Bilirubin-induced Neurologic Dysfunction Research Articles

Transcutaneous bilirubinometry for detecting jaundice in term or late preterm neonates.

The American Academy of Pediatrics and the Canadian Paediatric Society both advise that all newborns should undergo bilirubin screening before leaving the hospital, and this has become the standard practice in both countries. However, the US Preventive Task Force has found no strong evidence to suggest that this practice of universal screening for bilirubin reduces the occurrence of significant outcomes such as bilirubin-induced neurologic dysfunction or kernicterus. To evaluate the effectiveness of transcutaneous screening compared to visual inspection for hyperbilirubinemia to prevent the readmission of newborns (infants greater than 35 weeks' gestation) for phototherapy. We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, ICTRP, and ISRCTN in June 2023. We also searched conference proceedings, and the reference lists of included studies. We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, or prospective cohort studies with control arm that evaluated the use of transcutaneous bilirubin (TcB) screening for hyperbilirubinemia in newborns before hospital discharge. We used standard methodologic procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) and 95% confidence intervals (CI) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to evaluate the certainty of evidence. We identified one RCT (1858 participants) that met our inclusion criteria. The study included 1858 African newborns at 35 weeks' gestation or greater who were receiving routine care at a well-baby nursery, and were randomly recruited prior to discharge to undergo TcB screening. The study had good methodologic quality. TcB screening versus visual assessment of hyperbilirubinemia in newborns: - may reduce readmission to the hospital for hyperbilirubinemia (RR 0.25, 95% CI 0.14 to 0.46; P < 0.0001; moderate-certainty evidence); - probably has little or no effect on the rate of exchange transfusion (RR 0.20, 95% CI 0.01 to 14.16; low-certainty evidence); - may increase the number of newborns who require phototherapy prior to discharge (RR 2.67, 95% CI 1.56 to 4.55; moderate-certainty evidence). - probably has little or no effect on the rate of acute bilirubin encephalopathy (RR 0.33, 95% CI 0.01 to 8.18; low-certainty evidence). The study did not evaluate or report cost of care. Moderate-certainty evidence suggests that TcB screening may reduce readmission for hyperbilirubinemia compared to visual inspection. Low-certainty evidence also suggests that TcB screening probably has little or no effect on the rate of exchange transfusion compared to visual inspection. However, moderate-certainty evidence suggests that TcB screening may increase the number of newborns that require phototherapy before discharge compared to visual inspection. Low-certainty evidence suggests that TcB screening probably has little or no effect on the rate of acute bilirubin encephalopathy compared to visual inspection. Given that we have only identified one RCT, further studies are necessary to determine whether TcB screening can help to reduce readmission and complications related to neonatal hyperbilirubinemia. In settings with limited newborn follow-up after hospital discharge, identifying newborns at risk of severe hyperbilirubinemia before hospital discharge will be important to plan targeted follow-up of these infants.

Microstructure and Perfusion Alterations of Globus Pallidus in Neonates with Hyperbilirubinemia.

Previous studies have indicated the abnormality of the globus pallidus in neonates with hyperbilirubinemia. This study aims to explore the microstructure and cerebral perfusion of globus pallidus in neonatal hyperbilirubinemia by using Diffusion Tensor Imaging (DTI) and Arterial Spin Labeling (ASL) approaches. Thirty-seven neonates were enrolled in this study, which were classified into Bilirubin-Induced Neurologic Dysfunction (BIND) group (hyperbilirubinemia with BIND, n=12), non-BIND group (hyperbilirubinemia without BIND, n=15), and healthy controls (HC) group (n=10). The quantitative values of globus pallidus were calculated from DTI, including the Apparent Diffusion Coefficient (ADC), the Fractional Anisotropy (FA), and Volume Ratio (VR) values. Additionally, the relative Cerebral Blood Flow (rCBF) values were obtained from ASL. It was observed that the mean DTI signal of globus pallidus was significantly different among the three groups (p < 0.05). However, there were no significant differences in the rCBF of globus pallidus among the three groups (p > 0.05). A positive correlation was also observed between the fractional anisotropy (FA) value and serum bilirubin level (r = 0.561, p = 0.002), while the VR value showed a negative correlation with serum bilirubin level (r=-0.484, p=0.011). The area under the curve (AUC) of FA, VR, and FA and VR combined was 0.897, 0.858, and 0.933, respectively. The alterations of microstructure in globus pallidus, especially FA and VR value, may be valuable and sensitive at the early stage of hyperbilirubinemia encephalopathy, suggesting that early hyperbilirubinemia may lead to cytotoxic edema and decreased permeability of the cell membrane.

