High unbound bilirubin for age: a neurotoxin with major effects on the developing brain.

Neonatal hyperbilirubinemia is one of the most frequent diagnoses made in neonates. A high level of unconjugated bilirubin that is unbound to albumin is neurotoxic when the level exceeds age-specific thresholds or at lower levels in neonates with neurotoxic risk factors. Lower range of unbound bilirubin results in apoptosis, while moderate-to-high levels result in neuronal necrosis. Basal ganglia and various brain stem nuclei are more susceptible to bilirubin toxicity. Proposed mechanisms of bilirubin-induced neurotoxicity include excessive release of glutamate, mitochondrial energy failure, release of proinflammatory cytokines, and increased intracellular calcium concentration. These mechanisms are similar to the events that occur following hypoxic-ischemic insult in neonates. Severe hyperbilirubinemia in term neonates has been shown to be associated with increased risk for autism spectrum disorders. The neuropathological finding of bilirubin-induced neurotoxicity also includes cerebellar injury with a decreased number of Purkinje cells, and disruption of multisensory feedback loop between cerebellum and cortical neurons which may explain the clinical characteristics of autism spectrum disorders. Severe hyperbilirubinemia occurs more frequently in infants from low- and middle-income countries (LMIC). Simple devices to measure bilirubin, and timely treatment are essential to reduce neurotoxicity, and improve outcomes for thousands of neonates around the world.

Hyperbilirubinemia-induced pro-angiogenic activity of infantile endothelial progenitor cells.

OBJECTIVES: Bilirubin, a by-product of heme degradation, is suggested to have a role for vascular protection. There is increasing evidence that bilirubin may directly affect the function and secretory activity of endothelial cells. In this study, potential effect of hyperbilirubinemia on biological features of circulation endothelial progenitor cells (cEPCs) isolated from infants was investigated. METHODS: Circulation concentration, differentiation and migratory activity of cEPCs isolated from infants with (n = 111) or without (n = 73) hyperbilirubinemia were analyzed. Then, the potential beneficial effect of conditioned medium of cEPCs from infants with or without hyperbilirubinemia was examined on experimental mouse wounds. RESULTS: Our results revealed significantly higher percentages of cEPCs in infants with hyperbilirubinemia. Cell proliferation, and migratory properties of cEPCs isolated and expanded from infants with hyperbilirubinemia were significantly improved. Also, the conditioned medium of cEPCs from hyperbilirubinemic infants possessed a superior beneficial effect on wound healing, which was associated with increased protein levels of VEGF, IL-10, and Pho-ERK/ERK, and decreased TNF-α in the wound tissues. CONCLUSIONS: Our results showed that hyperbilirubinemia can activate migration, proliferating and angiogenic properties of cEPCs. Hyperbilirubinemia can promote the proangiogenic secretory activity of cEPCs, thereby resulting in enhancement of their regenerative wound healing properties.

Iron-mediated oxidative cell death is a potential contributor to neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia.

The review article discusses current knowledge of iron-mediated oxidative cell death (ferroptosis) and its potential role in the pathogenesis of neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia. The connection between metabolic conditions related to hemolysis (iron and bilirubin overload) and iron-induced lipid peroxidation is highlighted. Neurotoxicity of iron and bilirubin is associated with their release from destructed erythrocytes in response to hemolytic disease. Iron overload initiates lipid peroxidation through the reactive oxygen species production resulting to oxidative damage to cells. Excessive loading of immature brain cells by iron-induced formation of reactive oxygen species contributes to the development of various neurodevelopmental disorders. The causal relationship between iron overload and susceptibility of brain cells to oxidative damage by ferroptosis appears to be associated not only with the amount of redox-active iron involved in oxidative cell damage but also with the degree of maturity of the neonatal brain. Neuronal dysfunction induced by neonatal hemolytic disease can represent a specific model of ferroptosis. The mechanism by which iron overload triggers ferroptosis is not completely explained. However, hemolysis of neonatal red blood cells appears to be a determining factor. Potential therapeutic strategy with iron-chelating agents to inhibit ferroptosis has a promising future in postnatal care.

Attenuation of neuro-inflammation improves survival and neurodegeneration in a mouse model of severe neonatal hyperbilirubinemia.

