Neonatal jaundice

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Neonatal jaundice is a yellowing of the skin and other tissues of a newborn infant caused by increased levels of bilirubinin the blood. A bilirubin level of more than 85 umol/l (5 mg/dL) manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l (2 mg/dL) would look icteric. In newborns jaundice is detected by blanching the skin with digital pressure so that it reveals underlying skin and subcutaneous tissue. Jaundice newborns have an apparent icteric sclera, and yellowing of the face, extending down onto the chest. In neonates the dermal icterus is first noted in the face and as the bilirubin level rises proceeds caudal to the trunk and then to the extremities.

Neonatal jaundice was first described by the authors of some pediatrics texts in the 19th century. Some medical records showed several cases of icterum neonatorum in the period between 1885 and 1891. The Rh body antigens were discovered in 1940. Through the 20th century, the description of the inherited neonatal jaundice syndromes were described.

Neonatal jaundice can be classified based on the etiology of the jaundice into pathological jaundice, physiological jaundice, breastfeeding jaundice, and hemolytic jaundice.

Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert’s syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

Neonatal jaundice is caused by hemolysis of the RBCs mainly due to either intravascular causes or extravascular causes. Other causes include non-hemolytic causes such as cephalosporin induced jaundice, genetic mutations of the UGT enzyme, and hepatic causes.

Neonatal jaundice must be differentiated from other causes of jaundice as hepatocellular jaundice and cholestatic jaundice.

The prevalence of neonatal jaundice ranges from a low of 60,000 to high of 70,000 per 100,000 neonates. The prevalence of the neonatal jaundice decreases by increasing the gestational age of the neonate. The prevalence of neonatal jaundice is more in the East Asian, American Indian, and Greek races.

Common risk factors for neonatal jaundice include maternal risk factors and neonatal risk factors. Common maternal risk factors include mother of Asian race, usage of oxytocin during labor, exclusive breastfeeding, and prolonged labor. Neonatal risk factors include family history of siblings received phototherapy, ABO blood group incompatiblity, preterm neonates, and cephalhematoma. Less common risk factors for neonatal jaundice include maternal age more than 25 years, siblings with jaundice, male neonates, and black race neonates.

According to the American Academy of Pediatrics, screening tests recommended for neonatal jaundice include blood typing, clinical assessment of jaundice in the newborns, assessment of the total serum bilirubin level, measuring the level of G6PD enzyme. Also, it is recommended for all hospitals to provide information to the parents on jaundice and its consequences.

If left untreated, neonatal jaundice may lead to brain damage. Common complications of neonatal jaundice include acute bilirubin encephalopathy and kernicterus. Prognosis of neonatal jaundice is excellent with the proper treatment.

Bilirubin plasma level is the gold standard test for the diagnosis of jaundice. Usually the concentration of bilirubin in the blood must exceed 2–3 mg/dL for the coloration to be easily visible.

Family and maternal history obtaining is important for diagnosing of neonatal jaundice. Family history include the history of previous sibling who developed before neonatal jaundice, any other family member with liver disease, and family history of hemolytic anemia. Maternal history include obtaining the history of pregnancy and delivery, any maternal illnesses, breastfeeding history, and usage of any drugs. Symptoms of the neonatal jaundice include yellow color discoloration which is observed in the conjunctiva, mucus membranes, and skin.

Patients with neoanatal jaundice usually appear drowsy in severe cases. Physical examination of patients with neonatal jaundice is usually remarkable for yellow skin, petichia, yellow eye, hepatomegaly, seizures, and microcephaly in some cases.

An elevated concentration of serum bilirubin in neonates in the first 24 hours of life is diagnostic of neonatal jaundice. Transcutaneous bilirubin level measurement can be diagnostic in cases of mild jaundice. Other laboratory tests that can be performed include blood typing and Rhantibodies determination, liver function tests, direct Coombs test, serum albumin level, and reticulocyte count.

There are no ECG findings associated with neonatal jaundice.

There are no X-ray findings associated with neonatal jaundice.

There are no CT scan findings associated with neonatal jaundice.

