Neonatal hyperbilirubinemia: An evidence-based approach

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Applied Evidence

Neonatal hyperbilirubinemia: An evidence-based approach

J Fam Pract. 2019 January;68(1):E4-E11

By

Emma J. Pace, MD

Carina M. Brown, MD

Katharine C. DeGeorge, MD, MS

This review provides the latest advice on the screening and management of hyperbilirubinemia in term infants.

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PRACTICE RECOMMENDATIONS

› Diagnose hyperbilirubinemia in infants with bilirubin measured at >95th percentile for age in hours. Do not use visual assessment of jaundice for diagnosis as it may lead to errors. C

› Determine the threshold for initiation of phototherapy by applying serum bilirubin and age in hours to the American Academy of Pediatrics phototherapy nomogram along a risk curve assigned based on gestational age and neurotoxicity risk factors (not major and minor risk factors for severe hyperbilirubinemia). C

› Make arrangements to ensure that all infants are seen by a health care provider within 2 days of discharge (within 1 day if significant risk factors for development of severe hyperbilirubinemia are present). C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

References

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2. Sarici SU, Serdar MA, Korkmaz A, et al. Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns. Pediatrics. 2004;113:775-780.

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4. Maisels MJ. Neonatal jaundice. Pediatr Rev. 2006;27:443-454.

5. Gholitabar M, McGuire H, Rennie J, et al. Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia. Cochrane Database Syst Rev. 2012;12:CD009017.

6. Maruo Y, Morioka Y, Fujito H, et al. Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr. 2014;165:36-41.e1.

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9. 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.

10. Bertini G, Dani C, Tronchin M, et al. Is breastfeeding really favoring early neonatal jaundice? Pediatrics. 2001;107:E41.

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14. Wisnowski JL, Panigrahy A, Painter MJ, et al. Magnetic resonance imaging of bilirubin encephalopathy: current limitations and future promise. Semin Perinatol. 2014;38:422-428.

15. Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010;15:157-163.

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More than 60% of newborns appear clinically jaundiced in the first few weeks of life,¹ most often due to physiologic jaundice. Mild hyperbilirubinemia peaks at Days 3 to 5 and returns to normal in the following weeks.¹ However, approximately 10% of term and 25% of late preterm infants will undergo phototherapy for hyperbilirubinemia in an effort to prevent acute bilirubin encephalopathy (ABE) and kernicterus.²

Heightened vigilance to prevent these rare but devastating outcomes has made hyperbilirubinemia the most common cause of hospital readmission in infants in the United States³ and one with significant health care costs. This article summarizes the evidence and recommendations for the screening, evaluation, and management of hyperbilirubinemia in term infants.

But first, we begin with a quick look at the causes of hyperbilirubinemia.

Causes of conjugated vs unconjugated hyperbilirubinemia

Bilirubin is generated when red blood cells break down and release heme, which is metabolized into biliverdin and then to bilirubin. Unconjugated bilirubin binds to albumin in the blood and is transported to hepatocytes where conjugation occurs, allowing it to be excreted through the gastrointestinal tract. In neonates, most of the conjugated bilirubin that reaches the gut is then unconjugated, resulting in its recirculation. Additionally, neonates have an increased volume of red blood cells and a slow conjugating system. These factors all contribute to excess unconjugated bilirubin, which manifests as physiologic, nonpathologic jaundice.⁴TABLE 1^4-6 lists causes of unconjugated hyperbilirubinemia.

Elevated conjugated hyperbilirubinemia (conjugated bilirubin level ≥20% of total serum bilirubin [TSB]) is always pathologic and occurs due to intrahepatic or extrahepatic obstruction. TABLE 2⁷ lists causes of conjugated hyperbilirubinemia. Infants found to have conjugated hyperbilirubinemia should undergo an additional work-up to determine the cause and identify potential complications of this disease.⁸

Given that the differential for conjugated hyperbilirubinemia is so broad and that it is often associated with severe disease requiring complicated and invasive treatments, infants with conjugated hyperbilirubinemia should be referred to a pediatric tertiary care facility with pediatric gastroenterologists, infectious disease specialists, and surgeons.⁷

What puts newborns at risk?

Major and minor risk factors for the development of severe hyperbilirubinemia in well newborns ≥35 weeks’ gestation are listed in TABLE 3.⁹ Those that carry the highest risk include gestational age <38 weeks, having a sibling who required phototherapy, visible jaundice by the time of discharge, and exclusive breastfeeding.⁹ Several more recent cohort studies, however, suggest that breastfeeding may not be a significant risk factor.¹⁰ The more risk factors present, the higher the risk. Infants who are formula fed, age ≥41 gestational weeks, or have no major or minor risk factors have a very low likelihood of developing severe hyperbilirubinemia.⁹

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