All pre-term newborns and a high proportion of term newborns develop neonatal jaundice. Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute hyperbilirubinemia. Excessive hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities. Current therapies rely on the use of phototherapy and, in unresponsive cases, exchange transfusion, which is performed only in specialized centers. During bilirubin-induced neurotoxicity different molecular pathways are activated, ranging from oxidative stress to endoplasmic reticulum (ER) stress response and inflammation, but the contribution of each pathway in the development of the disease still requires further investigation. Thus, to increase our understanding of the pathophysiology of bilirubin neurotoxicity, encephalopathy and kernicterus, we pharmacologically modulated neurodegeneration and neuroinflammation in a lethal mouse model of neonatal hyperbilirubinemia. Treatment of mutant mice with minocycline, a second-generation tetracycline with anti-inflammatory and neuroprotective properties, resulted in a dose-dependent rescue of lethality, due to reduction of neurodegeneration and neuroinflammation, without affecting plasma bilirubin levels. In particular, rescued mice showed normal motor-coordination capabilities and behavior, as determined by the accelerating rotarod and open field tests, respectively. From the molecular point of view, rescued mice showed a dose-dependent reduction in apoptosis of cerebellar neurons and improvement of dendritic arborization of Purkinje cells. Moreover, we observed a decrease of bilirubin-induced M1 microglia activation at the sites of damage with a reduction in oxidative and ER stress markers in these cells. Collectively, these data indicate that neurodegeneration and neuro-inflammation are key factors of bilirubin-induced neonatal lethality and neuro-behavioral abnormalities. We propose that the application of pharmacological treatments having anti-inflammatory and neuroprotective effects, to be used in combination with the current treatments, may significantly improve the management of acute neonatal hyperbilirubinemia, protecting from bilirubin-induced neurological damage and death.

Clinical study on amplitude integrated electroencephalogram in cerebral injury caused by severe neonatal hyperbilirubinemia.

BACKGROUND: This study was designed in order to assess the validity of the use of amplitude-integrated electroencephalogram (aEEG) in cerebral injury caused by severe neonatal hyperbilirubinemia. METHODS: A total of 56 full-term neonates diagnosed with severe neonatal hyperbilirubinemia and admitted to the NICU of our hospital from July 2013 to December 2014 were continuously selected for the study. The total serum bilirubin (TSB) was higher than 342 µmol/L and was dominated by a higher amount of unconjugated bilirubin. Each patient underwent aEEG monitoring upon admission. And according to the results of the test, they were assigned into an aEEG normal group (N.=38) or an aEEG abnormal group (N.=18). Dynamic monitoring of bilirubin and blood biochemistry was also conducted for all the children after admission. Patients were treated with blue light, anti-infection agents, acidosis correction measures, transfusion exchanges, intravenous drips of albumin or globulin and other specific treatments as needed in each particular case. Brainstem auditory evoked potential (BAEP), MRI examination and a behavioral neurological assessment (NBNA) with 20-item examinations were provided within 4-17 days after admission. Follow-up observations were conducted on growth level (physical development and Gesell scores) at 3, 6, 12 and 18 months. RESULTS: The results of all the diagnostic tests performed in the patients of both groups all yielded a significantly higher abnormality rate in the aEEG abnormal group compared to the results in the aEEG normal group. Furthermore, the results of follow-up tests showing growth and child development also showed higher abnormality rates in the aEEG abnormal group than in the aEEG normal group. CONCLUSIONS: Since the results of our aEEG monitoring were consistent with the findings of other diagnostic tests, we proved the convenience and effectivity of aEEG for guiding the treatment and prognosis of severe hyperbilirubinemia in neonates.

Cotrimoxazole and neonatal kernicterus: a review.

