Neonatal Jaundice.pdf

PAEDIATRICS AND CHILD HEALTH
• NEONATOLOGY
• Neonatal Jaundice
Dr. Chongo Timothy Shapi (BSc.HB, MBChB)
- Medical Doctor.
2/21/2013 Dr. Chongo Shapi, BSc.HB, MBChB, CUZ. 1

What is Jaundice?
• Hyperbilirubinaemia, clinically
manifesting as yellowing of the:
•Sclera
•Skin
•Mucous membranes

Haem Metabolism
• In the reticulo-endothelial system (RES) e.g.
spleen, phagocytes destroy old and effete RBCs and
this releases hemoglobin which is converted to
haem and globin
• The globin part is turned into amino acids
• The haem part is converted to biliverdin by haem
oxygenase enzyme
• The biliverdin reductase converts biliverdin to free
unconjugated bilirubin which is NOT soluble in
water due to intramolecular hydrogen bonding
• Hence, it is bound to albumin and transported to
the hepatocytes

Haem Metabolism
• In the hepatocytes, it is released from albumin and combined
with GLUCURONIC ACID to form BILIRUBIN GLUCURONIDE by
the enzyme called uridine diphosphoglucuronosyl transferase
(UGT-1)
• This conjugation produces CONJUGATED BILIRUBIN (Direct
Bilirubin by the Van den Bergh reaction) which is soluble in
water
• The conjugated bilirubin is then excreted via active transport
into the biliary canaliculi to mix with other components of bile
and into the intestines at the major duodenal papilla of Vater in
the 2nd part of the duodenum
• 95% of the conjugated bilirubin in the intestines is deconjugated
by the beta glucuronidase enzyme on the brush border of the
small intestine to the unconjugated lipid soluble bilirubin for
reabsorption at the terminal ileum back into the portal
circulation to the liver where it is resecreted (enterohepatic
circulation)
2/21/2013
Dr. Chongo Shapi, BSc.HB, MBChB, CUZ.
.
4

Haem Metabolism
• The remaining 5% goes to the colon
• 50% of the 5% of conjugated bilirubin in the colon is acted
upon by intestinal normal bacterial flora
• The bacteria degrade it to UROBILINOGEN (water soluble)
• Fate of urobilinogen:
a. 95% is reabsorbed back into portal circulation for the
enterohepatic circulation, but 5% of the 95% is oxidized to
urobilin (water soluble) and excreted in urine giving the
yellow colour of urine
b. 5% is oxidized to stercobilin (water soluble) and excreted
in faeces giving the yellow colour of faeces
NB: Bilirubin is NOT supposed to appear in urine (dark urine).
If it does, then that is water soluble bilirubin (direct bilirubin)
accumulating in blood as a result of obstruction to already
conjugated bilirubin in the liver

Jaundice and Hyperbilirubinemia in the Newborn
• Hyperbilirubinemia is a common and, in most
cases, benign problem in neonates
• Jaundice in 1st wk of life is approximately:
- 60% of term infants and
- 80% of preterm infants
• The yellow colour usually results from the
accumulation of unconjugated, nonpolar, lipid-
soluble bilirubin pigment in the skin
• This unconjugated bilirubin (designated indirect
acting by nature of the Van den Bergh reaction) is
an end product of haem-protein catabolism

• It may also be due in part to deposition of
pigment from water soluble, conjugated bilirubin
(direct bilirubin)
• Although bilirubin may have a physiologic role as
an antioxidant, elevated levels of indirect,
unconjugated bilirubin are potentially neurotoxic
• Even though the conjugated form is not
neurotoxic, direct hyperbilirubinemia indicates
potentially serious hepatic disorders or systemic
illnesses

Aetiology
• During the neonatal period, metabolism of
bilirubin is in transition from the fetal stage to
adult stage
• In the fetal stage, the placenta is the principal
route of elimination of the lipid-soluble,
unconjugated bilirubin which goes to the
maternal liver for degradation
• In the adult stage, the water-soluble conjugated
form is excreted from hepatic cells into the biliary
system and GIT

