Hyperbilirubinemia of the Newborn

Hyperbilirubinemia of the newborn is a broad term that refers to various conditions that can cause accumulation of bilirubin during the first few days after birth. The condition is often noted because of visible yellowing of the skin and sclera secondary to bilirubin deposition. Because hyperbilirubinemia arises from physiological processes that accompany birth, it is usually an expected finding. However, hyperbilirubinemia in the neonate can also have pathological etiologies, including breastfeeding-related, blood group isoimmunization, metabolic disorders, and infection. Regardless of etiology, the primary goal of therapy in neonatal jaundice is to prevent the neurotoxic effect of indirect bilirubin, mainly kernicterus. When indicated, treatment mainly includes phototherapy and exchange transfusion.

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Overview

Definition

Hyperbilirubinemia of the newborn is defined as a yellow discoloration of the skin and sclera of the newborn usually due to the tissue deposition of unconjugated bilirubin, the end product of heme-protein catabolism.

Epidemiology

  • 60% of term infants and 80% of preterm infants have visible jaundice after birth.
  • More common in East Asians and Native Americans

Etiology

Increased indirect (unconjugated) bilirubin

Positive Coombs test: isoimmunization

  • ABO incompatibility
  • Rh incompatibility
  • Other alloimmunization

Negative Coombs test

  • Polycythemia:
    • Twin-to-twin transfusion
    • Maternal-fetal transfusion
    • Delayed cord clamping
    • Small for gestational age
  • Low/normal hemoglobin:
    • Increased reticulocyte count with abnormal morphology:
      • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
      • Pyruvate kinase (PK) deficiency
      • Other enzyme deficiency
      • Disseminated intravascular coagulation
      • Spherocytosis
      • Elliptocytosis
      • Stomatocytosis
      • Pyknocytosis
    • Increased/normal reticulocyte count with normal morphology:
      • Enclosed hemorrhage (cephalhematoma)
      • Increased enterohepatic circulation (delayed stooling, bowel obstruction)
      • Inadequate caloric intake
      • Asphyxia
      • Hypothyroidism
      • Breastfeeding
      • Gilbert’s syndrome
      • Crigler-Najjar syndrome

Increased direct (conjugated) bilirubin

  • Sepsis
  • Intrauterine infection
  • Bile duct disorders
  • Bile obstruction
  • Severe hemolytic disease
  • Choledochal cyst
  • Cystic fibrosis
  • Galactosemia
  • Alpha-1 antitrypsin deficiency
  • Tyrosinemia
  • Alagille syndrome
  • Hepatitis

Risk Factors

Major risk factors

  • Predischarge high-risk clinical features or serum bilirubin levels based on the Bhutani nomogram
  • Jaundice in the first 24 hours of life
  • Maternal/fetal blood group incompatibility and positive antiglobulin test
  • Gestational age 35–36 weeks
  • Prior phototherapy in siblings
  • Cephalohematoma or significant bruising
  • Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive
  • Known hemolytic disorder in the child
  • East Asian ethnicity (G6PD deficiency)

Minor risk factors

  • Having the last bilirubin reading prior to discharge high-intermediate-risk area based on the Bhutani nomogram
  • Gestational age 37–38 weeks
  • Jaundice observed before discharge
  • Sibling with prior jaundice
  • Diabetes-induced macrosomia
  • Maternal age ≥ 25 years
  • Male sex

Additional risk factors

  • Dehydration
  • Infection
  • Delay in passage of meconium
  • Drugs and substance: oxytocin (in mother), phenolic detergents (in nursery)
  • Polycythemia 
  • Sepsis 
  • Acidosis
  • Low serum albumin

Factors that decrease risk

  • Predischarge low-risk clinical or serum bilirubin levels
  • Gestational age ≥ 41 weeks
  • Exclusive bottle-feeding
  • African American
  • Discharge from hospital after 72 hours
Bhutani diagram

The Buthani nomogram identifying risk of subsequent total serum bilirubin level based on the hour-specific bilirubin level in newborns born at ≥ 35 weeks gestation

Image by Lecturio.

