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FACTORS AFFECTING SEVERITY
Thesis submitted for partial fulfillment of master degree in pediatrics
BY
HAGAR FAWZEY HASAN EL TAWEEL
(M.B.B.Ch)
Under Supervision by
PROF.Dr. AHMED KHASHBA
Professor of pediatrics
Faculty of Medicine
BENHA University
Dr. MOHAMED BAYOUMY
Lecturer of pediatrics
Faculty of Medicine
BENHA University
Faculty of Medicine
BENHA University
2012
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(())
(11)
Acknowledgement
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First, thanks to god for helping me to complete this study.
I would like to express my sincere gratitude and respect to
PROF.Dr. AHMED KHASHBAProfessor of pediatrics
Faculty of Medicine BENHA University, for the continuous guidance,
supervision and his kind encouragement and support throughout the
entire period of the study. It was indeed an honor to work under his
supervision.
I also wish to thank Dr. MOHAMED BAYOUMYLecturer of
pediatrics, Faculty of Medicine, BENHA University for his guidance,
extreme generosity and valuable advice through this study.
Last but not least, I am very grateful to all the babies that were
included in my study and I wish all the best to all babies everywhere.
Table of Contents
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Page
List of tables 5
List of figures 6
List of abbreviations 7
Aim of work 8
Introduction 10
Part 1: Review of literature
Chapter 1: Neonatal hyperbillirubineamiaChapter 2: ABO blood group system
Chapter 3: ABO hemolytic disease of newborn
Chapter 4: Coombs' test
13
14
37
44
56
Part 2: Practical work
Patients and method
Results and analysis of data
61
62
66
Part 3: Discussion
Part 4: Summary and Conclusion
Conclusion and recommendation
Summary
References
Arabic summary
List of Tables
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Table
No.Title
Page
No.
1 Causes of Unconjugated Hyperbilirubinemia 23
2 Causes of Conjugated Hyperbilirubinemia 24
3 Differential diagnosis of hyperbilirubinemia 28
4 Suggested maximum indirect serum bilirubin
concentrations (mg per/dL) in preterm infants
30
5 Interference according to total bilirubin levels 30
6 Bilirubin / Albumin ratio as an additional factor indetermining the need for exchange transfusion
38
7 Antigens of the ABO blood group 41
8 Antibodies produced against ABO blood group
antigens
42
9 Phenotype of ABO Blood Group System 42
10 Inheritance of ABO Blood Group 43
List of figures
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FIGURE
No.Title
Page
No.
1 The pathophysiology of neonatal
hyperbilirubinemia
20
2 Kramers rule 28
3 Total serum bilirubin and age chart 29
4 The management of hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation
31
5 Baby under phototherapy 36
6 Guidelines for exchange transfusion in infants 35
or more weeks gestation
37
7 Bombay phenotype inheritance 44
8 Direct Coombs' test 57
9 Indirect Coombs' test 58
List of abbreviations
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AIM OF THE WORK
The aim of the work is to:
1-Identify maternal, neonatal and environmental factors affecting the
course of ABO incompatibility neonatal jaundice and its severity
2- Compare between OA & O-B blood subgroups incompatibilities in
incidence and severity
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Introduction
Jaundice is one of the most common conditions requiring medical attention innewborn babies. Approximately 60% of term and 80% of preterm babies develop
jaundice in the first week of life, and about 10% of breastfed babies are still jaundiced at
1 month of age. (Piazza A.J and Stoll B. J., 2007)
Severe hyperbilirubinemia continues to be the most common cause of neonatal
readmission to hospitals. Long-term results of severe hyperbilirubinemia, including
bilirubin encephalopathy and kernicterus, were thought to be rare since the advent of
exchange transfusion, maternal rhesus immunoglobulin prophylaxis and phototherapy .
(Michael Sgro et al.; 2006)
The risk factors of neonatal hyperbilirubinemia include race of the patient as Asians
have the highest risk followed by Caucasian while the black infant have the lower risk.
Other risk factors include breast feeding, pregnancy induced hypertension, diabetes
mellitus, obstructed labor, oxytocin use, blood group incompatibility between mother
and her baby, passive smoking and prolonged premature rupture of membranes. Family
history of previously jaundiced baby as a child whose sibling needed phototherapy is 12
times more likely to also have significant jaundice. Neonatal risk factors include
prematurity, sepsis, perinatal asphyxia, delayed passage of meconium and congenitainfections, infant with bruising or cephalheamatoma. (Wennberg et al.; 2006)
In a study conducted to Michael sgro, douglas Campbell and vibhuti shah 2006
showed that the percentage of ABO incompatibility as a cause of severe neonata
hyperbilirubinemia is about 51% followed by G6PD about 21.5% other antibody
incompatibility about 13% and other causes about 14.5% ABO hemolytic disease of
newborn occurring in about 15% of infants with A or B blood type born to blood type O
mothers and, unlike non- hemolytic disease of newborn. ABO incompatibility is usually
a problem of the neonate rather than of the fetus, A and B antigens are only weakly
expressed on neonatal RBCs. ABO hemolytic disease of newborn therefore usually mild
and characterized by negative or weakly positive Coombs' test. ABO hemolytic disease
of newborn rarely requires whole blood exchange transfusion, in contrast to hemolytic
disease of newborn due to anti-D or other antibodies.(Kathryn Drabik-Clary et al; 2006)
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In a study of demographic characteristic of newborn who did and who did not
develop significant hyperbilirubinemia following serum bilirubin measurement and the
use of the critical bilirubin levels of 4 mg/dl and 6mg/dl at the sixth hours of life will
predict that the incidence of O-A blood group incompatibility is higher than that of O-B
blood group incompatibility in newborns who will develop significant
hyperbilirubineamia. (Olcay Oran et al.; 2002)
Several studies have established that ABO hemolytic disease is more common in
blacks and in children of mixed racial origin than among other races. For Caucasian
populations about one fifth of all pregnancies have ABO incompatibility between the
fetus and the mother. (Wang, M. et al.; 2005)
In a study of hemolysis and hyperbilirubinemia in ABO blood group incompatibility in
neonates it was documented that 62% of O-B incompatibility hemolytic disease develop
hyperbilirubinemia in contrast to 46.8% of O-A blood group incompatibility hemolytic
disease and it appear earlier in O-B incompatibility than O-A incompatibility despite that
hyperbilirubinemia in the first 24 hour about 48.1% caused by O-B incompatibility while
about 93.9% caused by O-A incompatibility. (Johnson l et al.; 2009)
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Review of literature
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Chapter 1: Neonatal Hyperbilirubinemia
Historical background
Neonatal jaundice may have first been described in a Chinese textbook 1000 years
ago. Medical theses, essays, and textbooks from the 18th and 19th centuries containdiscussions about the causes and treatment of neonatal jaundice. In 1875, Orth first
described yellow staining of the brain, in a pattern later referred to as kernicterus. (Thor
W.R. Hansen, 2011)
DefinitionJaundice is a yellowish discoloration of skin and mucous membranes. It is caused by elevated
serum concentration of bilirubin. Newborns appear jaundiced when it is >7mg/dl.,(Martin and
Cloerty, 2008)
Neonatal jaundice usually happens during the first weeks of life. There are many types of
jaundice, including:
* Physiologic jaundice * Breast-feeding jaundice
* Breast milk jaundice (human milk jaundice syndrome)
* Jaundice caused by hemolysis or increased bilirubin production
* Jaundice caused by inadequate liver function (due to inborn errors of metabolism,
prematurity, or enzyme deficiencies). The yellow coloring is caused by bilirubin, a waste
product created by the body when it breaks down red blood cells in the normal course of
metabolism. (J. Thomas Megerian, 2011)
IncidenceHyperbilirubinemia is a common and, in most cases, benign problem in neonate. Jaundice
is observed in 1st week of life in approximately 60% of term infant and 80% of preterm infant
(Piazza and Stoll, 2007)
The incidence of Jaundice is higher in breast- fed babies than in the formula- fed ones. Asian
male babies and Native American ones are reported to be most affected by Neonatal Jaundice
They are followed by Caucasian infants who in turn are followed by African Neonates. Babies
who are either small or large for gestational age are at an increased risk of developing
Neonatal Jaundice. (Sumana, 2011)
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Pathophysiology of hyperbilirubinemia
Bilirubin
Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of norma
heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells
Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is
responsible for the yellow color of bruises, the yellow color of urine (via its reduced
breakdown product, urobilin), the brown color of feces (via its conversion to stercobilin), and
the yellow discoloration in jaundice. (Pirone C. et al; 2009)
During the neonatal period, metabolism of bilirubin is in transition from the fetal stage during
which the placenta is the principal route of elimination of the lipid-soluble (unconjugated
bilirubin) to the adult stage, during which the water-soluble (conjugated form) is excreted
from hepatic cells into biliary system and gastrointestinal tract. (Piazza and Stoll, 2007)
Source of Bilirubin
Bilirubin is formed by breakdown of heme present in hemoglobin, myoglobin
cytochromes, catalase, peroxidase and tryptophan pyrrolase. Enhanced bilirubin formation is
found in all conditions associated with increased red cell turnover such as intramedullary or
intravascular hemolysis as (hemolytic, dyserythropoietic, and megaloblastic anemias). Heme
consists of a ring of four pyrroles joined by carbon bridges and a central iron atom
(ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme
mediated by two groups of enzymes: Heme oxygenase & Biliverdin reductase. (Namita Roy-
Chowdhury et al; 2012)
Metabolism of bilirubin
Bilirubin metabolism includes 5 steps:
1) Production 2) Transport
3) Uptake 4) Conjugation
5) Excretion
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1-Production of Bilirubin
Heme oxygenases are the initial and rate-limiting enzymes in the breakdown of heme
(iron protoporphyrin IX) that itself plays an essential role in the transport of oxygen and
mitochondrial electron transport as a cofactor of hemoglobin, myoglobin, and cytochromes
Degradation of heme generates carbon monoxide, iron, and biliverdin, the latter of which i
subsequently converted to bilirubin by biliverdin reductase.(Stuart T. Fraser et al; 2011)
a) The Fe released is reincorporated into hemoglobin.
