Relation between serum bilirubin levels ≥450 μmol/L and bilirubin encephalopathy; a Danish population‐based study

Ebbesen, Finn; Bjerre, Jesper Vandborg; Vandborg, Pernille Kure

doi:10.1111/j.1651-2227.2011.02565.x

Cited by 46 publications

(48 citation statements)

References 18 publications

(31 reference statements)

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“…2 In Denmark, extreme hyperbilirubinemia and chronic bilirubin encephalopathy (kernicterus) occur in 1 in 2000 live births and 1 in 95 000 live births, respectively. [3][4][5][6] These rates correspond well with reports from other parts of the privileged world, 7 but in the developing world, bilirubin encephalopathy persists as a frequent cause of neonatal morbidity. 8 Severalriskfactorsforhyperbilirubinemia are known, among these are blood type iso-immunization, congenital hemolytic diseases, gender, prematurity, race, starvation, and early discharge from hospital, but in a large number of patients, a causal factor is never established.…”

supporting

confidence: 73%

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Petersen

Henriksen²,

Hollegaard

et al. 2014

Pediatrics

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WHAT'S KNOWN ON THIS SUBJECT: For newborn infants, extreme hyperbilirubinemia ($24.5 mg/dL) is associated with risk for severe bilirubin encephalopathy. The causal factor of extreme hyperbilirubinemia is often not established. The genotype of Gilbert syndrome, the UGT1A1*28 allele, is considered a potential risk factor. WHAT THIS STUDY ADDS:The UGT1A1*28 allele was not associated with risk for developing extreme hyperbilirubinemia. abstract OBJECTIVES: Extreme hyperbilirubinemia (plasma bilirubin $24.5 mg/dL) is an important risk factor for severe bilirubin encephalopathy. Several risk factors for hyperbilirubinemia are known, but in a large number of patients, a causal factor is never established. UGT1A1 is the rate-limiting enzyme in bilirubin' s metabolism. The genotype of Gilbert syndrome, the UGT1A1*28 allele, causes markedly reduced activity of this enzyme, but its association with neonatal hyperbilirubinemia is uncertain and its relationship with extreme hyperbilirubinemia has not been studied. We examined whether the UGT1A1*28 allele is associated with extreme hyperbilirubinemia. METHODS:The UGT1A1*28 allele was assessed in a case-control study of 231 white infants who had extreme hyperbilirubinemia in Denmark from 2000 to 2007 and 432 white controls. Cases were identified in the Danish Extreme Hyperbilirubinemia Database that covers the entire population. Genotypes were obtained through the Danish Neonatal Screening Biobank. Subgroup analysis was done for AB0 incompatible cases. RESULTS:No association was found between the UGT1A1*28 allele and extreme hyperbilirubinemia. With the common genotype as reference, the odds ratio of extreme hyperbilirubinemia was 0.87 (range, 0.68-1.13) for UGT1A1*28 heterozygotes and 0.77 (range, 0.46-1.27) for homozygotes. Also, no association was found for AB0 incompatible cases.

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confidence: 73%

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Petersen

Henriksen²,

Hollegaard

et al. 2014

Pediatrics

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“…[1][2][3][4] Although there is no single threshold at which bilirubin becomes neurotoxic, 5 a 2003 Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored conference proposed that TSB levels $30 mg/dL be defined as "hazardous" hyperbilirubinemia because of the perceived higher risk of neurologic injury. 6 The incidence of hazardous hyperbilirubinemia in populations in Western Europe [7][8][9][10][11][12] and the United States [13][14][15][16][17] ranges from 2 to 12/100 000, with the lowest rates in Switzerland (where the mean postpartum stay after a vaginal delivery was 5.6 days) 11 and in US hospital systems after implementation of universal bilirubin screening. 14,15,17 The distribution of causes of hazardous hyperbilirubinemia varies in different populations, with isoimmunization more common in Europe 9,10,12 and glucose-6-phosphate dehydrogenase (G6PD) deficiency predominating in the United States and Canada.…”

