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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_acid

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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)

http://en.wikipedia.org/wiki/Infanthttp://en.wikipedia.org/wiki/Hyperbilirubinemiahttp://en.wikipedia.org/wiki/Hyperbilirubinemiahttp://en.wikipedia.org/wiki/Infant

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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/anemia

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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)

http://www.nice.org.uk/aboutnice/whoweare/board/chair/sir_michael_rawlins_chairman.jsphttp://www.nice.org.uk/aboutnice/whoweare/board/chair/sir_michael_rawlins_chairman.jsp

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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)

http://www.aap.org/http://www.aap.org/

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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_discoveries

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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)

http://en.wikipedia.org/wiki/ABO_blood_group_system#ABO_antigenshttp://en.wikipedia.org/wiki/ABO_blood_group_system#ABO_antigens

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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_biology

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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_VIII

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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)#Causes

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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.

http://www.childrenshospital.org/az/Site577/mainpageS577P0.htmlhttp://www.childrenshospital.org/az/Site577/mainpageS577P0.htmlhttp://www.childrenshospital.org/az/Site577/mainpageS577P0.html

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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-