b) The CO is excreted unchanged in the lung, where the amount serves as a measure of
bilirubin synthesis. (Shapiro, 2003)
Catabolism of 1 mol of hemoglobin produces 1 mol CO and bilirubin. Increased bilirubin
production as measured by CO excretion rate accounts for the higher bilirubin level seen in
Asian, Native American, and Greek infants. (Agarwal & Deorari, 2002)
2- Bilirubin Transport
Unconjugated bilirubin is extremely poorly soluble in water; it is present in plasma
strongly bound to albumin.The dissociation constant for the first albumin-binding site. (Johan
Fevery, 2008)
If the albumin-binding sites are saturated, or if unconjugated bilirubin is displaced from
the binding sites by medications (e.g. sulfisoxazole [Gantrisin], streptomycin, vitamin K), free
bilirubin can cross the blood-brain barrier. (Mocrschel et al., 2008)
Bilirubin Exists in 4 Different Forms in Serum:
1. Unconjugated bilirubin reversibly bound to albumin which makes up the major portion of
unconjugated bilirubin in serum.
2. A tiny fraction of unconjugated bilirubin not bound to albumin "free" bilirubin.
3. Conjugated bilirubin, water soluble and easily excreted in both urine and bile.
4. Conjugated bilirubin covalently bound to albumin called delta bilirubin. This fraction is
virtually absent in the first 2 weeks of life, but account for a significant portion of thetotal bilirubin in patients with cholestatic jaundice. (Chung et al., 2004)
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3-Uptake of Bilirubin:
In the liver, bilirubin dissociates from albumin and enters the hepatocyte probably by
carrier mediated diffusion. There is a significant amount of evidence indicating that bilirubin
movement across the hepatocyte membranes is bi-directional; it has been estimated that upto 40% of the bilirubin taken up by the hepatocyte refluxes unchanged back into plasma
Efficient hepatic uptake of bilirubin is dependent on adequate hepatic blood flow. Condition
associated with a persistent ducts venous shunt, hyperviscosity or hypovolemia can lead to
decreased hepatic perfusion, decreased hepatic bilirubin uptake and unconjugated
hyperbilirubinaemia. (Doumas et al., 2004)
4-Conjugation of Bilirubin:
In the liver it is conjugated withglucuronic acidby the enzymeglucuronyltransferase
making it soluble in water. Much of it goes into the bile and thus out into the small intestine
Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic
bacteria tourobilinogen, which is further metabolized tostercobilinogen, and finally oxidised
tostercobilin. This stercobilin gives feces its brown color. Some of the urobilinogen is
reabsorbed and excreted in the urine along with an oxidized form,urobilin. Although the
terms direct and indirect bilirubin are used equivalently with conjugated and unconjugatedbilirubin, this is not quantitatively correct, because the direct fraction includes both
conjugated bilirubin and delta bilirubin which appears in serum when hepatic excretion o
conjugated bilirubin is impaired in patients with hepatobiliary disease). (Kliegman & Behrman,
2007)
5-Bilirubin Secretion and ExcretionConjugation is an important step in unconjugated bilirubin (UCB) catabolism. A very
small amount of UCB is excreted into bile without conjugation. Unconjugated bilirubin in bile i
seldom more than 2% of total bilirubin and is believed to be derived in large part from
hydrolysis of secreted conjugates in the biliary tree. (Kuroda et al., 2004)
http://en.wikipedia.org/wiki/Glucuronic_acidhttp://en.wikipedia.org/wiki/Glucuronic_acidhttp://en.wikipedia.org/wiki/Glucuronic_acidhttp://en.wikipedia.org/wiki/Glucuronyltransferasehttp://en.wikipedia.org/wiki/Glucuronyltransferasehttp://en.wikipedia.org/wiki/Glucuronyltransferasehttp://en.wikipedia.org/wiki/Urobilinogenhttp://en.wikipedia.org/wiki/Urobilinogenhttp://en.wikipedia.org/wiki/Urobilinogenhttp://en.wikipedia.org/wiki/Stercobilinogenhttp://en.wikipedia.org/wiki/Stercobilinogenhttp://en.wikipedia.org/wiki/Stercobilinogenhttp://en.wikipedia.org/wiki/Stercobilinhttp://en.wikipedia.org/wiki/Stercobilinhttp://en.wikipedia.org/wiki/Stercobilinhttp://en.wikipedia.org/wiki/Urobilinhttp://en.wikipedia.org/wiki/Urobilinhttp://en.wikipedia.org/wiki/Urobilinhttp://en.wikipedia.org/wiki/Urobilinhttp://en.wikipedia.org/wiki/Stercobilinhttp://en.wikipedia.org/wiki/Stercobilinogenhttp://en.wikipedia.org/wiki/Urobilinogenhttp://en.wikipedia.org/wiki/Glucuronyltransferasehttp://en.wikipedia.org/wiki/Glucuronic_acid7/30/2019 hager 1 1 2013
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Enterohepatic circulation
Conjugated bilirubin is hydrolyzed in the intestine to UCB, which can be reabsorbed into
the enterohepatic circulation. Hydrolysis of conjugated bilirubin to UCB can occur none
enzymatically under the influence of mild alkaline conditions as in the duodenum or jejunum
(Halamek and Stevenson, 2002), and enzymatically by beta-glucuronidase. (Martin and
Cloerty, 2008)
Conjugated bilirubin must be hydrolyzed to UCB before the tetrapyrrole ring be reduced
to the colorless urobilinogens by the intestinal anaerobic bacteria (3 Clostridia species and
Bacteroides fragilis). Intestinal bacteria can prevent enterohepatic circulation of bilirubin by
converting CB to urobillinoids, which are not substrates for beta-glucuronidase. (Martin and
Cloerty, 2008)
Fetal Bilirubin Metabolism
Aged or damaged foetal RBCs are removed from the circulation by reticuloendothelial cells,
which convert heme to bilirubin. This bilirubin is transferred into hepatocytes. Glucuronyl
transferase then conjugates the bilirubin with uridine diphosphoglucuronic acid to form
bilirubin diglucuronide which is secreted actively into the bile ducts. Bilirubin diglucuronide
makes its way into meconium in gut but cannot be eliminated from the body, because the fetusdoes not normally pass stool. The enzyme -glucuronidase, present in the fetus' small-bowel is
released into the intestinal lumen, where it deconjugates bilirubin glucuronide; free
(unconjugated) bilirubin is then reabsorbed from the intestinal tract and re-enters the fetal
circulation. Fetal bilirubin is cleared from the circulation by placental transfer into the mother's
plasma. The maternal liver then conjugates and excretes the fetal bilirubin. (Merck, 2010)
At birth, the placenta is lost, and although the neonatal liver continues to take up,
conjugate, and excrete bilirubin into bile so it can be eliminated in the stool, neonates lack
proper intestinal bacteria for oxidizing bilirubin to urobilinogen in the gut; consequently,unaltered bilirubin remains in the stool, imparting a typical bright-yellow color. In many
neonates, feedings cause the gastrocolic reflex, and bilirubin is excreted in stool before most of
it can be deconjugated and reabsorbed. However in many other neonates, the unconjugated
bilirubin is reabsorbed and returned to the circulation from the intestinal lumen (enterohepatic
circulation of bilirubin), contributing to physiologic hyperbilirubinemia and jaundice.
(Merck, 2010)
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Bilirubin as Antioxidant
Bilirubin has the ability to function as an antioxidant in the brain, scavenging free radicals
and protecting the brain against oxidative damage. (Jay Gordon, 2011)
The proposed mechanisms by which heme oxygenase exerts cytoprotective effects include
its abilities to degrade the pro oxidative heme to produce biliverdin and subsequently bilirubin
and to generate carbon monoxide, which has anti proliferative and anti inflammatory as wel
as vasodilator properties (Morita, 2005).
Pathophysiology of neonatal hyperbilirubinemia
Figure (1): The pathophysiology of neonatal hyperbilirubinemia (Maisels, 2005).
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Risk factors of neonatal hyperbilirubinaemia
The following factors increase babies chances of developing newborn jaundice:
Premature babies born before 36 weeks of pregnancy. Babies who had a brother or sister treated for jaundice.
Baby has a different blood type than mother, resulting in hemolysis.
Babies of East Asian, Mediterranean, or Native American descent.
Babies who are not feeding well, breast or bottle.
Babies with large bruises or a condition called cephalhematoma (bleeding under the scalp
related to labor and delivery). Since many red blood cells are broken down when large
bruises heal, more bilirubin than usual is traveling in the blood. Babies with high bilirubin levels or signs of jaundice in the first 24 hours of life (before
leaving the hospital) will be watched carefully by the doctor even after they have left the
hospital.
Certain liver enzyme deficiencies.
Infection.