Unbound Bilirubin and Acute Bilirubin Encephalopathy in Infants Born Late Preterm and Term with Significant Hyperbilirubinemia

To compare the association of unbound bilirubin (UB), total serum bilirubin (TSB), and bilirubin:albumin molar ratio (BAMR) with acute bilirubin encephalopathy (ABE), as assessed by bilirubin-induced neurologic dysfunction (BIND) score, in infants with significant hyperbilirubinemia (TSB ≥20mg/dL or underwent exchange transfusion). In this prospective cohort study, infants ≥34weeks of gestational age with significant hyperbilirubinemia during the first 2 postnatal weeks were eligible, unless they had craniofacial malformations, chromosomal disorders, TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus and herpes simplex) infections, surgery, or a family history of congenital deafness. TSB, serum albumin, and UB were measured at hospital admission using the colorimetric, bromocresol green, and modified peroxidase method, respectively. Infants were evaluated on admission for ABE using a standardized neurologic examination and assigned a BIND score by trained physicians. Infants with a total BIND score of 0 were deemed to not have ABE, whereas those with a score ≥1 were deemed to have ABE. A total of 151 infants were studied, among whom 37 (24.5%) had ABE. Of these, 19 had mild ABE (BIND score 1-3) and 18 had moderate-to-severe ABE (BIND score 4-9). On logistic regression, UB, but not TSB or BAMR, was associated with ABE (aOR 1.64; 95% CI 1.17-2.3). On ordered logistic regression, UB, but not TSB or BAMR, was associated with severity of ABE (aOR 1.76; 95% CI 1.28-2.4). Our findings of the association between UB and ABE indicate that BIND scoring may be useful for evaluation of ABE in infants ≥34weeksof gestational age.

Magnetic resonance spectroscopy and auditory brain-stem response audiometry as predictors of bilirubin-induced neurologic dysfunction in full-term jaundiced neonates

The purpose of this research was to define the functions of MRS and ABR as predictors of bilirubin-induced neurologic dysfunction (BIND) in full-term neonates who required intervention (phototherapy and/or exchange transfusion). This prospective cohort study was done at the NICU of Tanta University Hospitals over a 2-year duration. Fifty-six full-term neonates with pathological unconjugated hyperbilirubinemia were divided according to MRS and ABR findings into 2 groups: group (1) included 26 cases with mild acute bilirubin encephalopathy (BIND-M score 1–4). Group (2) included 30 cases with neonatal hyperbilirubinemia only. In addition, 20 healthy neonates with similar ages were employed as the controls. When compared to group 2 and the control group, group 1’s peak-area ratios of NAA/Cr and NAA/Cho were found to be significantly reduced (P < 0.05). As compared to group 2 and the control group, group 1’s Lac/Cr ratio was significantly greater (P < 0.05), but the differences were not significant for group 2 when compared to the control group. Waves III and V peak latencies, I–III, and I–V interpeak intervals were significantly prolonged in group 1 in comparison to group 2 and controls (P < 0.05) with no significant difference between group 2 and control group. Conclusion: When the symptoms of ABE are mild and MRI does not show any evident abnormalities, MRS and ABR are helpful in differentiating individuals with ABE from patients with neonatal hyperbilirubinemia. Trial registration: ClinicalTrials.gov, Identifier: NCT06018012.What is Known:• MRS can be used as a diagnostic and prognostic tool for the differential diagnosis of patients with acute bilirubin encephalopathy, from patients with neonatal hyperbilirubinemiaWhat is New:• ABR is a useful diagnostic and prognostic tool in the care and management of neonates with significantly raised bilirubin. It can be used as early predictor of acute bilirubin encephalopathy in the earliest stage of auditory damage caused by bilirubin.