• Unconjugated hyperbilirubinemia may be caused or
increased by any factor that:
1. Increases the load of bilirubin to be metabolized
by the liver
- Haemolytic anaemias
- Polycythaemia
- Shortened RBC life as a result of immaturity or
transfused cells
- Increased entero-hepatic circulation
- Infection

2. Damages or reduces the activity of the
transferase enzyme or other related enzymes
- Genetic deficiency
- Hypoxia
- Infection
- Thyroid deficiency
3. Competes for or blocks the transferase enzyme
(drugs and other substances requiring glucuronic
acid conjugation)
4. Leads to an absence or decreased amounts of
the enzyme or to reduction of bilirubin uptake by
liver cells (genetic defect, and prematurity)

• The toxic effects of elevated serum levels of
unconjugated bilirubin are increased by factors that
reduce the retention of bilirubin in the circulation
• These include:
- Hypoproteinemia
- Displacement of bilirubin from its binding sites on
albumin by competitive binding of drugs such as
sulfonamides
- Acidosis
- Increased free fatty acid concentration secondary to
hypoglycemia
- Starvation
- Hypothermia
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11

• Neurotoxic effects are directly related to:
- The permeability of the blood-brain barrier
- Permeability of the nerve cell membranes
- Neuronal susceptibility to injury
• All of these are adversely influenced by asphyxia,
prematurity, hyperosmolality, and infection
• Early and frequent feeding decreases whereas
breast-feeding and dehydration increase serum
levels of bilirubin
• Delay in passage of meconium, which contains 1 mg
bilirubin/dL, may contribute to jaundice by
enterohepatic circulation after deconjugation by
intestinal glucuronidase

Risk factors for Hyperbilirubinemia
Acronym = JAUNDICE:
• Jaundice visible on the 1st day of life
• A sibling with neonatal jaundice or anemia
• Unrecognized hemolysis (ABO, Rh, other blood group,
incompatibility); UDP-glucuronosyl transferase deficiency
(Crigler-Najjar, Gilbert’s disease)
• Non-optimal feeding (formula or breast-feeding)
• Deficiency of glucose-6-phosphate dehydrogenase (G6PD)
• Infection (viral, bacterial). Infant of diabetic mother
(macrosomic). Immaturity (prematurity)
• Cephalohematoma or bruising. Central hematocrit >65%
(polycythemia)
• East Asian, Mediterranean, Native American heritage

Other risk factors:
• Gestational age 35–36 wk (major risk)
• Gestational age 37–38 wk (minor risk)
• Maternal age ≥25 yr
• Male gender

Decreased risk
• Low TSB
• Gestational age ≥41 wk
• Exclusive bottle feeding
• Black race
• Discharge from hospital after 72 hr

Clinical Manifestations
• Depending on the aetiology, jaundice may be present at
birth or may appear at any time during the neonatal
period
• Is usually apparent in a cephalocaudal progression starting
on the face and progressing to the abdomen and then
feet, as serum levels increase
• Dermal pressure may reveal the anatomic progression of
jaundice, called Kramer’s rule
• The rule is basically a clinical method of assessing the
degree of jaundice present before investigations are
undertaken
• The technique depends on blanching of the infant’s skin
with the examiner’s finger at standard zones (1-5) and
observing the colour in the blanched area
• The zones of jaundice reflect the downward progression of
dermal icterus

Zones of Kramer’s rule
• Zone 1: jaundice limited to head and neck
- Serum indirect bilirubin: 100umol/L
• Zone 2: over upper trunk
• Zone 3: over lower trunk, thighs
• Zone 4: over arms, forearm, legs
• Zone 5: hands and feet
- Serum indirect bilirubin: > 250umol/L

• Jaundice from deposition of indirect bilirubin in
the skin tends to appear bright yellow or orange
• Jaundice of the obstructive type (direct
bilirubin) has a greenish or muddy yellow cast
• Signs of kernicterus include:
- Lethargy
- Poor feeding and, without treatment
- Progresses to acute bilirubin encephalopathy