Sulfamethoxazole (SMX) and trimethoprim (TMP) individually and a combination known as cotrimoxazole (SMX-TMP) are widely used for the treatment of protozoan and bacterial infections. SMX-TMP is also one of the widely used antibiotics administered orally in neonates, along with gentamicin injection, for treating pneumonia and sepsis by home-based healthcare providers in Asian countries. Although the use of this drug has successfully reduced neonate mortality, there is a concern for it causing neurotoxicity. Previous clinical studies with sulfisoxazole have demonstrated occurrence of kernicterus in neonates. This sulfonamide is thought to displace bilirubin from its albumin-binding sites in plasma leading to an elevation of plasma bilirubin, which crosses the blood-brain barrier, reaches central neurons to cause kernicterus. We performed an extensive review of clinical and animal studies with cotrimoxazole, which showed no reported incidences of kernicterus with SMX-TMP use in neonates. EndNote, BasicBiosis, Embase, PubMed and Toxline database searches were conducted using specific keywords yielding 74 full-length articles relevant to the review. This review has taken into account various factors, including the disease itself, direct effects of the drug and its metabolism through conjugation and acetylation through a thorough review of the literature to examine the potentials of SMX-TMP to cause kernicterus in neonates. SMX-TMP in oral doses administered to neonates for 7-10 days is unlikely to cause kernicterus. Also, this review recommends warranting the need of future studies using animal models and clinical studies in humans to address SMX-TMP toxicity.

Clinical Analysis of Abnormal Brainstem Auditory Evoked Potential in Neonates with Hyperbilirubinemia.

BACKGROUND: Severe neonatal hyperbilirubinemia can cause hearing impairment. Bilirubin can be deposited in nerve cells, and the brainstem and the 8th nerve are especially sensitive to bilirubin toxicity. Abnormal changes in brainstem auditory evoked potential (BAEP) can be observed, and the BAEP test measures a nerve potential induced by short, high-frequency sound stimulation; thus, it is able to detect damage to the auditory conduction pathway in children. We aimed to identify relationships between clinical features and BAEP abnormalities in children with hyperbilirubinemia and to assess the predictive power of these risk factors for bilirubin-induced neurological damage. METHODS: Children with hyperbilirubinemia were evaluated with BAEP and retrospectively enrolled in the study between January 2012 and December 2018. Multivariate logistic regression was performed to identify independent predictors of BAEP abnormalities. RESULTS: Of the 561 children with hyperbilirubinemia enrolled, the BAEP anomaly group accounted for 198 (35.3%) cases. Except for body weight, there were no significant differences in the general data between the two groups with hyperbilirubinemia (p > 0.05). Univariate analysis showed that prematurity, abnormal umbilical cord, and gestational diabetes during pregnancy were significantly correlated with abnormal BAEP. Multivariate logistic regression analysis identified prematurity (p = 0.001), gestational diabetes (p = 0.03), Premature rupture of membranes (p = 0.013), total serum bilirubin (TSB), bilirubin/albumin (B/A) as independent risk factors for BAEP abnormalities. The prediction accuracy of TSB (Area Under Curve (AUC) = 0.557) and B/A (AUC = 0.566) was low, indicating that abnormal BAEP should be detected by multiple factors. CONCLUSIONS: Multivariate detection is beneficial for predicting the occurrence of auditory nerve injury in patients with hyperbilirubinemia.

Cross-talk between neurons and astrocytes in response to bilirubin: early beneficial effects.

Hyperbilirubinemia remains one of the most frequent clinical diagnoses in the neonatal period. This condition may lead to the deposition of unconjugated bilirubin (UCB) in the central nervous system, causing nerve cell damage by molecular and cellular mechanisms that are still being clarified. To date, all the studies regarding bilirubin-induced neurological dysfunction were performed in monotypic nerve cell cultures. The use of co-cultures, where astrocyte-containing culture inserts are placed on the top of neuron cultures, provides the means to directly evaluate the cross-talk between these two different cell types. Therefore, this study was designed to evaluate whether protective or detrimental effects are produced by astrocytes over UCB-induced neurodegeneration. Our experimental model used an indirect co-culture system where neuron-to-astrocyte signaling was established concomitantly with the 24 h exposure to UCB. In this model astrocytes abrogated the well-known UCB-induced neurotoxic effects by preventing the loss of cell viability, dysfunction and death by apoptosis, as well as the impairment of neuritic outgrowth. To this protection it may have accounted the induced expression of the multidrug resistance-associated protein 1 and the 3.5-fold increase in the values of S100B, when communication between both cells was established independently of UCB presence. In addition, the presence of astrocytes in the neuronal environment preserved the UCB-induced increase in glutamate levels, but raised the basal concentrations of nitric oxide and TNF-α although no UCB effects were noticed. Our data suggest that bidirectional signalling during astrocyte-neuron recognition exerts pro-survival effects, stimulates neuritogenesis and sustains neuronal homeostasis, thus protecting cells from the immediate UCB injury. These findings may help explain why irreversible brain damage usually develops only after the first day of post-natal life.

Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant.

BACKGROUND: There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4-14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T. METHODS: This was a case-control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCR-RFLP analysis and gene sequencing. RESULTS: G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean ± 1SD; 0.3 ± 0.2 U/gHb vs. 14.0 ± 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean ± 1SD; 16.8 ± 5.4 mg/dl vs. 13.8 ± 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean ± 1SD 2.9 ± 1.6 vs. 4.3 ± 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups. CONCLUSIONS: We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.

Hyperbilirubinemia: current guidelines and emerging therapies.

It is estimated that about two thirds of newborns will appear clinically jaundiced during their first weeks of life. As newborns and their mothers spend fewer days in the hospital after birth, the number of infants readmitted yearly in the United States for neonatal jaundice over the last 10 years has increased by 160%. A portion of these infants present to the emergency department, requiring a careful history and physical examination assessing them for the risk factors associated with pathologic bilirubin levels. Although the spectrum of illness may be great, the overwhelming etiology of neonatal jaundice presenting to an emergency department is physiologic and not due to infection or isoimmunization. Therefore, a little more than a good history, physical examination, and indirect/direct bilirubin levels are needed to evaluate an otherwise well-appearing jaundiced newborn. The American Academy of Pediatrics' 2004 clinical practice guidelines for "Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation" are a helpful and easily accessible resource when evaluating jaundiced newborns (available at http://aappolicy.aappublications.org/cgi/content/full/pediatrics;114/1/297). There are several exciting developments on the horizon for the diagnosis and management of hyperbilirubinemia including increasing use of transcutaneous bilirubin measuring devices and medications such as tin mesoporphyrin and intravenous immunoglobulin that may decrease the need for exchange transfusions.

Confirmed association between neonatal phototherapy or neonatal icterus and risk of childhood asthma.

We have previously demonstrated an association between neonatal phototherapy and/or neonatal icterus and risk of hospitalization for childhood asthma. This study included children who were prescribed anti-asthmatic medication on a population basis to study exposures during the foetal and neonatal period and risk of childhood asthma. The Swedish Medical Birth Register was linked to the Swedish Prescribed Drug Register. Perinatal data for singleton children who were prescribed anti-asthmatic medication (n = 61,256) were compared with corresponding data for all singleton children born in Sweden from 1 January 1990 to 30 June 2003 and surviving to 1 July 2005 (n = 1,338,319). Mantel-Haenszel's odds ratios were calculated after adjustment for various known confounders. Being the first-born child, maternal age above 44 yr, involuntary childlessness for more than 1 yr, maternal smoking during pregnancy, maternal diabetes mellitus of any kind, pre-eclampsia, caesarean section, and instrumental vaginal delivery were all associated with an increased prescription of anti-asthmatic medication during childhood. Preterm birth, low birth weight, being small for gestational age, respiratory problems, mechanical ventilation, and sepsis and/or pneumonia were also associated with increased drug prescriptions. Neonatal phototherapy and/or icterus were risk determinants for children who developed asthma before the age of 12. After controlling for confounders, the odds ratio for phototherapy and/or icterus remained at 1.30 (95% confidence interval 1.16-1.47). In conclusion, this large population-based study confirms an association between some maternal and perinatal factors and childhood asthma, including neonatal phototherapy and/or icterus.

Audiological assessment of neonatal hyperbilirubinemia.