(J. Thomas Megerian, 2011)
Classification of neonatal hyperbilirubinaemia
The causes of neonatal hyperbilirubinaemia can be classified into three groups based on
mechanisms of accumulation:a) Increased bilirubin production: This may occurs due to decreased RBC survival
increased ineffective erythropoiesis and increased enterohepatic circulation.
b) Defective uptake of bilirubin
c) Defective conjugation of bilirubin
d) Decreased hepatic excretion of bilirubin.
(Camilla and Clohert, 2003)
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Neonatal hyperbilirubinaemia can also be classified into:A) Physiological jaundice.
B) Pathological jaundice "Non - physiological ".
A) Physiological jaundice:
Most infants develop visible jaundice due to elevation of unconjugated bilirubin
concentration during their first week. This common condition is called physiological jaundice.
Essentials of diagnosis and typical features of physiologic jaundice:-
Visible jaundice appearing after 24 hours of age.
Total bilirubin rises by < 5 mg/dl (86 mmol/L) per day.
Peak bilirubin occurs at 3-5 days of age, with a total bilirubin of no more than 15 mg/d
(258 mmol/L).
Visible jaundice resolves by 1 week in the full-term infant and by 2 weeks in the preterm
infant. (Thilo and Rosenberg, 2009)
This pattern of jaundice classified into two periods:
In phase one the term infants' jaundice lasts for about 10 days with a rapid rise of
serum bilirubin up to12 mg/dL, but preterm infants' jaundice lasts for about two
weeks, with a rapid rise of serum bilirubin up to15 mg/dL.
In phase two bilirubin levels decline to about 2 mg/dL for two weeks. Preterm infants
can last more than one month.
(McDonagh.; 2007)
B) Pathological jaundice
Any of the following features characterizes pathological jaundice:
1. Clinical jaundice appearing in the first 24 hours or greater than 48hrs of life.
2. Increases in the level of total bilirubin by more than 8.5 umol/l (0.5 mg/dL) per hour or
(85 umol/l) 5 mg/dL per 24 hours.
3. Total bilirubin more than 331.5 umol/l (19.5 mg/dL) (hyperbilirubinemia).
4. Direct bilirubin more than 34 umol/l (2.0 mg/dL).
(Miguel Helft, 2007)
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Neonatal hyperbilirubinaemia can also be classified into:** Unconjugated hyperbilirubinemia:
Table (1) Causes of Unconjugated Hyperbilirubinemia
Hemolytic disease (hereditary or acquired)
-lsoimmune hemolysis (neonatal; acute or delayed transfusion reaction;
autoimmune)
-Rh incompatibility, AB0 incompatibility and other blood group
incompatibilities
-Congenital spherocytosis -Hereditary elliptocytosis -Infantile pyknocytosis
Erythrocyte enzyme defects
-G6PD deficiency -Pyruvate kinase deficiency
Hemoglobinopathy
-Sickle cell anemia -Thalassemia
Others-Sepsis -Hemolytic Uremic syndrome
-Drugs as vitamin K and maternal oxytocin
-infection -Polycythemia as in Diabetic mother, Fetal transfusion
(recipient) and Delayed cord clamping
Decreased delivery of UCB (in plasma) to hepatocytes:
-Right-sided congestive heart failure -Portacaval shunt
Decreased bilirubin uptake by hepatocytes membrane:
-Breast milk jaundice -Lucey- Driscoll syndrome-Hypothyroidism -Hypoxia -Acidosis
Decreased storage of UCB in cytosol:
-Competitive inhibition -Fever
Decreased conjugation:
-Neonatal jaundice (physiologic) -inhibition (drugs) -Gilbert disease
-Hereditary (Crigler-Najjar) Type I (complete enzyme deficiency) and Type Il
(partial deficiency)
INCREASED ENTEROHEPATIC CIRCULATION
-Breast milk Jaundice -intestinal obstruction
-Hirsch sprung disease -Cystic fibrosis
-Pyloric stenosis -Antibiotic administration
(Balistreri, 2008)
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** Conjugated hyperbilirubinemia:Conjugated hyperbilirubinemia is a sign of hepatobiliary dysfunction. It usually appears in
the newborn infants after the first week of life, when the direct bilirubin level is > 2.0
mg per dL and > 20% of the TsB. It is always pathologic. (Barasotti, 2004)
Table (2): Causes of Conjugated Hyperbilirubinemia
INFECTIOUSGeneralized bacterial sepsis, viral hepatitis, cytomegalovirus, rubella virus,herpes virus: H5V, HHV 6 and 7, varicella virus, coxsackie virus, echovirus,parvovirus B19, HIV, syphilis and tuberculosis.
TOXIC
Parenteral nutrition related, sepsis (urinary tract) with end-toxemia and drug
related
METABOLICDisorders of amino acid metabolism
Tyrosinemia, Wolman disease, Niemann- Pick disease&Gaucher disease,
Disorders of carbohydrate metabolism
Galactosemia, fructosemia and glycogenesis lV
Disorders of bile acid biosynthesis
Other metabolic defects
1-Antitrypsin deficiency, cystic fibrosis, idiopathic hypopituitarism,
hypothyroidism and childhood cirrhosis.
GENETIC/CHROMOSOMAL.
Trisomy E and Down syndrome
INTRAHEPATIC CHOLESTATIC SYNDROME
"ldiopathic neonatal hepatitis, familial intrahepatic cholestasis and congenital
hepatic fibrosis
EXTRAHEPATIC DISEASES
Biliary atresia, sclerosing cholangitis, choledochal- pancraeaticoductal
junction anomaly, choledochal cyst & bile/ mucous plug ('lnspisated bile')
MISCELLANEOUS
-Shock and hypo perfusion
-Associated with enteritis
-Associated with intestinal obstruction
-Neonatal lupus erythematosus
-Myeloproliferative disease (trisomy 21 )
(Bezerra &Balistreri, 2008)
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Complications of Neonatal Jaundice** Acute bilirubin encephalopathy
Bilirubin is toxic to cells of the brain. If a baby has severe jaundice, there's a risk of bilirubin
passing into the brain, a condition called acute bilirubin encephalopathy. Prompt treatment
may prevent significant permanent damage. The following signs may indicate acute bilirubinencephalopathy in a baby with jaundice:
Listless, sick or difficult to wake
High-pitched crying
Poor sucking or feeding
Backward arching of the neck and body
Fever
Vomiting (Lease M. et a; 2010)
** KernicterusCauses
It is a neurological syndrome resulting from the deposition of UCB in brain nuclei. In the
past UCB was shown to impair mitochondrial tissues in the brain. Paper showed that UCB
decrease cell membrane potential and disrupts transport of neurotransmitters. UCB also
inhibits protein phosphorylation in brain membranes and glycolysis in brain as well as
interferes with intracellular calcium homeostasis and glutamate efflux.(Shapiro 2005)
Microglia cells and astrocytes damaged by UCB produce cytokines that may contribute to braintoxicity. (Fernandes et al., 2006)
Symptoms
The symptoms depend on the stage of kernicterus.
Early stage:
- Extreme jaundice - Poor feeding or sucking
- Extreme sleepiness (lethargy)Mid stage:
- High-pitched cry - Seizures- Arched back with neck hyperextended backwards
Late stage (full neurological syndrome):
- High-frequency hearing loss - Mental retardation
- Muscle rigidity - Speech difficulties(Milton S. Hershey, 2011 )
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** NeonatalcholestasisAssessment:
History
- Scleral icterus may be apparent at conjugated bilirubin levels as low as 2
mg/dL.
- Dark urine at higher levels of conjugated bilirubin.
- Cutaneous jaundice
- Severe pruritus secondary to elevated bile acids.
(Poddar U. et al., 2009)
Physical
- Physical evidence of scratching or excoriation if they also have severe bile acid
retention.
- Xanthomas look like small white papules or plaques
- Failure to thrive with altered anthropometrics, such as reduced height and
reduced weight for height due to fat malabsorption. (Poddar U et al, 2009)
Laboratory Studies- Serum bilirubin levels (total and direct bilirubin levels)
- Total serum bile salt concentration levels
- Qualitative serum and urine bile acids
- The total serum cholesterol level
- Serum lipoprotein-X levels
- Serum alkaline phosphatase levels
- Serum 5'-nucleotidase levels- Serum gamma-glutamyl transferase (GGT) levels
(Suchy FJ. 2004)
Imaging Studies
- Ultrasonography of liver and bile ducts
- Abdominal CT scanning
- Biliary nuclear medicine study (i.e., hepatoiminodiacetic acid [HIDA] scanning)
- Endoscopic retrograde cholangiography
- Percutaneous trans-hepatic cholangiography
(Suchy FJ, 2004)Procedure
- Liver biopsy
- Exploratory surgery
- Operative cholangiography is simple, straightforward, time-efficient, and
definitive.
(Arnon R et al., 2012)
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Diagnosis of Hyperbilirubinaemia
A-History:
Family history:
A family history of anemia, splenectomy, or early gall bladder stones may be suggestive of
hereditary haemolytic blood disorder. A history of previous siblings with jaundice and anemia
may suggest blood group incompatibility, breast milk jaundice or G-6PD deficiency. A family
history of liver diseases may suggest galactosemia, alph1-antitrypsin deficiency or cystic
fibrosis. (Bhutani and Johnson, 2004)
Maternal history:
Maternal illnesses during pregnancy may point to maternal diabetes, congenital vira
infection or toxoplasmosis, and maternal medications should be reviewed. History o
instrumental delivery, oxytocin induced labor, delayed cord clamping, and Apgar score shouldbe obtained. (Diane and Madlon-Kay, 2002)
Neonatal history:
History of delayed passage of meconium or infrequent stool may suggest increased
enterohepatic circulation of bilirubin. History of vomiting may indicate sepsis, galactosemia, o
pyloric stenosis. (Bhutani and Johnson, 2004)
B-Physical Examination:
The jaundiced neonate requires a full physical examination with emphasis on the following:
General: Child look and difficulty feeding.