Globus pallidus/putamen T1WI signal intensity ratio in grading and predicting prognosis of neonatal acute bilirubin encephalopathy.

This study sought to investigate the relationship between the globus pallidus/putamen T1 weighted image (T1WI) signal intensity ratio (G/P ratio) and the acute bilirubin encephalopathy (ABE) in neonates, and to develop a new strategy for the grading and prognosis of ABE based on the G/P ratio. A total of 77 full-term neonates with ABE were scored according to bilirubin-induced neurological dysfunction and divided into mild, moderate, and severe groups. Cranial magnetic resonance imaging examinations were performed and the G/P ratio was recorded. The follow-up reexaminations were carried out at 6 months, 1 year, and 2 years after the initial examination. The neonates were then divided into two groups, the good prognosis group and the kernicterus spectrum disorder (KSD) group, according to the evaluation of Gesell Developmental Schedules and Brainstem Audio Electric Potential at 6 months. The differences of G/P ratios were statistically significant, not only among the mild, moderate, and severe ABE groups for the initial examinations but also between the KSD and the good prognosis groups for the follow-up reexaminations. Therefore, the ABE grading model and prognosis predicting model could be established based on the G/P ratio. In the KSD group, the area under the receiver operating characteristic curve of the G/P ratio-based predicting model was 93.5%, the optimal critical point was 1.29, the sensitivity was 88.2%, and the specificity was 93.3%. The G/P ratio can be used as an indicating parameter for both the clinical grading of neonatal ABE and the assessment of neonatal ABE prognosis. Specifically, the G/P ratio greater than 1.29 indicates a KSD of neonatal ABE.

Predictive and diagnostic measures for kernicterus spectrum disorder: a prospective cohort study.

Kernicterus spectrum disorder (KSD) resulting from neonatal hyperbilirubinemia remains a common cause of cerebral palsy worldwide. This 12-month prospective cohort study followed neonates with hyperbilirubinemia to determine which clinical measures best predict KSD. The study enrolled neonates ≥35 weeks gestation with total serum bilirubin (TSB) ≥ 20 mg/dl admitted to Aminu Kano Hospital, Nigeria. Clinical measures included brain MRI, TSB, modified bilirubin-induced neurologic dysfunction (BIND-M), Barry-Albright Dystonia scale (BAD), auditory brainstem response (ABR), and the modified KSD toolkit. MRI signal alteration of the globus pallidus was scored using the Hyperbilirubinemia Imaging Rating Tool (HIRT). Of 25 neonates enrolled, 13/25 completed 12-month follow-up and six developed KSD. Neonatal BIND-M ≥ 3 was 100% sensitive and 83% specific for KSD. Neonatal ABR was 83% specific and sensitive for KSD. Neonatal HIRT score of 2 was 67% sensitive and 75% specific for KSD; this increased to 100% specificity and sensitivity at 12 months. BAD ≥ 2 was 100% specific for KSD at 3-12 months, with 50-100% sensitivity. Neonatal MRIs do not reliably predict KSD. BIND-M is an excellent screening tool for KSD, while the BAD or HIRT score at 3 or 12 months can confirm KSD, allowing for early diagnosis and intervention. The first prospective study of children with acute bilirubin encephalopathy evaluating brain MRI findings over the first year of life. Neonatal MRI is not a reliable predictor of kernicterus spectrum disorders (KSD). Brain MRI at 3 or 12 months can confirm KSD. The modified BIND scale obtained at admission for neonatal hyperbilirubinemia is a valuable screening tool to assess risk for developing KSD. The Barry Albright Dystonia scale and brain MRI can be used to establish a diagnosis of KSD in at-risk infants as early as 3 months.

