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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function 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 Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding-related, blood group isoimmunization, metabolic disorders, and infection. Regardless of etiology, the primary goal of therapy in neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency
      • Pyruvate kinase (PK) deficiency
      • Other enzyme deficiency
      • Disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. 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 Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
      • Breastfeeding
      • Gilbert’s syndrome
      • Crigler-Najjar syndrome

Increased direct (conjugated) bilirubin

  • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Intrauterine infection
  • Bile duct disorders
  • Bile obstruction
  • Severe hemolytic disease
  • Choledochal cyst
  • Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis
  • Galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. 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 Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding, particularly if nursing is not going well and weight loss is excessive
  • Known hemolytic disorder in the child
  • East Asian ethnicity ( G6PD deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock 
  • 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice: unclear etiology, seen in exclusively breastfed infants
  • Breastfeeding (lactation failure) jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice: secondary to inadequate nutrition and hydration
  • Genetic causes leading to increased RBC hemolysis
    • Structural: hereditary spherocytosis Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). Hereditary Spherocytosis and elliptocytosis
    • Enzymatic: G6PD deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency, PK deficiency
  • Genetic causes leading to decreased clearance 
    • Crigler-Najjar syndrome
    • Gilbert’s syndrome
  • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock

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 Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia
    • Tyrosinemia

Diagnosis

History

  • Family history 
    • Sibling with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, splenectomy 
    • Bile stones in family suspicious for sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
  • Pregnancy/perinatal history 
    • Maternal infections
    • Illicit drug use or herbal remedy use during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice can be challenging under fluorescent lighting.
    • Must account for a child’s natural pigmentation
    • Neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures 
      • Altered cry
  • Other important findings: hepatosplenomegaly, microcephaly, congenital malformations, signs of dehydration, infection, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

Indications for laboratory testing

  • Jaundice in 1st 24 hours or jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
Bilirubin type Bilirubin peak (mg/dL) Bilirubin increase (mg/dL/day) Comments/diseases
May appear in 1st 24 hours
Hemolytic/hematoma (duration: variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables) Indirect Unlimited < 5
  • Incompatibility: RH, ABO, Kell
  • Drugs: vitamin K
Hemolytic + hepatotoxic (duration: variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables) Indirect/direct Unlimited < 5
  • Infection
  • Drugs: vitamin K
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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables) Indirect > 12–15 < 5
  • Hypoxia
  • Cretinism (may appear in 2nd week)
  • Breast milk jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice (may also appear in 2nd week)
  • Gilbert’s or Crigler-Najjar syndromes
Hepatocellular damage (duration: variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables) Indirect/direct Unlimited < 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 Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. 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 Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). 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 Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. 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 Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. 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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