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Hyperbilirubinemia of the Newborn

Hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice of the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn is a broad term that refers to various conditions that can cause accumulation of bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism 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. Skin: Structure and Functions and sclera Sclera The white, opaque, fibrous, outer tunic of the eyeball, covering it entirely excepting the segment covered anteriorly by the cornea. It is essentially avascular but contains apertures for vessels, lymphatics, and nerves. Eye: Anatomy secondary to bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism deposition. Because hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice arises from physiological processes that accompany birth, it is usually an expected finding. However, hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice in the neonate Neonate An infant during the first 28 days after birth. Physical Examination of the Newborn 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 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 Indirect Bilirubin Liver Function Tests, mainly kernicterus. When indicated, treatment mainly includes phototherapy and exchange transfusion.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice of the newborn Newborn An infant during the first 28 days after birth. Physical Examination 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. Skin: Structure and Functions and sclera Sclera The white, opaque, fibrous, outer tunic of the eyeball, covering it entirely excepting the segment covered anteriorly by the cornea. It is essentially avascular but contains apertures for vessels, lymphatics, and nerves. Eye: Anatomy of the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn usually due to the tissue deposition of unconjugated bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism, the end product Product A molecule created by the enzymatic reaction. Basics of Enzymes 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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism

Positive Coombs test: isoimmunization

Negative Coombs test

  • Polycythemia Polycythemia An increase in the total red cell mass of the blood. Renal Cell Carcinoma:
    • Twin-to-twin transfusion
    • Maternal-fetal transfusion
    • Delayed cord clamping
    • Small for gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care
  • Low/normal hemoglobin:
    • Increased reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count with abnormal morphology:
    • Increased/normal reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count with normal morphology:
      • Enclosed hemorrhage (cephalhematoma)
      • Increased enterohepatic circulation Enterohepatic Circulation Recycling through liver by excretion in bile, reabsorption from intestines (intestinal reabsorption) into portal circulation, passage back into liver, and re-excretion in bile. Pharmacokinetics and Pharmacodynamics (delayed stooling, bowel obstruction Bowel obstruction Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anal canal. Ascaris/Ascariasis)
      • Inadequate caloric intake Inadequate Caloric Intake Failure to Thrive
      • Asphyxia Asphyxia A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. Drowning
      • 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 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
      • Gilbert’s syndrome
      • Crigler-Najjar syndrome Crigler-Najjar Syndrome A familial form of congenital hyperbilirubinemia transmitted as an autosomal recessive trait. It is characterized by icterus and brain damage caused by a glucuronyl transferase deficiency in the liver and faulty bilirubin conjugation. Jaundice

Increased direct (conjugated) bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism

  • Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
  • Intrauterine infection
  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct disorders
  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy obstruction
  • Severe hemolytic disease
  • Choledochal cyst
  • Cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • 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 Alpha-1 antitrypsin Plasma glycoprotein member of the serpin superfamily which inhibits trypsin; neutrophil elastase; and other proteolytic enzymes. Alpha-1 Antitrypsin (AAT) Deficiency deficiency
  • Tyrosinemia Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis
  • Alagille syndrome
  • Hepatitis

Risk Factors

Major risk factors

  • Predischarge high-risk clinical features or serum bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism levels based on the Bhutani nomogram
  • 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 in the first 24 hours of life
  • Maternal/fetal blood group incompatibility and positive antiglobulin test
  • Gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care 35–36 weeks
  • Prior phototherapy in siblings
  • Cephalohematoma Cephalohematoma Von Willebrand Disease 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 Weight loss Decrease in existing body weight. Bariatric Surgery is excessive
  • Known hemolytic disorder in the child
  • East Asian ethnicity ( G6PD G6PD Pentose Phosphate Pathway deficiency)

Minor risk factors

  • Having the last bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism reading prior to discharge high-intermediate-risk area based on the Bhutani nomogram
  • Gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care 37–38 weeks
  • 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 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 Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria

