Updated October 2025

Neonatology

Neonatal Jaundice: Differential Diagnosis and Management

Neonatal jaundice is common and usually benign, but a subset requires urgent evaluation to prevent bilirubin-induced neurologic dysfunction. Differentiate unconjugated from conjugated hyperbilirubinemia, identify hemolysis and neurotoxicity risk, and manage per 2022 AAP thresholds with escalation to phototherapy or exchange transfusion as indicated. Serum bilirubin remains the diagnostic gold standard; transcutaneous tools aid screening.

Clinical question

How should clinicians differentiate and manage neonatal jaundice to prevent acute and chronic bilirubin neurotoxicity while minimizing unnecessary treatment?

NeonatologyHyperbilirubinemiaPhototherapyExchange TransfusionBreastfeedingCholestasis

Key points

Recognize red flags

Jaundice in first 24 hours, rapid rise in bilirubin, anemia, lethargy, hypotonia, poor feeding, or conjugated fraction ≥20% of total or ≥1 mg/dL require urgent evaluation ^[4], ^[5].

Confirm with serum bilirubin

Use transcutaneous bilirubin for screening; confirm and stage with total serum bilirubin to guide therapy—this remains the gold standard for decisions ^[1].

Apply risk-adjusted thresholds

Use 2022 AAP hour-specific nomograms, factoring gestational age, hemolysis, and neurotoxicity risk to start phototherapy and plan escalation ^[2], ^[3].

Differentiate conjugated vs unconjugated

Conjugated hyperbilirubinemia is never physiologic and mandates cholestasis workup; unconjugated causes span physiologic, breastfeeding, hemolysis, and enzyme defects ^[4], ^[5].

Escalate care early

Initiate intensive phototherapy promptly when at threshold; arrange exchange transfusion if rising despite intensive therapy or if at/above exchange level ^[2].

Evidence highlights

Essential for treatment decisions ^[1]

Serum bilirubin is diagnostic gold standard

2022 AAP CPG with 2024 summaries ^[2], ^[3]

Guideline anchor

Evaluation Pathway

Stepwise Approach to the Jaundiced Newborn

Prioritize timing of onset, fractionation (conjugated vs unconjugated), and hemolysis risk to guide investigations and timely treatment.

Initial risk stratification and history

Assess gestational age, birth weight, feeding pattern, weight loss, stool/urine color, timing of jaundice onset, family/ethnic history of hemolysis or G6PD deficiency, maternal diabetes or Rh/ABO status, and bruising/cephalohematoma. Jaundice <24 hours is pathologic until proven otherwise ^[4], ^[5].

Physical examination

Evaluate alertness, tone, hydration, hepatosplenomegaly, cephalohematoma, and degree of jaundice. Look for acholic stools or dark urine (suggest cholestasis). Any signs of acute bilirubin encephalopathy (lethargy, hypotonia/hypertonia, high-pitched cry) warrant emergent labs and treatment ^[4], ^[5].

Measure bilirubin accurately

Screen with transcutaneous bilirubin if available, but confirm with serum total bilirubin (TSB) for diagnosis and treatment decisions; obtain direct (conjugated) fraction when jaundice persists, is prolonged (>2–3 weeks), or if cholestasis suspected ^[1].

Laboratory evaluation based on fraction and risk

If unconjugated: CBC/reticulocytes, blood type and direct antiglobulin test (DAT), G6PD (especially at-risk ancestries), peripheral smear, consider TSH/free T4, and infection workup if ill. If conjugated: liver panel (ALT/AST, GGT, ALP), albumin, INR, abdominal ultrasound; evaluate for biliary atresia and neonatal hepatitis; stool color card if available ^[4], ^[5].

Plot TSB on hour-specific nomogram

Use the 2022 AAP hour-by-hour nomograms adjusted for gestational age and neurotoxicity risk (e.g., isoimmune hemolysis, G6PD deficiency, sepsis, albumin <3.0 g/dL). Decide on intensive phototherapy initiation, need for IVIG in isoimmune hemolysis, and whether to escalate to exchange transfusion ^[2], ^[3].

