Neonatal Hyperbilirubinemia: Department of Family Medicine, Naval Hospital Camp Pendleton, Calif an Evidence-Based Approach (Dr
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ONLINE EXCLUSIVE Emma J. Pace, MD; Carina M. Brown, MD; Katharine C. DeGeorge, MD, MS Neonatal hyperbilirubinemia: Department of Family Medicine, Naval Hospital Camp Pendleton, Calif An evidence-based approach (Dr. Pace); Department of Family Medicine, University of Virginia, Charlottesville This review provides the latest advice on the screening (Drs. Brown and DeGeorge) and management of hyperbilirubinemia in term infants. [email protected] The authors reported no potential conflict of interest relevant to this article. ore than 60% of newborns appear clinically jaun- The views expressed in this pub- PRACTICE diced in the first few weeks of life,1 most often due lication are those of the authors RECOMMENDATIONS and do not reflect the official to physiologic jaundice. Mild hyperbilirubinemia ❯ Diagnose hyperbiliru- M policy or position of the peaks at Days 3 to 5 and returns to normal in the following Department of the Navy, the binemia in infants with 1 Department of Defense, or the weeks. However, approximately 10% of term and 25% of late bilirubin measured at >95th US government. preterm infants will undergo phototherapy for hyperbilirubi- percentile for age in hours. nemia in an effort to prevent acute bilirubin encephalopathy Do not use visual assessment 2 of jaundice for diagnosis as (ABE) and kernicterus. it may lead to errors. C Heightened vigilance to prevent these rare but devastating outcomes has made hyperbilirubinemia the most common ❯ Determine the threshold for cause of hospital readmission in infants in the United States3 initiation of phototherapy by applying serum bilirubin and and one with significant health care costs. This article sum- age in hours to the American marizes the evidence and recommendations for the screening, Academy of Pediatrics photo- evaluation, and management of hyperbilirubinemia in term therapy nomogram along a infants. risk curve assigned based on But first, we begin with a quick look at the causes of gestational age and neurotox- hyperbilirubinemia. icity risk factors (not major and minor risk factors for se- vere hyperbilirubinemia). C Causes of conjugated vs ❯ Make arrangements to unconjugated hyperbilirubinemia ensure that all infants are Bilirubin is generated when red blood cells break down and seen by a health care provider release heme, which is metabolized into biliverdin and then within 2 days of discharge to bilirubin. Unconjugated bilirubin binds to albumin in the (within 1 day if significant blood and is transported to hepatocytes where conjugation risk factors for development occurs, allowing it to be excreted through the gastrointesti- of severe hyperbilirubine- nal tract. In neonates, most of the conjugated bilirubin that mia are present). C reaches the gut is then unconjugated, resulting in its recircula- Strength of recommendation (SOR) tion. Additionally, neonates have an increased volume of red A Good-quality patient-oriented evidence blood cells and a slow conjugating system. These factors all B Inconsistent or limited-quality contribute to excess unconjugated bilirubin, which manifests patient-oriented evidence as physiologic, nonpathologic jaundice.4 TABLE 14-6 lists causes C Consensus, usual practice, of unconjugated hyperbilirubinemia. opinion, disease-oriented evidence, case series ❚ 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 hyperbiliru- E4 THE JOURNAL OF FAMILY PRACTICE | JANUARY/FEBRUARY 2019 | VOL 68, NO 1 TABLE 1 Causes of unconjugated hyperbilirubinemia in neonates4-6 Increased bilirubin Increased enterohepatic Decreased clearance Metabolic Inborn errors production circulation of unconjugated conditions of metabolism bilirubin Hemolysis (immune-mediated, Insufficient breast milk/ Prematurity Hypothyroidism Galactosemia heritable) feeding G6PD deficiency Hypopituitarism Gilbert syndrome Extravasation Pyloric stenosis Crigler-Najjar syndrome (cephalohematoma) Bowel obstruction (I and II) Polycythemia Ileus Breast milk jaundice due Sepsis to other bilirubin UGT1A1 mutations Disseminated intravascular coagulation Tyrosinemia Macrosomic infants of Hypermethioninemia diabetic mothers G6PD, glucose-6-phosphate dehydrogenase; UGT1A1, uridine diphosphate-glucuronosyltransferase, family 1, polypeptide A1. binemia. Infants found to have conjugated ❚ The Bhutani curve11 is a widely used, hyperbilirubinemia should undergo an ad- validated nomogram based on pre-discharge ditional work-up to determine the cause hour-specific serum bilirubin measurements. and identify potential complications of this (Go to http://pediatrics.aappublications.org/ disease.8 