OBJECT: To evaluate the hearing of infants with history of neonatal hyperbilirubinemia using ABR. METHODS: A prospective randomized study carried on 100 infants whose hearing was assessed by ABR. Infants were allocated into two groups; case group which involve 60 infants with history of neonatal hyperbilirubinemia (bilirubin more than17 mg/dl and less than 30 mg/dl) and control group involve 40 healthy infants. Each group was divided into 3 groups based on their age i.e. ≤ 6 months, > 6-9 months &> 9-12 months. The evaluated variables were latency time & inter peak latency time. RESULTS: The mean latencies of wave III&V of ABR were significantly higher in the case group compared with the controls (P < 0.001) while the mean latencies of wave I did not show a significant difference between the two study groups (P > 0.05). The mean inter wave latencies I-III, I-V& III-V of ABR were significantly higher in the case group compared with the controls. There was a negative correlation between age and the studied variables. CONCLUSION: Hyperbilirubinemia have an adverse effect on neonatal hearing which was reflected by ABR parameters of this study.

Frequency-following response among neonates with progressive moderate hyperbilirubinemia.

OBJECTIVE: To evaluate the feasibility of auditory monitoring of neurophysiological status using frequency-following response (FFR) in neonates with progressive moderate hyperbilirubinemia, measured by transcutaneous (TcB) levels. STUDY DESIGN: ABR and FFR measures were compared and correlated with TcB levels across three groups. Group I was a healthy cohort (n = 13). Group II (n = 28) consisted of neonates with progressive, moderate hyperbilirubinemia and Group III consisted of the same neonates, post physician-ordered phototherapy. RESULT: FFR amplitudes in Group I controls (TcB = 83.1 ± 32.5µmol/L; 4.9 ± 1.9 mg/dL) were greater than Group II (TcB = 209.3 ± 48.0µmol/L; 12.1 ± 2.8 mg/dL). After TcB was lowered by phototherapy, FFR amplitudes in Group III were similar to controls. Lower TcB levels correlated with larger FFR amplitudes (r = -0.291, p = 0.015), but not with ABR wave amplitude or latencies. CONCLUSION: The FFR is a promising measure of the dynamic neurophysiological status in neonates, and may be useful in tracking neurotoxicity in infants with hyperbilirubinemia.

Effects of Massage Therapy on Indirect Hyperbilirubinemia in Newborns Who Receive Phototherapy.

OBJECTIVE: To evaluate the effects of massage therapy on total serum bilirubin (TSB) levels and frequency of defecation, urination, and feeding in newborns who receive phototherapy for indirect hyperbilirubinemia. DESIGN: A randomized controlled clinical trial. SETTING: Ankara University Cebeci Research and Training Hospital and 29 May State Hospital in Ankara, Turkey. PARTICIPANTS: Fifty full-term newborns with indirect hyperbilirubinemia who underwent phototherapy. METHODS: The newborns were randomly allocated to an intervention group (n = 25) or a control group (n = 25). Newborns in the intervention group received massage therapy throughout the duration of phototherapy for 15 minutes twice per day; newborns in the control group received routine care during phototherapy. Every 24 hours, TSB levels were measured, and the frequencies of defecation, urination, and feeding were also calculated for each newborn. RESULTS: We found no differences in the characteristics of the newborns or in TSB levels between groups at enrollment. After treatment, TSB levels were lower in the intervention group (p < .001). Frequencies of defecation, urination, and feeding were significantly greater in the intervention group than in the control group. CONCLUSION: Massage therapy had significant effects on TSB levels, feeding, breastfeeding, defecation, and urination in newborns who received phototherapy for indirect hyperbilirubinemia. Massage therapy can be added as routine care for full-term newborns with hyperbilirubinemia under phototherapy and may be an effective supplementary intervention.

UGT1A1 gene polymorphisms in North Indian neonates presenting with unconjugated hyperbilirubinemia.