There are no MRI findings associated with neonatal jaundice.

Ultrasound can be useful for assessing hepatomegaly, or liver enlargement, which can sometimes be seen in hemolytic diseases causing jaundice.

There are no other imaging findings associated with neonatal jaundice.

There are no other diagnsotic studies associated with neonatal jaundice.

The mainstay of treatment of patients with neonatal jaundice is phototherapy, intravenous immunoglobulins and blood exchange.

Surgery is not recommended for the management of neonatal jaundice.

Effective measures for the primary prevention of neonatal jaundice include breastfeeding of the infants and avoidance of dextrose water supplementation of the breastfeeded infants.

According to the American Academy of Pediatrics, secondary prevention of neonatal jaundice is achieved via proper screening tests which include blood typing, clinical assessment of jaundice in the newborns, assessment of the total serum bilirubin level, measuring the level of G6PD enzyme, and it is also recommended for all hospitals to provide information to the parents on jaundice and its consequences.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Neonatal jaundice was first described by the authors of some pediatrics texts in the 19th century. Some medical records showed several cases of icterus neonatorum in the period between 1885 and 1891. The Rh body antigens were discovered in 1940. Through the 20th century, the description of the inherited neonatal jaundice syndromes were described.

• In the 19th century, the authors of some pediatric texts described cases of yellowish discoloration in the newborns and named it “Icterus neonatorum”. They described the condition of icterus neonatorum as benign self-resolved disease.
• Between 1885 and 1891, some medical records from the original Providence hospital showed several cases of icterum neonatourm through the first week of life.
• In 1940, the Rh antigens were discovered and that confirmed the genetic basis of the neonatal jaundice disease.
• Between 1940 and 1950, some studies were performed on hemolytic diseases of the newborn in order to learn the pathogenesis of neonatal jaundice. These studies played a great role in development of a good perinatal and neonatal care.^[1]
• In 1950, Dr. London published an article describing the mechanism of bile metabolism inside the human body.^[2]
• In 1964, Dr. Arias was the first to describe the breast milk jaundice.^[3]

• Gilbert syndrome:^[4]
  • In 1901, Dr. Gilbert and Dr. Lereboulet described the Gilbert syndrome as a cause of neonatal jaundice.
  • It is now considered as the most common hereditary cause of hyperbilirubinemia in the neonates.
• Rotor syndrome:
  • In 1948, Dr. Rotor described a defect of hepatic reuptake of bilirubin resulting in hyperbilirubinemia.
• Crigler-Najjar syndrome:^[5]
  • In 1952, Dr. Crigler and Dr. Najjar described the one type of syndrome due to absence of UGT1A1 enzyme activity.
  • In 1962, Dr. Arias described another variation of the syndrome in which there is a reduced activity of UGT1A1 enzyme. The syndrome named either Crigler-Najjar syndrome type 2 or Arias syndrome.
• Dubin-Johnson syndrome:^[6]
  • In 1954, Dr. Dubin reported some cases of young adults with black liver and jaundice.
• Lucey-Driscoll syndrome:^[7]
  • In 1965, Dr. Lucey described another cause of severe . in the newborns during the first few days of life.

• In the 1960s, Dr. John Barrett, Dr. Frank Giunta, and Edwin Forman formed a consultation team for the newborns with jaundice in order to perform blood transfusion when needed.^[8]
• In 1958, the phototherapy was discovered at Rochford Hospital in Essex, England. However, most of the hospitals began using phototherapy ten years after its discovery when an American group made their own discovery.^[9]

• In 1968, Rh antiglobulin was developed and it is being given during pregnancy. After this development, the Rh erythroblastosis has been a rare disease now.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Neonatal jaundice can be classified based on the etiology of the jaundice into pathological jaundice, physiological jaundice, breastfeeding jaundice, and hemolytic jaundice.