Differential diagnosis
• On the 1st day (24 hrs) of life
- Haemolytic disease of the newborn (HDNB) or
erythroblastosis fetalis. Remember, with haemolysis the
rise in bilirubin is very fast
- Concealed haemorrhage (cephalohaematoma)
- Neonatal sepsis
- Congenital infections (TORCHES)
• On the 2nd -3rd day of life
- Physiologic jaundice
- Familial non-hemolytic icterus (Criggler Najjar, Gilbert’s)
- Breast feeding jaundice

Differential diagnosis
• After the 3rd day and appearing within the 1st
week of life
- Bacterial sepsis
- TORCHES
- Polycythaemia
- Cephalohaematoma

• After 1st week of life
- Breast milk jaundice (is not the same as breast feeding
jaundice)
- Septicaemia
- Congenital biliary atresia (CBA)
- Hepatitis
- Galactosaemia (galactose-1-phosphate uridyl transferase =
GALT). The enzyme is deficient
- Congenital hypothyroidism (this cause low BMR, hence
slows down the conjugation process in the liver)
- Congenital haemolytic anaemia crises related to RBC
morphology and enzyme deficiencies e.g. G6PD,
hereditary spherocytosis
- Cystic fibrosis (CF): meconium ileus and also thick bile
secretions block the bile ducts

• Persistent jaundice during the 1st month of life
- Hyperalimentation associated with cholestasis
- Hepatitis
- Cytomegalic inclusion disease
- TORCHES
- Familial non-haemolytic icterus e.g. Crigler Najjar
syndrome or Gilbert’s disease
- Congenital biliary atresia
- Galactosemia
- Inspissated bile syndrome (IBS) following HDNB
- Rarely physiologic jaundice in a patient with
hypothyroidism or pyloric stenosis

• Full-term, low-risk, asymptomatic infants may be
evaluated by monitoring total serum bilirubin (TSB)
levels
• Patients with significant hyperbilirubinemia and
symptomatic require a complete diagnostic
evaluation:
- Determination of direct and indirect bilirubin
fractions
- Haemoglobin
- Reticulocyte count
- Blood type
- Coombs test
- Examination of a peripheral blood smear

• Haemolysis may be suggested by:
- Indirect hyperbilirubinemia
- Reticulocytosis
- Evidence of RBC destruction on peripheral smear
• In the absence of blood group incompatibility,
non–immunologically induced haemolysis should
be considered

• Direct hyperbilirubinemia:
- Hepatitis
- Congenital bile duct disorders e.g. atresia
- Cholestasis
- Inborn errors of metabolism e.g. galactosaemia
- CF
- Sepsis
• Indirect hyperbilirubinemia:
- If the reticulocyte count, Coombs test, and direct
bilirubin are normal

Differential Diagnosis

Remember, jaundice can be:
a. Physiologic or
b. Pathologic

Physiologic Jaundice (Icterus Neonatorum)
• Normal level of indirect-reacting bilirubin in umbilical
cord serum is 1–3 mg/dL
• This rises at a rate of <5 mg/dL/24 hr
• Thus, jaundice becomes visible on the 2nd–3rd day
• Usually peaks between day 2 and 4 at 5–6 mg/dL
• It then decreases to below 2 mg/dL between the 5th
and 7th days of life
• Jaundice associated with these changes is designated
physiologic jaundice (Icterus Neonatorum)
• Is due to breakdown of fetal RBCs combined with
inability to conjugate bilirubin by the immature
neonatal liver
• Remember, neonates have more RBCs and hence a
higher Hb than adults

• Diagnosis of physiologic jaundice in term or preterm
infants can be established only by excluding known
causes of jaundice based on history, clinical findings,
and laboratory data
• In general, a search to determine the cause of
jaundice should be made if:
1. It appears in the 1st 24–36 hr of life
2. Serum bilirubin is rising at a rate faster than 5
mg/dL/24 hr
3. TSB is >12 mg/dL in full-term infants or 10–14
mg/dL in preterm infants
4. Jaundice persists after 10–14 days of life
5. Direct-reacting bilirubin is >2 mg/dL at any time

