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Extreme neonatal hyperbilirubinemia and kernicterus spectrum disorder in Denmark during the years 2000–2015

Journal of Perinatology volume 40, pages 194–202 (2020)Cite this article

Subjects

Abstract

Objective

To determine the incidence and etiology of extreme neonatal hyperbilirubinemia, defined as total serum bilirubin (TSB) ≥450 µmol/L, and kernicterus spectrum disorder (KSD) in Denmark between 2000 and 2015.

Study design

We identified all infants born between 01.01.2000 and 31.12.2015 with TSB ≥450 µmol/L, ratio of conjugated to TSB <0.30, gestational age ≥35 weeks, and postnatal age ≤4 weeks, using Danish hospitals’ laboratory databases.

Result

We included 408 infants. The incidence of extreme neonatal hyperbilirubinemia among infants with gestational age ≥35 weeks was 42/100,000 during the study period with a seemingly decreasing incidence between 2005 and 2015. Twelve of the 408 infants developed KSD, (incidence 1.2/100,000) Blood type ABO isohemolytic disease was the most common explanatory etiology.

Conclusions

Our study stresses the importance of a systematic approach to neonatal jaundice and ongoing surveillance of extreme neonatal hyperbilirubinemia and KSD.

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References

  1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.

    Google Scholar 

  2. Volpe J Bilirubin and Brain Injury. Neurology of the Newborn. 5. Edition ed. Philadelphia: Saunders Elsevier; 2008. p. 619–51.

  3. Hansen TW, Nietsch L, Norman E, Bjerre JV, Hascoet JM, Mreihil K, et al. Reversibility of acute intermediate phase bilirubin encephalopathy. Acta Paediatr. 2009;98:1689–94.

    PubMed  Google Scholar 

  4. Le Pichon J, Riordan S, Watchko J, Shapiro S. The neurological sequelae of neonatal hyperbilirubinemia: definitions, diagnosis and treatment of the kernicterus spectrum disorders (KSDs). Curr Pediatr Rev. 2017;13:199–209.

    PubMed  Google Scholar 

  5. Iskander I, Gamaleldin R, El Houchi S, El Shenawy A, Seoud I, El Gharbawi N, et al. Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy. Pediatrics. 2014;134:1330–9.

    Google Scholar 

  6. Manning D, Todd P, Maxwell M, Jane Platt M. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child. 2007;92:342–6.

    Google Scholar 

  7. Sgro M, Campbell D, Barozzino T, Shah V. Acute neurological findings in a national cohort of neonates with severe neonatal hyperbilirubinemia. J Perinatol. 2011;31:392–6.

    CAS  PubMed  Google Scholar 

  8. Weng Y, Chiu Y, Cheng S, Hsieh M. Risk assessment for adverse outcome in term and late preterm neonates with bilirubin values of 20 mg/dL or more. Am J Perinatol. 2011;28:405–12.

    PubMed  Google Scholar 

  9. Ebbesen F, Bjerre JV, Vandborg PK. Relation between serum bilirubin levels ≥450 µmol/L and bilirubin encephalopathy; a Danish population-based study. Acta Paediatr. 2012;101:384–9.

    CAS  PubMed  Google Scholar 

  10. Ebbesen F. Recurrence of kernicterus in term and near-term infants in Denmark. Acta Paediatr. 2000;89:1213–7.

    CAS  PubMed  Google Scholar 

  11. Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR, et al. Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta Paediatr. 2005;94:59–64.

    CAS  PubMed  Google Scholar 

  12. Bjerre JV, Petersen JR, Ebbesen F. Surveillance of extreme hyperbilirubinaemia in Denmark. A method to identify the newborn infants. Acta Paediatr. 2008;97:1030–4.

    CAS  PubMed  Google Scholar 

  13. Vandborg PK, Hansen BM, Greisen G, Mathiasen R, Kasper F, Ebbesen F. Follow-up of extreme neonatal hyperbilirubinaemia in 5- to 10-year-old children: a Danish population-based study. Dev Med Child Neurol. 2015;57:378–84.

