Neonatal Jaundice

Outline
• Introduction
• Definition
• Aetiology
• Pathophysiology
• Clinical manifestations
• Investigations
• Complications
• Diagnosis
• Management
• Prognosis
Learning Objectives
• List 5 causes of jaundice according to the age of presentation
• List the 2 clinical forms of jaundice
• Categorise the aetiology of jaundice
• List 5 clinical manifestations of jaundice
• Outline the algorithm for investigation of jaundice
• List the management principles employed in the care of patients with
neonatal jaundice
Definition
• Development of hyperbilirubinemia with consequent yellowing of the
skin and sclera in the neonatal period

• A common and, in most cases, benign problem in neonates

• Usually observed during the 1st wk. after birth in approximately 60%
of term infants and 80% of preterm infants
Definition
• The yellow colour usually results from the accumulation of
unconjugated, non-polar, lipid-soluble bilirubin pigment in the skin.

• It may also be caused by deposition of pigment from conjugated

bilirubin which has undergone conjugation in the liver cell microsome
by the enzyme uridine diphosphoglucuronic acid (UDP)–glucuronyl
transferase to form the polar, water-soluble glucuronide of bilirubin
Clinical Significance
• Physiologic role as an antioxidant

• Elevations of indirect, unconjugated bilirubin are potentially

neurotoxic.

• The conjugated form is not neurotoxic but direct hyperbilirubinemia

indicates a potentially serious hepatic disorders or a systemic illness
Aetiology
• Unconjugated hyperbilirubinemia may be caused or increased by any
factor that
• (a) increases the load of bilirubin to be metabolized by the liver
(haemolytic anaemias, polycythaemia, bruising or internal
haemorrhage, shortened red blood cell life as a result of immaturity
or transfusion of cells, increased enterohepatic circulation, infection)

• (b) damages or reduces the activity of the transferase enzyme or

other related enzymes (genetic deficiency, hypoxia, infection, thyroid
deficiency);
Aetiology
• (c) competes for or blocks the transferase enzyme (drugs and other
substances requiring glucuronic acid conjugation); or

• (d) leads to an absence or decreased amounts of the enzyme or to

reduction of bilirubin uptake by liver cells (genetic defect, and
prematurity).
 Aetiology

• Categorised according to the age of onset

• The age of onset is a useful guide to the likely cause of the jaundice.

• On this basis jaundice is classified into -

• A. Jaundice less than 24 hrs

• B. Jaundice between 24 hrs and 2 weeks
• C. Jaundice Beyond 2 weeks
a. Jaundice <24 h of age
• Haemolytic disorders:

• Erythroblastosis fetalis
• Rhesus incompatibility, ABO incompatibility

• G6PD deficiency

• Congenital infection - Torches , enterovirus infection

• Sepsis
• Concealed haemorrhage
b. 24 h to 2 weeks of age
• Breast milk jaundice
• Physiological jaundice
• Infection, e.g. urinary tract infection , bacterial sepsis
• Haemolysis, e.g. G6PD deficiency, ABO incompatibility

• Bruising
• Polycythaemia

• Crigler-Najjar syndrome
c. Jaundice at >2 weeks of age
• Unconjugated:
• Physiological jaundice
• Breast milk jaundice
• Infection (particularly urinary tract infection)
• Hypothyroidism
• Haemolytic anaemia, e.g. G6PD deficiency
• High gastrointestinal obstruction
• Galactosaemia
• Cystic fibrosis

• Conjugated (>20% of total bilirubin):

• Bile duct obstruction
• Paucity of bile ducts
Pathophysiology
• Hyperbilirubinemia occurs because

• There is marked physiological release of haemoglobin from the

breakdown of red cells due to the high Hb concentration at birth

• The red cell life span of newborn infants (70 days) is markedly
shorter than that of adults (120 days)

• Hepatic bilirubin metabolism is less efficient in the first few days of

life.
Pathophysiology
Pathophysiology
• The toxic effects of elevated serum concentrations of unconjugated
bilirubin are increased by factors that reduce the retention of bilirubin
in the circulation.
• These include
• Hypoproteinaemia
• Displacement of bilirubin from its binding sites on albumin by competitive
binding of drugs such as sulfisoxazole, Cotrimoxazole , ceftriaxone and
moxalactam
• Acidosis
• Increased free fatty acid concentration secondary to hypoglycaemia,
starvation, or hypothermia.
Risk Factors
• Neurotoxic effects are directly to the permeability of the blood–brain
barrier and nerve cell membranes
• Neurotoxic effects are also related to neuronal susceptibility to injury,
which is adversely affected by asphyxia, prematurity, hyperosmolality,
and infection.
• Early and frequent feeding decreases serum levels of bilirubin.
• Breastfeeding and dehydration increase serum levels of bilirubin
• Delay in passage of meconium, which contains 1 mg bilirubin/dL, may
contribute to jaundice by enterohepatic recirculation after
deconjugation by intestinal glucuronidase
Risk Factors
• Drugs such as oxytocin (in the mother) and chemicals used in the
nursery such as phenolic detergents may also produce unconjugated
hyperbilirubinemia.