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confidence: 99%

Incidence, Etiology, and Outcomes of Hazardous Hyperbilirubinemia in Newborns

et al. 2014

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WHAT'S KNOWN ON THIS SUBJECT: Total serum bilirubin levels $30 mg/dL have been labeled as "hazardous." Levels this high are rare, occurring in 3 to 10 per 100 000 births. Few studies have examined etiologies and long-term outcomes in these infants.WHAT THIS STUDY ADDS: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a major identifiable cause, but is underassessed. Chronic, bilirubin-induced neurotoxicity is rare and only occurred in the setting of additional risk factors (prematurity, G6PD deficiency, sepsis) and at levels far above recommended exchange transfusion thresholds. abstract BACKGROUND AND OBJECTIVES: Total serum bilirubin (TSB) levels $30 mg/dL are rare but potentially hazardous. A better understanding of their incidence, causes, and outcomes could help inform preventive efforts. METHODS:We identified infants born $35 weeks' gestational age from 1995-2011 in Kaiser Permanente Northern California (n = 525 409) and examined the medical records of infants with a TSB $30 mg/dL to determine etiology and the occurrence of acute bilirubin encephalopathy. We reviewed inpatient and outpatient encounters through 2013 for evidence of sensorineural hearing loss (SNHL) or cerebral palsy (CP). RESULTS:We identified 47 infants with TSB $30 mg/dL (8.6 per 100 000 births). In 44 infants (94%), the hyperbilirubinemia occurred after the initial birth hospitalization. The etiology was not identified in 33 (70%). Glucose-6-phosphate dehydrogenase (G6PD) activity was measured in only 25 (53%) of whom 10 (40%) were deficient. Four children had acute bilirubin encephalopathy of whom 2 developed both CP and SNHL, and 1 developed isolated SNHL. These 3 infants all had G6PD deficiency and TSB .40 mg/dL. One additional 35-week infant with TSB 38.2 mg/dL had SNHL.CONCLUSIONS: Hazardous ($30 mg/dL) hyperbilirubinemia is a rare event. No etiology could be identified from the clinical record in most cases. G6PD deficiency was the leading cause of hazardous hyperbilirubinemia when an etiology was identified, but many were not tested. Chronic, bilirubin-induced neurotoxicity was uncommon and occurred only in the setting of additional risk factors and TSB values well over (.15 mg/dL)

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“…Although it is generally regarded as safe, 1, 2 the number needed to treat to prevent 1 infant from reaching exchange transfusion levels may be >1000, 3 and very few of those reaching exchange levels have adverse effects. [4][5][6][7][8] Thus, even rare adverse effects of phototherapy could warrant changes in treatment thresholds. 9 Concerns about a possible carcinogenic effect of neonatal phototherapy date back to the 1970s, when Speck and Rosenkranz 10 reported positive results on the Ames test for mutagenicity of blue light in salmonellae.…”

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confidence: 99%

Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California

et al. 2016

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OBJECTIVE: To investigate the association between neonatal phototherapy use and childhood cancer.METHODS: This retrospective cohort study included 499 621 children born at ≥35 weeks' gestation from 1995 to 2011 in Kaiser Permanente Northern California hospitals, who survived to hospital discharge and were followed ≥60 days. We obtained data on home and inpatient phototherapy, covariates, and cancer incidence from electronic records. We used propensity-adjusted Cox and Poisson models to control for confounding and unequal follow-up times.RESULTS: There were 60 children with a diagnosis of cancer among 39 403 exposed to phototherapy (25 per 100 000 person-years), compared with 651 of 460 218 unexposed children (18 per 100 000 person-years; incidence rate ratio [IRR] 1.4; P = .01). Phototherapy was associated with increased rates of any leukemia (IRR 2.1; P = .0007), nonlymphocytic leukemia (IRR 4.0; P = .0004), and liver cancer (IRR 5.2; P = .04). With adjustment for a propensity score that incorporated bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, associations were no longer statistically significant: Adjusted hazard ratios (95% confidence intervals) were 1.0 (0.7-1.6) for any cancer, 1.6 (0.8-3.5) for any leukemia, 1.9 (0.6-6.9) for nonlymphocytic leukemia, and 1.4 (0.2-12) for liver cancer. Upper limits of 95% confidence intervals for adjusted 10-year excess risk were generally <0.1% but reached 4.4% for children with Down syndrome. CONCLUSIONS:Although phototherapy use was associated with increased cancer rates (particularly nonlymphocytic leukemia), control for confounding variables eliminated or attenuated the associations. Nonetheless, the possibility of even partial causality suggests that avoiding unnecessary phototherapy may be prudent.

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Relation between serum bilirubin levels ≥450 μmol/L and bilirubin encephalopathy; a Danish population‐based study

Abstract: The incidence of infants with TsB ≥450 μmol/L was 45/100,000/year. Infants with a TsB ≥600 μmol/L had a substantial risk of developing acute advanced and chronic bilirubin encephalopathy, and the incidence of these conditions was 0.6 per 100,000.

Cited by 46 publications

References 18 publications

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Incidence, Etiology, and Outcomes of Hazardous Hyperbilirubinemia in Newborns

Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California

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