Jaundice and Hyperbilirubinemia in the Newborn Dr. M.A.Fallahi Pediatric Board degree Shiraz Medical University

CONTENTS: INTRODUCTION P/E PATHOPHYSIOLOGY RISK FACTORS PREVENTION CAUSES DIFFERENTIAL DIAGNOSIS TREATMENT

INTRODUCTION Bilirubin is the end product of heme degradation Most of the daily production comes from the breakdown of RBCs in the RES Heme biliverdin bilirubin Bilirubin is released & bound to serum albumin Bilirubin is uptake & conjugated with glucuronic acid Finally conjugated bilirubin is excreted in bile

PATHOPHYSIOLOGY UNCONJUGATED B. CONJUGATED B. Tightly compounded to s. albumin Normally very small amount is present as albumin free Insoluble in water can not be excreted in urine Toxic Non toxic Water soluble Loosely bound to albumin

Neonatal jaundice is a condition marked by high levels of bilirubin in the blood, yellowish discoloration of skin and mucous membrane, bilirubin level more than 5 mg/dl (85 µmol/lit) Normally s. bilirubin level vary b/w 0.3 & 1.2mg/dl. The rate of systemic bilirubin production is equal to the rate of hepatic uptake, conjugation & biliray excretion .

Levels as high as 30 to 40mg/dl can occur with sever disease Jaundice occurs when the bilirubin production &clearance is disturbed by one or more of the following mechanisms: Excessive production of bilirubin Reduced hepatic uptake Impaired conjugation Decreased hepatocellular excretion Impaired bile flow

Enterohepatic circulation Uridine diphosphate glucuronyl transferase (UDPGT) Enterohepatic circulation

Increased rbc’s Shortened rbc lifespan Immature hepatic uptake & conjugation Increased enterohepatic Circulation

Risk Factors Major Risk Factors Minor Risk factors Decreased Risk factors

Major Risk Factors Total bilirubin or transcutaneous bilirubin in the high- risk zone. Jaundice observed in the first 24 hours. Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease Gestational age 35-36 weeks.

Major Risk Factors Previous sibling received phototherapy Cephalohematoma or significant bruising Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive East Asian race

Breast Feeding and Jaundice Breastfeeding is considered one of the most important risk factors for hyperbilirubinemia. Exclusive breastfeeding is most strongly associated with increased risk of jaundice Breast fed infants are 3 times more likely to have TSB >12mg/dL than formula fed infant Bilirubin levels peak later in breastfed infants 1/3 of all breastfed infants are clinically jaundiced beyond 2 weeks of age Despite the increased risk, exclusive breastfeeding is still the recommended feeding choice of the AAP Goal is to optimize breastfeeding, hydration and nutrition while observing for signs of excessive hyperbilirubinemia

Minor Risk Factors Predischarge total serum bilirubin or transcutaneous bilirubin in the high-intermediate risk zone Gestational age 37-38 weeks Jaundice observed before discharge Previous sibling with jaundice

Minor Risk Factors Macrosomic infant of a diabetic mother Maternal age greater than or equal to 25 years Male gender

Decreased Risk Factors Total serum bilirubin or transcutaneous bilirubin in the low-risk zone Gestational age greater than or equal to 41 weeks Exclusive bottle feeding

Decreased Risk Factors Black race Discharge from hospital after 72 hours of age

Secondary Prevention All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies. If the mother was not screened or is Rh-negative, a direct antibody test, blood type, and an Rh type on the infant’s blood is strongly recommended.

Secondary Prevention Newborns should be routinely monitored for jaundice and nurseries should have established protocols for jaundice assessment. Jaundice assessment protocols should include the conditions under which a nurse can obtain a total serum bilirubin or transcutaneous bilirubin level.