Additional risk factors

  • Dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
  • Infection
  • Delay in passage of meconium Meconium The thick green-to-black mucilaginous material found in the intestines of a full-term fetus. It consists of secretions of the intestinal glands; bile pigments; fatty acids; amniotic fluid; and intrauterine debris. It constitutes the first stools passed by a newborn. Prenatal and Postnatal Physiology of the Neonate
  • Drugs and substance: oxytocin (in mother), phenolic detergents (in nursery)
  • Polycythemia Polycythemia An increase in the total red cell mass of the blood. Renal Cell Carcinoma 
  • Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock 
  • Acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Low serum albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests

Factors that decrease risk

  • Predischarge low-risk clinical or serum bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism levels
  • Gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care ≥ 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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism level based on the hour-specific bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism level in newborns born at ≥ 35 weeks gestation

Image by Lecturio.

Classification

Indirect hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice

  • unconjugated
  • Physiologic (always unconjugated or indirect): due to increased production of bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism 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: Anatomy to conjugate bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism
    • 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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism 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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism (TSB) levels (> 15 mg/dL) in the presence of risk factors  
  • Increased enterohepatic circulation Enterohepatic Circulation Recycling through liver by excretion in bile, reabsorption from intestines (intestinal reabsorption) into portal circulation, passage back into liver, and re-excretion in bile. Pharmacokinetics and Pharmacodynamics of bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism
  • 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 ( lactation failure Lactation failure A medical condition characterized by insufficient milk production or absence of the let-down reflex in response to suckling Breastfeeding) 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 G6PD Pentose Phosphate Pathway deficiency, PK deficiency
  • Genetic causes leading to decreased clearance 
    • Crigler-Najjar syndrome Crigler-Najjar Syndrome A familial form of congenital hyperbilirubinemia transmitted as an autosomal recessive trait. It is characterized by icterus and brain damage caused by a glucuronyl transferase deficiency in the liver and faulty bilirubin conjugation. Jaundice
    • Gilbert’s syndrome
  • Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock

Direct hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice

  • → conjugated 
  • Obstructive causes
  • Infectious Infectious Febrile Infant causes
  • Genetic causes
  • 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 Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis

Diagnosis

History

  • Family history Family History Adult Health Maintenance 
    • 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 Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen 
    • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy 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 Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care/perinatal history 
    • Maternal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Illicit drug use or herbal remedy use during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
    • History of trauma to the infant during delivery
  • Postnatal history 
    • Acholic stool
    • Abnormal weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, especially when exclusively breastfed 
    • RhoGAM® administration
    • Signs of infection