Risk Stratification of Term Neonates for Development of Significant Hyperbilirubinemia by Cord Serum Bilirubin and Albumin Ratio

ABSTRACT Background: Neonatal hyperbilirubinemia is a common neonatal problem. Although benign in the majority of the cases, few neonates develop bilirubin-induced neurological dysfunction further progressing to kernicterus. Due to early hospital discharge of healthy-term neonates, there is need of a reliable tool for early prediction of significant hyperbilirubinemia in them. Aim: The aim of this study is to determine the utility of cord total serum bilirubin/albumin ratio as an early predictor of significant neonatal hyperbilirubinemia in healthy-term newborns. Settings and Design: This is a tertiary care hospital-based prospective cohort study. Subjects and Methods: The study was conducted on 100 sequentially born healthy-term neonates. Cord bilirubin/albumin ratio was calculated and neonates were divided into two groups on the basis of 50th percentile value. Serum bilirubin was also measured at 72 h of life in all neonates and value ≥17 mg/dl was taken as significant requiring intervention. Statistical Analysis Used: Continuous variables were summarized as mean and standard deviation while nominal/categorical variables as percentage. Association between total serum bilirubin at 72 h of life and cord bilirubin/albumin ratio was assessed using two-sample independent t-test and Pearson correlation coefficient formula. Cutoff value of the ratio was derived using receiver operating characteristics (ROC) curve analysis. Results: Statistically significant association was observed between cord bilirubin/albumin ratio with the development of neonatal hyperbilirubinemia. On ROC analysis, cutoff point to predict significant hyperbilirubinemia was found to be &gt;0.66 (92.9% sensitivity, 60.5% specificity, and PPV 79.61%). Conclusions: Cord total serum bilirubin/albumin ratio is a good parameter to predict significant neonatal hyperbilirubinemia in healthy-term neonates.

Imaging of nerve injury in neonatal acute bilirubin encephalopathy using 1H-MRS and Glu-CEST techniques.

To investigate the significance of proton magnetic resonance spectroscopy (1H-MRS) and glutamate chemical exchange saturation transfer (Glu-CEST) techniques in assessing the condition and prognosis of acute bilirubin encephalopathy patients and to understand the mechanism of nerve injury in this disease. From September 2019 to February 2021, 31 neonates with acute bilirubin encephalopathy and 16 healthy neonates were enrolled in this study. All the quantitative results of 1H-MRS, Glu-CEST, and conventional magnetic resonance imaging (MRI) of all neonates were analyzed. The associations between statistically significant indicators of imaging and developmental quotients (DQ) were analyzed. The 31 cases were assigned to the mild subgroup (n = 21) and moderate and severe subgroup (n = 10) according to the bilirubin-induced neurologic dysfunction (BIND) scores. The case group had elevated Cho and GABA absolute concentrations compared to the normal control group (all p < 0.05). Compared with the normal control group, the absolute concentration of GABA of the moderate and severe subgroup was significantly larger (p < 0.05). Compared with the normal control group, the Glu-CEST% values in the left basal ganglia, right thalamus, left frontal cortex and bilateral medial geniculate body of the case group was significantly larger (all p < 0.05). The moderate and severe subgroup had higher Glu-CEST% values in the left basal ganglia, right thalamus, and bilateral medial geniculate body than the normal control group (all p < 0.05). A negative association was revealed between the DQ scores and the Glu-CEST% values in the left basal ganglia (r = -0.888, p < 0.05). The combination of 1H-MRS and Glu-CEST techniques can monitor the intracerebral metabolite level of acute bilirubin encephalopathy and evaluate the illness severity.

Bilirubin induces microglial NLRP3 inflammasome activation in vitro and in vivo

Despite current advancements in neonatal care, hyperbilirubinemia resulting in bilirubin-induced neurological dysfunction (BIND) continues to be one of the major reasons of mortality or lifelong disability. Although the exact mechanisms underlying brain injury upon bilirubin exposure remains unelucidated, inflammation is considered to be one of the major contributors to BIND. This study investigates the role of the NLRP3 inflammasome in bilirubin-induced injury using in vitro and in vivo models. We successfully demonstrated that the upregulation of NLRP3 expression is significantly associated with the release of active caspase-1 and IL-1β in N9 microglial cells exposed to bilirubin. Functional in vitro experiments with NLRP3 siRNA confirms that bilirubin-induced inflammasome activation and cell death are mediated by the NLRP3 inflammasome. Following injection of bilirubin into the cisterna magna of a neonatal mouse, activation of the NLRP3 inflammasome and microglia were determined by double staining with Iba1-NLRP3 and Iba1-Caspase-1. Upon injection of bilirubin into the cisterna magna, neuronal loss was significantly higher in the wild-type mouse compared to Nlrp3−/− and Caspase-1−/− strains. Collectively, these data indicate that NLRP3 inflammasome has a crucial role in microglial activation and bilirubin-induced neuronal damage.

