Jaundice – (neonatal)
- Jaundice = visible yellowing of skin and sclera due to elevated serum bilirubin
- Prevalence
- Term infants: ~60 % develop clinically visible jaundice in first week
- Preterm infants: up to 80 % in first week
- Cause:
- Imbalance in bilirubin production, conjugation, and elimination.
- Complication:
- Kernicterus, a rare but severe neurological condition from unconjugated hyperbilirubinemia.
Underlying Pathophysiology
Jaundice occurs when unconjugated bilirubin (insoluble) accumulates in tissues faster than the immature neonatal liver can conjugate and excrete it. Three processes are involved:
- Production – from haemoglobin breakdown in senescent or damaged red cells
- Conjugation – via the UGT1A1 enzyme in hepatocytes
- Elimination – into bile, with some enterohepatic recycling in the gut
Any factor that ↑ production, ↓ conjugation or ↑ enterohepatic re-uptake will raise serum bilirubin.
Physiological Jaundice
Cause: normal maturational delay of bilirubin clearance combined with a transient ↑ in red-cell turnover.
| Feature | Explanation |
|---|---|
| Onset | 48–72 hours of life |
| Peak | Day 3–5 (term); slightly earlier in preterm |
| Duration | Resolves by 10–14 days (term) or ≤21 days (preterm) |
| Conjugated bilirubin | Remains < 17 μmol/L (i.e. < 20 % of total) |
Key Risk Factors
- Prematurity (< 37 weeks):
- immature hepatic UGT enzyme system → reduced conjugation; ↑ enterohepatic circulation due to slower gut motility.
- Bruising/Cephalohaematoma: extra blood breakdown → ↑ bilirubin load
- Polycythaemia: greater red-cell mass → more haem turnover
- Breastfeeding-associated:
- Inadequate intake/dehydration → slower gut transit allows increased β-glucuronidase activity in gut flora → bilirubin deconjugation and reabsorption.
- East Asian/Mediterranean ethnicity:
- Higher prevalence of UGT1A1 polymorphisms and G6PD deficiency variants → reduced conjugation and increased haemolysis.
Pathological Jaundice
Cause: any condition causing excessive haemolysis, cholestasis or enzyme inhibition beyond normal newborn physiology. Requires prompt investigation.
| Feature | Indicator |
|---|---|
| Onset | < 24 hours old |
| Rise | > 85 μmol/L per 24 h or total bilirubin exceeds treatment thresholds for age |
| Duration | Persists > 14 days (term) or > 21 days (preterm) |
| Conjugated bilirubin | ≥ 17 μmol/L or ≥ 20 % of total → cholestatic work-up |
Key Risk Factors
- Immune-mediated haemolysis
- ABO incompatibility (group O mother → A/B baby)
- RhD alloimmunisation (anti-D)
- Other red-cell antibodies (Kell, Duffy, etc.)
- Enzyme defects
- G6PD deficiency → oxidative haemolysis
- UGT1A1 mutations (e.g. Crigler-Najjar, Gilbert’s)
- Sepsis/Infection
- Cytokine downregulation of UGT, cholestasis, possible haemolysis
- Cholestatic liver disease
- Biliary atresia, metabolic (α1-antitrypsin), neonatal hepatitis
- Breastmilk jaundice (late onset)
- Milk-born inhibitors of UGT and ↑ enterohepatic cycling
- Genetic syndromes
- Haemoglobinopathies, storage disorders
Physiology vs Pathology
| Feature | Physiological Jaundice | Pathological Jaundice |
|---|---|---|
| Onset | After 24 h (typically 48–72 h) | Within first 24 h |
| Peak bilirubin | Day 3–5 (term), lower peak in preterm | Rapid rise (>85 μmol/L/day) or very high levels |
| Resolution | ≤10–14 days (term); ≤21 days (preterm) | Persists >14 days (term) or >21 days (preterm) |
| Conjugated bilirubin | <17 μmol/L | ≥17 μmol/L or >20 % of total bilirubin |
| General condition | Well, feeding normally | Unwell, poor feeding, lethargy, hypotonia |
ABO Incompatibility (Group O Mother → A or B Baby)
- Mechanism:
- Mothers with blood group O naturally have anti-A and anti-B IgG antibodies.
- If the baby’s red cells express A or B antigens, maternal IgG crosses the placenta and binds neonatal RBCs.
- This leads to extravascular haemolysis (in the spleen), releasing extra unconjugated bilirubin.
- Clinical Features:
- Often mild; babies may show low-grade anaemia, positive direct antiglobulin test (DAT), and modest jaundice, peaking earlier than physiological jaundice.
- Investigation:
- Maternal and neonatal blood groups, DAT (Coombs test), and antenatal antibody screen.
RhD Alloimmunisation (Anti-D)
- Mechanism:
- An RhD–negative mother can become sensitised (after prior pregnancy or transfusion) to RhD antigen.
- On subsequent RhD-positive pregnancies, maternal anti-D IgG crosses the placenta and causes brisk haemolysis of fetal RhD-positive RBCs.