• Additional risk factors include

• Polycythaemia
• Infection
• Prematurity, and
• Having a diabetic mother
Clinical Manifestations
• Appears during the early neonatal period
• Appearance depends on the aetiology
• Cephalocaudal progression
• Starts on the face and progresses to the abdomen and then the feet, as serum
levels increase.
• Dermal pressure may reveal the anatomic progression of jaundice
• (face, ≈ 5 mg/dL; mid-abdomen, ≈ 15 mg/dL; soles, ≈ 20 mg/dL)
• Clinical examination cannot be depended on to estimate serum levels
Clinical Manifestations
• Jaundice from deposition of ind. bil. - bright yellow / orange jaundice

• Obstructive type (direct bilirubin) - greenish or muddy yellow cast

• Severe - Lethargy and poor feeding

• Jaundice > 2 wk. associated with acholic stools and dark urine suggest
biliary atresia
Complications
Kernicterus
• Develops in 30% of infants (all gestational ages) with untreated
haemolytic disease and bilirubin levels >25-30 mg/dL.
• Preterm infants is 2-16%
• Overt neurologic signs have a poor prognosis
• > 75% of infants die
• 80% of survivors have bilateral choreoathetosis with involuntary
muscle spasms.
• Mental retardation, deafness, and spastic quadriplegia are common.
Diagnosis
• Clinical diagnosis
• Complete diagnostic evaluation
• Includes
• Direct & indirect bilirubin fractions
• Haemoglobin
• Reticulocyte count
• Blood type
• Coombs test
• Peripheral blood smear.
• G6PD
Differential Diagnosis
• Haemolysis is suggested by

• A rapid rise in serum bilirubin concentration (>0.5 mg/dL/hr),

• Anaemia
• Reticulocytosis
• Hepatosplenomegaly, and
• A positive family history.
Management
• The goal of therapy is to prevent neurotoxicity related to indirect-
reacting bilirubin

• Primary treatment modalities

• Phototherapy
• Exchange transfusion if phototherapy is unsuccessful
• Intravenous immunoglobulins
• Metalloporphyrins
Phototherapy
• Lack of consensus regarding the exact bilirubin level at which
to initiate phototherapy.

• May require 6-12 hr to have a measurable effect

• Underlying medical causes of elevated bilirubin and physiologic

factors that contribute to neuronal susceptibility should be treated
e.g. antibiotics for septicaemia and correction of acidosis
Phototherapy
• Clinical jaundice and indirect hyperbilirubinemia are reduced by
exposure to a high intensity of light in the visible spectrum

• Bilirubin absorbs light maximally in the blue range (420-470 nm)

• Types of light
• Broad-spectrum white light
• Blue light
• Special narrow-spectrum (super) blue light
Mechanism of Action

Toxic unconjugated
Reversible 4Z,15Z-bilirubin to
Bilirubin in the skin Excreted in bile without
photoisomerization unconjugated
absorbs light energy conjugation.
reaction configurational isomer,
4Z,15E bilirubin
Mechanism of action
• Other major product from phototherapy – lumirubin

• An irreversible structural isomer converted from native bilirubin

• Can be excreted by the kidneys in the unconjugated state.

Maximizing Phototherapy
• Depends on

• Light energy emitted in the effective range of wavelengths

• “special blue” fluorescent tubes

• Distance between the lights and the infant

• 15 to 20cm

• The surface area of exposed skin

• Double phototherapy or Bili blanket

• The rate of haemolysis

• In vivo metabolism and excretion of bilirubin.

