What is the differential diagnosis (DDX) for jaundice noted on the second day of life?

Differential Diagnosis of Jaundice on Day 2 of Life

Jaundice appearing on the second day of life is pathological and requires immediate evaluation, as physiological jaundice typically does not manifest until day 3-4 of life.

Critical Timing Consideration

Jaundice noted on day 2 of life falls outside the normal timeline for physiological jaundice and demands urgent investigation to identify potentially serious underlying conditions that could lead to kernicterus or indicate life-threatening disease 1.

Primary Differential Diagnoses

Hemolytic Causes (Most Common for Early Jaundice)

• ABO incompatibility - occurs when maternal blood type is O and infant is A or B 1
• Rh incompatibility - maternal Rh-negative with inadequate RhoGAM prophylaxis 1
• G6PD deficiency - particularly in infants of Mediterranean, African, or Asian descent 1
• Hereditary spherocytosis - family history of anemia or splenectomy 1
• Other red blood cell enzyme defects - pyruvate kinase deficiency 1

Infectious Etiologies

• Sepsis - bacterial infection causing hemolysis and hepatic dysfunction 2, 1
• TORCH infections - toxoplasmosis, rubella, CMV, herpes, syphilis causing conjugated hyperbilirubinemia 1
• Urinary tract infection - can present with unconjugated hyperbilirubinemia 1

Metabolic/Genetic Disorders

• Crigler-Najjar syndrome - severe unconjugated hyperbilirubinemia due to UGT1A1 deficiency 1
• Galactosemia - presents with jaundice, hepatomegaly, and reducing substances in urine 1
• Hypothyroidism - prolonged jaundice with poor feeding and hypotonia 1

Biliary Obstruction (Conjugated Hyperbilirubinemia)

• Biliary atresia - though typically presents later, can manifest early 3
• Choledochal cyst - congenital bile duct malformation 3
• Neonatal hepatitis - idiopathic giant cell hepatitis 3

Other Causes

• Cephalohematoma or significant bruising - increased bilirubin load from blood resorption 1
• Polycythemia - increased red blood cell breakdown 1
• Breast milk jaundice - though typically appears later (after day 4-5) 1

Immediate Diagnostic Approach

Laboratory Evaluation (First Priority)

• Total and fractionated (direct/conjugated) bilirubin - essential to differentiate unconjugated vs conjugated hyperbilirubinemia 4, 3
• Complete blood count with smear - evaluate for hemolysis, spherocytes, or infection 4, 1
• Blood type and Coombs test (direct antiglobulin test) - identify immune-mediated hemolysis 1
• Reticulocyte count - elevated in hemolytic processes 1
• G6PD level - screen for enzyme deficiency 1
• Blood and urine cultures - if sepsis suspected 1

Additional Testing Based on Initial Results

• If conjugated bilirubin >1.0 mg/dL (>17 μmol/L) - indicates cholestasis requiring urgent hepatobiliary evaluation and referral to pediatric gastroenterology 3
• If unconjugated hyperbilirubinemia with negative Coombs - consider G6PD, hereditary spherocytosis, metabolic disorders 1
• Thyroid function tests - if prolonged jaundice or clinical signs of hypothyroidism 1

Critical Management Considerations

Urgent Treatment Thresholds

• Rapidly rising bilirubin places infant at risk for acute bilirubin encephalopathy and kernicterus, requiring immediate phototherapy or exchange transfusion 1
• Any conjugated hyperbilirubinemia (direct bilirubin >1.0 mg/dL) warrants urgent evaluation as it may indicate biliary atresia, which requires surgical intervention (Kasai procedure) ideally before 60 days of life 3

Common Pitfall to Avoid

The most dangerous error is dismissing day 2 jaundice as "physiological" - physiological jaundice does not appear before day 3 of life in term infants 5, 1. Early-onset jaundice always indicates pathology requiring investigation.

Risk Stratification

Infants with the following features require more aggressive monitoring and treatment 1:

• Gestational age <38 weeks
• Previous sibling with significant jaundice
• Exclusive breastfeeding with poor intake
• East Asian ethnicity
• Visible jaundice in first 24-48 hours