Genetic factors are implicated in pathogenesis of neonatal hyperbilirubinemia. In this nested case-control study, we determined 1) frequency of thymine-adenine (TA)n promoter polymorphism and Gly71Arg mutation in uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene in neonates > or =35-wk gestation presenting with bilirubin levels > or =18 mg/dL and controls, 2) interaction among (TA)n promoter polymorphism, glucose-6-phosphate dehydrogenase (G6PD) gene mutations, and peak bilirubin. The number of TA repeats was assessed by PCR-single-strand conformation polymorphism (SSCP) analysis and Gly71Arg mutation by PCR-RFLP. Fifty samples of both mutations were verified with DNA sequencing. One hundred twenty-seven neonates were enrolled (77 hyperbilirubinemics, 50 controls). The incidence of (TA)n polymorphism was higher in babies with hyperbilirubinemia [89.6% vs. 50%, OR 8.63 (95% CI, 3.2-24.1)]. Gly71Arg mutation was not found either in hyperbilirubinemics or controls. A novel polymorphism (Ala72Pro) at codon position 72 of exon 1 was detected in all 50 samples (21 hyperbilirubinemics, 29 controls), which were sequenced. Presence of variant (TA)n promoter (adjusted OR, 10.6; 95% CI, 3.3-34.2), G6PD deficiency (adjusted OR, 20.6; 95% CI, 3.6-117.3), and history of jaundice in sibling requiring phototherapy (adjusted OR, 12.6; 95% CI, 1.1-141.6) were independent risk factors for bilirubin levels > or =18 mg/dL.

Changes in BAER wave amplitudes in relation to total serum bilirubin level in term neonates.

INTRODUCTION: Whether the severity of bilirubin neurotoxicity is closely related to the level of total serum bilirubin (TSB) remains to be determined. MATERIALS AND METHODS: We studied the amplitudes of brainstem auditory evoked response (BAER) components in 83 term neonates with TSB >10 mg/dL to detect any differences in bilirubin ototoxic effect on the amplitudes between different levels of TSB. RESULTS AND DISCUSSION: Compared to age-matched normal controls, the amplitudes of BAER waves III and V were reduced significantly (P<0.01 and 0.001). The V/I and V/III amplitude ratios were also decreased significantly (P<0.001 and 0.01). Although all amplitudes tended to be lower at higher TSB levels than at lower levels, none of the amplitudes correlated significantly with the level of TSB. Neither the V/I amplitude ratio nor the V/III amplitude ratio correlated with the TSB. No significant differences were found in any BAER wave amplitudes among the TSB levels 11-15, 16-20 and >20 mg/dL. In the comparison of amplitude data between any two of the three TSB levels, only wave V amplitude showed significant difference between TSB levels 11-15 and >20 mg/dL (P < 0.05). CONCLUSION: BAER wave amplitudes were significantly reduced in neonates with hyperbilirubinemia. However, there was no close correlation between the degree of amplitude reduction and the level of TSB. These results indicate that bilirubin toxicity to the neonatal brain is not closely related to the level of TSB.

A randomized control trial of phototherapy and 20% albumin versus phototherapy and saline in Kilifi, Kenya.

OBJECTIVE: The study evaluated the efficacy of phototherapy and 20% albumin infusion to reduce total serum bilirubin (TSB) in neonates with severe hyperbilirubinemia. The primary outcome was a reduction of TSB at the end of treatment. The secondary outcomes were the need for exchange transfusion, inpatient mortality, neurological outcomes at discharge, and development outcomes at 12-months follow-up. RESULTS: One hundred and eighteen neonates were randomly assigned to phototherapy and 20% albumin (n = 59) and phototherapy and saline (n = 69). The median age at admission was 5 (interquartile range (IQR) 3-6) days, and the median gestation was 36 (IQR 36-38) weeks. No significant differences were found in the change in TSB (Mann-Whitney U =609, p = 0.98) and rate of change in TSB per hour after treatment (Mann-Whitney U = 540, p = 0.39) between the two groups. There were no significant differences between the two groups in the proportion of participants who required exchange transfusion (χ2 (2) = 0.36, p = 0.546); repeat phototherapy (χ2 (2) = 2.37, p = 0.123); and those who died (χ2 (2) = 0.92, p = 0.337). Trial registration The trial was registered in the International Standardized Randomized Controlled Trial Number (ISRCTN); trial registration number ISRCTN89732754.

Unusual cause of severe neonatal hyperbilirubinaemia: a twin case.