Classification

Indirect hyperbilirubinemia

  • unconjugated
  • Physiologic (always unconjugated or indirect): due to increased production of bilirubin caused by fetal erythrocyte breakdown and transient limitation of the liver to conjugate bilirubin
    • Expected to appear after the 1st 24 hours and peak by day 24 at 56 mg/dL and then fall to < 2 mg/dL by the end of the 1st week
    • Normal bilirubin levels by 1014 days is < 1 mg/dL
  • Exaggerated physiologic jaundice (always unconjugated or indirect): 
    • May reach high total serum bilirubin (TSB) levels (> 15 mg/dL) in the presence of risk factors  
  • Increased enterohepatic circulation of bilirubin
    • Breast milk jaundice: unclear etiology, seen in exclusively breastfed infants
  • Breastfeeding (lactation failure) jaundice: secondary to inadequate nutrition and hydration
  • Genetic causes leading to increased RBC hemolysis
    • Structural: hereditary spherocytosis and elliptocytosis
    • Enzymatic: G6PD deficiency, PK deficiency
  • Genetic causes leading to decreased clearance 
    • Crigler-Najjar syndrome
    • Gilbert’s syndrome
  • Sepsis

Direct hyperbilirubinemia

  • → conjugated 
  • Obstructive causes
    • Biliary atresia
    • Biliary cyst
    • Neonatal sclerosing cholangitis
  • Infectious causes
    • Congenital infections (TORCH pathogens)
    • Acquired perinatal infections
  • Genetic causes
    • Alagille syndrome
    • Alpha-1 antitrypsin deficiency
  • Metabolic causes
    • Galactosemia
    • Tyrosinemia

Diagnosis

History

  • Family history 
    • Sibling with jaundice, splenectomy 
    • Bile stones in family suspicious for sickle cell disease
  • Pregnancy/perinatal history 
    • Maternal infections
    • Illicit drug use or herbal remedy use during pregnancy
    • History of trauma to the infant during delivery
  • Postnatal history 
    • Acholic stool
    • Abnormal weight loss, especially when exclusively breastfed 
    • RhoGAM® administration
    • Signs of infection

Physical examination

  • General 
    • Note for tone and level of activity of the neonate
    • Infants with hyperbilirubinemia are often drowsy.
  • Skin exam
    • Evaluating jaundice can be challenging under fluorescent lighting.
    • Must account for a child’s natural pigmentation
    • Neonatal jaundice progresses cephalocaudally:
      • Rule of thumb:
        • Jaundice to face (approximately 5 mg/dL)  
        • Jaundice to mid abdomen (approximately 15 mg/dL) 
        • Jaundice to soles (approximately 20 mg/dL)
    • Also evaluate for
      • Cephalohematoma
      • Petechiae
  • Neurologic exam
    • Signs requiring immediate phototherapy:
      • Decreased muscle tone
      • Seizures 
      • Altered cry
  • Other important findings: hepatosplenomegaly, microcephaly, congenital malformations, signs of dehydration, infection, fever

Indications for laboratory testing

  • Jaundice in 1st 24 hours or jaundice appearing excessive for infant’s age: check TSB
  • Consider risk assessment based on the Bhutani nomogram
  • If TSB rising rapidly or infant requiring phototherapy, check:
    • CBC and smear
    • Blood type and Coombs test
    • Direct bilirubin and repeat TSB within 24 hours
    • Reticulocyte count, G6PD, albumin, end-tidal carbon monoxide in breath (ETCO) (if available), blood gases (acidosis)
  • Elevated direct bilirubin: perform urinalysis, urine culture, and sepsis workup
  • Jaundice present > 3 weeks: check hypothyroidism and galactosemia screen and check direct bilirubin
Table: Diagnostic features of neonatal jaundice
Bilirubin typeBilirubin peak (mg/dL)Bilirubin increase (mg/dL/day)Comments/diseases
May appear in 1st 24 hours
Hemolytic/hematoma (duration: variable)IndirectUnlimited< 5
  • Incompatibility: RH, ABO, Kell
  • Drugs: vitamin K
Hemolytic + hepatotoxic (duration: variable)Indirect/directUnlimited< 5
  • Infection
  • Drugs: vitamin K
May appear in 2–4 days
Physiologic (disappears in 4–9 days)Indirect10–15< 5Duration/severity increases with degree of prematurity
Metabolic (duration: variable)Indirect> 12–15< 5
  • Hypoxia
  • Cretinism (may appear in 2nd week)
  • Breast milk jaundice (may also appear in 2nd week)
  • Gilbert’s or Crigler-Najjar syndromes
Hepatocellular damage (duration: variable)Indirect/directUnlimited< 5
  • May also appear after 1st week
  • Congenital bile duct disorders (biliary atresia), cholestasis, cystic fibrosis, galactosemia, hepatitis, infection/sepsis