Vitals: In hemolytic states, there can be an increase in heart rate and respiration rate as wel
as poor perfusion. Fever also detected.
Growth Parameters: Obtain length, weight and head circumference and compare to
measurements taken at birth.
Surface: Is there pallor? Sclerae and mucous membranes should be closely inspected fo
jaundice. Look for cephalohematoma or bruising.
Cardiovascular: Heart rate, pulse, blood pressure, apex site, perfusion. Severe haemolytic
processes can result in heart failure.
Respiratory: Respiration rate and rhythm and oxygen saturation. If the neonate is in hear
failure, there may be respiratory signs.
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Abdomen: Is the abdomen distended? Are there any masses? Check for hepatomegaly and
splenomegaly and or areas of tenderness?
Neurologic: Level of consciousness. Cranial nerves, tone, gross motor movements, quality of
the cry, and primitive reflexes (Moro, grasps, tonic-neck and step).
Figure (2):dermal zones and indirect bilirubin levels (Maisels, 2006)
Differential Diagnosis
The differential diagnoses of neonatal hyperbilirubinemia are summarized in(Table 3).
Table (3): Differential diagnosis of hyperbilirubinemia.
Jaundice appearing at birth or within 24 hours: sepsis, erythroblastosis fetalis, concealed
hemorrhage, rubella, congenital toxoplasmosis.
Jaundice appearing on the 2nd or 3rd day: physiologic jaundice of the newborn -severe
type-, Crigler- Najjar syndrome.
Jaundice appearing after the 3rd day, within the 1st week: septicemia, syphilis, and
toxoplasmosis.
Jaundice appearing after the 1st week: breast milk jaundice, septicemia, hepatitis, biliary
atresia, galactosemia, hypothyroidism, spherocytosis (congenital hemolytic anemia) and
G6PD
Jaundice persisting during the 1st month: inspissated bile syndrome, hepatitis, syphilis,
toxoplasmosis, familial non-hemolytic icterus, congenital atresia of bile ducts,
galactosemia, rarely physiologic jaundice, pyloric stenosis, and hypothyroidism).
(Stoll and Kliegman, 2004)
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C- Laboratory Evaluation of Neonatal Hyperbilirubinemia:
Laboratory StudiesA. Serum bilirubin is conventionally measured by spectrophotometry based on the Van den
Bergh (diazo) reaction. Conjugated (direct) bilirubin reacts rapidly with diazo reagents.
Unconjugated (indirect) bilirubin reacts slowly. Indirect bilirubin is calculated as the
difference between total bilirubin and direct bilirubin fraction. Direct bilirubin consists of
conjugated bilirubin and -bilirubin.B. Complete blood count: Useful in detecting hemolysis, indicated by the presence ofanemia
with fragmented erythrocytes and increased reticulocytes on the smear.
Thrombocytopenia is typically seen in patients with portal hypertension.
C. Liver function tests: Isolated hyperbilirubinemia with otherwise normal liver function
suggests hemolytic disease or bilirubin metabolism defects.
D. Coagulation profile
(Bhutani VK, 2011)
D-Imaging Studies:
Ultrasonography: Ultrasonography of the liver and bile ducts is warranted in infants
with laboratory or clinical signs of cholestatic disease.
Radionuclide scanning: A radionuclide liver scan for uptake of hepatoiminodiacetic
acid (HIDA) is indicated if extrahepatic biliary atresia is suspected. At the author's
institution, patients are pretreated with phenobarbital 5 mg/kg/d for 3-4 days before
performing the scan.
(Ahlfors CE & Parker AE. 2008)
Figure (3:)total serum bilirubin and age chart (AAP .; 2005)
https://www.pediatriccareonline.org/pco/ub/view/Point-of-Care-Quick-Reference/397051/0/anemiahttps://www.pediatriccareonline.org/pco/ub/view/Point-of-Care-Quick-Reference/397083/0/hypertensionhttps://www.pediatriccareonline.org/pco/ub/view/Point-of-Care-Quick-Reference/397083/0/hypertensionhttps://www.pediatriccareonline.org/pco/ub/view/Point-of-Care-Quick-Reference/397051/0/anemia7/30/2019 hager 1 1 2013
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Management of Neonatal Hyperbilirubinemia
Regardless of etiology, the goal of therapy is to prevent the concentration of indirect
reacting bilirubin in the blood from reaching levels at which neurotoxicity may occur. It is
recommended that phototherapy and, if unsuccessful, exchange transfusion be used to keep
the maximum total bilirubin below the toxic levels. (Valaes and Harvey-Wilkes, 1999)
1- Preterm Infants:Table (4): Suggested maximum indirect serum bilirubin concentrations (mg per/dL) in premature infants
Birth weight (gm) Uncomplicated Complicated
1000 12-13 10-12
1000-1250 12-14 10-12
1251-1499 14-16 12-14
1500-1999 16-20 15-17
2000-2500 20-22 18-20
(Stoll and Kliegman, 2000).2- Newborn infant 37 or more weeks of gestation:
Age(hours)
Bilirubin measurement (micromole/litre) divide the score in micromol/L by 88.4 to get mg/dL
0 - - >100 >100
6 >100 >112 > 125 > 150
12 > 100 > 125 > 150 > 200
18 > 100 > 137 > 175 > 250
24 > 100 > 150 > 200 > 300
30 > 112 > 162 > 212 > 350
36 > 125 > 175 > 225 > 400
42 > 137 > 187 > 237 > 450
48 > 150 > 200 > 250 > 450
54 > 162 > 212 > 262 > 450
60 > 175 > 225 > 275 > 450
66 > 187 > 237 > 287 > 450
72 > 200 > 250 > 300 > 450
78 - > 262 > 312 > 450
84 - > 275 > 325 > 450
90 - > 287 > 337 > 450
96+ - > 300 > 350 > 450
ActionRepeat bilirubinmeasurement in 612hours
Consider phototherapy andrepeat bilirubin measurement in6 hours
Startphototherapy
Perform an exchange transfusion unless thebilirubin level falls below threshold while thetreatment is being prepared
Table (5) Interference according to total bilirubin levels (Michael Rawlins et al.; 2010)
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The management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation
is summarized inFigure (4).
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Current accepted modes of intervention:
Hydration.
Phototherapy.
Exchange transfusion.
Pharmacological agents.
Drug that increase conjugation. Inhibiting reabsorption (binding in the gut).
Inhibiting bilirubin production (Valaes and Harvey-Wilkes, 1999).
I- Hydration:
It is important to maintain adequate hyration and urine output during phototherapy since
urinary excretion of lumirubin is the principle mechanism by which phototherapy reduces TsB.
Thus, during phototherapy, infants should continue oral feeding by breast or bottle. For TsB
levels that approach the exchange transfusion level, phototherapy should be continuous until
the TsB has declined to about 20 mg/dL (342 micromol/L). Thereafter phototherapy can be
interrupted for feeding. Intravenous hydration may be necessary to correct hypovolemia in
infants with significant volume depletion whose oral intake is inadequate; otherwise,
intravenous fluid is not recommended. (Buhutani VK, 2004)
II-Phototherapy:A) Background:
Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.
This therapeutic principle was discovered rather serendipitously in England in the 1950s and is
now arguably the most widespread therapy of any kind (excluding prophylactic treatments)
used in newborns. ) Kumar P. et al; 2011(B) Consideration should be taken:
The level of total serum bilirubin The gestational age of the infant
The age of the infant in hours since birth
The presence or absence of risk factors, including isoimmune hemolytic disease, glucose
6-phosphate dehydrogenase deficiency, asphyxia, lethargy, temperature instability, seps
acidosis, and hypoalbuminemia.
(M. Jeffrey Maisels et al; 2008)
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C) Indications of phototherapy:
1- Phototherapy should be used when the level of bilirubin may be harmful to the
infant , and has not reached levels requiring exchange transfusion.
2- Prophylactic phototherapy may be indicated in special circumstances, such a
extremely low - birth weight infants or severely bruised infants. In hemolytic disease of
the newborn, phototherapy is stared immediately and while waiting for exchange
transfusion. (McDonagh et al.; 2008)
D) Mechanism of Action
Phototherapy uses light energy to change the shape and structure of bilirubin, converting i
to molecules that can be excreted even when normal conjugation is deficient. Absorption o
light by dermal and subcutaneous bilirubin induces a fraction of the pigment to undergo
several photochemical reactions that occur at very different rates. These reactions generate
yellow stereoisomers of bilirubin and colorless derivatives of lower molecular weight. The
products are less lipophilic than bilirubin, and unlike bilirubin, they can be excreted in bile ourine without the need for conjugation. Bilirubin elimination depends on the rates o
formation as well as the rates of clearance of the photoproducts. Photoisomerization occurs
rapidly during phototherapy, and isomers appear in the blood long before the level of plasma
bilirubin begins to decline. Bilirubin absorbs light most strongly in the blue region of the
spectrum near 460 nm, a region in which penetration of tissue by light increases markedly
with increasing wavelength. Only wavelengths that penetrate tissue and are absorbed by
bilirubin have a phototherapeutic effect. Taking these factors into account, lamps with outpu
predominantly in the 460-to-490-nm blue region of the spectrum are probably the mosteffective for treating hyperbilirubinemia. A common misconception is that ultraviolet (UV
light (
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phototherapy. Because light can be toxic to the immature retina, the infant's eyes should
always be protected with opaque eye patches. (Maisels et al.; 2008)
E) Adverse effects:
Insensible water loss may occur, but data suggest that this issue is not as important as
previously believed. Rather than instituting blanket increases of fluid supplements to all
infants receiving phototherapy, the author recommends fluid supplementation tailoredto the infant's individual needs, as measured through evaluation of weight curves, urine
output, urine specific gravity, and fecal water loss.