The important points in P/E of neonatal jaundice Yellow skin Yellow sclera Sleepiness Poor feeding in infants Brown urine Fever High-pitch cry Vomiting

EXAMINATION color of skin severity of jaundice anemia liver spleen ascites

Grading Extent of Jaundice

Grading Extent of Jaundice Area of body Billirubin levels mg/dl (*17=umol) Face 4-8 Upper trunk 5-12 Lower trunk & thighs 8-16 Arms and lower legs 11-18 Palms & soles > 15

PREDOMINANTLY DIRECT HYPERBILIRUBINEMIA CAUSES OF JAUNDICE PREDOMINANTLY DIRECT HYPERBILIRUBINEMIA PREDOMINANTLY INDIRECT HYPERBILIRUBINEMIA

Excessive production of bilirubin PREDOMINANTLY INDIRECT HYPERBILIRUBINEMIA Excessive production of bilirubin hemolytic anemia's resorption of blood from internal hemorrhage. ineffective erythropoiesis

Reduced hepatic uptake: drugs some cases of Gilbert syndrome

Impaired bilirubin conjugation: physiologic jaundice breast milk jaundice genetic deficiency of glcuronosyl transferase decreased expression of glcuronosyl transferase diffuse hepatocellular diseases

Decrease excretion of conjugated bilirubin: PREDOMINATLY DIRECT HYPERBILIRUBINEMIA Decrease excretion of conjugated bilirubin: deficiency in canalicular membrane transport drug induced canalicular membrane dysfunction hepatocelluler damage or toxicity

Decreased intrahepatic bile flow : inflammatory destruction of intrahepatic bile ducts

Extra hepatic biliary obstruction: gall stone obstruction of biliary tree extra hepatic biliary atresia biliary stricture & choledochal cyst primary sclerosing cholangitis liver fluke infestation carcinoma

Causes of neonatal jaundice Best classified by age of onset and duration: Early: within 24 hrs of life Intermediate: 2 days to 2 weeks Late: persists for >2 weeks

Causes of neonatal jaundice Early Intermediate Late/prolonged Haemolytic causes: Rh isoimmunisation ABO incompatibility G6PD deficiency Congenital infection Physiological jaundice Breast milk jaundice (inadequate intake) Sepsis Haemolysis Crigler-Najjar syndrome (glucuronyl transferase absent/reduced) Polycythaemia, bruising Conjugated (dark urine, pale stools): Bile duct obstruction Biliary atresia Neonatal hepatitis Unconjugated: Physiological Breast milk jaundice Infection Hypothyroidism Blood group incompatibility: Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia Most severe cases - hydrops fetalis Breast milk jaundice Early: due to lower calorie intake (so check weight gain) and slower passage of meconium Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation Management: usually reassurance - do not stop breast feeding unless very severe!

Causes of neonatal jaundice Early Intermediate Late/prolonged Haemolytic causes: Rh isoimmunisation ABO incompatibility G6PD deficiency Congenital infection Physiological jaundice Breast milk jaundice (inadequate intake) Sepsis Haemolysis Crigler-Najjar syndrome (glucuronyl transferase absent/reduced) Polycythaemia, bruising Conjugated (dark urine, pale stools): Bile duct obstruction Biliary atresia Neonatal hepatitis Unconjugated: Physiological Breast milk jaundice Infection Hypothyroidism Blood group incompatibility: Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia Most severe cases - hydrops fetalis Breast milk jaundice Early: due to lower calorie intake (so check weight gain) and slower passage of meconium Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation Management: usually reassurance - do not stop breast feeding unless very severe!

Early jaundice Apparent before 24 hours of age Always pathological The main cause for early jaundice is haemolysis such as: Rhesus isoimmunisation ABO incompatibility G6PD deficiency

Investigations for early jaundice Serum bilirubin level Blood group Maternal blood group Direct coombs test Consider G6PD level

Causes of neonatal jaundice Early Intermediate Late/prolonged Haemolytic causes: Rh isoimmunisation ABO incompatibility G6PD deficiency Congenital infection Physiological jaundice Breast milk jaundice (inadequate intake) Sepsis Haemolysis Crigler-Najjar syndrome (glucuronyl transferase absent/reduced) Polycythaemia, bruising Conjugated (dark urine, pale stools): Bile duct obstruction Biliary atresia Neonatal hepatitis Unconjugated: Physiological Breast milk jaundice Infection Hypothyroidism Blood group incompatibility: Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia Most severe cases - hydrops fetalis Breast milk jaundice Early: due to lower calorie intake (so check weight gain) and slower passage of meconium Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation Management: usually reassurance - do not stop breast feeding unless very severe!