Diagnostics Value of Quantitative Magnetic Resonance Imaging (MRI) in Neonatal Acute Bilirubin Encephalopathy.

Background: This study was designed to investigate the diagnostic value of relative signal intensity of globus pallidus on T1-weighted magnetic resonance imaging (MRI) in neonatal acute bilirubin encephalopathy (ABE). Methods: Participants who were recruited in hospital from April 2019 to May 2020 were grouped into mildly increased total serum bilirubin (TSB) group (n = 30), severely increased TSB group (n = 25), or extremely increased TSB group (n = 10) based on the total serum bilirubin level. Bilirubin-induced neurologic dysfunction scale score was used to determine if participants had acute bilirubin encephalopathy. All neonates underwent conventional brain MRI and the relative signal intensity of globus pallidus was measured on T1-weighted images. The diagnostic value of these 3 indices was assessed by receiver operating characteristic curve analysis. Results: There was a significant correlation between relative signal intensity of globus pallidus and total serum bilirubin level in neonates with hyperbilirubinemia (r = 0.551, P < .001). Relative signal intensity of globus pallidus in the extremely increased TSB group was significantly higher than that in severely increased TSB, mildly increased TSB, and healthy control groups. Relative signal intensity of globus pallidus in the acute bilirubin encephalopathy group was significantly higher than that in the non-acute bilirubin encephalopathy group (P < .01). The area under the receiver operating characteristic curve of the relative signal intensity of globus pallidus was 0.765 (P < .01), with sensitivity of 0.655 and specificity of 0.861. The area under the curve of the total serum bilirubin and visual inspection of globus pallidus signal was 0.621 and 0.579, respectively. The area under the curve of relative signal intensity was significantly greater than that of total serum bilirubin and visual inspection (P = .04 for both). Conclusion: Relative signal intensity of globus pallidus, which is an objective assessment, has the potential to be used as a diagnostic tool for acute bilirubin encephalopathy.

Universal screening for hyperbilirubinemia in term healthy newborns at discharge: A systematic review and meta-analysis.

All term healthy neonates are screened for jaundice before hospital discharge as a standard clinical practice, but methods vary from clinical screening (visual inspection and/or risk factor assessment) to transcutaneous bilirubin (TcB) or total serum bilirubin (TSB) testing, depending on the setting. This systematic review of randomized and non-randomized studies evaluated the effectiveness of universal TcB and universal TSB screening at discharge compared to clinical screening alone for term healthy neonates. The outcomes were neonatal mortality, readmission for jaundice, severe hyperbilirubinemia (>20 mg/dL), jaundice requiring exchange transfusion, and bilirubin-induced neurological dysfunction (BIND). We searched MEDLINE via Ovid, EBM reviews, Embase, CINAHL, clinical trials databases, and reference lists of retrieved articles. Two authors separately evaluated the risk of bias, extracted data, and synthesized effect estimates using relative risk (RR) for randomized and odds ratio (OR) for non-randomized studies. For universal TcB at discharge, we included one randomized trial enrolling 1858 participants and four non-randomized studies enrolling 375 956 participants. No study reported neonatal mortality. The randomized trial suggested that universal TcB at discharge may decrease readmission for jaundice (risk ratio (RR) = 0.24, 95% confidence interval (CI) = 0.13 to 0.46; low certainty evidence) and severe hyperbilirubinemia (RR = 0.27, 95% CI = 0.08 to 0.97; low certainty evidence), but the effect on jaundice requiring exchange transfusion (RR = 0.20, 95% CI = 0.01 to 41.6) and BIND (RR = 0.33, 95% CI = 0.01 to 8.17) was uncertain. Meta-analysis of non-randomized studies suggested that TcB may decrease severe hyperbilirubinemia (odds ratio (OR) = 0.25, 95% = CI 0.12 to 0.52; low certainty evidence) and jaundice requiring exchange transfusion (OR = 0.28, 95% CI = 0.19 to 0.42; low certainty evidence), but the effect on readmission for jaundice was uncertain (OR = 1.01, 95% CI = 0.38 to 2.7; very low certainty evidence). For universal TSB, we included three studies from the United States enrolling 490 426 participants. The effect on severe hyperbilirubinemia (OR = 0.37, 95% CI = 0.15 to 0.88), jaundice requiring exchange transfusion (OR = 0.53, 95% CI = 0.13 to 2.25) and readmission for jaundice (OR = 1.01, 95% CI = 0.62 to 1.67) was uncertain. Universal TcB at discharge may improve clinical outcomes for term healthy neonates. Evidence for universal TSB is uncertain. PROSPERO 2020 CRD42020187279.