In the NRN phototherapy trials in premature infants of less than 1000 gram birthweight,
mortality was increased by 5 percentage points in the subgroup of 501-750 gram birth
weight receiving aggressive phototherapy.[ Morris BH, Oh W, Tyson JE, 2008] Although
not significant, it should be noted that the study was underpowered for this analysis,
and a negative effect of aggressive phototherapy on the smallest and most immature
infants cannot be ruled out with certainty.
Phototherapy may be associated with loose stools. Increased fecal water loss maycreate a need for fluid supplementation.
Retinal damage has been observed in some animal models during intense phototherapy
In an NICU environment, infants exposed to higher levels of ambient light were found to
have an increased risk of retinopathy. Therefore, covering the eyes of infants
undergoing phototherapy with eye patches is routine. Care must be taken lest the
patches slip and leave the eyes uncovered or occlude one or both nares.
The combination of hyperbilirubinemia and phototherapy can produce DNA-strand
breakage and other effects on cellular genetic material. In vitro and animal data have
not demonstrated any implication for treatment of human neonates. However, becausemost hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding
may be moot.
Skin blood flow is increased during phototherapy, but this effect is less pronounced in
modern servo controlled incubators. However, redistribution of blood flow may occur in
small premature infants. An increased incidence of patent ductus arteriosus (PDA) has
been reported in these circumstances. The appropriate treatment of PDA has been
reviewed.
Hypocalcaemia appears to be more common in premature infants under phototherapy
lights. This has been suggested to be mediated by altered melatonin metabolism.Concentrations of certain amino acids in total parenteral nutrition solutions subjected to
phototherapy may deteriorate. Shield total parenteral nutrition solutions from light as
much as possible.
Regular maintenance of the equipment is required because accidents have been
reported, including burns resulting from a failure to replace UV filters.
(Madan JC, Kendrick D., etc. 2009)
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F) Methods of administration:
i- Conventional phototherapy:
With "Conventional phototherapy", the irradiance of the light is less, but actual numbers
vary significantly between different manufacturers. In general, it is not necessary to routinely
measure irradiance when administering phototherapy, but units should be checked
periodically to ensure that the lamps are providing adequate irradiance, according to themanufacturer's guidelines. (Bernstein JA, 2012)
ii-Fiber optic phototherapy:
Fiberoptic light is also used in phototherapy units. These units deliver high energy
levels, but to a limited surface area. Efficiency may be comparable to that of
conventional low-output overhead phototherapy units but not to that of overhead units
used with maximal output. Advantages include the following :
Low risk of overheating the infant
No need for eye shields
Ability to deliver phototherapy with the infant in a bassinet next to the mother's
bed
Simple deployment for home phototherapy
The possibility of irradiating a large surface area when combined with
conventional overhead phototherapy units (double/triple phototherapy)
(Kumar P. et al.; 2011)
iii-Double & Triple phototherapy:
"Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3
phototherapy units to treat the same patient, has often been used in the treatment of
infants with very high levels of serum bilirubin. The studies that appeared to show a
benefit with this approach were performed with old, relatively low-yield phototherapy
units. Newer phototherapy units provide much higher levels of irradiance, which may in
fact be close to the apparent saturation level of bilirubin photoisomerization. Whether
double or triple phototherapy also confers a benefit with the newer units, has not been
tested in systematic trials.
(Huizing K. et al.; 2008)
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v-Home phototherapy:
Home phototherapy for a term infant with neonatal jaundice is considered medically
appropriate if ALL of the following criteria are met:
Elevated bilirubin not due to any primary hepatic disorder
Hospitalization is no longer required
Diagnostic evaluation is performed prior to the therapy and should include ALL of the
following:
History and physical examination
Hemoglobin concentration or hematocrit
WBC count and differential count
Blood smear for red cell morphology platelets
Reticulocyte count
Total and direct-reacting bilirubin concentration
Maternal and infant blood typing and Coombs test
Urinalysis including a test for reducing substances
(Watchko J.; 2009)
vi-LASER phototherapy:
The word LASER is derived from English and means "Light Amplification by Stimulated
Emission of Radiation". The LASER converts electrical energy into optical energy. This
energy commonly referred to as the LASER beam is carried to the tissues through
fiber optic as in the case of Argon LASER or a series of hollow tubes as in the case oCarbon dioxide LASER to be absorbed by the tissues or cellular components. All LASER
machines have three elements, the LASER medium, power supply and .mirrors. The
medium is stimulated by the power supply to emit light that is amplified as it reflect
between mirrors, reaching a critical energy level and emerging through a partially
transmitting mirror. The energy is released as an intense beam of monochromatic
coherent light. The LASER emits a narrow beam of photons, all of which have the same
energy, therefore a very pure light of single color and wavelength is produced, the
Argon LASER emits a blue green light. (Palmieri, 1985).
Figure (5) baby under phototherapy
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III. Exchange transfusion:
AIM
To modify abnormal values of the circulating bloods composition, by removing one or more
components whilst maintaining a close to constant blood volume.
INDICATIONS Hyperbilirubinaemiato lower serum bilirubin (SBR) levels and prevent Kernicterus
Rhesus/ABO incompatibilityremoval of red blood cells with antibodies or free circulating
antigens to reduce degree of red cell destruction
Severe Anaemiareplace volume with that containing a higher red blood cell mass
Hydrops Foetalisto regulate blood volume and allay potential heart failure
Other rare indicationsHyperkalaemia, Drug toxicity, Disseminated Intravascular
Coagulation (DIC)
(Jennifer Orms.; 2011)
Risks
Blood clots
Changes in blood chemistry (high or low potassium, low calcium, low glucose, change
in acid-base balance in the blood)
Heart and lung problems
Infection (very low risk due to careful screening of blood)
Shock if not enough blood is replaced (Maheshwari A., 2011)(Saunthararajah S.,2008.)
Fig. (6):Guidelines for exchange transfusion in infants 35 or more weeks gestation.
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The following Bilirubin/Albumin ratios can be used together with but in not in lieu of the TSB
level as an additional factor in determining the need for exchange transfusion.
Table (6): Bilirubin / Albumin ratio as an additional factor in determining the need for
exchange transfusion.
Risk CategoryB/A Ratio at Which Exchange Transfusion
Should be Considered
TSB mg/dL/Alb, g/dL TSB _mol/L/Alb, _mol/L
- Infants _38 0/7 wk
- Infants 35 0/736 6/7
wk and well or _38 0/7
wk if higher risk or
isoimmune hemolytic
disease or G6PD
deficiency
- Infants 35 0/737 6/7
wk if higher risk or
isoimmune hemolytic
disease or G6PD
deficiency
8.0
7.2
6.8
0.94
0.84
0.80
If the TsB is at or approaching the exchange level, send blood for immediate type and cros
match. Blood for exchange transfusion is modified whole blood (red cells and plasma) cross
matched against the mother and compatible with the infant. (Bhutan et al.; 2004)
IV. Pharmacological Treatments: Phenobarbitone.
Intravenous immunoglobins.
Albumin.
Others (e.g. Agar therapy and Charcoal feeds)
* Phenobarbital:
Phenobarbital, an inducer of hepatic bilirubin metabolism, has been used to enhance
bilirubin metabolism. Several studies have shown that phenobarbital is effective in reducing
mean serum bilirubin values during the first week of life. Phenobarbital may be administeredprenatally in the mother or postnatal in the infant. In populations in which the incidence of
neonatal jaundice or kernicterus is high, this type of pharmacologic treatment may warrant
consideration. However, concerns surround the long-term effects of phenobarbital on these
children. Therefore, this treatment is probably not justified in populations with a low
incidence of neonatal jaundice.
(Thor. WR Hansen., 2011)
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* Intravenous Immunoglobulin:
The American Academy of Pediatrics routinely uses 500 mg/kg infused intravenously over
a period of 2 hours for Rh or ABO incompatibility when the total serum bilirubin level
approach or surpass the exchange transfusions limits. The author has, on occasion, repeated
the dose 2-3 times. In most cases, when this is combined with intensive phototherapy
avoiding exchange transfusion is possible. In the authors' institution, with about 750 NICU
admissions per year, the use of exchange transfusions has decreased to 0-2 per yea
following the implementation of IVIG therapy for Rh and ABO isoimmunization.
(Huizing K. and Roislien J., 2008)
*Albumin:
Bilirubin in circulation is predominantly bound to albumin. Although the binding ratio i
potentially 1:1 and avid, albumin levels are lower in premature and sick infants, and binding
affinity is often diminished. Furthermore, some drugs can compete with bilirubin for binding
to albumin, causing displacement of bilirubin, therefore, prior to exchange transfusionalbumin can be administrated 1g per Kg to improve the efficacy of the exchange.