- This can lead to severe anaemia (hydrops fetalis) and very high bilirubin load at birth.
- Prevention & Management:
- Antenatal prophylaxis: routine anti-D immunoglobulin at 28 weeks and after any sensitising event.
- Investigation: antenatal antibody titres, fetal middle cerebral artery Dopplers for anaemia, neonatal DAT.
- Clinical Significance:
- Without prophylaxis, risk of severe haemolytic disease is high; exchange transfusion often required.
Other Red-Cell Alloantibodies (Kell, Duffy, Kidd, etc.)
- Mechanism:
- Maternal sensitisation to minor blood group antigens (e.g. Kell, Duffy) through pregnancy or transfusion.
- Resulting IgG antibodies target corresponding antigen on fetal RBCs, causing haemolysis.
- Particular Notes:
- Anti-Kell: suppresses fetal erythropoiesis as well as causing haemolysis → can lead to anaemia even with lower bilirubin.
- Anti-Duffy, Anti-Kidd: typically milder than anti-D but still increase bilirubin and anaemia risk.
- Investigation & Monitoring:
- Maternal antibody screen early in pregnancy; monitor titres if positive.
- Assess fetal anemia risk with Doppler ultrasound; plan for in-utero transfusion if severe.
| Immune‐Mediated Cause | Mechanism | Clinical Features/Investigation | Management/Notes |
|---|---|---|---|
| ABO incompatibility (Group O mother → A or B baby) | Maternal anti‐A/B IgG crosses placenta → binds fetal A/B RBCs → extravascular haemolysis ↑ unconjugated bilirubin | – Mild neonatal anaemia – Jaundice peaking earlier than physiological – Positive direct antiglobulin test (DAT) | – Usually self‐limited – Monitor bilirubin on nomogram – Phototherapy if thresholds exceeded |
| RhD alloimmunisation (anti-D) | RhD– mother sensitised to D antigen → anti-D IgG crosses placenta in subsequent D+ pregnancy → brisk haemolysis → severe anaemia & ↑ bilirubin load | – May present with hydrops fetalis antenatally – High-risk TSB rise at birth – Positive DAT – Anaemia, elevated reticulocyte count | – Antenatal prophylaxis with anti-D Ig at 28 wk & after sensitising events – Monitor maternal titres & MCA Doppler – Exchange transfusion if severe postnatal hyperbilirubinaemia |
| Other alloantibodies (e.g. Kell, Duffy, Kidd) | Maternal IgG to minor RBC antigens crosses placenta → haemolysis (and with anti-Kell, suppression of erythropoiesis) → ↑ bilirubin & risk of anaemia | – Variable severity (anti-Kell can cause anaemia even with modest haemolysis) – Positive antenatal antibody screen – DAT may be weakly positive depending on titre | – Early antenatal antibody screening – Titre monitoring – MCA Doppler for fetal anaemia – In-utero transfusion if indicated; postnatal phototherapy/exchange as per thresholds |
History
Timing and Progression
- < 24 hours: Always pathological
- 24 h–14 days (term) / 24 h–21 days (preterm): May be physiological or early pathology
- >14 days (term) or >21 days (preterm): Suggests prolonged jaundice or cholestasis
Perinatal and Feeding History
- Birth details: Gestational age, birth weight, delivery method, trauma (e.g. forceps, cephalohematoma)
- Maternal history: Blood group, antibodies (ABO/Rh), diabetes, medication use
- Feeding: Type (breast/formula), volume, frequency, vomiting, weight loss percentage
- Elimination: Urine output/colour, stool colour (pale suggests cholestasis), meconium timing
- Behaviour: Lethargy, high-pitched cry, arching (concerns for encephalopathy)
- Family history: Haemolytic disorders (e.g. G6PD, hereditary spherocytosis), thyroid disease, sibling jaundice
Examination
- General: Tone, activity level, hydration status
- Jaundice: Extent (cephalocaudal progression), intensity
- Skin: Bruising, cephalohematoma
- Abdomen: Hepatomegaly ± splenomegaly
- Neurological: Reflexes, signs of encephalopathy
Red Flags – Indicators of Serious Pathology
- Onset of jaundice within < 24 hours of life
- Conjugated bilirubin > 20 µmol/L or >10% of total bilirubin
- Unwell or febrile neonate
- Dark urine and pale stools (suggestive of cholestasis)
- Weight loss > 10% of birth weight by day 7
- Cephalohematoma or significant bruising
- Anaemia with hepatomegaly
- Persistent jaundice > 14 days (term) or > 21 days (preterm)
Initial Investigations
| Test | Purpose |
|---|---|
| Total + direct bilirubin | Differentiate conjugated vs unconjugated hyperbilirubinaemia |
| Transcutaneous bilirubin | Screening tool in infants ≥ 35 weeks GA, ≥ 24 hours old |
| FBC + reticulocytes | Assess for anaemia and haemolysis |
| Blood group + direct Coombs | Detect isoimmune haemolytic disease |
| LFTs + albumin | Assess hepatic function and cholestasis |
| TFTs | Screen for congenital hypothyroidism (if not previously done) |
| G6PD assay | In at-risk populations or unexplained haemolysis |
| Urine reducing substances | Rule out galactosaemia |
| Urine culture | Evaluate for sepsis or cholangitis |
Always plot bilirubin on a gestational age-specific nomogram (e.g. ETG, AAP) to guide phototherapy/exchange transfusion thresholds.