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.

Narrative review of bilirubin measurement and binding

: It is well accepted that infants with an imbalance in bilirubin production and excretion and/or poor plasma bilirubin binding have an increased risk of bilirubin-induced neurological dysfunction (BIND). The objective of this narrative review is to provide current literature on bilirubin measurement and bilirubin binding in premature and term infants with unconjugated hyperbilirubinemia. We provide evidence to support the notion that both total serum bilirubin (TSB) and bilirubin binding measurement contribute critical information about the risk of BIND in premature and term infants. We have reviewed and provided the evidence supporting the usefulness of free or unbound bilirubin as a better predictor of BIND compared to TSB in premature and term infants. We have also discussed promising newer developing technologies as point-of-care (POC) methods for bilirubin and bilirubin binding measurement. Overall, the improved knowledge of bilirubin binding over the last 20 years and recent development of promising newer point of care technologies for bilirubin and binding measurement augur well for development of pragmatic intervention trials to reduce mortality and morbidity associated with unconjugated hyperbilirubinemia in premature and term infants.

A prospective study on etiological factors and clinical indicators in term and near term neonates admitted with hyperbilirubinemia in nicu in a tertiary care hospital in Hyderabad, India

1.To study the etiology and risk factors of neonatal hyperbilirubinemia in term and near-term infants. 2. To study the clinical course of these infants during NICU stayThe present study was conducted at NICU, Department of Pediatrics, Princess Esra hospital, Deccan Medical College, Hyderabad, India, from October 2019 to October 2020. Term and late preterm infants admitted in NICU with Serum Bilirubin levels more than 12mg/dl were included in the study. The risk factors, etiology and clinical profile of these infants during NICU stay were studied. 210 neonates were admitted in NICU with hyperbilirubinemia (Serum Bilirubin &amp;#62;12mg/dl) during the study period, out of which 118 were male (56.20%) and 92 were female (43.80%). Neonates were further distributed based on gestational age, in which 46 (21.90%) were late pre-terms i.e. between 34-37 weeks and 164 neonates (78.10%) were full term i.e. greater than 37 weeks. The neonates were also classified based on their birth weight, with neonates between 2500-3000 grams having the highest incidence (46.19%). Lastly, the etiological and risk factors were assessed and quantified, with physiological jaundice occurring as the major cause and late prematurity as the most common risk factor associated with neonatal hyperbilirubinemia. The average duration of phototherapy was 2.50 days and 3 babies required Double Volume Exchange Transfusion (DVET) for significant hyperbilirubinemia.None of the babies requiring DVET had clinical features of Bilirubin Induced Neurological Dysfunction (BIND) during NICU stay. 1. Most common cause of neonatal hyperbilirubinemia was found to be Physiological followed by Septicemia and Idiopathic etiologies. Blood group incompatibilities were less common causes. 2. Phototherapy is a cheap and effective way to reduce bilirubin levels in neonatal jaundice. 3. Exchange transfusion is a safe procedure and should be considered when indicated, to decrease the incidence of BIND. All cases requiring DVET were due to blood group incompatibility.