• Other factors suggesting a non-physiologic cause
of jaundice are:
- Family history of haemolytic disease
- Pallor
- Hepatosplenomegaly
- Failure of phototherapy to lower bilirubin
- Light-coloured stools
- Dark urine positive for bilirubin
- Signs of kernicterus

Pathologic Jaundice
• Jaundice and its underlying hyperbilirubinemia
are considered pathologic if:
A. There is significant variation from that of
physiologic jaundice in:
1. Time of appearance
2. Duration
3. Pattern
B. The course is compatible with physiologic
jaundice but other reasons exist to suspect that the
infant is at special risk for neurotoxicity

Pathologic Jaundice
• High unconjugated hyperbilirubinemia =
development of bilirubin-induced neurologic
dysfunction
• The development of kernicterus (bilirubin
encephalopathy) is dependent on:
1. Level of indirect bilirubin
2. Duration of exposure to elevated levels
3. Cause of jaundice
4. Infant's well-being

Pathologic Jaundice
• Neurologic injury including kernicterus occurs at
lower bilirubin levels in:
1. Preterm infants
2. Presence of asphyxia
3. Intraventricular haemorrhage
4. Haemolysis
5. Drugs that displace bilirubin from albumin e.g.
septrin
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Jaundice Associated with Breastfeeding
• Significant breast-milk jaundice develops in an
estimated 2% of breast-fed term infants after the
7th day of life
• Maximal concentrations as high as 10–30 mg/dL
are reached during the 2nd–3rd week
• If breast-feeding is continued, the bilirubin
gradually decreases but may persist for 3–10 wk
at lower levels
• Phototherapy may be of benefit
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Jaundice Associated with Breastfeeding

The difference between Breastfeeding
Jaundice and Breast-Milk Jaundice
• Breastfeeding Jaundice
- Is due to lack of breast feeding the infant
- Can also be due to reduced amount of milk
intake
- This causes inadequate bowel movements to
remove bilirubin in the body and hence is a
mechanical problem resulting in accumulation of
bilirubin in the neonate (unconjugated)
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• Breast-Milk Jaundice
- Is a biochemical problem
Factors responsible
1. Unusual metabolite of progesterone
(pregnane-3-alpha 20 beta-diol) inhibits UGT-
1 enzyme
2. The lipoprotein lipase in breast milk produces
increased concentrations of non-esterified
free fatty acids that inhibit UGT-1

3. Increased enterohepatic circulation of bilirubin due
to:
a. Delayed establishment of enteric flora in breast fed
infants. Remember, that initially the GI of the
neonate is sterile with no normal flora
b. Because of lack of normal flora, the beta
glucuronidase in some breast milk deconjugates the
bilirubin and hence deconjugated bilirubin is
reabsorbed and accumulates in blood
4. High epidermal growth factor in breast milk which
cause reduced GI motility and increased bilirubin
absorption and uptake
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Familial Non-Haemolytic Icterus
Unconjugated
1. Gilbert's syndrome
2. Crigler-Najjar syndrome
Conjugated
1. Dubin-Johnson syndrome
2. Rotor’s syndrome

Gilbert’s syndrome
• This is the most common familial hyperbilirubinaemia
• Hepatic glucuronidation is approximately 30% of
normal
• This results in an increased proportion of bilirubin
monoglucuronide in bile
• Most patients have reduced levels of UDP-
glucuronosyl transferase (UGT-1) activity, the enzyme
that conjugates bilirubin with glucuronic acid
• Mutations occur in the gene (HUG-Br1) encoding this
enzyme
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Crigler-Najjar syndrome
• This is very rare
• There are 2 types:
- Type I: autosomal recessive, there is absence of
UGT-1. Patients do not survive into adult life
- Type II: autosomal dominant, with a decrease of
UGT-1. Patients survive into adult life
• There is mutation of the HUG-Br1 gene for UGT-1
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Dubin-Johnson and Rotor’s syndrome
• DJS is autosomal recessive
• Rotor's syndrome is possibly autosomal dominant
• Are syndromes that are due to defects in bilirubin
excretion from hepatocytes into the bile canaliculi
• The prognosis is good in both
• In the Dubin-Johnson syndrome there are mutations
in both multidrug resistance protein 2 (MRP2)
transporter genes
• In DJS, the liver is black owing to melanin deposition

