Outcomes among Newborns with Total Serum Bilirubin Levels of 25 mg per Deciliter or More

Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States
New England Journal of Medicine (Impact Factor: 55.87). 06/2006; 354(18):1889-900. DOI: 10.1056/NEJMoa054244
Source: PubMed


The neurodevelopmental risks associated with high total serum bilirubin levels in newborns are not well defined.
We identified 140 infants with neonatal total serum bilirubin levels of at least 25 mg per deciliter (428 micromol per liter) and 419 randomly selected controls from a cohort of 106,627 term and near-term infants born from 1995 through 1998 in Kaiser Permanente hospitals in northern California. Data on outcomes were obtained from electronic records, interviews, responses to questionnaires, and neurodevelopmental evaluations that had been performed in a blinded fashion.
Peak bilirubin levels were between 25 and 29.9 mg per deciliter (511 micromol per liter) in 130 of the newborns with hyperbilirubinemia and 30 mg per deciliter (513 micromol per liter) or more in 10 newborns; treatment involved phototherapy in 136 cases and exchange transfusion in 5. Follow-up data to the age of at least two years were available for 132 of 140 children with a history of hyperbilirubinemia (94 percent) and 372 of 419 controls (89 percent) and included formal evaluation at a mean (+/-SD) age of 5.1+/-0.12 years for 82 children (59 percent) and 168 children (40 percent), respectively. There were no cases of kernicterus. Neither crude nor adjusted scores on cognitive tests differed significantly between the two groups; on most tests, 95 percent confidence intervals excluded a 3-point (0.2 SD) decrease in adjusted scores in the hyperbilirubinemia group. There was no significant difference between groups in the proportion of children with abnormal neurologic findings on physical examination or with documented diagnoses of neurologic abnormalities. Fourteen of the children with hyperbilirubinemia (17 percent) had "questionable" or abnormal findings on neurologic examination, as compared with 48 controls (29 percent; P=0.05; adjusted odds ratio, 0.47; 95 percent confidence interval, 0.23 to 0.98; P=0.04). The frequencies of parental concern and reported behavioral problems also were not significantly different between the two groups. Within the hyperbilirubinemia group, those with positive direct antiglobulin tests had lower scores on cognitive testing but not more neurologic or behavioral problems.
When treated with phototherapy or exchange transfusion, total serum bilirubin levels in the range included in this study were not associated with adverse neurodevelopmental outcomes in infants born at or near term.

