Bhutani et al. calculated the chronic kernicterus risk as one in seven for infants with TSB > 30 mg/dL [24]. One study suggested that TSB (above 25 mg/dL) was a poor predictor of ABE when other risk factors were present [25]. Another study reported that raised UB levels are associated with higher mortality or poor neurodevelopmental outcomes despite any clinical condition. Increased TSB levels are directly related to an increased risk of unstable, as opposed to stable, infant death and neurodysplasia [26]. UB is still one of the main reasons for neonatal morbidity and hospitalization. Occasionally, UB can reach critically high levels and cause brain injury [27]. The measurement of UB is important for assessing the risk of neurotoxicity and for proper intervention in high-risk neonates with hyperbilirubinemia [28].
Lower UB concentrations can cause neuronal apoptosis, while high concentrations of UB can lead to necrosis. Bilirubin toxicity is more likely to affect the brain stem nuclei and basal ganglia with neurotoxicity resulting from excess glutamate production, mitochondrial dysfunction, the action of pro-inflammatory cytokines, and raised intracellular calcium levels [29, 30]. Moderate to high UB levels are associated with oxidative stress and the changes caused by oxidative stress may be early predictors of adverse outcomes. Lower bilirubin levels can also cause DNA damage, suggesting that UB may have genotoxic effects [27]. Experimental studies on brain tissue exposed to UB have shown axonal damage, including significant decreases in myelination, fewer compact axons, and the presence of debris [31]. The presence of UB in the brain can cause neurological dysfunction, the acute form of which is ABE.
In this study, 46 infants received ET; the mean UB value in these children was 450.1 ± 105.4 μmol/L and 18 were diagnosed with ABE. Patients who met the ET criteria as per AAP guidelines [3] but did not receive ET treatment were not included in the analysis. Twenty-nine patients’ parents refused consent to perform ET; this included one patient with ABE. There were significant differences in the TSB values between the 29 infants (24.46 ± 2.80 mg/dL) who did not receive ET and the 46 infants (29.02 ± 6.82 mg/dL) who received ET. The TSB levels in most of the 29 infants were not far above the ET threshold level, and there was no nervous system involvement. Neither the doctors nor the families had a positive attitude towards ET. All the 29 infants received phototherapy and were fully recovered on discharge. It is possible that parental consent may have been influenced by the pediatricians descriptions of the severity of the disease. While we cannot completely rule out some influence on the results using these data, the data used in the analysis include almost all of the ABE patients, which we consider meaningful for discussing the relationships of UB levels with ABE in SNE.
Ebbesen et al. [32] identified 32 infants in whom the TSB values exceeded the indications for ET, 11 with evidence of ABE. The exact level of bilirubin that is likely to cause neurotoxicity in any individual baby varies, and depends on the interplay of multiple factors. Correlations between ABE and circulating bilirubin levels are poor [12]. Brito et al. reporting on a preterm neonate with kernicterus, proposed that UB increases the blood vessel density in the hippocampus and striatum related to the nucleus macula, triggering an immune response mediated by VEGF and VEGFR-2, and allowing albumin infiltration into the brain [33]. When the bilirubin-binding ability of the blood is raised or when there is competition for the bilirubin-binding site on albumin, UB enters the cerebrum. Gestational age, hemolysis, infection, sepsis, and, particularly, Rh isoimmunization, which are associated with neuronal susceptibility, are additional risk factors for kernicterus [11]. Measures to prevent extreme jaundice and reverse neurotoxicity include measuring bilirubin levels during the infant’s stay in the maternity ward, assessing other risk factors (such as the presence of possible hemolytic diseases, hypothermia, hypoglycemia, and sepsis, amongst others), and educating parents. Emergency treatment should include immediate phototherapy, consideration of intravenous immunoglobulin administration, and preparation for ET treatment [2, 10, 12]. In our data, we found no significant difference in infection, hemolysis, and gestational age between the ABE and non-ABE groups, which may be a consequence of the relatively small sample size (Table 1).
Our research included 5317 neonatal admissions over 3 years, of which 1776 (33.4%) were admitted for neonatal hyperbilirubinemia. The incidence of ABE and ET were 10.7% (n = 19) (including 3 deaths) and 25.9% (n = 46), respectively. Similarly, one study reported that the incidence of bilirubin encephalopathy in hyperbilirubinemic infants ranged from 7 to 22% between centers [21]. Another study of 1118 hyperbilirubinemic infants reported that the incidence of ABE and ET were 17.0 and 31.5% respectively [23]. This study also identified the peak TSB level as predictive of ABE, while peak TSB, ABE, and ABO incompatibility were predictors of ET [23]. The risk evaluation of kernicterus based on TSB levels alone has often proved insufficient; TSB levels at the start of ET also lack uniformity even in the presence of the clinical symptoms of ABE and hemolytic disease. Although ET is an effective treatment for BIND in newborns with SNH, it nevertheless carries risks and should be used only after a careful assessment of the risk of kernicterus [4]. The precise role of TSB and UB in calculating ABE risk remains unknown. However, data, both clinical and laboratory, indicate that measurement of UB is superior to TSB in detecting the bilirubin toxicity risk in SNH [34].
Emerging evidence suggests that UB may be superior to TSB in predicting BIND in both pre-term and term infants [28, 35, 36]. Our study considered the effects of age, sex, red blood cell count, birth weight, blood glucose, hemolysis, and phototherapy administration before ET on the UB levels and ABE relationships when adjusting for covariates (OR: 1.41, 95%CI 1.05, 1.91) (Table 2). This finding is consistent with several reports showing a significant relationship between UB, rather than TSB or the bilirubin: albumin ratio and chronic auditory toxicity [17, 37]. Another report showed a significant association between auditory brainstem damage and UB, but not TSB, concentration [38]. Similarly, one study showed that UB levels were significantly associated with kernicterus development [39].
In our study, we observed significant differences in age, blood glucose, red blood cell count, UB, and phototherapy administration before ET between the ABE group and non-ABE groups (P < 0.05) with the occurrence of ABE. The results were maintained in the fully adjusted model (Model 3) where all covariates shown in Table 2 were adjusted for each additional mg/dL of the UB levels.
The present study offers the first documentation of an independent association between UB levels and ABE in infants who had undergone ET. These findings should assist future research on the diagnosis and prediction of ABE. Our study has several limitations. Firstly, as the research subjects were infants who had undergone ET, the findings may lack universality and, secondly, because ABE neonates who had not undergone ET were excluded, the findings may be further restricted in their application.