Before Phototherapy
• The infant’s eyes should be covered
• This prevents light exposure and corneal damage.
• Body temperature should be monitored
• Irradiance should be measured directly.
• Monitor for devt of anaemia in infants with haemolytic disease
• Anaemia may develop despite lowering of bilirubin levels.
The Process
• Done continuously
• The infant is turned frequently for maximal skin surface area exposure.
• Discontinued as soon as the indirect bilirubin concentration has reduced
to levels considered safe with respect to the infant’s age and condition.
• Serum bilirubin levels and haematocrit should be monitored every 4-8 hr
• In infants with haemolytic disease and those with bilirubin levels near toxic range
for the individual infant
• May be monitored every 12 to 24hours for low risk neonates
The Process
• Serum bilirubin monitoring should continue for at least 24 hr after
cessation of phototherapy in patients with haemolytic disease
• Unexpected rises in bilirubin may occur, requiring further treatment.
• Skin colour cannot be relied on for evaluating the effectiveness of
phototherapy
• Intravenous fluid supplementation added to oral feedings may be
beneficial in dehydrated patients or infants with bilirubin levels
nearing those requiring exchange transfusion.
Guidelines for Phototherapy
Complications of Phototherapy
• Loose stools
• Erythematous macular rash
• Purpuric rash associated with transient porphyrinemia
• Overheating
• Dehydration (increased insensible water loss, diarrhoea)
• Hypothermia from exposure
• Bronze baby syndrome – a benign condition which occurs in the presence
of direct hyperbilirubinemia.
• Long-term adverse biologic effects of phototherapy are absent, minimal, or
unrecognized
Bronze Baby Syndrome
• Dark, greyish brown skin discolouration in infants undergoing
phototherapy.
• Have significant elevation of direct-reacting bilirubin
• Results from photo-induced modification of porphyrins, which are
often present during cholestatic jaundice
• May last for many months.
• Phototherapy can continue if needed despite the discolouration
 Exchange transfusion
• Required if the bilirubin rises to levels which are considered potentially
dangerous.
• Particularly if there is associated anaemia from haemolysis or the serum albumin
is low.
• Performed via an umbilical venous catheter.
• Done by alternately withdrawing 10-20 ml aliquots of the baby's blood and
replacing them with donor blood.
• Can be performed more efficiently by infusing the blood via a peripheral vein
while extracting blood from an arterial line.
• This avoids the complications associated with umbilical vein cannulation.
 Exchange transfusion
• Volume of blood exchanged – 2x the infant's blood volume (2 × 80 ml/kg).

• Donor blood should be as fresh as possible

• The donor blood should be screened to exclude CMV, hepatitis B and C and HIV
infection.

• The procedure carries some risk of morbidity and mortality

Initiating
• Various factors may influence the decision to perform a double
volume exchange transfusion in an individual patient.
• The appearance of clinical signs suggesting kernicterus is an indication
for exchange transfusion at any level of serum bilirubin.
• A healthy full-term infant with physiologic or breast milk jaundice may
tolerate a concentration slightly higher than 25 mg/dL with no
apparent ill effect, whereas kernicterus may develop in a sick
premature infant at a significantly lower level of serum bilirubin.
Initiating
• A level approaching that considered critical for the individual infant
may be an indication for exchange transfusion during the 1st or 2nd
day after birth when a further rise is anticipated

• This is not typically after the 4th day in a term infant or after the 7th
day in a preterm infant because an imminent fall may be anticipated
as the hepatic conjugating mechanism becomes more effective
 Exchange transfusion
• No bilirubin levels known to be safe or which will definitely cause kernicterus.
• Kernicterus could be prevented if the bilirubin was kept below 340 mmol/L (20
mg/dl) in patients with Rh haemolytic disease.
• No consensus among paediatricians on the bilirubin levels at which phototherapy
and exchange transfusion should be performed.
• Each unit should have clear guidelines for the management of jaundice.
• Severely jaundiced infants with low serum albumin, e.g. preterm, may be given
intravenous albumin, although its efficacy is uncertain.
Guidelines for Initiating
Exchange Transfusion
• Potential complications include
• Metabolic acidosis
• Electrolyte abnormalities - Hypocalcaemia
• Hypoglycaemia
• Thrombocytopenia
• Volume overload
• Arrhythmias
• NEC
• Infection
• Graft-versus-host disease, and
• Death.
• Repeated if necessary to keep indirect bilirubin levels in a safe range
Intravenous Immunoglobulin
• An adjunctive treatment for hyperbilirubinemia caused by iso-immune
haemolytic disease.

• Its use is recommended when serum bilirubin is approaching exchange

levels despite phototherapy.

• Intravenous immunoglobulin (0.5-1.0 g/kg/dose; repeat in 12 hr)

• Reduces the need for exchange transfusion in both ABO and Rh

haemolytic disease, by reducing haemolysis.
Metalloporphyrins
• Snmesoporphyrin (SnMP)

• Competitive enzymatic inhibition of the rate-limiting conversion of

heme-protein to biliverdin (an intermediate metabolite in the
production of unconjugated bilirubin) by hemeoxygenase

• Single intramuscular dose on the 1st day of life

Metalloporphyrins
• May reduce the need for subsequent phototherapy & duration of
hospital stay

• Indicated when
• Jaundice is anticipated - ABO incompatibility , G6PD deficiency, or
• When blood products are objected to - Jehovah’s Witness parents

• Complications
• Transient erythema if the infant is receiving phototherapy.
Prognosis
• Depends on whether treatment is initiated early or whether
kernicterus sets in

• Mostly bad prognosis and risk of death is kernicterus develops

• Risk of chorea athetoid Cerebral palsy with developmental delay