(Stevenson et al., 2005)
*Others:
Oral bilirubin oxidase can reduce serum bilirubin levels, presumably by reducing
enterohepatic circulation; however, its use has not gained wide popularity. The same may
be said for agar or charcoal feeds, which act by binding bilirubin in the gut. Bilirubin oxidase
is not available as a drug, and for this reason, its use outside an approved research protoco
probably is proscribed in many countries. (Hansen, 2003)
V. Surgical Care:
Surgical care is not indicated in infants with physiologic neonatal jaundice. Surgical therapy
is indicated in infants in whom jaundice is caused by bowel or external bile duct atresia.
(Thor WR H., 2004)
Mortality and MorbidityDeath from physiologic neonatal jaundice not occurs.
Death from kernicterus may occur, particularly in countries with less developed
medical care system. Mortality figures in this setting are not available.
(Bhutani et al., 2004)
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Chapter 2 : ABO blood group system
History of discoveries
At the beginning of the 20th century an Australian scientist, Karl Landsteiner,
noted that the RBCs of some individuals were agglutinated by the serum from
other individuals. He made a note of the patterns of agglutination and showed that
blood could be divided into groups. This marked the discovery of the first blood
group system, ABO, and earned Landsteiner a Nobel Prize.
(Dean L. Bethesda 2005)
Thirty major blood group systems (including the AB and Rh systems) are currently
recognised by the International Society of Blood Transfusion (ISBT). Thus, in
addition to the ABO antigens and Rhesus antigens, many otherantigens are
expressed on the red blood cell surface membrane. For example, an individual
can be AB RhD positive, and at the same time M and N positive (MNS system), K
positive (Kell system), and Lea
or Leb
positive (Lewis system).(Dr GL Daniels et al.; 2009)
The ABO blood group system is the most important blood type system (or blood
group system) in human blood transfusion. The associated anti-A and anti-
B antibodies are usually IgM antibodies, which are usually produced in the first
years of life by sensitization to environmental substances such as food, bacteria,
and viruses. ABO blood types are also present in some otheranimals, for
example apes such as chimpanzees, bonobos, and gorillas.
(Maton et al.; 1993)
http://en.wikipedia.org/wiki/ABO_blood_group_system#History_of_discoverieshttp://en.wikipedia.org/wiki/ABO_blood_group_system#History_of_discoverieshttp://en.wikipedia.org/wiki/International_Society_of_Blood_Transfusionhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/MNS_antigen_systemhttp://en.wikipedia.org/wiki/Kell_antigen_systemhttp://en.wikipedia.org/wiki/Lewis_antigen_systemhttp://en.wikipedia.org/wiki/Blood_typehttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Antibodieshttp://en.wikipedia.org/wiki/IgMhttp://en.wikipedia.org/wiki/Blood_type_(non-human)http://en.wikipedia.org/wiki/Apehttp://en.wikipedia.org/wiki/Chimpanzeehttp://en.wikipedia.org/wiki/Bonobohttp://en.wikipedia.org/wiki/Gorillahttp://en.wikipedia.org/wiki/Gorillahttp://en.wikipedia.org/wiki/Bonobohttp://en.wikipedia.org/wiki/Chimpanzeehttp://en.wikipedia.org/wiki/Apehttp://en.wikipedia.org/wiki/Blood_type_(non-human)http://en.wikipedia.org/wiki/IgMhttp://en.wikipedia.org/wiki/Antibodieshttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Blood_typehttp://en.wikipedia.org/wiki/Lewis_antigen_systemhttp://en.wikipedia.org/wiki/Kell_antigen_systemhttp://en.wikipedia.org/wiki/MNS_antigen_systemhttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/International_Society_of_Blood_Transfusionhttp://en.wikipedia.org/wiki/ABO_blood_group_system#History_of_discoverieshttp://en.wikipedia.org/wiki/ABO_blood_group_system#History_of_discoveries7/30/2019 hager 1 1 2013
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ABO antigens & antibodies
** Antigens of the ABO blood group
Number of
antigens
4: A, B, AB, and A1
Antigenspecificity
CarbohydrateThe sequence of oligosaccharides determines whether the antigen is A,B, or A1.
Antigen-carrying
molecules
Glycoproteins and glycolipids of unknown functionThe ABO blood group antigens are attached to oligosaccharide chainsthat project above the RBC surface. These chains are attached toproteins and lipids that lie in the RBC membrane.
Molecularbasis
The ABO gene indirectly encodes the ABO blood group antigens.The ABO locus has three main allelic forms: A, B, and O. The A and Balleles each encode a glycosyltransferase that catalyses the final step inthe synthesis of the A and B antigen, respectively. The A/Bpolymorphism arises from several SNPs in the ABO gene, which result in
A and B transferases that differ by four amino acids. The O alleleencodes an inactive glycosyltransferase that leaves the ABO antigenprecursor (the H antigen) unmodified.
Frequencyof ABO
blood groupantigens
A: 43% Caucasians, 27% Blacks, 28% AsiansB: 9% Caucasians, 20% Blacks, 27% Asians
A1: 34% Caucasians, 19% Blacks, 27% AsiansNote: Does not include AB blood groups.
Frequencyof ABO
phenotypes
Blood group O is the most common phenotype in most populations.Caucasians: group O, 44%; A1, 33%; A2, 10%; B, 9%; A1B, 3%; A2B,1%
Blacks: group O, 49%; A1, 19%; A2, 8%; B, 20%; A1B, 3%; A2B, 1%Asians: group O, 43%; A1, 27%; A2, rare; B, 25%; A1B, 5%; A2B, rareNote: Blood group A is divided into two main phenotypes, A1 and A2
Table (7):Antigens of the ABO blood group (Reid ME. et al.; 2004)
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** Antibodies produced against ABO blood group antigens
Antibody type IgG and IgMNaturally occurring. Anti-A is found in the serum of people with bloodgroups O and B. Anti-B is found in the serum of people with bloodgroups O and A.
Antibodyreactivity
Capable of haemolysisAnti-A and anti-B bind to RBCs and activate the complement cascade,which lyses the RBCs while they are still in the circulation(intravascular haemolysis).
Haemolyticdisease of the
newborn
No or mild diseaseHDN may occur if a group O mother has more than one pregnancywith a child with blood group A, B, or AB. Most cases are mild and donot require treatment.
Table (8)Antibodies produced against ABO blood group antigens (D.L. Bethesda., 2005)
Phenotypes
The table below shows the possible permutations of antigens and antibodieswith the corresponding ABO type ("yes" indicates the presence of a componentand "no" indicates its absence in the blood of an individual).
ABO
Blood Type Antigen A Antigen B Antibody Anti-A Antibody Anti-B
A yes no no yes
B no yes yes no
O no no yes yes
AB yes yes no no
Table (9)Phenotype of ABO Blood Group System (Dennis O'Neil 2011)
GenotypeThe ABO locus encodes specific glycosyltransferases that synthesize A and B
antigens on RBCs. For A/B antigen synthesis to occur, a precursor called the Hantigen must be present. In RBCs, the enzyme that synthesizes the H antigen isencoded by the H locus. (Dean L. Bethesda., 2005)
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Non-antigen biology
The carbohydrate molecules on the surfaces of red blood cells have roles in cell
membrane integrity, cell adhesion, membrane transportation of molecules, and
acting as receptors for extracellular ligands, and enzymes. ABO antigens are
found having similar roles on epithelial cells as well as red blood cells.
(Mohandas et al.; 2005)
Inheritance
ABOblood types are inherited through genes on chromosome 9, and they do
not change as a result of environmental influences during life. An individual's ABO
type is determined by the inheritance of 1 of 3 alleles (A, B, or O) from each
parent. The possible outcomes are shown below:
Association with von Willebrand factor
The ABO antigen is also expressed on the von Willebrand
factor(vWF) glycoprotein, (Sarode, R., 2000)which participates
in haemostasis (control of bleeding). In fact, having type O blood predisposes to
The possible ABO alleles for one
parent are in the top row and the
alleles of the other are in the left
column. Offspring genotypes
are shown in black. Phenotypes
are red.
Parent AllelesA B O
A AA(A)
AB(AB)
AO(A)
BAB
(AB)
BB
(B)
BO
(B)
OAO
(A)
BO
(B)
OO
(O)
Table (10): inheritance of ABO Blood Group
http://en.wikipedia.org/wiki/ABO_blood_group_system#Nonantigen_biologyhttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Epithelial_cellhttp://en.wikipedia.org/wiki/ABO_blood_group_system#Inheritancehttp://en.wikipedia.org/wiki/ABO_blood_group_system#Inheritancehttp://anthro.palomar.edu/blood/glossary.htm#alleleshttp://en.wikipedia.org/wiki/ABO_blood_group_system#Association_with_von_Willebrand_factorhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/Glycoproteinhttp://en.wikipedia.org/wiki/Glycoproteinhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/ABO_blood_group_system#Association_with_von_Willebrand_factorhttp://anthro.palomar.edu/blood/glossary.htm#alleleshttp://en.wikipedia.org/wiki/ABO_blood_group_system#Inheritancehttp://en.wikipedia.org/wiki/Epithelial_cellhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/ABO_blood_group_system#Nonantigen_biology7/30/2019 hager 1 1 2013
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bleeding, (O'Donnell, 2001)as 30% of the total genetic variation observed in
plasma vWF is explained by the effect of the ABO blood group, and individuals
with group O blood normally have significantly lower plasma levels of vWF
(and Factor VIII) than do non-O individuals. (Shima. M., 1995)
In addition, vWF is degraded more rapidly due to the higher prevalence of blood
group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF).