    PubMed  Google Scholar 

  14. Vandborg PK, Hansen BM, Greisen G, Jepsen M, Ebbesen F. Follow-up of neonates with total serum bilirubin levels ≥25 mg/dL: a Danish population-based study. Pediatrics. 2012;130:61–6.

    PubMed  Google Scholar 

  15. Rosenthal P. Direct bilirubin measurements in term newborns-a waste of time and money? J Pediatr Gastroenterol Nutr. 1992;15:220–1.

    CAS  PubMed  Google Scholar 

  16. Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics. 2003;112:1256–63.

    PubMed  Google Scholar 

  17. Herschel M, Karrison T, Wen M, Caldarelli L, Baron B. Isoimmunization is unlikely to be the cause of hemolysis in ABO-incompatible but direct antiglobulin test-negative neonates. Pediatrics. 2002;110:127–30.

    PubMed  Google Scholar 

  18. Sgro M, Kandasamy S, Shah V, Ofner M, Campbell D. Severe neonatal hyperbilirubinemia decreased after the 2007 Canadian guidelines. J Pediatr. 2016;171:43–7.

    PubMed  Google Scholar 

  19. McGillivray A, Polverino J, Badawi N, Evans N. Prospective surveillance of extreme neonatal hyperbilirubinemia in Australia. J Pediatr. 2016;168:82–7.

    PubMed  Google Scholar 

  20. Gotink MJ, Benders MJ, Lavrijsen SW, Rodrigues Pereira R, Hulzebos CV, Dijk PH. Severe neonatal hyperbilirubinemia in the Netherlands. Neonatology. 2013;104:137–42.

    PubMed  Google Scholar 

  21. Bhutani VK, Meng NF, Knauer Y, Danielsen BH, Wong RJ, Stevenson DK, et al. Extreme hyperbilirubinemia and rescue exchange transfusion in California from 2007 to 2012. J Perinatol. 2016;36:853–7.

    CAS  PubMed  Google Scholar 

  22. Zoubir S, Mieth R, Berrut S, Roth-Kleiner M. Swiss Paediatric SU. Incidence of severe hyperbilirubinaemia in Switzerland: a nationwide population-based prospective study. Arch Dis Child. 2011;96:310–1.

    Google Scholar 

  23. Sgro M, Campbell D, Kandasamy S, Shah V. Incidence of chronic bilirubin encephalopathy in Canada, 2007–2008. Pediatrics. 2012;130:886–90.

    Google Scholar 

  24. Kuzniewicz M, Wickremasinghe A, Wu Y, McCulloch C, Walsh E, Wi S, et al. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatrics. 2014;134:504–9.

    PubMed  Google Scholar 

  25. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks' gestation)—Summary. Paediatr Child Health. 2007;12:401–7.

  26. Kaplan M, Merlob P, Regev R. Israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus. J Perinatol. 2008;28:389–97.

    CAS  PubMed  Google Scholar 

  27. Mah M, Clark S, Akhigbe E, Englebright J, Frye D, Meyers J, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics. 2010;125:1143–8.

    Google Scholar 

  28. Eggert L, Wiedmeier S, Wilson J, Christensen R. The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006;117:855–62.

    Google Scholar 

  29. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics. 2009;124:1031–9.

    PubMed  PubMed Central  Google Scholar 

  30. Alkalay A, Bresee C, Simmons C. Decreased neonatal jaundice readmission rate after implementing hyperbilirubinemia guidelines and universal screening for bilirubin. Clin Pediatr. 2010;49:830–3.

    Google Scholar 

  31. Kaplan M, Hammerman C. The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective. J Perinatol. 2009;29 Suppl 1:46–52.

    Google Scholar 

  32. Varela-Lema L, Paz-Valinas L, Atienza-Merino G, Zubizarreta-Alberdi R, Villares R, López-García M. Appropriateness of newborn screening for classic galactosaemia: a systematic review. J Inherit Metab Dis. 2016;39:633–49.