Management

  • The goal of therapy in unconjugated neonatal hyperbilirubinemia is to avoid neurotoxicity and prevent kernicterus. 
  • Phototherapy:
    • First-line therapy for unconjugated hyperbilirubinemia
    • Considered when indirect bilirubin levels reach 50%70% of maximum
    • Provokes conformational changes that turn bilirubin into the soluble form lumirubin, which is excreted in urine and bile
    • 420–470 nm are the light frequencies that produce the best results.
    • Complications include: 
      • Dehydration
      • Hypothermia from exposure
      • Bronze baby syndrome (in the presence of direct hyperbilirubinemia)
      • Corneal damage (if eyes not appropriately covered)
  • Intravenous immune globulin (IVIG): in isoimmune hemolytic anemia not responsive to phototherapy and reaching maximum levels of indirect bilirubin
  • Exchange transfusion: 
    • When phototherapy fails to control hyperbilirubinemia
    • When there are signs of kernicterus regardless of bilirubin levels
    • At bilirubin levels approaching the maximum for that infant, especially during the 1st 48 hours
    • In cases of severe hyperbilirubinemia, severe anemia, and hydrops (used when phototherapy and IVIG fail)
  • Adjunct treatment: enteral feeding is encouraged, fluid resuscitation in dehydrated babies
Neonatal hyperbilirubinemia

A child receiving phototherapy

Image: “Baked Bean” by shannonpatrick17. License: CC BY 2.0

Complications

Bilirubin-induced neurologic dysfunction (BIND):

  • Occurs when bilirubin crosses the blood-brain barrier, causing tissue damage
  • Subtle long-term effects causing disorders in: 
    • Vision
    • Hearing
    • Speech
  • Acute bilirubin encephalopathy:
    • 1st 48 hours: lethargy, poor feeding, loss of Moro reflex, increasingly ill appearance, respiratory distress 
    • Middle of 1st week: extensor hypertonia, opisthotonos, and fever
    • After 1st week: hypertonia  
  • Chronic bilirubin encephalopathy (kernicterus):
    • 1st year: hypotonia, increased deep tendon reflexes, delayed motor skills
    • After 1st year: choreoathetosis, ballismus, tremor, upward gaze, sensorineural hearing loss

References

  1. Kaplan, M., Wong, R. J., Burgis, J. C., Sibley, E., & Stevenson, D. K. (2020). Neonatal jaundice and liver diseases. In Martin, Richard J., MBBS, FRACP, Fanaroff, Avroy A., MD, FRCPE, FRCPCH & Walsh, Michele C., MD, MSE (Eds.), Fanaroff and martin’s neonatal-perinatal medicine (pp. 1788-1852). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323567114000912
  2. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297
  3. Doan, Q. H., & Kissoon, N. (2016). Neonatal emergencies and common neonatal problems. In J. E. Tintinalli, J. S. Stapczynski, O. J. Ma, D. M. Yealy, G. D. Meckler & D. M. Cline (Eds.), Tintinalli’s emergency medicine: A comprehensive study guide, 8e. New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1121507183
  4. Kliegman RB, ST Geme JW, Blum MJ, Shah SS, Tasker RC, Wilson KM, Behrman RE. Nelson’s Textbook of Pediatrics (20th Ed.). Philadelphia, PA: Elsevier; 2016.

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