(Bowen, DJ. & Collins PW., 2005).
Subgroups
A1 and A2
The A blood type contains about twenty subgroups, of which A1 and A2 are the
most common (over 99%). A1 makes up about 80% of all A-type blood, with A2making up the rest. These two subgroups are interchangeable as far astransfusion is concerned, but complications can sometimes arise in rare caseswhen typing the blood. (The Owen Foundation., 2008)
Bombay phenotype
Figure (7): Bombay phenotype inheritance
The H antigen is a precursor to the A and B antigens. For instance, the B allelemust be present to produce the B enzyme that modifies the H antigen to becomethe B antigen. It is the same for the A allele. However, if only recessive alleles for
the H antigen are inherited (hh), as in the case above, the H antigen will notproduced. Subsequently, the A and B antigens also will not be produced. Theresult is an O phenotype by default since a lack of A and B antigens is the Otype. This seemingly impossible phenotype result has been referred to asa Bombay phenotype because it was first described in that Indian city. The ABOblood system is further complicated by the fact that there are two subtypes of type
A and two of AB. These are referred to as A1, A2, A1B, and A2B.(Dennis O'Neil., 2011)
http://en.wikipedia.org/wiki/Factor_VIIIhttp://en.wikipedia.org/wiki/Polymorphism_(biology)http://en.wikipedia.org/wiki/ABO_blood_group_system#Subgroupshttp://en.wikipedia.org/w/index.php?title=Blood_type_A&action=edit&redlink=1http://en.wikipedia.org/wiki/ABO_blood_group_system#Bombay_phenotypehttp://en.wikipedia.org/wiki/ABO_blood_group_system#Bombay_phenotypehttp://en.wikipedia.org/w/index.php?title=Blood_type_A&action=edit&redlink=1http://en.wikipedia.org/wiki/ABO_blood_group_system#Subgroupshttp://en.wikipedia.org/wiki/Polymorphism_(biology)http://en.wikipedia.org/wiki/Factor_VIII7/30/2019 hager 1 1 2013
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Chapter (3): Hemolytic disease of the
newborn (ABO)
HISTORICAL BACKGROUNDHaemolytic disease of the newborn (HDN) used to be a major cause of fetal
loss and death among newborn babies. The first description of HDN is thought to
be in 1609 by a French midwife who delivered twinsone baby was swollen and
died soon after birth, the other baby developed jaundice and died several days
later. For the next 300 years, many similar cases were described in which
newborns failed to survive. (Dean L. Bethesda., 2005)
Incidence and prevalence
ABO incompatibility between the mother and the baby occurs in 15-20% of all
pregnancies, which produces HDN in 10% of these cases The fact prevealed
ABO incompatibility is not always a benign condition and should be considered in
all babies who have haemolysis and whose mothers are group O, even in the
presence of a negative DAT. Asians and blacks have a higher prevalence of DAT-
positive ABO HDN than Caucasians.(Neelam Marwaha& Hari Krishan
Dhawan, 2009)Thirty-eight per cent mothers were ABO incompatible with their
babies, whereas 62% mothers were compatible.(Bashiru S. etal.; 2011)
In a study conducted to Michael sgro, douglas Campbell and vibhuti shah
2006showed that the percentage of ABO incompatibility as a cause of severe
neonatal hyperbilirubinemia is about 51% followed by G6PD about 21.5% other
antibody incompatibility about 13% and other causes about 14.5% ABO hemolytic
disease of newborn occurring in about 15% of infants with A or B blood type born
to blood type O mothers and, unlike non- hemolytic disease of newborn. ABO
http://en.wikipedia.org/wiki/Hemolytic_disease_of_the_newborn_(ABO)#Causeshttp://www.ijpmonline.org/searchresult.asp?search=&author=Neelam+Marwaha&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijpmonline.org/searchresult.asp?search=&author=Hari+Krishan+Dhawan&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijpmonline.org/searchresult.asp?search=&author=Hari+Krishan+Dhawan&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ajts.org/searchresult.asp?search=&author=Bashiru+S+Oseni&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ajts.org/searchresult.asp?search=&author=Bashiru+S+Oseni&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijpmonline.org/searchresult.asp?search=&author=Hari+Krishan+Dhawan&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijpmonline.org/searchresult.asp?search=&author=Hari+Krishan+Dhawan&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijpmonline.org/searchresult.asp?search=&author=Neelam+Marwaha&journal=Y&but_search=Search&entries=10&pg=1&s=0http://en.wikipedia.org/wiki/Hemolytic_disease_of_the_newborn_(ABO)#Causes7/30/2019 hager 1 1 2013
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incompatibility is usually a problem of the neonate rather than of the fetus, A and B
antigens are only weakly expressed on neonatal RBCs. ABO hemolytic disease of
newborn therefore usually mild and characterized by negative or weakly positive
Coombs' test. ABO hemolytic disease of newborn rarely requires whole blood
exchange transfusion, in contrast to hemolytic disease of newborn due to anti-D or
other antibodies. (Kathryn Drabik-Clary et al; 2006)
MECHANISM
Haemolysis associated with ABO incompatibility exclusively occurs in type-O
mothers with foetuses who/ have type A or type B blood, although it has rarely
been documented in type-A mothers with type-B infants with a high titre of anti-B
IgG. In mothers with type A or type B, naturally occurring antibodies are of the IgMclass and do not cross the placenta, whereas 1% of type-O mothers have a high
titre of the antibodies of IgG class against both A and B. They cross the placenta
and cause haemolyses in foetus. Haemolysis due to anti-A is more common than
haemolyses due to anti-B, and affected neonates usually have positive direct
Coombs test results. However, haemolyses due to anti-B IgG can be severe and
can lead to exchange transfusion. Because A and B antigens are widely
expressed in various tissues besides RBCs, only a small portion of antibodies
crossing the placenta are available to bind to foetal RBCs.
(Luchtman-Jones L. & Schwartz AL. 2006)
The reasons for the mildness of ABO erythroblastosis are that the foetal RBC
membrane has fewer A and B antigenic sites; most anti-A and anti-B is IgM and
does not cross into the foetal circulation; the small amount of anti-A or anti-B that
is IgG and does cross into the foetal circulation has many antigenic sites in tissue
and secretions other than on the RBCs to which it can bind. Because only a small
amount of antibody is fixed to each RBC membrane, the direct antiglobulin test is
only weakly positive when cord RBCs are tested and may be negative when
capillary blood is tested at 1 or 2 days of age. (Bowman J., 2011)
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Moderating factors
In about a third of all ABO incompatible pregnancies maternal IgG anti-A or
IgG anti-B antibodies pass through the placenta to the foetal circulation leading to
a weakly positive direct Coombs test for the neonate's blood. However, ABO HDN
is generally mild and short-lived and only occasionally severe because:
IgG anti-A (or IgG anti-B) antibodies that enter the fetal circulation from the
mother find A (or B) antigens on many different fetal cell types, leaving
fewer antibodies available for binding onto fetal red blood cells.
Fetal RBC surface A and B antigens are not fully developed during
gestation and so there are a smaller number of antigenic sites on fetal
RBCs.(Wang, M. et al.; 2005)
Diagnosis
ABO incompatibility occurs in 20-25% of pregnancies, but laboratory evidenceof haemolytic disease occurs only in 1 of 10 such infants, and the haemolyticdisease is severe enough to require treatment in only 1 in 200 cases. There are anumber of reasons why ABO incompatibility is rarely serious:
1. Most anti-A and anti-B antibodies are IgM (hence they dont cross the placenta). 2. Neonatal RBCs express A and B poorly (the expression of A and B antigensincreases as the baby grows).3. Many cells other than red cells express A and B antigens and thus sop up someof the transferred antibody. (Kristine Krafts., 2009)
ABO haemolytic disease occurs almost exclusively in infants of A or B typeborn of group O mothers. Normal anti-A and anti-B antibodies are IgM andtherefore dont cross the placenta. For reasons not understood, however, somegroup O women have IgG anti-A and anti-B even without prior sensitization! In thissituation, a firstborn child may be affected. Fortunately, even with transplacentallyacquired antibodies, lysis of infant red cells is minimal. ABO incompatibility isdiagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betketest). Theres no effective protection against ABO incompatibility reactions! Goodthing theyre not very common.(Kristine Krafts., 2009)
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Clinical picture
The typical diagnostic findings are jaundice, pallor, hepatosplenomegaly, and
foetal hydrops in severe cases. The jaundice typically manifests at birth or in the
first 24 hours after birth with rapidly rising unconjugated bilirubin level. Anaemia ismost often due to destruction of antibody-coated RBCs by the reticuloendothelial
system, and, in some infants, anaemia is due to intravascular destruction. The
suppression of erythropoiesis by intravascular transfusion (IVT) of adult Hb to an
anaemic foetus can also cause anaemia. Extra medullary haematopoiesis can
lead to hepatosplenomegaly, portal hypertension, and ascites.
(Moise KJ. ., 2008)
Postnatal problems also include:
Asphyxia
Pulmonary hypertension
Pallor (due to anemia)
Edema (hydrops, due to low serum albumin)
Respiratory distress
Coagulopathies ( platelets & clotting factors)
Jaundice
Kernicterus (from hyperbilirubinemia): explained previously.
Hypoglycemia (due to hyperinsulinemnia from islet cell hyperplasia)
(William H. Tooley., 2004)
ComplicationsComplications of hemolytic disease of the newborn during pregnancy:
Mild anemia: When the babys red blood cell count is deficient, his blood
cannot carry enough oxygen from the lungs to all parts of his body, causing
his organs and tissues to struggle.
