What are the definition, classification, risk assessment, treatment thresholds, and management strategies—including phototherapy, exchange transfusion, and intravenous immunoglobulin—for neonatal jaundice?

Neonatal Jaundice: Comprehensive Overview

Definition and Pathophysiology

Neonatal jaundice is the yellowing of skin and sclera caused by elevated serum bilirubin levels, affecting approximately 80% of newborns, and results from increased red blood cell turnover, immature hepatic conjugation, and delayed intestinal clearance. 1, 2

• Hyperbilirubinemia becomes clinically apparent when total serum bilirubin (TSB) exceeds 5-7 mg/dL 1
• Newborns are particularly vulnerable due to higher red blood cell mass, shorter RBC lifespan (70-90 days vs 120 days in adults), and immature UDP-glucuronosyltransferase enzyme activity 1
• The condition is typically benign and self-limited but can progress to kernicterus—permanent neurologic damage—if severe hyperbilirubinemia remains untreated 1, 2

Classification Systems

By Timing of Onset

• Early jaundice (first 24 hours): Always pathologic, suggests hemolytic disease (ABO/Rh incompatibility, G6PD deficiency) requiring immediate evaluation 3
• Physiologic jaundice (days 2-5): Peaks at 3-5 days in term infants, typically resolves by 1-2 weeks 1
• Prolonged jaundice (>2 weeks term, >3 weeks preterm): Requires evaluation for conjugated hyperbilirubinemia, hypothyroidism, or breast milk jaundice 3

By Etiology

• Hemolytic causes: ABO incompatibility, Rh disease, G6PD deficiency, hereditary spherocytosis 3, 4
• Non-hemolytic causes: Physiologic jaundice, breast milk jaundice, breastfeeding jaundice, polycythemia, cephalohematoma 3, 4
• Conjugated hyperbilirubinemia: Direct bilirubin >1.0 mg/dL when TSB ≤5 mg/dL, or >50% of total—requires specialist consultation for biliary atresia or metabolic disease 3

Risk Assessment and Screening

Universal Screening Protocol

• Measure TSB or transcutaneous bilirubin (TcB) on all infants before discharge to assess risk using hour-specific nomograms 5, 3
• TSB must be obtained if TcB is within 3.0 mg/dL of phototherapy threshold, exceeds threshold, or is ≥15 mg/dL 5
• Visual assessment alone is unreliable and should never guide treatment decisions 6

High-Risk Factors Requiring Lower Treatment Thresholds

• Gestational age <38 weeks (particularly 35-37 6/7 weeks) 5, 3, 7
• Neurotoxicity risk factors: Sepsis, acidosis, albumin <3.0 g/dL, lethargy, temperature instability 5, 3
• Isoimmune hemolytic disease: Positive direct antiglobulin test (DAT), ABO incompatibility, Rh disease 5, 6
• G6PD deficiency: Particularly high risk in infants of Mediterranean, African, or Asian descent 5, 3

Rate of Rise Assessment

• A rapid rise of ≥0.3 mg/dL per hour in first 24 hours or ≥0.2 mg/dL per hour thereafter suggests ongoing hemolysis and requires urgent evaluation 5, 3, 7
• Calculate rate of rise when multiple measurements available to identify hemolytic disease early 5

Diagnostic Evaluation

Initial Laboratory Assessment (TSB ≥13 mg/dL)

• Total and direct serum bilirubin 3
• Blood type and Coombs test (direct antiglobulin test) 3
• Complete blood count with differential and reticulocyte count 3
• Serum albumin (consider bilirubin/albumin ratio if <3.0 g/dL) 3
• G6PD enzyme activity if jaundice of unknown cause, TSB rises despite intensive phototherapy, or sudden rise after initial decline 5, 3

Critical Pitfall in G6PD Testing

• G6PD levels can be falsely elevated during active hemolysis—a normal level does not exclude deficiency 3
• Repeat testing at 3 months if clinical suspicion remains high despite normal initial result 3