We present twins born to the 31-year-old, multigravida mother, who were referred to our centre at 90 hours of life for severe hyperbilirubinaemia. Twin 1 had already received two double volume exchange transfusions at 55 and 83 hours of life, in view of the persistent rise in bilirubin despite receiving phototherapy. Twin 2 had received phototherapy and 1 packed red blood cell transfusion in view of the fall in haematocrit. Mother's blood group was B positive and that of both twins was O positive. Both the twins were started on intensive phototherapy and their serum bilirubin and haematocrit were evaluated. On investigation, a minor blood incompatibility was found. Double volume exchange transfusion was done for twin 2 at 100 hours of life in view of the rapid rise in serum bilirubin. Both the babies were monitored for their serum bilirubin and treated for sepsis and discharged after 15 days.

Auditory brainstem responses as a clinical evaluation tool in children after perinatal encephalopathy.

UNLABELLED: Auditory brainstem responses (ABR) reveals the neurophysiological status of the neural axis. In this study we compared the ABR of healthy children, under 1-year-old, with children who suffered from perinatal encephalopathy (PE). OBJECTIVE: The purpose of this study was to characterize the ABR differences between children with PE and healthy children in order to identify groups with specific neurophysiological profiles, associated with their neurological condition. METHODS: Thirty-six children with perinatal encephalopathy (PE) and 36 healthy children, ages 1-12 months, were studied. The variables considered were: latencies of waves I, II, N1, III, V, and N2; interpeak latency interval (IPL) of waves I-III, III-V, and I-V; as well as amplitudes of waves I, III, and V. The results were analyzed using ANOVA, as well as Ji(2), and Ward's cluster analysis. RESULTS: The absolute latencies of the ABR showed an inverse correlation with the children's age. Latencies of waves I, II, N1, V, and N2, IPL III-V, and amplitude of waves III and V show significant differences (p<0.05) between healthy and PE children. Children with PE showed greater absolute latencies and larger wave amplitudes than the control group. Ward's cluster analysis, used to define the groups with similar functional characteristics, revealed three groups: fast, intermediate, and slow-responders, depending on their wave latencies and IPL wave amplitudes. These groups were gender- (p<0.03), age- (p<0.0001), and neurological damage- (p<0.01) related. CONCLUSIONS: Our data clearly show that the ABR obtained from PE children differ from ABR obtained from healthy children. PE infants showed larger wave latencies, intervals amplitudes than the control group. Three functional profiles resulted from the groups established using the Ward's method, and these indicate their neurological functional condition.

Hyperthyroxinemia at birth: a cause of idiopathic neonatal hyperbilirubinemia?

BACKGROUND: Some neonates develop idiopathic hyperbilirubinemia (INHB) requiring phototherapy, yet with no identifiable causes. We searched for an association between abnormal thyroid levels after birth and INHB. METHODS: Of 5188 neonates, 1681 (32.4%) were excluded due to one or more risk factors for hyperbilirubinemia. Total thyroxine (TT4) and thyroid stimulating hormone values were sampled routinely at 40-48 hours of age and measured in the National Newborn Screening Program. RESULTS: Of the 3507 neonates without known causes for hyperbilirubinemia, 61 (1.7%) developed INHB and received phototherapy. Univariate analyses found no significant association between mode of delivery and INHB (vacuum-delivered neonates were a priori excluded). Nonetheless, in cesarean-delivered (CD) neonates, two variables had significant association with INHB: TT4 ≥ 13 µg/dL and birth at 38-38.6 weeks. In vaginally delivered (VD) born neonates, INHB was associated with weight loss > 7.5% up to 48 hours of age. Multivariate logistic regression analysis showed a strong effect of mode of delivery on possible significant association with INHB. In CD neonates, such variables included: TT4 ≥ 13 µg/dL [P = 0.025, odds ratio (OR) 5.49, 95% confidence interval (CI) 1.23-24.4] and birth at 38-38.6 weeks (P = 0.023, OR 3.44, 95% CI 1.19-9.97). In VD neonates, weight loss > 7.5% (P = 0.019, OR 2.1, 95% CI 1.13-3.83) and 1-min Apgar score < 9 (P < 0.001, OR 3.8, 95% CI 1.83-7.9), but not TT4, showed such an association. CONCLUSIONS: INHB was significantly associated with birth on 38-38.6 week and TT4 (≥ 13 µg/dL) in CD neonates, and with a weight loss > 7.5% in VD neonates. We herein highlight some acknowledged risk factors for neonatal hyperbilirubinemia, and thus minimize the rate of INHB.