What is the appropriate workup and treatment for hyperbilirubinemia in newborns, children, and adults?

Hyperbilirubinemia: Workup and Treatment Across Age Groups

Newborns (≥35 weeks gestation)

Initial Assessment and Measurement

Measure total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) immediately on any jaundiced newborn, particularly if jaundice appears in the first 24 hours or seems excessive for age. 1, 2

• Never rely on visual estimation alone—this leads to dangerous errors, especially in darkly pigmented infants 1, 3
• Interpret all bilirubin levels according to the infant's exact age in hours (not days) using hour-specific nomograms 1, 3
• Plot TSB values on the Bhutani nomogram to determine risk zone (low, intermediate, or high risk for severe hyperbilirubinemia) 1

Risk Stratification

Assess for major risk factors that dramatically increase kernicterus risk:

• Hemolytic disease (ABO/Rh incompatibility with positive Coombs test, G6PD deficiency—which causes 31.5% of kernicterus cases) 1, 2
• Jaundice in first 24 hours 1
• Gestational age 35-36 weeks 1
• Cephalohematoma or significant bruising 1
• Exclusive breastfeeding with poor intake and excessive weight loss 1, 3
• Previous sibling who received phototherapy 1
• East Asian race (increased risk) vs. Black race (decreased risk) 1, 2

Laboratory Workup

For jaundice in first 24 hours or rapidly rising bilirubin:

• Blood type and Coombs test (if not obtained from cord blood) 1
• Complete blood count with smear 1, 3
• Direct/conjugated bilirubin 1, 3
• Reticulocyte count 1, 3
• G6PD testing (especially in Mediterranean, Middle Eastern, African, or Asian infants) 1, 3

For jaundice persisting ≥3 weeks:

• Total and direct bilirubin to evaluate for cholestasis 1
• Urinalysis and urine culture 1
• Newborn thyroid and galactosemia screening results 1

Treatment Thresholds

Phototherapy initiation (for term infants without risk factors):

• Age 25-48 hours: TSB ≥15 mg/dL (257 μmol/L) 4
• Age 49-72 hours: TSB ≥18 mg/dL (308 μmol/L) 4
• Age >72 hours: TSB ≥20 mg/dL (342 μmol/L) 4
• Lower thresholds apply for infants with gestational age <38 weeks, hemolytic disease, or albumin <3.0 g/dL 3

For a 3-day-old with TSB 17.5 mg/dL (289 μmol/L):

• This is above the 95th percentile and approaching phototherapy threshold 2
• Initiate phototherapy immediately if risk factors present 2, 3
• Recheck TSB within 4-24 hours depending on trajectory and risk factors 2
• Within 4-12 hours if hemolysis suspected or rapid rise 2

Phototherapy Protocol

When phototherapy is initiated:

• Feed every 2-3 hours (breast milk or formula) to maintain hydration 3
• Continue breastfeeding during phototherapy when possible 3
• Supplement with formula or expressed breast milk if weight loss >12% or dehydration present 3
• Recheck TSB to verify efficacy based on initial level 2, 3
• Discontinue when TSB falls below 13-14 mg/dL 3
• Consider rebound check 24 hours after stopping, especially if hemolytic disease 3

Emergency Interventions

TSB ≥25 mg/dL (428 μmol/L) is a medical emergency:

• Immediate hospital admission for intensive phototherapy 3
• Type and crossmatch for possible exchange transfusion 3
• Administer IV immunoglobulin 0.5-1 g/kg over 2 hours for isoimmune hemolytic disease if TSB rising despite intensive phototherapy 3
• Exchange transfusion performed only in NICU by trained personnel with full monitoring 3

Discharge Planning and Follow-up

Before discharge, every newborn requires risk assessment:

• Predischarge TSB or TcB measurement plotted on nomogram AND/OR clinical risk factor assessment 1
• Infants discharged before 72 hours need particularly careful assessment 1

Follow-up timing:

• Within 1-2 days if discharged before bilirubin peaks (typically days 3-5 in term infants) 2
• Within 24 hours for infants with bilirubin near treatment thresholds 2
• Provide parents verbal and written information about jaundice monitoring and when to seek care 2

Critical Pitfalls to Avoid

• Do NOT subtract direct bilirubin from total bilirubin when making treatment decisions 3
• Do NOT discharge without ensuring appropriate follow-up, especially if risk factors present 2
• Do NOT use visual assessment alone—always measure bilirubin levels 2, 3

Children and Adults

The provided evidence focuses exclusively on neonatal hyperbilirubinemia. For older children and adults, the workup differs fundamentally:

Initial approach requires determining if hyperbilirubinemia is:

• Unconjugated (indirect): Suggests hemolysis, Gilbert syndrome, or Crigler-Najjar syndrome
• Conjugated (direct >20% of total): Indicates hepatobiliary disease requiring evaluation for cholestasis, hepatitis, biliary obstruction, or infiltrative liver disease

Essential workup includes:

• Fractionated bilirubin (direct vs. indirect)
• Complete blood count with smear and reticulocyte count
• Liver function tests (AST, ALT, alkaline phosphatase, albumin)
• Hepatitis serologies
• Abdominal imaging (ultrasound or CT) if conjugated hyperbilirubinemia
• Additional testing based on pattern (hemolysis workup, autoimmune markers, genetic testing)

Treatment depends entirely on the underlying cause identified through this workup, ranging from observation for Gilbert syndrome to urgent intervention for biliary obstruction or acute liver failure.