Neonatal Hyperbilirubinemia

Jaundice attributable to immaturity of the newborn organ and systems

CRITERIA FOR PHYSIOLOGIC JAUNDICE

• Onset— Not before 24hours
• Daily rise— Does not exceed 5mg/dl
• Peak level— 12mg/dl in Term and 15mg/dl in Preterms
• Peak duration— 3rd – 5th day in Term; 5th – 7th in Preterms
• Duration— 7-10days in term babies and 2-3weeks in preterms
• Conjugated fraction— Does not exceed 10% of total

MECHANISM OF PHYSIOLOGIC JAUNDICE

• Increased Bilirubin load on liver cell
• Increase RBC volume, decrease RBC survival, increased E-H circulation
• Defective hepatic uptake of bilirubin
• Decrease Ligandin (Y-protein)
• Defective bilirubin conjugation
• Decrease activity of transferase enzyme (UDPGT – Uridyldiglucoronosyl Transferase)
• Defective bilirubin excretion.
• Excretion impaired but not rate-limiting

Major Reasons why a baby will have physiologic jaundice

1. Increased red cell mass
2. Reduced red cell survival
3. Reduction in activity of UDPGT

In addition

• Infants lack the bacterial flora necessary to convert bilirubin to urobilinogen, so unconjugated bilirubin persists throughout the entire GI tract.
• Also, meconium contains large amounts of unconjugated bilirubin
• Intensity and duration of physiologic jaundice varies widely

• Jaundice due to other aggravating factors
• Failure to meet at LEAST ONE of the CRITERIA for Physiological HB
• Note however that in majority of cases etiology is unknown

CAUSES OF UNCONJUGATED NON-PHYSIOLOGICAL HYPERBILIRUBINAEMIA

1. Over Production of Bilirubin

Haemolytic

• Antibody mediated haemolysis
• ABO Incompatibility, Rh Incompatibility
• Minor blood group incompatibility (anti-E & c, anti-Kell)
• Red Cell Enzyme defects
• G-6-P-D, Pyruvate kinase deficiency
• Red Cell Membrane defects
• Hereditary spherocytosis, Elliptocytosis

Extravascular Blood

• Bruises, IVH, Cephalohaematoma, Subgaleal hematoma

Drug Induced Hemolysis

• Vitamin K3 induced haemolysis

Polycythaemia

2. Conjugation Defects

Inherited reduction in glucoronosyl transferase

• Familial non-haemolytic jaundice (Crigler-Najjar type I)
• Autosomal recessive, Severe
• Familial non-haemolytic jaundice (Crigler-Najjar type II)
• Autosomal dominant, milder cause

Abnormal glucoronyl transferase

• Gilbert Syndrome

Acquired inhibition of glucorosyl tranferase

• Breast milk jaundice (5-b-pregnane-3a,20-b-diol or nonesterified long chain fatty acids) glucoronidase in some milk

CAUSES OF CONJUGATED NON-PHYSIOLOGICAL HYPERBILIRUBINAEMIA

1. Decreased Secretion

Impaired transport of the hepatocytes

• Congenital transport defect: Dubin-Johnson, Rotor syndrome
• Hepatocellular damage secondary to metabolic disorders (galactosaemia)

Obstruction of bile flow:

• Biliary atresia, extrinsic obstruction (intestinal obstruction) choledochal cyst
2. Mixed
• Prenatal infections
• Sepsis
• Multi-system disorders
• IDM, Perinatal asphyxia

ABO Haemolytic Disease

Description

• Action of maternal anti-A or anti-B antibodies on fetal erythrocytes of the corresponding blood group
• It is the commonest cause of Non-physiologic hyperbilirubinaemia

Pathogenesis

• Group O subjects have Anti-A or Anti-B antibodies of the IgG and IgM subclass in their plasma.
• In the event of a pregnancy with appropriate set up the IgG anti-A or anti-B antibodies cross the placenta to attack the fetal RBC
• These results in damage to erythrocytes and their destruction by the RES
• Attempts at repairing the partially damaged erythrocytes results in the formation of microspherocytes.

Characteristics of ABO disease

• May affect first child
• Degree of severity is similar among siblings
• Early non-physiological jaundice
• Anaemia may be mild or non-existent

Criteria for diagnosis

• Unconjugated hyperbilirubinaemia
• Jaundice during the first 24 hours
• An A or B baby of an O mother
• Increased number of microspherocytes
• Positive Coombs test
• Increased RBC production in the blood
• Reticulocytosis

Rhesus incompatibility

Description

• Due to action of maternal anti-D antibodies on the Rhesus antigen of fetal erythrocytes

Pathogenesis

• It is due to the entry of fetal cells into the maternal circulation
• As few as 0.05-0.1ml of cells is enough to produce immunization
• Following sensitization, Rh-negative subjects produce anti-D antibodies of the IgG class
• The antibodies crosses the placenta to attack fetal RBC
• The anti-body coated RBC is removed by the spleen in the fetus
• Before birth the main danger is anaemia
• After birth it is severe hyperbilirubinaemia
• In utero there is increase rate of erythrocyte production-
• Reticulocytosis and Nrbc
• Resulting in increased extramedullary erythropoiesis – liver, spleen and lungs
• Most severe infants manifest hydrops fetalis
• Massive edema, ascites and pleural effusion.
• Can lead to baby being stillborn

