (AUC 0.76) with sensitivity of 82% and specificity of 64% and these results were statistically significant, whereas TSB cutoff value of 28.55 mg/dl showed sensitivity of 66% and specificity of 84% and these results were statistically significant . identified B/A cutoff value for predicting acute BIND of 8 (AUC 0.957) with sensitivity of 100% and specificity of 94%, whereas a TSB cutoff value of 25 mg/dl in their study showed sensitivity of 100% and specificity of 85%. According to this finding, B/A ratio was more specific than TSB in the prediction of poor neurological outcome. Variations in the expanded buffering capacity combined with variation in blood-brain barrier function and host defenses at the cellular level provide the only explanation for the limited specificities of TSB and B/A in predicting outcome.
Until now, the precise threshold at which TSB or bilirubin albumin ratio may be neurotoxic in a given infant is unknown. We therefore agree with  that it is very important to study and identify the individual differences in the ability to destroy bilirubin in the brain and the factors that expedite or delay its neuronal exit which may help identify the baby prone to neuronal damage and therefore aid in the prevention of kernicterus.
Among the group of patients with neurological manifestations showed a male predominance (54%), nine (33%) of them had ABO incompatibility, seven of them (25%) had RH incompatibility, none of them had sepsis, and 13 had jaundice of unknown cause. The TSB and B/A ratio were significantly higher in all the patients with neurological manifestations. All received intensive phototherapy in the Bilisphere and all had exchange transfusions.