Download full-text


Available from: Yvonne Wu,
  • Source
    • "The encephalopathy frequently evolves into kernicterus. Previous studies have revealed that the neonatal auditory system is very sensitive to high level of serum bilirubin, and can be selectively damaged in hyperbilirubinemia [4] [9] [12] [13] [19] [40]. BAER wave V originates from the rostral regions of the auditory brainstem [14] [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: We studied maximum length sequence brainstem auditory evoked response in term neonates with hyperbilirubinemia to further our understanding of hyperbilirubinemia on the neonatal auditory brainstem and to determine if maximum length sequence technique improves detection of brainstem auditory impairment due to bilirubin neurotoxicity. Methods: Maximum length sequence brainstem auditory evoked response was recorded and analysed shortly after confirming total serum bilirubin levels greater than 15mg/dL in fifty-seven term neonates with hyperbilirubinemia. Results: Most wave latencies and interpeak intervals in maximum length sequence brainstem auditory evoked response in the neonates with hyperbilirubinemia were correlated with the level of total serum bilirubin at some or most click rates used. Compared with age-matched normal term controls, wave V latency in these neonates was increased significantly at all 91-910/s click rates (p<0.05-0.001). The I-V and I-III interpeak intervals were also increased significantly at all these rates, and the III-V interval increased at 227-910/s clicks (p<0.05-0.001). The differences between the neonates with hyperbilirubinemia and the controls were more significant at higher than at lower click rates. The slopes of wave V latency-rate function and I-V and III-V interval-rate functions were all significantly increased. By comparison, the abnormalities in conventional BAER were less significant, with only I-III and I-V intervals were increased (both p<0.05). Conclusions: Functional status of the auditory brainstem is impaired in neonatal hyperbilirubinemia. Maximum length sequence technique at high click rates improves detection of bilirubin neurotoxicity to the neonatal auditory brainstem, particularly for the more rostral regions.
    Brain & development 04/2013; 36(3). DOI:10.1016/j.braindev.2013.03.003 · 1.88 Impact Factor
  • Source
    • "While <10% of infants with NNJ in most parts of the developed world will eventually have clinically significant NNJ, the burden is likely to be substantially higher in Africa, South Asia and the Middle East, where glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent (WHO 1989; Cappellini & Fiorelli 2008). Early detection and prompt treatment with phototherapy or EBT are effective in curtailing the adverse consequences of severe NNJ (Newman et al. 2006; American Academy of Pediatrics (AAP) 2004). Similarly, population screening of newborns for G-6-PD deficiency facilitates early identification and management of pathological jaundice (WHO 1989; Yu et al. 1992; Muzaffer 2005; Pao et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To establish the incidence, correlates and hearing screening outcomes of infants with severe neonatal jaundice in Nigeria. Community-based study in which all infants attending Bacille Calmette-Guérin immunisation clinics in inner-city Lagos were enrolled into a universal hearing screening programme during which correlates of severe neonatal jaundice (requiring phototherapy and/or exchange blood transfusion) were explored with multivariable logistic regression. Of the 5262 infants enrolled, only 48.7% were born in hospitals although almost all mothers (97.9%) attended antenatal clinics. 6.7% had a history of neonatal jaundice of whom 5.5% (95% CI:4.9-6.2) received phototherapy and 1.9% (95% CI:1.5-2.3) had an exchange blood transfusion. Factors independently associated with severe neonatal jaundice were maternal religion, occupation, use of herbal preparations during pregnancy, infant's gender, weight at screening, multiple gestation and place of birth. All but two infants with severe neonatal jaundice were exclusively breast-fed. Of those who failed the hearing tests, 17.3% were treated with phototherapy and 11.3% had an exchange blood transfusion. At least 8.9% of infants requiring phototherapy and 17.3% of those requiring exchange blood transfusion were at risk of sensorineural hearing loss. Severe neonatal jaundice is a significant condition associated with modifiable risk factors in this population. Policy initiatives for prevention, early detection followed by appropriate and timely intervention are urgently needed to reduce the disease burden.
    Tropical Medicine & International Health 02/2009; 14(3):301-10. DOI:10.1111/j.1365-3156.2009.02223.x · 2.33 Impact Factor
  • Source
    • "The core clinical features of UCB encephalopathy may range from mild mental retardation and subtle cognitive disturbances to deafness and severe cerebral palsy, seizure or death from kernicterus [2], [5]. Data from several prospective controlled studies have revealed cognitive disturbances in children with elevated levels of UCB in the infant period [6]–[9]. Hence, considerable interest is now focused on understanding the molecular mechanisms by which UCB exerts such neurodevelopmental abnormality in order to generate effective therapeutic strategies targeting these pathways for treatment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Jaundice is one of the most common problems encountered in newborn infants, due to immaturity of hepatic conjugation and transport processes for bilirubin. Although the majority of neonatal jaundice is benign, some neonates with severe hyperbilirubinemia develop bilirubin encephalopathy or kernicterus. Accumulation of unconjugated bilirubin (UCB) in selected brain regions may result in temporary or permanent impairments of auditory, motor, or cognitive function; however, the molecular mechanisms by which UCB elicits such neurotoxicity are still poorly understood. The present study is undertaken to investigate whether prolonged exposure of rat organotypic hippocampal slice cultures to UCB alters the induction of long-term synaptic plasticity. Using electrophysiological recording techniques, we find that exposure of hippocampal slice cultures to clinically relevant concentrations of UCB for 24 or 48 h results in an impairment of CA1 long-term potentiation (LTP) and long-term depression (LTD) induction in a time- and concentration-dependent manner. Hippocampal slice cultures stimulated with UCB show no changes in the secretion profiles of the pro-inflammatory cytokines, interleukin-1beta and tumor necrosis factor-alpha, or the propidium ioide uptake. UCB treatment produced a significant decrease in the levels of NR1, NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptors through a calpain-mediated proteolytic cleavage mechanism. Pretreatment of the hippocampal slice cultures with NMDA receptor antagonist or calpain inhibitors effectively prevented the UCB-induced impairment of LTP and LTD. Our results indicate that the proteolytic cleavage of NMDA receptor subunits by calpain may play a critical role in mediating the UCB-induced impairment of long-term synaptic plasticity in the hippocampus. These observations provide new insights into the molecular mechanisms underlying UCB-induced impairment of hippocampal synaptic plasticity which, in turn, might provide opportunities for the development of novel therapeutic strategies that targets these pathways for treatment.
    PLoS ONE 02/2009; 4(6):e5876. DOI:10.1371/journal.pone.0005876 · 3.23 Impact Factor
Show more