Topiramate and darbepoetin alpha ameliorate bilirubin-induced neuronal cell damage.

The aim of this study was to determine whether prophylactic darbepoetin alpha and/or topiramate administration could prevent bilirubin neurotoxicity (BNTx) in experimental model of kernicterus. A total of 60 Wistar albino rat puppies with experimental kernicterus model were included in the study. The Kernicterus was established administering a bilirubin injection via a cisterna magna puncture 30 minutes after ip drug injection. The puppies were divided into five groups with 12 in each group as shown below: a control group, bilirubin group, darbepoetin alpha group, topiramate group and darbepoetin alpha+ topiramate group. Darbepoetin alpha and/or topiramate were administered on day 5 intraperitoneally (ip). At the 6th and 24th hours, bilirubin induced neurological dysfunction (BIND) score was used to assess behavioral changes. Hearing functions were evaluated on days 10 and 28. On day 30, the Water Maze water tank test was implemented to evaluate spatial memory. The rats were sacrificed on days 6 and 34 and apoptosis in the globus pallidus and hippocampus was examined. The BIND score was improved following darbepoetin alpha treatment. Neither darbepoetin alpha nor topiramate therapy ameliorate spatial memory. There were no significant differences between groups in terms of the auditory brainstem response (ABR). The combined use of darbepoetin alpha and topiramate lead to slight decrease in apoptosis. Darbepoetin alpha or topiramate administration ameliorates bilirubin induced neurological dysfunction in experimental model of kernicterus.

The biology of bilirubin production: overview of detection and inhibition

: Newborn jaundice is a benign condition commonly seen in the first postnatal week of life (or the transitional period). It is primarily due to an imbalance between the rate of production of the yellow-orange pigment bilirubin and its elimination by the liver. Infants with high bilirubin production rates (such as those who are undergoing hemolysis) or with insufficient hepatic bilirubin conjugating ability [such as those with uridine 5'-diphosho-glucuronosyltransferase (UGT1A1) deficiencies] can subsequently develop excessive circulating total serum/plasma bilirubin (TB) levels or hyperbilirubinemia. Bilirubin is formed during the degradation of heme, derived from the turnover of red blood cells (RBCs). In this reaction, which is catalyzed by the rate-limiting enzyme heme oxygenase (HO), carbon monoxide (CO), iron (Fe2+), and bilirubin are produced in equimolar quantities. As a result, measurements of total body CO production rates can be used as indices of bilirubin production. Standard treatment strategies for hyperbilirubinemia involves the use of phototherapy (specifically narrow-band blue wavelength light) and/or exchange transfusion. However, if infants with excessive hyperbilirubinemia are not identified or treated in a timely manner, they are at risk for developing bilirubin neurotoxicity, which can manifest as bilirubin-induced neurologic dysfunction (BIND) and result in neurologic sequelae (such as acute or chronic bilirubin encephalopathy. Here, we review the biology of bilirubin production and current technologies and approaches to identify and treat these high-risk infants.

Normalizing hyperactivity of the Gunn rat with bilirubin-induced neurological disorders via ketanserin.

Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear. The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses. Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat. It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations. We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations. Ketanserin normalizes hyperlocomotion of Gunn rats. To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

Amplitude-integrated electroencephalography improves the predictive ability of acute bilirubin encephalopathy