• Neonatal jaundice can be classified based on the etiology of jaundice into:^[1]
  • Pathological jaundice: It can be classified based on the type of the hyperbilirubinemia into two subtypes:
    • Conjugated hyperbilirubinemia
    • Unconjugated hyperbilirubinemia
  • Physiological jaundice
  • Breastfeeding jaundice
  • Hemolytic jaundice

Neonatal jaundice

Unconjugated bilirubin

Conjugated bilirubin

Pathologic

Physiologic

Hepatic

Post-hepatic

Hemolytic

Non-hemolytic

Intrinsic causes

Extrinsic causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert’s syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

• Bilirubin is the final catabolic product of the heme. The heme is a component of various biological molecules and enzymes but, it is mainly incorporated in the hemoglobin which is the primary component of the red blood cells.^[1][2]
• Bilirubin is formed mainly in the liver and spleen through two steps which include:^[3][4]
  • Heme oxygenase enzyme degrades the porphyrin ring of the heme and breaks it down. A green compound called biliverdin is then formed as a result of the previous reaction. Carbon monoxide is released as a result of the reaction.
  • Biliverdin reductase enzyme catalyzes the formation of bilirubin from biliverdin.
• Bilirubin is a toxic metabolite so, the body has physiologic processes to eliminate the bilirubin. Bilirubin elimination process includes:^[5]
  • Hepatic uptake:^[6]
    • After the formation of the bilirubin and its secretion into the bloodstream, bilirubin becomes bound to the albumin to facilitate its transportation to the liver.
    • The hepatocytes then reuptake the bilirubin and prepare it for excretion.
  • Conjugation:^[7][8]
    • Bilirubin is then conjugated with glucuronic acid producing bilirubin diglucuronide which is water soluble.
    • Being water soluble, hence, the conjugated bilirubin can be excreted into bile.
    • The conjugation process occurs by the glucuronosyltransferase enzyme in the liver cells.
  • Clearance and excretion:^[9]
    • After conjugation of the bilirubin in the liver, it is secreted into the bile then into the gastrointestinal tract.
    • In the GIT, the conjugated bilirubin is metabolized by the gut enzymes into urobilinogen which is oxidized into urobilin.
    • Metabolism of the conjugated bilirubin occurs properly in the adults. However, the newborns have sterile gastrointestinal canal which impedes the catalyzation of the conjugated bilirubin.
    • The sterile tract ends up with a small amount of excreted bile.
    • The remaining conjugated bilirubin is unconjugated by the beta-glucuronidase enzyme in the neonatal intestine.
    • The unconjugated bilirubin is reabsorbed back into the blood and to the liver through the enterohepatic circulation of bilirubin.
    • A small amount of bilirubin is cleared into the urine as urobilinogen.

• Neonatal jaundice may be a result of physiological or pathological mechanisms. The different mechanisms for development of jaundice may be concluded into either an increase in the bilirubin production, increase the enterohepatic circulation, or decrease bilirubin elimination.^[10]
• Physiological jaundice:^[11][12]
  • The children have red blood cells twice or more than twice the number compared with the adults have and with shorter lifespan.
  • Increased rate of the red blood cells destruction produces elevated levels of bilirubin which ends up in jaundice.
  • The newborn gastrointestinal gut is considered sterile so, a small amount of the unconjugated bilirubin is converted to conjugated and excreted. Most of the unconjugated bilirubin is recirculated through the enterohepatic circulation.
  • Unconjugated hyperbilirubinemia is the predominant form of physiological jaundice.
  • Physiological jaundice is benign and resolves within 10 to 14 days of life.
• Pathological jaundice: ^[13]
  • The majority of neonatal jaundice is due to pathological conditions. Pathological neonatal jaundice is due to acquired or inherited conditions.
  • Pathological jaundice is the result of an increase in the level of unconjugated bilirubin which is named as “Indirect hyperbilirubinemia“.
  • It includes some features like the appearance of jaundice within the first day of life, persistent jaundice manifestations more than two weeks, and dark urine.
  • Acquired pathological neonatal jaundice develops mainly due to hemolysis of the red blood cells via three main diseases:^[14]
    • Rhesus (Rh) hemolytic disease
    • ABO blood group incompatibility
    • Glucose-6-phosphate dehydrogenase enzyme deficiency (G6PD deficiency)
  • Inherited pathological neonatal jaundice occurs due to a defect in the bilirubin metabolism and it include:^[15]
    • Defective hepatic uptake and storage of the bilirubin
    • Defective bilirubin conjugation to glucuronic acid and it include:
      • Gilbert syndrome
      • Crigler-Najjar syndrome
      • Lucey-Driscoll syndrome
      • Breast milk jaundice
    • Defective excretion of bilirubin into the bile and this syndrome called Dubin-Johnson syndrome
    • Defective reuptake of the conjugated bilirubin through the enterohepatic circulation. This syndrome called Rotor syndrome.