Physiological jaundice Physiological jaundice is jaundice that is present between day 2 and day 10

Physiological jaundice Physiological jaundice is due to: High bilirubin production (fetal Hb, high Hb) Reduced bilirubin excretion (UDPGT concentrations at term are 1% of adult concentrations)

Physiological jaundice Characteristics: Appears after 24 hours Maximum intensity by 4th-5th day in term & 7th day in preterm Serum level less than 15 mg / dl Clinically not detectable after 14 days Disappears without any treatment

Factors that can increase the severity of physiological jaundice Prematurity Sepsis Bruising Cephalohematoma Polycythaemia Delayed passage of meconium Breast feeding Certain ethnic groups, esp Chinese

Breast Milk Jaundice Elevated unconjugated bilirubin Prolongation of physiologic jaundice 66% of breastfed babies jaundiced into 3rd week of life May persist up to 3 months May have second peak at day 10 Average max TSB = 10-12 mg/dL

Breast feeding Jaundice Elevated unconjugated bilirubin Benign or pathologic Elevated bilirubin in the 1st week of life tends to worsen breast milk jaundice during later weeks Equivalent to starvation jaundice in adults No water or dextrose supplementation

Pathological jaundice Appears within 24 hours of age Increase of bilirubin > 5 mg / dl / day Serum bilirubin > 15 mg / dl Jaundice persisting after 14 days Stool clay / white colored and urine staining clothes yellow Direct bilirubin> 2 mg / dl

Causes of neonatal jaundice Early Intermediate Late/prolonged Haemolytic causes: Rh isoimmunisation ABO incompatibility G6PD deficiency Congenital infection Physiological jaundice Breast milk jaundice (inadequate intake) Sepsis Haemolysis Crigler-Najjar syndrome (glucuronyl transferase absent/reduced) Polycythaemia, bruising Conjugated (dark urine, pale stools): Bile duct obstruction Biliary atresia Neonatal hepatitis Unconjugated: Physiological Breast milk jaundice Infection Hypothyroidism Blood group incompatibility: Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia Most severe cases - hydrops fetalis Breast milk jaundice Early: due to lower calorie intake (so check weight gain) and slower passage of meconium Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation Management: usually reassurance - do not stop breast feeding unless very severe!

Prolonged Jaundice Jaundice persisting after 14 days in the term infants Or Jaundice persisting after 21days in the preterm infant 48

Kernicterus The chronic form of bilirubin encephalopathy, manifested by cerebral palsy, auditory dysfunction, dental-enamel dysplasia, paralysis of upward gaze, and less often intellectual handicaps.

Kernicterus * Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.

Mechanism of neurotoxicity in kernicterus Bilirubin accumulates at nerve terminals Binds to cell components Impairs mitochondrial functions neurotransmitter synthesis Dysfunction and death of neurons Bilirubin staining of affected areas Long term clinical sequelae

Kernicterus: signs and symptoms Acute Form : Phase 1 (1-2 days):Poor suck, hypotonia, stupor and seizures Phase 2 (middle of 1st week):hypertonia of extensor muscles, opisthotonos, retrocollis and fever Phase 3 (after the 1st week):hypertonia

Chronic Form: 1st year: hypotonia,active deep tendon reflexes, obligatory tonic neck reflexes and delayed motor skills After 1st year: movement disorders (choreoathetosis, ballismus, tremor), upward gaze and sensorineural hearing loss

Risk of Kernicterus TSB level > 25-30 mg/dl Acidosis Increased free bilirubin low albumin, drug displacement Blood-brain barrier disruption prematurity, sepsis, ischemia

Pathologic Jaundice Increase load: Hemolytic Disease Features: elevated reticulocytes, decreased Hgb Coomb’s + Rh incompatibility, ABO incompatibility Coomb’s - G6PD, spherocytosis, pyrovate kinase deficiency