| Unconjugated (Indirect) Hyperbilirubinaemia | Conjugated (Direct) Hyperbilirubinaemia (Cholestasis) |
| Increased production: Haemolysis (ABO/Rh incompatibility, G6PD, spherocytosis) Bruising/cephalohematoma Reduced clearance: Prematurity Hypothyroidism Breastfeeding jaundice (<7 days): Suboptimal intake Breast milk jaundice (>7 days): Diagnosis of exclusion; benign | Biliary atresia Neonatal hepatitis Alpha-1 antitrypsin deficiency TPN-associated cholestasis Sepsis Inborn errors of metabolism |
| Type | Causes | Investigations |
| Early Onset: ( <24 hours) PATHOLOGICAL All should have: FBE SBR Coombs | Sepsis | Please refer to Recognition of the seriously unwell neonate and young infant |
| Haemolysis: Isoimmunisation – ABO or Rhesus D alloantibodies RBC enzyme defects – G6PD, hereditary spherocytosis, alpha thalassemia Haemorrhage – cerebral, intra-abdominal Blood extravasation – (bruising/birth trauma) | FBE, film and reticulocytes Neonatal blood group Direct antiglobulin test (Coombs) (G6PD screen) | |
| Peak Onset (24 hours – 14 days) No further investigations needed unless red flags | Physiological jaundice | No further investigations required unless red flags |
| Dehydration/insufficient feeding | Serum sodium, BGL No further investigations required | |
| Sepsis | Please refer to Recognition of the seriously unwell neonate and young infant | |
| Haemolysis | FBE, film and reticulocytes Neonatal blood group Direct antiglobulin test (Coombs) (G6PD screen) | |
| Breastmilk jaundice | Diagnosis of exclusion after considering above causes | |
| Bruising, birth trauma | No further investigations required | |
| Prolonged/ conjugated (>2 weeks) All should have: – SBR (unconjugated/ conjugated) – FBE, film and reticulocytes – TFTs – group and DAT – LFTs if conjugated bilirubin >10% | Sepsis | Please refer to Recognition of the seriously unwell neonate and young infant |
| Haemolysis | FBE, film and reticulocytes Neonatal blood group Direct antiglobulin test (Coombs) (G6PD screen) | |
| Dehydration/ insufficient feeding | Serum sodium, BGL No further investigations required | |
| Breastmilk jaundice | Diagnosis of exclusion after considering above causes | |
| Hypothyroidism | TFTs (to exclude central hypothyroidism) | |
| Conjugated (At any age point) If conjugated fraction >10% of total bilirubin Refer to a specialty unit | Neonatal hepatitis | LFTs, maternal infectious serology, metabolic screening |
| Extrahepatic obstruction: – Biliary atresia – choledochal cyst – bile plug | LFTs, coags, abdominal US Note: a normal ultrasound does not exclude biliary atresia | |
| α 1 antitrypsin deficiency | Alpha-1 anti-trypsin levels, urinary reducing substances | |
| Drugs/Parenteral nutrition | Investigations as appropriate after history and exam |
Management
-1 Supportive Care
- Maintain adequate hydration and nutrition
- Continue breastfeeding or formula feeding as per usual care
-2 Phototherapy
- Initiate based on gestational age-adjusted bilirubin thresholds
- Use intensive phototherapy when required
- Position infant naked (with nappy) under lights, shield eyes
- Monitor temperature, hydration, and light distance
-3 Exchange Transfusion
- Indicated for:
- Bilirubin above exchange thresholds
- Clinical signs of kernicterus
- Performed in NICU under specialist supervision
-4 Specialist Referral
- Conjugated bilirubin > 20 µmol/L or >10% of total
- Pale stools, persistent or worsening jaundice
- Neurological signs (encephalopathy)
When to Consult/Transfer
- Unwell neonate or unclear diagnosis
- Conjugated bilirubin > 20 µmol/L or >10% total
- Rising bilirubin despite phototherapy
- Indication for exchange transfusion
Discharge Criteria and Follow-Up
-1 Discharge Criteria
- Full-term, afebrile, feeding well
- Bilirubin below treatment threshold
- No red flag features
-2 Follow-Up Plan
- GP review within 1–2 days:
- Assess intake, hydration, weight
- Repeat bilirubin if needed
-3 Parental Advice
- Feed every 3 hours, waking infant if necessary
- Observe for jaundice beyond 2–3 weeks
- Return if:
- Poor feeding
- Lethargy
- Dark urine or pale stools
Sunlight exposure is not recommended due to unpredictable intensity and risk of burns
Breast-Milk Jaundice
- Diagnosis of exclusion
- Onset typically day 5–10
- Infant otherwise well and thriving
- May persist for 3–12 weeks
- Continue breastfeeding with reassurance and monitoring