Preparation for Exchange Transfusion (TSB ≥25 mg/dL or ≥20 mg/dL in sick/preterm infant)

• Blood type and crossmatch must be sent immediately 3, 6
• Measure TSB every 2-3 hours to monitor trajectory 6

Treatment Thresholds and Phototherapy

Hour-Specific Phototherapy Thresholds

Phototherapy thresholds are hour-specific and vary dramatically based on infant age in hours, gestational age, and presence of neurotoxicity risk factors—not just absolute bilirubin level. 3

• Highest risk period: First 24-48 hours when neurotoxicity risk is greatest and thresholds are lowest 3
• Term infants ≥38 weeks without risk factors: Thresholds range from approximately 12-15 mg/dL at 24-48 hours to 15-18 mg/dL at 72+ hours 5, 3
• Infants 35-37 6/7 weeks or with risk factors: Thresholds approximately 2-3 mg/dL lower than term infants 5, 6

When Phototherapy May NOT Be Needed After Day 5-7

• In healthy term newborns beyond 5-7 days of life, phototherapy is generally not indicated even if bilirubin exceeds typical thresholds, as neurotoxicity risk diminishes substantially with postnatal age 3
• Exceptions requiring continued vigilance: Hemolytic disease, rapid rate of rise, TSB approaching exchange levels, or signs of acute bilirubin encephalopathy 3

Intensive Phototherapy Implementation

Technical Specifications

• Use special blue light in 430-490 nm spectrum with irradiance ≥30 μW/cm²/nm 3, 7
• Blue-green (turquoise) LED phototherapy is effective alternative 5
• Position light source as close as safely possible to maximize irradiance 3

Maximizing Effectiveness

• Remove diaper and minimize eye mask obstruction when bilirubin approaches exchange transfusion range 3, 7
• Maximize exposed body surface area by removing all unnecessary coverings 3, 7
• Consider adding second phototherapy device (dual phototherapy) for plateauing or critically high levels 7
• Verify spectral irradiance regularly using radiometer 7

Expected Response to Phototherapy

• TSB should decline >2 mg/dL within 4-6 hours of initiating intensive phototherapy 3, 7
• For extremely high levels (>30 mg/dL), expect decline of up to 10 mg/dL within few hours and at least 0.5-1 mg/dL per hour in first 4-8 hours 3
• Failure to achieve expected decline suggests inadequate phototherapy intensity or ongoing hemolysis 3, 7

Monitoring During Phototherapy

• TSB ≥25 mg/dL: Repeat measurement within 2-3 hours 3, 6
• TSB 20-25 mg/dL: Repeat within 3-4 hours 3
• TSB <20 mg/dL: Repeat in 4-6 hours 3
• Continue monitoring every 4-6 hours for infants <38 weeks with ABO incompatibility or other high-risk features 7

Hydration and Feeding

• Continue breastfeeding or bottle-feeding every 2-3 hours during phototherapy 3
• Supplement with formula or expressed breast milk for infants with dehydration signs or weight loss >12% from birth 3
• Milk-based formula inhibits enterohepatic circulation of bilirubin and helps lower serum levels 3
• Optimize breastfeeding frequency to 8-10 times per 24 hours 7

Discontinuation of Phototherapy

Criteria for Stopping Treatment

Discontinue phototherapy when TSB has declined by 2-4 mg/dL below the hour-specific threshold at which phototherapy was initiated. 3

• For readmitted infants, discontinue when TSB falls below 13-14 mg/dL 3
• Consider initial TSB level, cause of hyperbilirubinemia, difference between TSB and threshold, and rebound risk 5, 3

Post-Phototherapy Follow-Up

High-Risk Infants (Requiring Closer Monitoring)

• Phototherapy initiated <48 hours of age 5
• Gestational age <38 weeks 5
• Positive DAT or suspected hemolytic disease 5

Follow-up protocol: Measure TSB 8-12 hours after discontinuation, then additional TSB the following day 5, 3

Standard-Risk Infants

• Follow-up TSB within 1-2 days after phototherapy discontinuation 5, 3
• TcB can be used instead of TSB if ≥24 hours have passed since phototherapy stopped 5, 3