Treatment and escalation

Start intensive phototherapy when at threshold; ensure effective irradiance and maximal skin exposure. In isoimmune hemolysis with rising TSB despite intensive phototherapy, give IVIG 0.5–1 g/kg per guideline considerations, and prepare for double-volume exchange if approaching/at exchange levels or if signs of encephalopathy are present ^[2].

Post-therapy monitoring and follow-up

Monitor TSB decline (target ≥2–3 mg/dL within 4–6 h of intensive phototherapy). Watch for rebound, especially with hemolysis or early initiation; recheck TSB 6–12 h after stopping if risk is high. Ensure feeding support, lactation assistance, and early outpatient reassessment ^[2].

Differential & Workup

Differential Diagnosis, Red Flags, and Tests

Differentiate by timing, conjugation status, and hemolysis; investigate promptly to prevent kernicterus.

Unconjugated hyperbilirubinemia

Physiologic jaundice (peak day 3–5 term; later/preterm) ^[4], ^[5]

Breastfeeding jaundice (suboptimal intake/weight loss) vs breast milk jaundice (late, persistent) ^[4], ^[5]

Hemolysis: ABO/Rh isoimmunization (positive DAT), G6PD deficiency, hereditary spherocytosis, sepsis ^[4], ^[5]

Extravascular blood: cephalohematoma, bruising, polycythemia ^[4]

Enzyme/endocrine: hypothyroidism, Crigler–Najjar, Gilbert ^[4]

Drugs and maternal diabetes as contributing factors ^[4], ^[5]

Conjugated hyperbilirubinemia (cholestasis)

Biliary atresia (acholic stools, dark urine, early onset) — time-critical referral ^[4], ^[5]

Neonatal hepatitis/idiopathic cholestasis; infections (CMV, sepsis) ^[4]

Metabolic/genetic: alpha-1 antitrypsin deficiency, PFIC, galactosemia, tyrosinemia ^[4]

Endocrine: hypothyroidism, hypopituitarism ^[4]

TPN-associated cholestasis in preterm/critical illness ^[4]

Red flags: direct bilirubin ≥1 mg/dL if TSB ≤5 or ≥20% of TSB; persistent jaundice >2–3 weeks ^[4], ^[5]

Essential investigations

TSB (gold standard) with direct fraction; TcB for screening only ^[1]

CBC, reticulocytes, DAT, blood type; G6PD level when indicated ^[4], ^[5]

Liver panel, INR, albumin; abdominal ultrasound if conjugated ^[4]

TSH/free T4; consider sepsis workup if clinically ill ^[4], ^[5]

Consider serum albumin when assessing neurotoxicity risk and exchange thresholds ^[2]

Management anchors (AAP 2022)

Use hour-specific phototherapy and exchange thresholds by gestational age and risk factors ^[2], ^[3]

Start intensive phototherapy promptly at threshold; ensure irradiance ≥30–40 µW/cm²/nm at 460–490 nm, maximize skin exposure, and avoid interruptions ^[2]

IVIG for isoimmune hemolysis if TSB rising despite intensive phototherapy or near exchange levels ^[2]

Exchange transfusion if at/above exchange line or with acute encephalopathy; stabilize, ensure airway, correct hypoglycemia, acidosis ^[2]

Feeding optimization; consider temporary supplementation for excessive weight loss/dehydration; avoid routine water or dextrose water ^[5], ^[2]

When to refer or admit

Jaundice in first 24 hours of life or rapid TSB rise (>0.2–0.3 mg/dL/h) ^[4], ^[5]

Conjugated hyperbilirubinemia or acholic stools (evaluate for biliary atresia urgently) ^[4], ^[5]

TSB at/near treatment thresholds without reliable follow-up ^[2]

Evidence of hemolysis, G6PD deficiency, sepsis, or signs of encephalopathy ^[4], ^[2]

Quality and systems considerations

Implement universal predischarge bilirubin screening with TcB/TSB and risk assessment ^[2], ^[3]

Use standardized order sets and phototherapy devices with measured irradiance; track time-to-light metrics ^[2]

Educate caregivers on feeding, output, and warning signs; schedule early follow-up based on discharge age/TSB proximity to threshold ^[2]

In low-resource settings, WHO-aligned early phototherapy for high-risk clinical jaundice can reduce severe hyperbilirubinemia when labs are limited ^[6]

References

Source material

Primary literature that informs this article.