Congenital atresia of the bile ducts
• Jaundice persisting for more than 2 wk or
associated with acholic stools and dark urine
suggests biliary atresia
• All such infants must have an immediate
diagnostic evaluation, including determination of
direct bilirubin

Galactosaemia
• Is an autosomal recessive disorder in which there is
inborn error of metabolism of galactose
• Dietary lactose is broken down by lactase to glucose
and galactose
• In a 3 step process (LELOIR pathway), galactose is
converted to glucose
• Enzymes involved: galactose-1-phosphate uridyl
transferase (GALT), galactose kinase, UDP galactose
epimerase
• This metabolic pathway is particularly vital for the
newborn, whose main carbohydrate source is lactose
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Galactosaemia
a. Type 1 (Classic galactosaemia)
- Most common variant
- There is deficiency of GALT
b. Type 2: Deficiency of galactose kinase
c. Type 3: defieiciency of UDP galactose epimerase
• This results in accumulation of galactose-1-
phosphate and other precursors causing damage to
many organs, tissues and cells including liver, spleen,
kidney, ocular lens, cardiac muscle, brain, gonadal
tissue and RBCs

How Sepsis Causes Jaundice
• Severe conjugated hyperbilirubinemia can be due sepsis
involving both gram-positive and gram-negative bacteria
• Gram negative are more common
• Serum alkaline phosphatase activity and cholesterol levels
are usually low
• This suggests an isolated defect in excretion of conjugated
bilirubin
• In jaundice associated with sepsis, liver pathology is
nonspecific and includes canalicular cholestasis and slight
fat accumulation
• Portal tracts may contain excess inflammatory cells and
variable bile ductule proliferation
• Occasionally, dilated ductules are filled with inspissated bile

Kernicterus (bilirubin encephalopathy)
• From Greek: kern = nucleus, icterus = jaundice
• Is a neurologic syndrome resulting from the
deposition of unconjugated (indirect) bilirubin in
the basal ganglia and brainstem nuclei
• Multifactorial pathogenesis
• Involves an interaction of the following:
- Unconjugated bilirubin levels
- Albumin binding
- Unbound bilirubin levels
- Passage across the BBB, and
- Neuronal susceptibility to injury

Kernicterus (bilirubin encephalopathy)
• Disruption of the BBB by disease, asphyxia, and
other factors and maturational changes in BBB
permeability affect risk
• Rare in healthy term infants and in the absence
of haemolysis if the serum level is <25 mg/dL
• Has developed in healthy term infants when
bilirubin levels exceed 30 mg/dL
• Onset is usually in the 1st wk of life, but may be
delayed to the 2nd–3rd wk
• The more immature the infant is the greater the
susceptibility to kernicterus

Clinical manifestations of Kernicterus
• Signs and symptoms appear:
- 2–5 days after birth in term infants
- 7th day in premature infants
• Hyperbilirubinemia may lead to encephalopathy
at any time during the neonatal period
• The early signs are indistinguishable from those
of sepsis, asphyxia, hypoglycemia, intracranial
hemorrhage, and other acute systemic illnesses in
a neonate

Clinical manifestations of Kernicterus
• Lethargy
• Poor feeding
• Loss of the Moro reflex
• Diminished tendon
reflexes
• Respiratory distress
• Opisthotonos
• Bulging fontanel
• Twitching of the face or
limbs
• High-pitched cry
• Convulsions
• Spasm (stiffly extending
their arms in an inward
rotation with the fists
clenched)
• Rigidity
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Treatment of hyperbilirubinemia
AIM: prevent kernicterus
Medical:
1. Phototherapy:
a. Conventional
b. Intensive: irradiance of light ≥ 30uW/cm2/nm
2. Exchange transfusion (ET)
3. IV immunoglobulin (IVIG) used as adjunct therapy in isoimmune haemolytic
disease
Phototherapy and, if unsuccessful, ET remain the primary treatment modalities
used to keep the maximal TSB below the pathologic levels
NB: Haem oxygenase inhibitors currently under research. Haem is excreted in
bile