    CAS  PubMed  Google Scholar 

  33. Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot USA kernicterus registry (1992 to 2004). J Perinatol. 2009;29 Suppl 1:25–45.

    Google Scholar 

  34. Christensen RD, Lambert DK, Henry E, Eggert LD, Yaish HM, Reading NS, et al. Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis. 2013;50:105–9.

    CAS  PubMed  Google Scholar 

  35. Christensen RD, Nussenzveig RH, Yaish HM, Henry E, Eggert LD, Agarwal AM. Causes of hemolysis in neonates with extreme hyperbilirubinemia. J Perinatol. 2014;34:616–9.

    CAS  PubMed  Google Scholar 

  36. Christensen RD, Agarwal AM, George TI, Bhutani VK, Yaish HM. Acute neonatal bilirubin encephalopathy in the State of Utah 2009–18. Blood Cells Mol Dis. 2018;72:10–13.

    PubMed  Google Scholar 

  37. Hansen T. Acute management of extreme neonatal jaundice-the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta Paediatr. 2008;86:843–6.

    Google Scholar 

  38. Danish Paediatric Society. Guideline for treatment of neonatal hyperbilirubinemia. 2012. http://www.paediatri.dk/images/pdf_filer/dps_vejl/neo/008neo.pdf.

  39. Katar S, Akay H, Taskesen M, Devecioglu C. Clinical and cranial magnetic resonance imaging (MRI) findings of 21 patients with serious hyperbilirubinemia. J Child Neurol. 2008;23:415–7.

    PubMed  Google Scholar 

  40. Yilmaz Y, Alper G, Kiliçoglu G, Celik L, Karadeniz L, Yilmaz-Degirmenci S. Magnetic resonance imaging findings in patients with severe neonatal indirect hyperbilirubinemia. J Child Neurol. 2001;16:452–5.

    CAS  PubMed  Google Scholar 

  41. Harris MC, Bernbaum JC, Polin JR, Zimmerman R, Polin RA. Developmental follow-up of breastfed term and near-term infants with marked hyperbilirubinemia. Pediatrics. 2001;107:1075–80.

    CAS  PubMed  Google Scholar 

  42. Johnson L, Brown A, Bhutani V. BIND—a clinical score for bilirubin induced neurologic dysfunction in newborns. Pediatrics. 1999;104:746–7.

    Google Scholar 

  43. El Houchi S, Iskander I, Gamaleldin R, El Shenawy A, Seoud I, Abou-Youssef H, et al. Prediction of 3- to 5-Month outcomes from signs of acute bilirubin toxicity in newborn infants. J Pediatr. 2017;183:51–5.

    CAS  PubMed  Google Scholar 

  44. Bhutani V, Johnson L, Jeffrey Maisels M, Newman T, Phibbs C, Stark A, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004;24:650–62.

    PubMed  Google Scholar 

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Acknowledgements

We would like to thank all biochemical, pediatric, radiological, and audiological departments throughout Denmark for their great help in collecting the material.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark

    Mette Line Donneborg, Pernille Kure Vandborg & Finn Ebbesen

  2. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Mette Line Donneborg & Finn Ebbesen

  3. Department of Pediatrics, Herlev Hospital, Copenhagen, Denmark

    Bo Moelholm Hansen

  4. Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark

    María Rodrigo-Domingo

  5. Psychiatry, Aalborg University Hospital, Aalborg, Denmark

    María Rodrigo-Domingo

Authors
  1. Mette Line Donneborg
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Correspondence to Mette Line Donneborg.

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The authors declare that they have no conflict of interest.

Ethics

The study was approved by the Danish Data Protection Agency, 2008-58-0028/ 2016-71, and the Danish Health Authority, 3-3013-1624/1.

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Donneborg, M.L., Hansen, B.M., Vandborg, P.K. et al. Extreme neonatal hyperbilirubinemia and kernicterus spectrum disorder in Denmark during the years 2000–2015. J Perinatol 40, 194–202 (2020). https://doi.org/10.1038/s41372-019-0566-8

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