• The following table contains the different hemolytic mechanisms which lead to neonatal jaundice:^[16][17]

Hemolytic disease	Pathogenesis
Rhesus factor (Rh) hemolytic disease	It is known as the Rh hemolytic disease of the newborns (RHDN). RHDN is the result of alloimmunization of the maternal red blood cells when the mother is pregnant with a Rh-positive fetus. In the first pregnancy, if the fetus is a Rh-positive, some of the fetal blood is mixed with the maternal blood during birth. The maternal body forms antibodies (IgG) against the fetal Rh antigen but the first born is not affected. In the second birth, if the fetus is a Rh-positive, the pre-formed maternal anti-Rh antibodies will cause hemolysis to the fetal blood. This condition may lead to either mild or severe hemolytic anemia and may occasionally end up with hydrops fetalis.
ABO blood group incompatibility	ABO blood group incompatibility is another form of the alloimmunization of the maternal blood cells against the fetal erythrocytes. ABO incompatibility occurs when the mother has O group of the blood and pregnant with a fetus with A or B blood group. The maternal blood cells will form anti-A antibodies or anti-B antibodies (IgM) which can cross the placenta and causes hemolysis of the fetal erythrocytes causing increased unconjugated bilirubin and jaundice. This condition, unlike RHDN, develops in the first newborn.
G6PD deficiency	Glucose-6-phosphate dehydrogenase (G6PD) is an important enzyme found in the red blood cells and incorporated in the hexose monophosphate pathway. G6PD collaborates in the production of NADPH and reduction of glutathione thus, helping in decrease the oxidative stress around the RBCs. A deficiency in the G6PD occurs due to a genetic defect which leads to increased oxidative stress in the RBCs and the hemolysis of the fetal blood cells.

• The following table includes the different causes of inherited neonatal jaundice:

Defective mechanism		Pathogenesis
Defective bilirubin hepatic reuptake and storage[18]		Defective hepatic uptake and storage of bilirubin are not well understood. There are recent studies that revealed the correlation between mutations in the GST gene and neonatal jaundice. The gene deletion in GST-M gene class is believed to cause the dysfunction of the GSTM1 enzyme and defective hepatic uptake of bilirubin
Disorder of bilirubin conjugation	Gilbert syndrome:[19]	Gilbert syndrome, the most common inherited neonatal jaundice syndrome, is an autosomal recessive disease which is one of the causes of neonatal jaundice due to a defect (not total absence) in the Uridine diphosphate Glucuronsyl Transferase (UGT) enzyme. It is accompanied by several gene mutations (about 100 different mutations). The most common gene mutation occurs in the TA sequence of the TATAA box of the promoter region of UGT1A1 gene.
	Crigler-Najjar syndrome type I:[20][21]	Crigler-Najjar syndrome type I is characterized by a total absence of the UGT1A1 enzyme, unlike Gilbert syndrome. Gene mutation of the UGT1A1 enzyme occurs due to deletion of the amino acid sequences of the exons of the UGT1A1 enzyme. Genetic mutations in the introns may also lead to frameshift of the amino acid sequences or create prematu1e stop codons which result in cessation of the enzyme formation.
	Crigler-Najjar syndrome type II (Arias syndrome):[22]	Crigler-Najjar syndrome type II has a reduced activity of the UGT1A1 enzyme (not completely inactive). The gene mutation in the UGT1A1 gene is point mutation which results in amino acid substitution not stop codon. Hereby, reduction in the UGT enzyme activity occurs.
	Lucey-Driscoll syndrome:[23]	Also known as the transient familial neonatal hyperbilirubinemia as it is a rare familial disease which results in severe hyperbilirubinemia in the first 24 hours of life. It is believed that Lucey-Driscoll syndrome is associated with an inhibitor of the UGT1A1 enzyme and this inhibitor is unidentified until the moment.
	Breast milk jaundice:[24]	Breast milk jaundice is one of the benign causes of neonatal jaundice with no specific pathogenesis. It is considered as the continuation of physiologic jaundice beyond one week. It is believed that a combination of genetic mutation and environmental (breast milk components) factors lead to the development of jaundice. The beta-glucuronidase enzyme, one of the milk substances, may be one of the causes that increase the bilirubin and develop jaundice. In a Japanese study, a correlation between a genetic mutation in UGT1A1 gene and breast milk jaundice has been considered.
Disorders of excretion into Bile	Dubin-Johnson syndrome:[25]	Dubin-Johnson syndrome is a result of a genetic mutation in the ABCC2/MRP2 transporter resulting in absence of the transporter expression. Other mutations which may lead to Dubin-Johnson syndrome include base deletion, nonsense mutation, or exon skipping.
Disorders of reuptake	Rotor syndrome (RS):[26]	Rotor syndrome is an autosomal recessive disease which results in a defect of the hepatic reuptake of the bilirubin. Genetic mutation of SLCO1B1/OATP1B1 and SLCO1B3/OATP1B3 leads to absence of the OATP1B1 and OATP1B3 transporters of bilirubin.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Neonatal jaundice is caused by hemolysis of the RBCs mainly due to either intravascular causes or extravascular causes. Other causes include non-hemolytic causes such as cephalosporin induced jaundice, genetic mutations of the UGT enzyme, and hepatic causes.

• Common causes of neonatal jaundice include the following:^[1][2]
  • Increase bilirubin production due to hemolysis. Hemolytic causes include:
    • Intrinsic causes of hemolysis
      • Spherocytosis
      • Hereditary elliptocytosis
    • Systemic contitions
      • Splenomegaly
      • Sepsis
      • Arteriovenous malformation
    • Enzyme conditions
      • Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
      • Pyruvate kinase deficiency
    • Globin synthesis defect
      • Alpha-thalassemia
    • Extrinsic causes of hemolysis
      • Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal blood gives a positive indirect Coombs test)
      • Hemolytic disease of the newborn (ABO)
      • Rh disease

• Less common causes of neonatal jaundice include the following disorders:^[3][4]
  • Non-hemolytic causes
    • Cephalhematoma
    • Polycythemia
    • Sepsis
    • Hypothyroidism
    • Gilbert’s syndrome
    • Crigler-Najjar syndrome

• Hepatic causes
  • Infections
    • Sepsis
    • Hepatitis B
    • TORCH infections
  • Metabolic
    • Galactosemia
    • Alpha-1-antitrypsin deficiency
    • Cystic fibrosis
  • Drugs:
    • Losartan
    • Hydrochlorothiazide
  • Total parenteral nutrition

• Post-hepatic
  • Biliary atresia
• Bile duct obstruction

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Losartan, Hydrochlorothiazide
Ear Nose Throat	No underlying causes
Endocrine	Hypothyroidism
Environmental	No underlying causes
Gastroenterologic	Gilbert’s syndrome, Crigler-Najjar syndrome, Alpha-1-antitrypsin deficiency, Biliary atresia, Bile duct obstruction
Genetic	Cystic fibrosis, Alpha-1-antitrypsin deficiency
Hematologic	Cephalhematoma, Polycythemia
Iatrogenic	No underlying causes
Infectious Disease	Sepsis, Hepatitis B, TORCH infections
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	Galactosemia, Total parenteral nutrition
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Alpha-1-antitrypsin deficiency
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Neonatal jaundice must be differentiated from other causes of jaundice as hepatocellular jaundice and cholestatic jaundice.