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Hyperbilirubinemia and jaundice: The breakdown of red blood cells
produces bilirubin, a brownish yellow substance that is difficult for a baby to
discharge and can build up in his blood (hyperbilirubinemia) and make his
skin appear yellow.
Severe anemiawith enlargement of the liver and spleen: The babys body
tries to compensate for the breakdown of red blood cells by making more of
them very quickly in the liver and spleen, which causes the organs to get
bigger. These new red blood cells are often immature and unable to function
completely, leading to severe anemia.
Hydrops fetalis:When the babys body cannot cope with the anemia, his
heart begins to fail and large amounts of fluid build up in his tissues and
organs. (Louis Diamond., 2010)
Complications of hemolytic disease of the newborn after birth:
Severe hyperbilirubinemia and jaundice: Excessive buildup of bilirubin in
the babys blood causes his liver to become enlarged.
Kernicterus:Buildup of bilirubin in the blood is so high that it spills over into
the brain, which can lead to permanent brain damage.
(Louis Diamond., 2010)
LABORATORY FINDINGS
a) CBC count findings
i. Anaemia
ii. Increased nucleated RBCs, reticulocytosis, polychromasia,
anisocytosis, spherocytosis, and cell fragmentation
iii. Neutropenia
iv. Thrombocytopenia
(Christensen RD, Henry E., 2010)
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v. Hypoglycaemia is common and is due to islet cell hyperplasia and
hyperinsulinism. The abnormality is thought to be secondary to release
of metabolic by-products such as glutathione from lysed RBCs.
Hypokalaemia, hyperkalaemia, and hypocalcaemia are commonly
observed during and after exchange transfusion
(Vidnes., 1977)
b) Serologic test findings
Indirect Coombs test and direct antibody test results are positive in the mother
and affected newborn. Unlike Rh alloimmunization, direct antibody test results are
positive in only 20-40% of infants with ABO incompatibility.
(Romano EL et al.; 1973)
In a recent study, positive direct antibody test findings have a positive predictive
value of only 23% and a sensitivity of only 86% in predicting significant haemolysis
and need for phototherapy, unless the findings are strongly positive (4+).
(Murray NA., 2007)
This is because foetal RBCs have less surface expression of type-specific
antigen compared with adult cells. Although the indirect Coombs test result
(neonate's serum with adult A or B RBCs) is more commonly positive in neonates
with ABO incompatibility, it also has poor predictive value for haemolysis. This is
because of the differences in binding of IgG subtypes to the Fc receptor ofphagocytic cells and, in turn, in their ability to cause haemolysis.
(Bakkeheim E. & Bergerud U., 2009)
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Treatment of ABO HDN
1. Phototherapyis sufficient. Discussed previously.
2. Exchange transfusionmay be needed. Discussed previously.
(Karen L. Dallas., 2012)
3. New trends in therapy for HDN:
Improved phototherapy
The changing clinical practice surrounding HDN is, in no small way, the result ofimprovements in both the understanding and delivery phototherapy. Since then
considerable advances have been made and it is now appreciated more fully that
the efficacy of phototherapy in reducing neonatal hyperbilirubinaemia is dependent
on a number of factors: (Verman HU. Et al.; 2004)
The spectral qualities of the delivered light (optimal wave length range 400
520 nm, with peak emissions of 460 nm)
Irradiance (intensity of light)
Body surface area receiving phototherapy
Skin pigmentation
Total serum bilirubin concentration at commencement of phototherapy
Duration of exposure. (Hart G. et al.; 2005)
Modern phototherapy devices are designed to maximise the efficacy of
phototherapy to the neonate and clinicians are more appreciative of the importance
of ensuring such devices are employed correctly (i.e. ensuring correct distance
between device and patient, proper maintenance and servicing of phototherapy
units). Phototherapy units are now smaller, easier to use around the cot, more
efficient - particularly high-intensity gallium nitride light-emitting diodes (LEDs), and
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more powerful- the total irradiance that can be applied to an individual neonate has
vastly increased. In short phototherapy is now a viable alternative to the planned
use of exchange transfusion in the therapy of even moderate to severe HDN, and
as devices continue to develop and improve phototherapy is likely to play an even
greater role in the therapy of HDN. For a fuller description of developments in
neonatal phototherapy since its first use the reader is referred to recent reviews.
(Irene A.G. Roberts., 2008)
High dose intravenous immunoglobulin
In the last 1015 years a number of studies of high dose intravenous
immunoglobulin (IVIG) as adjuvant treatment for HDN have been published and two
systematic reviews have been carried out.
In 2004 Miqdad et al., reported the use of IVIG in a study of 112 well term
neonates with hyperbilirubinaemia resulting from DATpositive ABO HDN. In addition
to phototherapy the intervention group (n=56) received 500 mg/kg IVIG over 4 h if
the serum bilirubin was rising by 8.5 mmol/L per hour or greater. Exchange
transfusion was carried out in all neonates if the serum bilirubin exceeded 340
mmol/L, or was rising by greater than 8.5 mmol/L per hour in the phototherapy only
group. In the phototherapy only group 16 neonates were treated with exchange
transfusion whereas only 4 neonates in the IVIG group required exchange
transfusion. The duration of phototherapy was also reduced in the IVIG group. No
side-effects of IVIG were seen.
Also Alpay et al. in 1999 studied 116 neonates with hyperbilirubinaemia
resulting from DAT-positive ABO or Rh HDN of whom 58 received IVIG 1 g/kg over
4 h when the serum bilirubin exceeded 204 mmol/L. Exchange transfusion was
performed if the serum bilirubin exceeded 290 mmol/L or was rising by more than
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17 mmol/L per hour. In the phototherapy only group 22 neonates were treated with
exchange transfusion whereas only 8 neonates in the IVIG group required
exchange transfusion. Again the duration of phototherapy and hospital stay were
significantly reduced in the IVIG group. No adverse effects of IVIG were reported.
Similar results have been found in previous smaller studies assessing the use of
IVIG in the treatment of HDN. Despite the positive benefits of IVIG suggested by
these studies there are methodological difficulties and questions about the safety of
IVIG that potentially limit the size of the role IVIG may have in the treatment of
HDN. The preponderance of ABO HDN in the larger studies suggests that the
neonates assessed are relatively well and the vast majority would be expected to
respond to intensive phototherapy alone unless low thresholds for exchange
transfusion (bilirubin 290340 mmol/L) are employed. There is also variation in
the timing of administration and dose of IVIG between studies. Late anaemia may
be more prevalent in those treated with IVIG, presumably because fewer neonates
have exchange transfusion and therefore removal of maternal antibody. No major
side effects have been reported in the neonates treated with IVIG but since IVIG is
a pooled blood product the potential for transmission of blood borne infections
remains. (Hayakawa F. et al.; 2002) (Quinti I. et al.; 2002)
Given these facts how should neonatal paediatricians approach the use of IVIG
in patients with HDN. The current trial evidence clearly points to positive benefits,
particularly the reduction in the need for exchange transfusion.
Paediatricians are less experienced with this technique due to the reduction of ABO
disease and so morbidity associated with this procedure may increase in the future.
Therefore the use of a more straightforward but effective therapy should be
considered in the limited number of patients where the likelihood of exchange
transfusion is greatest. These would include neonates with red cell alloimmunisation
unmodified by antenatal therapy or neonates with potential ABO HDN where a
previous sibling has suffered from severe disease requiring exchange transfusion.
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Also the neonate with severe DAT-positive hyperbilirubinaemia readmitted from the
community, where the serum bilirubin already exceeds local guidelines for
exchange transfusion, but where initial therapy with IVIG is liable to be available
more quickly than exchange transfusion. In these relatively rare circumstances
adjuvant therapy with IVIG seems justified. A single dose of IVIG of 500 mg/kg
appears to be as effective as any other regimen.
(Irene A.G. Roberts., 2008)
Metalloporphyrins
Metalloporphyrins are heme analogs that competitively inhibit the activity of
heme oxygenase, the rate-limiting enzyme in heme catabolism. This action reduces
the formation of bilirubin and makes them potential agents for both the prophylactic
and therapeutic reduction of hyperbilirubinaemia in the newborn. Tin (Sn)
mesoporphyrins are the most fully studied compounds in this context.
In 1988 Kappas et al. reported the prophylactic use of Sn-Protoporphyrin(SnPP) in 122 term infants with DAT-positive ABO incompatability. At doses up to
2.25 mg/kg body weight, administered by 2 or 3 intramuscular injections, they
demonstrated a significant reduction in the rate of rise of plasma bilirubin levels
beginning at 48 h post SnPP administration that continued until 96 h. The only
reported side effect in SnPP treated neonates was transient erythema during the
concurrent use of phototherapy in two neonates.
In 1994 Valaes et al., reported the results of 5 sequential studies of the
prophylactic use of Sn-Mesoporphyrin (SnMp) in preterm neonates between 30 and
36 weeks gestational age. SnMp was administered at doses up to 6 mg/ kg body
weight by intramuscular injection beginning within the first 24 h of life. 517 neonates
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were studied over 4 years between 1988 and 1992. As the study population were
preterm newborns prophylactic phototherapy was commenced at predetermined
low levels and the main outcome of the study was a reduction in the requirement for
phototherapy in SnMp treated neonates. This was most marked in those neonates
receiving the highest dose of Sn-