Non-hemolytic Disease normal reticulocytes Extravascular sources (cephalohematoma) Polycythemia Exaggerated enterohepatic circulation (CF, GI obstruction)

Decreased Bilirubin Conjugation Elevated unconjugated bilirubin Crigler-Najjar Gilbert Syndrome Hypothyroidism

Impaired Bilirubin Excretion Elevated unconjugated and conjugated bilirubin (> 2 mg/dL or > 20% of TSB) Biliary Obstruction Structural defects (biliary atresia) Genetic defects – Rotor’s & Dubin-Johnson syndromes Infection – sepsis, TORCH Metabolic Disorders – I.e. alpha1 antitrypsin deficiency Chromosomal Abnormalities Drugs – I.e. ASA, erythromycin

Treatment of Neonatal Jaundice Depends on the cause and level and type of bilirubin Unconjugated hyperbilirubinaemia: Ensure adequate fluid intake Phototherapy IV immunoglobulin Exchange transfusion Conjugated hyperbilirubinaemia: Ensure adequate nutrition Treat underlying problem

Treatment of Indirect Hyperbilirubinemia: Phototherapy:

Phototherapy Mechanism: converts bilirubin to water soluble form that is easily excreted Forms: Fluorescent lighting Fiberoptic blankets Goal is to decrease TSB by 4-5 mg/dL or < 15 mg/dL total Breastfed infants are slower to recover

Bilirubin absorbance and transmittance Phototherapy Phototherapy is NOT: Ultraviolet light Infrared light Ultraviolet light (10 – 400 nm) Infrared light (400 – 700 nm) Spectrum of light Blue is most effective (460 - 490 nm) Figure 3. Important Factors in the Efficacy of Phototherapy. The absorbance spectrum of bilirubin bound to human serum albumin (white line) is shown superimposed on the spectrum of visible light. Clearly, blue light is most effective for phototherapy, but because the transmittance of skin increases with increasing wavelength, the best wavelengths to use are probably in the range of 460 to 490 nm. Term and near-term infants should be treated in a bassinet, not an incubator, to allow the light source to be brought to within 10 to 15 cm of the infant (except when halogen or tungsten lights are used), increasing irradiance and efficacy. For intensive phototherapy, an auxiliary light source (fiber-optic pad, light-emitting diode [LED] mattress, or special blue fluorescent tubes) can be placed below the infant or bassinet. If the infant is in an incubator, the light rays should be perpendicular to the surface of the incubator in order to minimize loss of efficacy due to reflectance. The efficacy of phototherapy depends on the irradiance (energy output) of the light source. Irradiance is measured with a radiometer or spectroradiometer in units of watts per square centimeter or in microwatts per square centimeter per nanometer over a given wavelength band. Bilirubin absorbance Bilirubin absorbance and transmittance Maisels MJ et al. N Engl J Med 2008;358:920-8

Phototherapy Mechanism of action Technique Skin exposure to lights causing geometric photoisomerization and bilirubin photooxidation allowing diffusion and albumin binding Not useful in neonates with elevated conjugated bilirubin Technique wave length: 420-500nm change bulbs every 2000 hours Positioned 15-20cm above infant

When to start phototherapy?

Complications of Phototherapy Dehydration increased insensible water loss loose stools Irritability or lethargy Skin rashes Overheating Retinal injury Oxidize essential fatty acids, decreases vitamins and calcium in premature infants Tanning/Bronze Baby Syndrome

Exchange Transfusion: Double-volume exchange 2 x blood volume = 2 x 80 cc/kg = 160 cc/kg Takes about 1-1.5 hours Exchange at rate of ~5cc/kg/3 min

Exchange Transfusion Mechanism: removes bilirubin and antibodies from circulation and correct anemia Most beneficial to infants with hemolysis Generally never used until after intensive phototherapy attempted

Complications: Thrombocytopenia Portal vein thrombosis/perforation Necrotizing Enterocolitis Cardiac arrythmias Hypo- Calcemia, magnesemia, glycemia HIV, Hepatitis B & C infection

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