The differential diagnosis for jaundice, click here.

The differential diagnosis for jaundice and RUQ pain, click here.

The differential diagnosis for jaundice and pruritis, click here.

The differential diagnosis for jaundice and fever, click here.

The differential diagnosis for jaundice, fever, and RUQ pain, click here.

The differential diagnosis for jaundice, pruritis and RUQ pain, click here.

Differential diagnosis of jaundice are: ^{[1][2][3][4][5]}

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALP BLR Indirect BLR Direct Viral serology Jaundice Hepatocellular Jaundice Infiltrative liver disorders: Hemochromatosis, amyloidosis + – -/+ – ↑ ↑ ↑/N ↑/N N – Ferritin ↑ (hemochromatosis) Liver biopsy Wilson’s disease + – -/+ – ↑ ↑ N ↑/N N – ↑ Serum ceruloplasmin Liver biopsy Viral hepatitis – -/+ – – ↑ ↑ N ↑/N N + Specific viral antibody for each type – Alcoholic hepatitis – -/+ -/+ – ↑↑ ↑ N ↑/N N – – – Drug induced hepatitis – -/+ – – ↑ ↑ N ↑/N N – – – Autoimmune hepatitis -/+ – – -/+ ↑ ↑ N ↑/N N – Anti-LKM antibody Liver biopsy Cirrhosis -/+ -/+ -/+ – ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platate Small liver on ultrasond Nonalcoholic steatohepatitis -/+ – – – ↑ ↑ N ↑/N N – Dyslipidemia liver biopsy Ischemic hepatopathy -/+ – -/+ – ↑ ↑ N ↑/N N – Cardiovascular risk factors – Cholestatic Jaundice Common bile duct stone -/+ – + + N N ↑ N ↑ – Dilated ducts on ultrasound CT/ERCP Hepatitis A (cholestatic type) – -/+ + + N/↑ N/↑ ↑ N ↑ + HAV- Ab Abdominal ultrasound EBV / CMV hepatitis – -/+ + + N N ↑ N ↑ + Positive serology – Primary biliary cirrhosis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – AMA positive Liver biopsy Primary sclerosing cholangitis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – ↑Autoantibodies (P-ANCA), hypergammaglobulinemia MRCP, Liver biopsy Sickle cell disease + – – +/- N/↑ N/↑ ↑ N ↑ – Genetic testing Pancreatic carcinoma + – -/+ -/+ N/↑ N/↑ ↑ N ↑ – – CT scan for diagnosis AIDS cholangiopathy – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – HIV Ab Ultrasound or ERCP Parasites induces cholestasis – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – Serology Ultrasound or ERCP Intrahepatic cholestasis of pregnancy -/+ – -/+ + ↑ ↑ ↑ N ↑ – Thrombocytopenia Diagnosed clinically Isolated Jaundice Crigler-Najjar type 2 + – – – N N N ↑ ↑ – Genetic testing Gilbert + – – – N N N ↑ ↑ – Genetic testing Rotor syndrome + – – – N N N N ↑ – Genetic testing Liver biopsy Dubin-Johnson syndrome + – – – N N N N ↑ – Genetic testing Liver biopsy Hereditary spherocytosis + – -/+ – N N N ↑ N – Genetic testing Osmotic fragility G6PD deficiency + – – – N N N ↑ N – Genetic testing Thalassemia + – – – N N N ↑ N – Genetic testing Paroxysmal nocturnal hemoglobinuria – – – – N N N ↑ N – Flocytometery Immune hemolysis – -/+ – – N N N ↑ N – Autoantibodies Hematoma – -/+ – – N N N ↑ N – Anemia Truma or surgery in history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The prevalence of neonatal jaundice ranges from 60,000 to 70,000 per 100,000 neonates. The prevalence of the neonatal jaundice decreases as the gestational age of the neonate increases. The prevalence of neonatal jaundice is more in the East Asian, American Indian, and Greek races.

