Neonatal jaundice

Neonatal jaundice is one of the most common conditions occurring in newborn infants and is characterized by elevated levels of bilirubin in the blood (total serum bilirubin concentration > 5 mg/dL or > 85.5 μmol/L). The most common cause of neonatal jaundice is a physiological rise in unconjugated bilirubin, which results from hemolysis of fetal hemoglobin and an immature hepatic metabolism of bilirubin. Physiological neonatal jaundice is harmless and occurs in most infants between the second and the eighth day of life. Pathologic neonatal jaundice can be conjugated or unconjugated and is typically a symptom of an underlying disease. Possible conditions include hemolytic anemias, blood group incompatibilities, Gilbert syndrome and Crigler-Najjar syndrome, G6PD deficiency, and congenital biliary flow obstructions. Hyperbilirubinemia can cause drowsiness and poor feeding in the newborn, and in severe cases, unconjugated bilirubin can cross the blood-brain barrier and cause permanent neurological damage (kernicterus). The degree of hyperbilirubinemia can be measured by transcutaneous and/or serum bilirubin measurements. Treatment modalities include phototherapy, intravenous immune globulin (IVIG), and exchange transfusion, in addition to specific therapies for the respective underlying conditions. Treatment is targeted at reducing the risk of kernicterus and hence permanent neurological sequelae.

Physiological neonatal jaundice ^[5]

• Unconjugated hyperbilirubinemia caused by
  • Short lifespan of erythrocytes in the newborn
  • Insufficient hepatic bilirubin metabolism: due to immature UDP-glucuronosyltransferase
  • ↑ Enterohepatic circulation of bilirubin

Pathological neonatal jaundice ^[5]

• Hyperbilirubinemia can be caused by multiple mechanisms
  • Increased production of bilirubin (e.g., conditions with increased hemolysis)
  • Decreased hepatic uptake (e.g., due to liver immaturity)
  • Decreased conjugation (e.g., Crigler-Najjar syndrome)
  • Impaired excretion (e.g., conditions with cholestasis, gastrourinary malformations)
  • Increased enterohepatic circulation (e.g., conditions with decreased intestinal motility, breastfeeding jaundice)

Breastfeeding jaundice ^[5]

• Definition: a type of neonatal jaundice caused by insufficient breastfeeding
• Pathophysiology: insufficient breast milk intake; → lack of calories and inadequate quantities of bowel movements to remove bilirubin from the body → ↑ enterohepatic circulation → increased reabsorption of bilirubin from the intestines → unconjugated hyperbilirubinemia
• Clinical features: onset within 1 week
• Treatment: : increase breastfeeding sessions, rehydration

Breast milk jaundice ^[5]

• Definition: a type of neonatal jaundice caused by increased levels of β-glucuronidase in maternal breast milk
• Pathophysiology: increased concentration of β-glucuronidase in breast milk → ↑ deconjugation and reabsorption of bilirubin → persistence of physiologic jaundice with unconjugated hyperbilirubinemia
  • β-Glucuronidase is found in breast milk and the intestinal brush border.
  • Deconjugation of bilirubin by bacterial β-glucuronidase can lead to pigment stone formation. ^[6]
• Clinical features: : onset within 2 weeks after birth; lasts for 4–13 weeks
• Treatment
  • Continued breastfeeding and supplementation with formula feeds
  • Phototherapy, if required

• Physiological neonatal jaundice
  • Asymptomatic, except for transient icterus
  • Jaundice manifests after 1^st day of life and usually resolves without treatment in 1 week (in term infants) or 2 weeks (in preterm infants).
  • Usually most severe on the 5^th day
• Pathological neonatal jaundice
  • Jaundice can appear < 24 hours after birth and persist > 1 week in term infants and > 2 weeks in preterm infants.
  • Clinical features of the underlying cause

• Physical examination for icterus: The American Academy of Pediatrics (AAP) recommends regular assessment of all neonates for jaundice (every 8–12 hours) while in the hospital.
• Bilirubin tests ^[7][8]
  • Transcutaneous bilirubin measurement (TcB)
    • Bilirubin levels > 95^thpercentile on nomogram indicate neonates at high risk for developing neurological sequelae.
  • Serum bilirubin measurement
    • Total serum bilirubin measured
    • Differentiation of direct (conjugated) and indirect (unconjugated) bilirubin
    • Assessment of degree of jaundice based on nomogram → infants > 95^thpercentile must be evaluated for pathological jaundice (See “Other laboratory tests” below.)
• Other laboratory tests
  • Complete blood count (including reticulocyte count)
  • Blood group
  • Direct and indirect Coombs' test (See “Rh incompatibility.”)
  • Markers of inflammation
  • Liver enzymes
  • Total serum protein and serum albumin
  • TSH and free T₄
  • G6PD activity (in patients with G6PD deficiency)

Physiological neonatal jaundice is a diagnosis of exclusion. Laboratory tests should first rule out all pathological causes of neonatal jaundice.

