What is the approach to differentiate physiologic from pathologic jaundice in term (≥37 weeks) and preterm (≤34 weeks) newborns, including recommended laboratory evaluation, phototherapy thresholds, and indications for exchange transfusion?

Approach to Newborn Jaundice

Differentiating Physiologic from Pathologic Jaundice

Jaundice appearing in the first 24 hours of life is always pathologic and requires immediate measurement of total serum bilirubin (TSB) or transcutaneous bilirubin (TcB), urgent laboratory evaluation for hemolytic disease, and consideration of phototherapy or exchange transfusion based on hour-specific nomograms. 1, 2

Timing-Based Differentiation

First 24 Hours (Always Pathologic):

• Any visible jaundice before 24 hours of age demands immediate TSB/TcB measurement—never rely on visual assessment 1, 2
• Obtain blood type and direct antibody test (Coombs), complete blood count with peripheral smear, direct/conjugated bilirubin, reticulocyte count, and G6PD level 2, 3
• Most common causes include isoimmune hemolytic disease (ABO or Rh incompatibility), G6PD deficiency, sepsis, and significant bruising or cephalohematoma 2

24 Hours to 2 Weeks (May Be Physiologic):

• Physiologic jaundice typically peaks at 3-5 days in term infants and 5-7 days in preterm infants 4, 5
• Use hour-specific Bhutani nomogram to plot bilirubin level—values above the 95th percentile indicate high risk for severe hyperbilirubinemia 2, 3
• Physiologic jaundice is characterized by predominantly unconjugated hyperbilirubinemia with normal feeding, adequate weight gain, and appropriate stooling 1, 4

Beyond 2-3 Weeks (Requires Evaluation):

• Any infant still visibly jaundiced at 2 weeks (term) or 3 weeks (preterm) requires measurement of total and direct/conjugated bilirubin 3, 6
• Check newborn thyroid and galactosemia screening results 3
• Ask about stool color (pale stools) and urine color (dark urine) to identify cholestasis 6

Laboratory Evaluation

Initial Workup for Pathologic Jaundice

Mandatory First-Line Tests:

• Total serum bilirubin (TSB) with direct/conjugated fraction 1, 2
• Blood type and direct antibody test (Coombs) on both infant and mother 2, 3
• Complete blood count with peripheral smear and reticulocyte count 2, 3
• G6PD level, particularly in infants of African American, Mediterranean, or Asian descent 2, 3

Critical Pitfall: G6PD levels can be falsely elevated during active hemolysis—a normal level does not rule out G6PD deficiency in a hemolyzing neonate; repeat testing at 3 months is necessary if strongly suspected 2

Interpretation of Direct/Conjugated Bilirubin

• If direct bilirubin is >1.0 mg/dL when TSB ≤5 mg/dL, this is abnormal and warrants investigation for cholestasis 2
• Never subtract direct bilirubin from total bilirubin when making phototherapy or exchange transfusion decisions 1, 2

Phototherapy Thresholds

Term Infants (≥38 Weeks, Well, No Risk Factors)

Use the AAP hour-specific phototherapy nomogram with risk stratification: 1, 2, 3

• Low-risk curve: For infants ≥38 weeks gestation who are well with no risk factors
• Phototherapy threshold at 24 hours: ~12 mg/dL
• Phototherapy threshold at 48 hours: ~15 mg/dL
• Phototherapy threshold at 72 hours: ~17 mg/dL

Medium-Risk Infants

Apply lower thresholds for: 2, 3

• Gestational age 35-37 6/7 weeks without additional risk factors
• Term infants (≥38 weeks) with risk factors: isoimmune hemolytic disease, G6PD deficiency, sepsis, acidosis, or albumin <3.0 g/dL

Phototherapy thresholds are approximately 2-3 mg/dL lower than low-risk infants at each time point.

High-Risk Infants

Use the lowest threshold curve for: 2, 3

• Gestational age 35-37 6/7 weeks with additional risk factors (hemolytic disease, G6PD deficiency, sepsis, acidosis, albumin <3.0 g/dL)

Phototherapy thresholds are approximately 4-5 mg/dL lower than low-risk infants at each time point.

Preterm Infants ≤34 Weeks

These guidelines apply only to infants ≥35 weeks gestation. 1 Infants ≤34 weeks require NICU-level care with lower, weight-based and gestational age-specific phototherapy thresholds that are not addressed in these AAP guidelines. Do not treat 35-37 week infants as term infants—they require closer monitoring and have lower treatment thresholds. 6

Phototherapy Implementation

Maximize efficacy by: 1

• Exposing maximum skin surface area—minimize diapers, head covers, eye patches, and electrode patches
• Using intensive phototherapy (irradiance ≥30 μW/cm²/nm in the 430-490 nm band)
• Expecting bilirubin decrease of >2 mg/dL within 4-6 hours if phototherapy is effective 2

Monitor response: 1

• Recheck TSB within 4-12 hours depending on rate of rise and risk factors 2, 3
• If bilirubin rises despite adequate phototherapy, investigate for unrecognized hemolytic process 6

Contraindications: 1

• Congenital porphyria or family history of porphyria (absolute contraindication)
• Concomitant use of photosensitizing drugs or agents

Exchange Transfusion Indications

Exchange transfusion should be considered when: 1

• TSB reaches exchange transfusion threshold on hour-specific nomograms (typically 5-7 mg/dL above phototherapy thresholds, depending on risk category)
• Infant shows signs of acute bilirubin encephalopathy: lethargy, hypotonia, poor feeding, high-pitched cry, opisthotonus, seizures 1, 5
• TSB is in the intensive phototherapy range and phototherapy does not promptly lower TSB, particularly in infants with bronze infant syndrome (cholestatic jaundice) 1
• Bilirubin continues to rise rapidly despite intensive phototherapy 1

Do not subtract direct bilirubin from TSB when making exchange transfusion decisions. 1

Breastfeeding Management

Support breastfeeding while managing jaundice: 1

• Advise mothers to nurse at least 8-12 times per day in the first several days 1
• Frequent feeding (9-10 times daily) is associated with lower bilirubin concentrations 1
• Poor intake and dehydration contribute to hyperbilirubinemia development 1

Phototherapy is not an indication to stop breastfeeding or supplement with formula unless: 1

• Bilirubin levels are approaching exchange transfusion thresholds
• There are clear signs of dehydration or inadequate intake
• When supplementation is necessary, use expressed maternal milk preferentially 1

Follow-Up and Monitoring

Discharge timing and follow-up: 2, 3

• Infants discharged before 24 hours must be seen by 72 hours of age
• Infants discharged between 24-48 hours must be seen by 96 hours of age
• Infants discharged between 48-72 hours must be seen by 120 hours of age
• Infants with TSB in high-intermediate or high-risk zone (>95th percentile on Bhutani nomogram) require follow-up within 24 hours of discharge 3

Never discharge an infant with jaundice in the first 24 hours without objective bilirubin measurement and clear follow-up plan. 2

Critical Pitfalls to Avoid

• Visual estimation is unreliable: Always obtain objective TSB or TcB measurements, particularly in darkly pigmented infants 1, 2, 3
• Do not treat 35-37 week infants as term: They are at higher risk and require lower treatment thresholds 2, 3, 6
• Late-rising bilirubin suggests G6PD deficiency: Consider ethnic background and obtain G6PD testing 6
• Prolonged jaundice beyond 2-3 weeks: Measure direct bilirubin to rule out cholestasis, even in breastfed infants 3, 6
• Do not supplement with water or dextrose water: This does not reduce bilirubin and may interfere with breastfeeding 2