content/114/1/297 and see Figure 2.) It is the Given that the differential for conjugated most reliable way to assess the risk for subse- hyperbilirubinemia is so broad and that it is quent development of significant hyperbili- often associated with severe disease requir- rubinemia requiring phototherapy.9 As such, ing complicated and invasive treatments, it is the basis for several online calculators infants with conjugated hyperbilirubinemia and apps such as BiliTool (bilitool.org). should be referred to a pediatric tertiary care ❚ An alternative nomogram developed facility with pediatric gastroenterologists, in- by Varvarigou et al12 is available for predict- fectious disease specialists, and surgeons.7 ing significant hyperbilirubinemia based on transcutaneous bilirubin assessment. (Go to https://pdfs.semanticscholar.org/a9a6/5a9 What puts newborns 88dba7a3442bcebc149ad5aea5e3c35d5.pdf at risk? and see Figure 3.) The American Academy of Major and minor risk factors for the develop- Pediatrics (AAP) supports the use of either ment of severe hyperbilirubinemia in well bilirubin assessment for the screening and newborns ≥35 weeks’ gestation are listed in diagnosis of hyperbilirubinemia in infants TABLE 3.9 Those that carry the highest risk ≥35 weeks’ gestation.9 include gestational age <38 weeks, having a ❚ Neurotoxicity risk factors. It is im- sibling who required phototherapy, visible portant to differentiate the major and minor jaundice by the time of discharge, and ex- risk factors for severe hyperbilirubinemia clusive breastfeeding.9 Several more recent from neurotoxicity risk factors, also listed in cohort studies, however, suggest that breast- TABLE 3.9 Neurotoxicity risk factors are indica- feeding may not be a significant risk factor.10 tive of conditions that may affect albumin The more risk factors present, the higher the binding of bilirubin and are thought to lower risk. Infants who are formula fed, age ≥41 ges- the threshold at which bilirubin may cross tational weeks, or have no major or minor risk the blood-brain barrier and render the brain factors have a very low likelihood of develop- more susceptible to damage from bilirubin. ing severe hyperbilirubinemia.9 These neurotoxicity risk factors should be MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE E5 TABLE 2 Causes of conjugated hyperbilirubinemia7 Intrahepatic Extrahepatic Alagille syndrome Biliary atresia (surgical emergency) Hepatitis B infection Mucous plugging Congenital infections Choledochal cyst • Rubella Caroli disease • Cytomegalovirus • Herpes simplex infection • Toxoplasmosis applied to the AAP phototherapy nomogram ❚ The total cost of testing is lower with (see Figure 3 at pediatrics.aappublications. TcB ($4-$15 per patient17) than with TSB org/content/114/1/297) to determine the when the cost of supplies and personnel are threshold for initiation of phototherapy in considered.24 Although more recent evidence infants with hyperbilirubinemia.9 suggests that TcB is an acceptable way to Hyperbilirubi- Few investigators have attempted to measure bilirubin in premature infants, no nemia is the define risk factors for the development of professional society currently recommends most common poor neurologic outcomes associated with the use of TcB for the diagnosis of hyperbili- cause of hospital hyperbilirubinemia. Evidence to date has rubinemia in infants25 <35 weeks’ gestation. readmission of not allowed the determination of a specific infants in the bilirubin level at which subsequent develop- United States. ment of kernicterus occurs.9 The limited data Screening recommendations available suggest a poor correlation between lack consensus TSB level and bilirubin-induced neurologic There is a lack of consensus among profes- dysfunction.13 sional societies on appropriate screening for (For more on kernicterus, as well as ABE neonatal hyperbilirubinemia, likely due to and bilirubin-induced neurologic dysfunc- limited available data, necessitating expert- tion [BIND], see “Why do we worry about hy- driven recommendations. perbilirubinemia?”9,14-16 on page E9.) The AAP recommends universal screen- ing of infants ≥35 weeks’ gestation prior to discharge with measurement of TSB/TcB Diagnosis relies on TSB and/or TcB and/or clinical assessment.9 The Canadian TSB measurement is the traditional and most Pediatric Society recommends universal widely used method for screening and diag- screening with TSB/TcB measurement in all nosing neonatal hyperbilirubinemia, but the infants in the first 72 hours of life.26 blood draw is invasive and carries a risk (albeit The US Preventative Services Task Force, low) of infection and anemia.17 Transcutane- however, found insufficient evidence to rec- ous bilirubin (TcB) assessment is a noninvasive