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 reticulocyte count with abnormal morphology:
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
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 2–4 at 5–6 mg/dL and then fall to < 2 mg/dL by the end of the 1st week
- Normal bilirubin levels by 10–14 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)
- Rule of thumb:
- Also evaluate for
- Cephalohematoma
- Petechiae
- Neurologic exam
- Signs requiring immediate phototherapy:
- Decreased muscle tone
- Seizures
- Altered cry
- Signs requiring immediate phototherapy:
- 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
| Bilirubin type | Bilirubin peak (mg/dL) | Bilirubin increase (mg/dL/day) | Comments/diseases | |
|---|---|---|---|---|
| May appear in 1st 24 hours | ||||
| Hemolytic/hematoma (duration: variable) | Indirect | Unlimited | < 5 |
|
| Hemolytic + hepatotoxic (duration: variable) | Indirect/direct | Unlimited | < 5 |
|
| May appear in 2–4 days | ||||
| Physiologic (disappears in 4–9 days) | Indirect | 10–15 | < 5 | Duration/severity increases with degree of prematurity |
| Metabolic (duration: variable) | Indirect | > 12–15 | < 5 |
|
| Hepatocellular damage (duration: variable) | Indirect/direct | Unlimited | < 5 |
|
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
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
- 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
- American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297
- 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
- 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.