BackgroundTo establish a clinical prediction model of acute bilirubin encephalopathy (ABE) using amplitude-integrated electroencephalography (aEEG).MethodsA total of 114 neonatal hyperbilirubinemia patients in the Beijing Chaoyang Hospital from August 2015 to October 2018 were enrolled in this study. There were 62 (54.38%) males, and the age of patients undergoing aEEG examination was 2–23 days, with an average of 7.61±4.08 days. Participant clinical information, peak bilirubin value, albumin value, hyperbilirubinemia, and the graphic indicators of aEEG were extracted from medical records, and ABE was diagnosed according to a bilirubin-induced neurological dysfunction (BIND) score >0. Multivariable logistic regression was used to establish a clinical prediction model of ABE. Furthermore, decision curve analysis (DCA) was performed to evaluate the model’s predictive value.ResultsAccording to the BIND score, there were a total of 23 (20.18%) ABE cases. The multivariable logistic regression analysis showed that the value of bilirubin/albumin (B/A), presence of hyperbilirubinemia risk factors, number of sleep-wake cycling (SWC) within 3 hours, widest bandwidth, duration of SWC, and type of SWC were significantly associated with ABE. A clinical prediction model was developed as: p=ex/ (1+ex), X=0.278+0.713*B/A+2.602*with risk factors (with risk factors equals 1) − 1.500*SWC number within 3 hours + 0.219*the widest bandwidth-0.065*the duration of one SWC + 1.491* SWC (mature SWC equals 0, immature SWC equals 1). The area under the curve (AUC) was 0.85 [95% confidence interval (CI): 0.75–0.94], which was significantly higher than the AUC only based on conventional clinical information of B/A (AUC: 0.58, 95% CI: 0.45–0.72). The DCA also showed good predictive ability compared to B/A.ConclusionsA clinical prediction model can be established based on the patients’ B/A, presence of risk factors for hyperbilirubinemia, number of SWC within 3 hours, widest bandwidth, duration of 1 SWC, and the type of SWC. It has good predictive ability and may improve the diagnostic accuracy of ABE.

Kernicterus: The continuing occurrence of a preventable chronic disabling neurologic condition

Background: Kernicterus is a preventable condition that has become increasingly rare in many countries in the world. It is chronic severe form of bilirubin-induced neurological dysfunction that is associated with a variety of metal and neurological abnormalities resulting from bilirubininduced brain damage mostly in the basal ganglia and during the neonatal period. Despite the condition has been increasingly considered as preventable, it is still seen in some geographic areas where diagnostic and preventive interventions continue to experience failures. The aim of this paper is to emphasize the continuing occurrence of a preventable chronic disabling neurologic condition, and also to warn from the lack of advancement of preventive services in this geographic region. Patients and methods: Two unrelated patients with kernicterus observed at the Children Teaching Hospital of Baghdad Medical City are described. Results: The first patient was a seven-year old boy who was seen during the year 2019. He experienced neonatal hyperbilirubinemia of 28 mg/dL, and developed kernicterus presenting with mental retardation associated with delayed motor and speech development despite normal hearing, over-activity and behavioral abnormalities. The second patient was a two-year and eight months old girl who was also seen during the year 2019. She developed neonatal hyperbilirubinemia of 24 mg/dL that was attributed to ABO blood incompatibility, and required an exchange transfusion. The girl was spastic and had delayed speech and development and was unable to sit or stand without support. The patients were initially treated based on our extensive published experiences with the treatment of various neurologic disorders including cerebral palsy and kernicterus. However, they couldn’t be followed because of the emergence of covid-19 global pandemic. Conclusion: Although kernicterus has become increasingly rare in many countries in the world, it is still seen in areas with poor preventive services.

BIND score: A system to triage infants readmitted for extreme hyperbilirubinemia

Extreme hyperbilirubinemia [EHB, total serum bilirubin (TB) >25 mg/dL]) can lead to death, acute bilirubin encephalopathy (ABE), exchange transfusion, and/or bilirubin-induced neurologic dysfunction (BIND). In specific low- to middle-income countries, an “epidemic” exists, therefore, a simplified triage management system is needed. Here, we studied a cohort of 72 infants readmitted for EHB (TB: 28.1 ± 2.5; range: 25–42 mg/dL). Of these, 15/72 (20.8%) newborns had BIND scores ≥4. Eleven (15.3%) infants with BIND scores of 4 to 6 developed moderate ABE, with 6/11 (54.5%) with TB of 28.1 ± 4.8 mg/dL having post-icteric sequelae. Eight infants (TB of 32.1 ± 3.5 mg/dL) had BIND scores >6 and developed adverse outcomes. One infant, who had Rh disease and a BIND score of 8 died. We report that the key determinants for adverse outcomes were TB >30 mg/dL and a BIND score ≥4 and may be useful for a systems approach to triage infants readmitted for EHB.