Rebound Hyperbilirubinemia

• Rebound is rare but possible, especially with hemolytic disease or early discharge (before 3-4 days) 3
• Monitor for rate of rise ≥0.2 mg/dL per hour suggesting ongoing hemolysis 5, 7

Exchange Transfusion

Absolute Indications

Exchange transfusion must be performed immediately if ANY signs of acute bilirubin encephalopathy are present, regardless of bilirubin level. 6

Clinical Signs of Acute Bilirubin Encephalopathy

• Early phase: Lethargy, hypotonia, poor feeding, high-pitched cry 3, 6, 7
• Intermediate phase: Irritability, hypertonia, opisthotonus, retrocollis, fever 3, 6
• Advanced phase: Seizures, coma 6

TSB-Based Thresholds for Exchange Transfusion

• Infants ≥38 weeks: TSB ≥20-25 mg/dL depending on age in hours and neurotoxicity risk factors 6
• Infants 35-37 6/7 weeks or with isoimmune hemolytic disease/G6PD deficiency: TSB ≥18-20 mg/dL 6
• TSB continues rising despite intensive phototherapy or fails to decline after 6 hours 6
• TSB within 0-2 mg/dL below exchange threshold: Prepare for possible exchange, intensify phototherapy 6

Procedure Requirements and Risks

• Must be performed only by trained personnel in NICU with full monitoring and resuscitation capabilities 6
• Mortality risk approximately 3 per 1000 procedures 3
• Significant morbidity in 5% of cases 3
• Despite risks, exchange transfusion is life-saving when acute bilirubin encephalopathy present 3

Emergent Management Algorithm When TSB Approaches Exchange Level

1. Send blood for type and crossmatch immediately 6
2. Initiate emergent intensive phototherapy (irradiance ≥30 μW/cm²/nm, maximize skin exposure) 6
3. Provide intravenous hydration 6
4. Measure TSB every 2-3 hours 6
5. Transfer to NICU if not already there 6

Intravenous Immunoglobulin (IVIG)

While not extensively detailed in the provided guidelines, IVIG (0.5-1 g/kg over 2 hours) is used in isoimmune hemolytic disease when TSB continues rising despite phototherapy or is within 2-3 mg/dL of exchange threshold. This reduces the need for exchange transfusion by blocking antibody-mediated hemolysis.

Safety Considerations and Side Effects

Phototherapy Safety Measures

• Maintain adequate hydration and temperature control during treatment 5
• Protect eyes with appropriate shields 5
• Monitor for side effects: loose stools, skin rashes, temperature instability 4
• Side effects are generally not serious and well-controlled 4

Long-Term Considerations

• Phototherapy has been used safely for over 50 years and greatly reduced exchange transfusion rates 4, 8
• More research needed on potential long-term sequelae of specific durations and magnitudes of hyperbilirubinemia 5

Critical Pitfalls to Avoid

• Never rely on visual assessment alone—TSB or TcB measurement is mandatory 6
• Never subtract direct bilirubin from total bilirubin when making treatment decisions 3, 6
• Never use sunlight exposure as therapeutic tool 3
• Never delay treatment by sending infants to emergency department when TSB ≥25 mg/dL 6
• Never use TcB to determine treatment decisions—only TSB guides therapy 6
• Avoid unnecessary prolongation of phototherapy as it separates mother-infant and interferes with breastfeeding 3
• Do not discharge infants <38 weeks or with hemolytic disease without ensuring 24-hour follow-up 5, 3

Parental Education

Warning Signs Requiring Immediate Evaluation

• Worsening jaundice (yellowing spreading to arms, legs, or whites of eyes) 3
• Altered feeding patterns (poor feeding, decreased intake) 3
• Lethargy or difficulty arousing 3
• High-pitched or inconsolable crying 3
• Abnormal muscle tone (stiffness or floppiness) 3
• Arching of neck or body (opisthotonus) 3
• Fever 3