Jaundice in a term newborn less than 24 hours old is always pathologic.

Phototherapy ^[2][7][9]

Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.

• Indications
  • For infants born ≥ 35 weeks gestation, threshold bilirubin levels (TSB) for treatment are based on the American Academy of Pediatrics (AAP) phototherapy nomogram, which divides the infants into three risk groups: ^[7]
    • Low-risk infants: ≥ 38 weeks and well
    • Medium-risk infants: ≥ 38 weeks with risk factors (e.g., isoimmune hemolytic disease, G6PD deficiency, sepsis), or 35-37 weeks and well
    • High-risk infants: 35-37 weeks with risk factors
  • For infants born < 35 weeks gestation, threshold bilirubin levels for treatment are lower because premature infants are at a greater risk of neurotoxicity. ^[10]
• Procedure
  • Exposure to blue light (non-UV, wavelength: 420–480 nm) → photoisomerization (major mechanism) and photooxidation (minor mechanism) of unconjugated (hydrophobic) bilirubin in skin to water-soluble forms → excretion of water-soluble form in urine and/or bile
  • Continued until total bilirubin levels < 15 mg/dL
  • Adequate fluid supplementation to prevent dehydration
  • Eye protection to prevent retinal damage
• Contraindications
  • Concomitant use of photosensitizing medications
  • Congenital erythropoietic porphyria
  • Family history of porphyria
• Side effects
  • Diarrhea, dehydration
  • Changes in skin hue (bronzing) and skin rashes
  • Separation of the neonate from the mother
  • ↑ Risk of AML
  • Bronze baby syndrome (rare)
    • Occurs in infants with elevated direct bilirubin (conjugated bilirubin > 2mg/dL) following phototherapy
    • Thought to be caused by abnormal accumulation of bronze-colored pigments (photoisomers of bilirubin) within the skin
    • Presents with a reversible grayish-brown discoloration of the skin, urine, and serum
    • Usually resolves slowly after cessation of phototherapy without complications

Newborns with TSB levels below the phototherapy threshold usually do not require treatment. ^[11]

Exchange transfusion

Most rapid method for lowering serum bilirubin concentrations

• Indications
  • Threshold in a 24-hour-old term baby is a total serum bilirubin value > 20 mg/dL
  • Inadequate response to phototherapy, or a rapid rise in the total serum bilirubin level (> 1 mg/dL/hour in less than 6 hours)
  • Acute bilirubin encephalopathy
  • Hemolytic disease, severe anemia
• Procedure
  • Use ABO-matched and Rh-negative erythrocyte concentrate.
  • Exchange blood in quantities of 5–20 mL via an umbilical venous catheter until total serum bilirubin is < 95^thpercentile on nomogram.
• Side effects
  • Higher mortality and morbidity from infections
  • Acidosis
  • Thrombosis
  • Hypotension
  • Electrolyte imbalances

IV immunoglobulin

• Indications: used in cases with immunologically mediated conditions, or in the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice
• Dose range for IVIG: 500–1000 mg/kg

Acute bilirubin encephalopathy

• Onset within first days of life
• Lethargy, infantile hypotonia, poor feeding
• Fever, shrill cry
• Stupor, apnea, seizures
• Possibly fatal if neurotoxicity is severe

Kernicterus (chronic bilirubin encephalopathy)

• Develops over first years of life
• Pathophysiology: deposition of unconjugated bilirubin (liposoluble) in the basal ganglia and/or brain stem nuclei
• Clinical features
  • Cerebral paresis, hearing impairment, vertical gaze palsy
  • Movement disorder (choreoathetosis)
  • Apparent intellectual and developmental disabilities
  • Dental enamel hypoplasia

We list the most important complications. The selection is not exhaustive.

• Favorable in most cases
• In rare cases, kernicterus may occur, resulting in permanent neurological sequelae.

Interruption of enterohepatic circulation with adequate enteral nutrition ^[7]

• Frequent feeds with breast milk
• Protein-rich nutrition in the form of breast milk or special formula feeds
• In the case of dehydration, protein-rich feeding solutions are preferred over glucose or water.