Physical examination

  • General 
    • Note for tone and level of activity of the neonate Neonate An infant during the first 28 days after birth. Physical Examination of the Newborn
    • Infants with hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice are often drowsy.
  • 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. Skin: Structure and Functions 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 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 to face (approximately 5 mg/dL)  
        • 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 to mid abdomen (approximately 15 mg/dL) 
        • 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 to soles (approximately 20 mg/dL)
    • Also evaluate for
  • Neurologic exam
    • Signs requiring immediate phototherapy:
      • Decreased muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction
      • 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 Hepatosplenomegaly Cytomegalovirus, microcephaly Microcephaly A congenital abnormality in which the cerebrum is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (desk reference for neuroscience, 2nd ed. ). Fetal Alcohol Spectrum Disorder, congenital malformations Congenital malformations Congenital malformations or teratogenic birth defects are developmental disorders that arise before birth during the embryonic or fetal period. The rate of incidence for children born alive is approximately 3%. Teratogenic Birth Defects, signs of dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and 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 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 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 Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care based on the Bhutani nomogram
  • If TSB rising rapidly or infant requiring phototherapy, check:
    • CBC and smear
    • Blood type and Coombs test
    • Direct bilirubin Direct bilirubin Liver Function Tests and repeat TSB within 24 hours
    • Reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count, G6PD G6PD Pentose Phosphate Pathway, albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests, end-tidal carbon monoxide Carbon monoxide Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. Carbon Monoxide Poisoning in breath (ETCO) (if available), blood gases ( acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis)
  • Elevated direct bilirubin Direct bilirubin Liver Function Tests: perform urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children, urine culture Urine culture Urinary tract infections (UTIs), and sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock workup
  • 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 present > 3 weeks: check 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 and 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 screen and check direct bilirubin Direct bilirubin Liver Function Tests
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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism type Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism peak (mg/dL) Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism increase (mg/dL/day) Comments/diseases
May appear in 1st 24 hours
Hemolytic/ hematoma Hematoma A collection of blood outside the blood vessels. Hematoma can be localized in an organ, space, or tissue. Intussusception (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 Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies
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 Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies
May appear in 2–4 days
Physiologic (disappears in 4–9 days) Indirect 10–15 < 5 Duration/severity increases with degree of prematurity Prematurity Neonatal Respiratory Distress Syndrome
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 Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage
  • Cretinism Cretinism A condition in infancy or early childhood due to an in-utero deficiency of thyroid hormones that can be caused by genetic or environmental factors, such as thyroid dysgenesis or hypothyroidism in infants of mothers treated with thiouracil during pregnancy. Endemic cretinism is the result of iodine deficiency. Clinical symptoms include severe mental retardation, impaired skeletal development, short stature, and myxedema. Hypothyroidism (may appear in 2nd week)
  • Breast milk jaundice Breast Milk Jaundice Breastfeeding (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 Congenital Chorioretinitis bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct disorders (biliary atresia Atresia Hypoplastic Left Heart Syndrome (HLHS)), cholestasis, cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans, 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, hepatitis, infection/ sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock

Management

  • The goal of therapy in unconjugated neonatal hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice is to avoid neurotoxicity and prevent kernicterus. 
  • Phototherapy:
    • First-line therapy for unconjugated hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice
    • Considered when indirect bilirubin Indirect Bilirubin Liver Function Tests levels reach 50%70% of maximum
    • Provokes conformational changes that turn bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism into the soluble form lumirubin, which is excreted in urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat and bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy
    • 420–470 nm are the light frequencies that produce the best results.
    • Complications include: 
      • Dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and 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 Exposure ABCDE Assessment
      • Bronze baby syndrome (in the presence of direct hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice)
      • Corneal damage (if eyes not appropriately covered)
  • Intravenous immune globulin ( IVIG IVIG Dermatomyositis): 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 Indirect Bilirubin Liver Function Tests
  • Exchange transfusion: 
    • When phototherapy fails to control hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice
    • When there are signs of kernicterus regardless of bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism levels
    • At bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism levels approaching the maximum for that infant, especially during the 1st 48 hours
    • In cases of severe hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice, 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 Types, and hydrops Hydrops Cholecystitis (used when phototherapy and IVIG IVIG Dermatomyositis fail)
  • Adjunct treatment: enteral feeding is encouraged, fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome 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 Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism crosses the blood-brain barrier Blood-brain barrier Specialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Systemic and Special Circulations, causing tissue damage
  • Subtle long-term effects causing disorders in: 
  • Acute bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism encephalopathy Encephalopathy Hyper-IgM Syndrome:
    • 1st 48 hours: lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia, poor feeding, loss of Moro reflex Moro Reflex Primitive Reflexes, increasingly ill appearance, respiratory distress 
    • Middle of 1st week: extensor hypertonia Hypertonia Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. Neurological Examination, 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 Hypertonia Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. Neurological Examination  
  • Chronic bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism encephalopathy Encephalopathy Hyper-IgM Syndrome (kernicterus):
    • 1st year: hypotonia Hypotonia Duchenne Muscular Dystrophy, increased deep tendon reflexes Deep Tendon Reflexes Neurological Examination, delayed motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills
    • After 1st year: choreoathetosis, ballismus, tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies, 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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