• The prevalence of neonatal jaundice ranges from a low of 60,000 to high of 70,000 per 100,000 neonates in the first week of birth. ^[1]
• The prevalence of severe hyperbilirubinemia ranges from a low of 8,000 to high of 9,000 per neonates in the first week of birth.

• The prevalence of neonatal jaundice decreases as the gestational age increases.^[2]

• Neonatal jaundice affects male more than female neonates.

• The prevalence of neonatal jaundice is more in the East Asian, American Indian, and Greek races.
• Black races are less likely to develop jaundice. Black neonates presenting with jaundice most probably have G6PD deficiency disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common risk factors for neonatal jaundice include maternal risk factors and neonatal risk factors. Common maternal risk factors include mother of Asian race, usage of oxytocin during labor, exclusive breastfeeding, and prolonged labor. Neonatal risk factors include family history of siblings received phototherapy, ABO blood group incompatiblity, preterm neonates, and cephalhematoma. Less common risk factors for neonatal jaundice include maternal age more than 25 years, siblings with jaundice, male neonates, and black race neonates.

• Common risk factors for neonatal jaundice include the following:^[1][2]

Maternal risk factors	Neonatal risk factors
Asian race Usage of oxytocin during labor Exclusive breastfeeding Herbal drug during pregnancy Prolonged labor	Family history of siblings received phototherapy Developing jaundice in the first 24 hours of delivery is an indicator of severe hyperbilirubinemia ABO blood group incompatibility Preterm neonates Cephalhematoma

• Less common risk factors for neonatal jaundice include the following:
  • Maternal age more than 25 years
  • Siblings with jaundice
  • Predischarge total bilirubin in the intermediate high risk zone
  • Male neonates
  • Black race neonates

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

According to the American Academy of Pediatrics, screening tests recommended for neonatal jaundice include blood typing, clinical assessment of jaundice in the newborns, assessment of the total serum bilirubin level, measuring the level of G6PD enzyme. Also, it is recommended for all hospitals to provide information to the parents on jaundice and its consequences.

• According to the American Academy of Pediatrics, screening for neonatal jaundice is recommended. Screening tests include the following:^[1]
  • Blood typing: Testing the pregnant women for the ABO blood group and Rh autoantibodies.
  • Clinical assessment: Jaundice assessment in the newborns every 8-12 hours. Assessment is performed by blanching the skin to know the color. It should be done in the daylight.
  • Laboratory evaluation: Measuring the level of the total serum bilirubin level in all newborns in the first day of life.
  • Estimating the cause of the jaundice: Measuring the level of the G6PD enzyme.
  • Risk Assessment: The newborns should be assessed for the risk of developing jaundice before discharge.
  • Also, it is recommended for all hospitals to provide information to the parents on jaundice and its consequences.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

If left untreated, neonatal jaundice may lead to brain damage. Common complications of neonatal jaundice include acute bilirubin encephalopathy and kernicterus. Prognosis of neonatal jaundice is excellent with the proper treatment.

• If left untreated, neonatal jaundice may develop bilirubin related brain damage.

• Common complications of neonatal jaundice include the following:
  • Acute bilirubin encephalopathy:^[1][2][3]
    • Bilirubin is toxic to the brain and high levels may cause acute bilirubin encephalopathy.
    • In the beginning, it may be asymptomatic or the infant is sleepy and hypotonic.
    • If the encephalopathy not diagnosed early, more complications will develop as lethargy, seizures, inability to feed, and apnea in severe cases.
    • It is better to diagnose it early in order not to develop severe cases of encephalopathy.
  • Kernicterus:^[4][5]
    • Kernicterus is the chronic neurologic dysfunction that results from high levels of bilirubin.
    • Kernicterus occurs due to damage of the basal ganglia with the precipitating bilirubin.
    • Kernicterus can present with the following features:
      • Hearing impairement
      • Gaze abnormality
      • Cerebral palsy like features
    • The neurological manifestations of Kernicterus are reversible with exchange transfusion and decreasing the high bilirubin levels.

• Prognosis of neonatal jaundice is excellent with receiving the proper treatment.

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