Characteristics of Rh disease

• Spares the first pregnancy
• Increasing degree of severity with subsequent pregnancies
• Early non-physiological jaundice
• Anaemia usually profound
• Hepatosplenomegally

Criteria for diagnosis

• Unconjugated hyperbilirubinaemia
• Jaundice during the first 24 hours
• Rh-Positive baby of Rh-negative mother
• Low Hb or PCV
• Strongly positive Coombs test
• Reticulocytosis
• Elevated levels of carboxyhaemoglobin

Prevention

• Focuses primarily on the administration of anti-D immunoglobulin to mothers after delivery or abortion of an Rh-positive fetus.
• This is in the form of human anti-D concentrate called RhoGAM (300ug)
• Acid elution test of Kleihauer and Betke can be used to detect cases of massive transplacental haemorrhage that will require larger doses of anti-D immunoglobulin

Pathogenesis

• RBC are liable to damage from oxidants
• Resulting in the formation of oxidized Hb which precipitates as Heinz bodies
• G6PD necessary for protecting the RBC from this oxidative stress
• Reduced GSH donates H- to reduce Oxidized Hb
• The Oxidized GSSH is reduced by NADPH
• The NADPH is derived from the HMP shunt at the G-6-PD step

Precipitants of acute haemolysis include

• Drugs
• Primaquine
• Nitrofurantoin
• Sulfonamides
• Nalidixic Acid
• Methylene blue
• Infections
• Naphthalene balls

• There is significant and prolonged elevation of un-conjugated Br
• Incidence is very low
• Usually a diagnosis of exclusion
• Thought to be due to
• The inhibition of the Glucoronosyl transferase by a steroid 3-a,20β pregnanediol
• Excess lipase librating FFA which interfere with protein binding and conjugation

Clinical course

• Usually noticed from the 5th day
• Continues to increase to the second week
• Essentially un-conjugated
• Has now been reported to be associated with Br Encephalopathy (previously, it was thought that it couldn’t result in encephalopathy)

• When did the jaundice start?
• How has it been progressing? Jaundice progresses from face downwards, by the time jaundice is seen on the feet, it has become very severe.
• Clinical features of jaundice- vomiting, inability to suck, features of failure to thrive, abdominal distension
• Colour of urine/stool
• Feeding history, weight loss
• Care so far
• Maternal history
• Antenatal— booking, illnesses, infections
• Drugs— sulfa, NSAIDS, herbals
• Blood group (mother’s and father’s), haemolytic diseases, liver disease, recurrent jaundice
• Family history— siblings with jaundice, familial jaundice, liver disease
• Birth history— trauma, cord clamping

• Jaundice usually becomes apparent in a cephalocaudal progression, starting on the face and progressing to the abdomen and then the feet, as serum level increase.
• Pallor
• Dehydration
• Weight loss
• Fever or hypothermia
• Hepato/splenomegaly
• Evidence of birth trauma or injuries
• Evidence of kernicterus

• Serum bilirubin— total, conjugated
• Full blood count and blood smear
• Haemoglobin concentration
• Reticulocyte count
• Blood group
• Coombs test
• Urinalysis
• Urine m/c/s
• Electrolyte, urea and creatinine
• Liver function test (AST/ALT, ALP/GGT)
• G6PD assay
• Ultrasound
• Thyroid function test

• Anticipatory care
• Phototherapy
• EBT

Phototherapy

• An effective means of reducing serum bilirubin level
• Acts by converting extra-vascular (skin and cutaneous) bilirubin to less lipophilic products that diffuse back into the blood and can be excreted in the bile without the requirement for conjugation

Mechanism

• Yellow pigment absorbs light maximally at 450-460nm. Following absorption light reduces Bilirubin by
• Photo-oxidation
• Occurs too slowly to be of clinical importance
• Configurational Photo-isomerization
• Converts 4Z, 15Z bilirubin to photo-isomers (4Z, 15E),
• Structural Photo-isomerization
• Irreversible formation of Lumirubin, which is excreted unchanged in bile and urine

Indication

• To prevent the need for EBT
• Hence 2/3rd of projected Exchange value

Type of light

• Narrow Spectrum (special blue lights)
• May also use green light
• Both lights obscure assessment of cyanosis, jaundice and causes discomfort to the staff

When to stop

• Once indication for its use has been averted

Side Effects

• Diarrhoea
• Skin rashes
• Temperature instability
• Dehydration
• Retinal damage
• Eye injury & nasal occlusion from bandages
• Bronze Baby Syndrome
• Infants with conjugated hyperbilirubinaemia

Exchange Blood Transfusion

Objective

• To Prevent Bilirubin Encephalopathy

Determinants of when

• Level of unconjugated bilirubin
• ≥20mg/dl or 342umol/l in term babies
• Rule of 10 in preterms (10 x bt wt in kg)
• Rate of rise of serum bilirubin
• No magic figure but serves as guide for projecting the need for EBT
• Clinical condition of the patient
• HIE, Acidosis, prolonged hypothermia

EBT Complications

• Catheter
• Air embolism, gut perforation
• Arrhythmia
• Infection, NEC
• Procedure
• Hypothermia, Hypovolaemia/hypervolaemia
• Blood
• Transmission of organisms
• Hyperkalaemia
• Hypocalcaemia
• Blood incompatibility
• Hypoglycaemia

Management of Conjugated Hb

• Surgical hyperbilirubinemia
• Investigations; LFT, ABD USS
• Specific treatment depends on the cause
• Kasai procedure for biliary atresia