Treatment of hyperbilirubinemia
• Goal of therapy is to prevent kernicterus
• The risk of injury to the CNS from bilirubin must be
balanced against the potential risk of treatment
• There is lack of consensus regarding the exact
bilirubin level at which to initiate phototherapy
• Phototherapy requires 6–12 hr to have a measurable
effect
• Hence, must be started at bilirubin levels below those
indicated for ET
• Treat the underlying cause if identified e.g. antibiotics
for septicemia 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)
• Broad-spectrum white, blue, and special narrow-
spectrum (super) blue lights have been effective
in reducing bilirubin levels
• Bilirubin in the skin absorbs light energy, causing
several photochemical reactions

Phototherapy
MOA:
1. Photo-oxidation: minimal contribution
2. Configurational isomerization to 3 water soluble IBs:
4Z, 15Z ↔ 4Z, 15E (predominant); 4E, 15Z; 4E, 15E.
3. Irreversible structural isomerization: lumirubin
- No consensus regarding the exact bilirubin
level at which to initiate phototherapy
- Rule of thumb:
TSB > 5 times the birth weight:
e.g.
1 kg = 5 mg/dL
2 kg = 10mg/dL and so on

Bhutani Graph
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55

• Phototherapy causes a reversible photo-
isomerization reaction converting the toxic native
unconjugated 4Z, 15Z-bilirubin into an
unconjugated configurational isomer 4Z,15E-
bilirubin
• The product is then excreted in bile in an
unconjugated state
• The other major product from phototherapy is
lumirubin, which is an irreversible structural
isomer converted from native bilirubin and can be
excreted by the kidneys in the unconjugated state

• The therapeutic effect of phototherapy depends on:
1. The light energy emitted in the effective range of
wavelengths
2. The distance between the lights and the infant, and
3. The surface area of exposed skin
4. The rate of haemolysis and in vivo metabolism and
excretion of bilirubin
• The use of phototherapy has decreased the need for
ET in term and preterm infants with haemolytic and
non-haemolytic jaundice

Precautions of Phototherapy
1. The infant's eyes should be closed and
adequately covered to prevent light exposure and
corneal damage
2. Body temperature should be monitored
3. Infant should be shielded from bulb breakage
4. Irradiance should be measured directly and
details of the exposure recorded:
- Type and age of the bulbs
- Duration of exposure
- Distance from the light source to the infant

Always Shield the Eyes
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Complications of Phototherapy
1. Diarrhoea
2. Erythematous macular rash
3. Purpuric rash associated with transient
porphyrinemia (Phototherapy is a
contraindication in the presence of porphyria)
4. Overheating
5. Dehydration (increased insensible water loss,
diarrhoea)
6. Hypothermia from exposure
7. Bronze baby syndrome (BBS) due to
hyperbiliverdemia. Differential of BBS is gray baby
syndrome (GBS) due to chloramphenicol
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Exchange Transfusion (ET)
• Indications for double
volume ET:
1. Failure of phototherapy to
reduce bilirubin levels to a
safe range
2. Kernicterus at any level of
bilirubin
• Potential complications of
ET:
- Metabolic acidosis
- Electrolyte abnormalities
- Hypoglycemia
- Hypocalcemia
- Thrombocytopenia
- Volume overload
- Arrhythmias
- Necrotising enterocolitis
(NEC)
- Infection
- Graft versus host disease

Exchange transfusion
Indications:
1. Failure of intensive phototherapy
2. Kernicterus
- Has more complications
than phototherapy
- Thus, intensive phototherapy
recommended before ET

Intravenous immunoglobulin
• Is an adjunctive treatment for hyperbilirubinemia
due to isoimmune haemolytic disease
• Its use is recommended when serum bilirubin is
approaching exchange levels despite maximal
interventions including phototherapy
• IV immunoglobulin (0.5–1.0 g/kg/dose; repeat in
12 hr) has been shown to reduce the need for ET
in both ABO and Rh haemolytic disease,
presumably by reducing haemolysis

Thank You!

Neonatal Jaundice.pdf

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