HyperbilirubinemiaMSN 621

Hyperbilirubinemia in Infants

T. Allen Merri6, M.D. Loma Linda Childrens

Hospital, Loma Linda, Ca.

Pick a topic to get started!

Introduction

Diagnosis

Pathophysiology

Treatment

Genetics

References

Risk Factors & Symptoms

Hyperbilirubinemia

Links

How To Use This Tutorial Each page will have acDon bu6ons that allow the user to go back or to move forward found in the lower right hand corner

There are acDon bu6ons on the main page that allow the user to navigate to main topics, reference pages, and other internet links that might be of interest

To reach the main page aFer you are in a topic, there will be a home bu6on located in the lower leF hand corner that allows the user to go back to the main page

How To Use This Tutorial

Throughout this tutorial all italicized words are dened if you roll over the word with the mouse

Please note there are sound eects throughout the presentaDon

Purpose

The purpose of this tutorial is to provide informaDon regarding the pathophysiology, risk factors, symptoms, diagnosis, and current treatment recommendaDons regarding hyperbilirubinemia in infants

ObjecDves

To understand the pathophysiology of hyperbilirubinemia

To idenDfy risk factors for hyperbilirubinemia To idenDfy signs and symptoms of hyperbilirubinemia To understand diagnosing of hyperbilirubinemia in infants

To understand current treatment recommendaDons

What Is Hyperbilirubinemia?

Hyperbilirubinemia (also known as jaundice) is an increased level of bilirubin in the blood

It may occur due to physiologic factors that are seen as normal in the newborn

It may be due to pathologic factors that alter the usual process in bilirubin metabolism (1)

What Is Hyperbilirubinemia?

A. An increase in the amount of bilirubin in the blood

B. A decrease in the amount of bilirubin in the blood

C. There is no change in the amount of bilirubin in the blood

Correct

Hyperbilirubinemia is an increase of bilirubin in the blood

Incorrect

Try again If you break the word apart it

helps you to dene the word. For example

hyper = high, excessive bilirubin = bilirubin

emia = blood

Incorrect

Try again If you break the word apart

it helps you dene the word. For example

hyper = high, excessive bilirubin = bilirubin

emia = blood

What Is Bilirubin?

Bilirubin is the by product of the breakdown of heme which is found in red blood cells (1)

Normal red blood cell destrucDon accounts for 80% of daily bilirubin produced in the newborn (10)

Infants produce twice as much bilirubin per day than as an adult (1)

There are two types of bilirubin - unconjugated (indirect) bilirubin and conjugated (direct) bilirubin

Unconjugated Bilirubin

Unconjugated (indirect) bilirubin Fat-soluble Not yet metabolized by by the liver Is not easily excreted Is the biggest concern for newborn jaundice If it is not converted it can be deposited into the skin which causes the yellowing of the skin or into the brain which can lead to kernicterus (1)

Conjugated Bilirubin

Conjugated (direct) bilirubin Water soluble It is metabolized by the liver It is mostly excreted in stool and some in the urine

True or False

Unconjugated (indirect) bilirubin is bilirubin that is broken down by the liver and is excreted through the urine and stool

Incorrect

Unconjugated (indirect) bilirubin is bilirubin that has not yet been broken down

by the liver

Correct

Conjugated (direct) bilirubin is bilirubin that is broken down by the liver and is excreted in urine or stool

Bilirubin Metabolism

Red blood cells are broken down in the Reticuloendothelial System (1)

Red blood cells break down to hemoglobin which is further broken down to iron, globin, and heme (1)

Iron Globin

Heme

Biliverdin

Unconjugated bilirubin

Hemoglobin Red blood cells

Liver

Conjugated bilirubin

Urobilinogen Stercobilin

Reticuloendothelial System

Bilirubin albumin complex


Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin


Unconjugated bilirubin is then carried to the liver by albumin (1)

Heme is further broken down to biliverdin then to unconjugated bilirubin by the enzyme biliverdin reductase (1) Bilirubin albumin complex

Bilirubin Metabolism Iron

Globin

Heme

Biliverdin



Liver




The liver then converts unconjugated bilirubin to conjugated bilirubin where it is excreted in the intestines (1) The intestines

then convert the conjugated bilirubin into urobilinogen and then stercobilin (1)



Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin


Urobilinogen is excreted in the urine (1)

Stercobilin is excreted in the stool (1)


Click On The Correct Response To Complete The Diagram

Red blood cells are broken down to hemoglobin

Unconjugated bilirubin is carried to the liver by albumin

Urobilinogen is excreted in the urine

Stercobilin is excreted in the stool

Intestines convert conjugated bilirubin into urobilinogen and stercobilin

Liver converts unconjugated bilirubin to conjugated bilirubin where it is excreted in the intestines

Hemoglobin is further broken down to iron, globin, and heme

Heme is further broken down to bilverdin then to unconjugated bilirubin by the enzyme biliverdin reductase

What Is Physiologic Jaundice?

Physiologic jaundice is an exaggerated normal process seen in 60% of term infants, and 80% of premature infants (1)

It normally occurs during the rst week of life It is normally benign and self-limiDng Associated with a bilirubin level greater than 5-7mg/dL (1)

Factors That Contribute To Physiologic Jaundice

Prematurity Polycythemia

Prematurity & Hyperbilirubinemia

Premature infants are more suscepDble to hyperbilirubinemia due to:

Immature hepa6c system Delayed enteral feedings Decrease in serum albumin levels


Immature hepa6c system - leads to decreased eliminaDon of bilirubin from the system; therefore, higher levels of indirect bilirubin are in the blood which leads to hyperbilirubinemia

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin




Delayed enteral feedings - if feedings are delayed it decreases intesDnal moDlity and removal of meconium, which leads to reabsorpDon of direct bilirubin, which is converted back to indirect bilirubin. Which means bilirubin increases in the blood and leads to hyperbilirubinemia (10)

Iron Globin

Heme

Biliverdin



Liver Conjugated bilirubin





Decrease in serum albumin levels - if there is a decrease in the amount of albumin receptors available, bilirubin does not bind to the albumin; therefore, is considered free bilirubin. Which means bilirubin increases in the blood and leads to hyperbilirubinemia (1)

Iron Globin

Heme

Biliverdin



Liver

Conjugated bilirubin Urobilinogen

Stercobilin



Polycythemia & Hyperbilirubinemia

Polycythemia is an increased level of red blood cells (RBCs) in the circulatory system

A infant has more RBCs than an adult, and the lifespan of an RBC is shorter in neonates (1)

Increased RBCs and a shorter lifespan leads to increased destrucDon of RBCs, which leads to more bilirubin in the blood, which leads to hyperbilirubinemia

What percent of term infants have jaundice?

A. 80% B. 50% C. 60%

Incorrect

Please try again

Correct

60% of term infants have physiologic jaundice

What Is Pathologic Jaundice?

Pathologic jaundice is due to factors that alter the process of bilirubin metabolism

It usually appears within 24 hours of life Associated with a bilirubin level increase of 0.5 mg/dL/ hour or 5mg/dL per day (10)

Persists for longer than 7 to 10 days (10)

Factors That Contribute To Pathologic Jaundice

HemolyDc anemia Rh incompaDbility ABO incompaDbility

G6PD (glucose-6-phosphate deciency) deciency

HemolyDc Anemia & Hyperbilirubinemia

HemolyDc anemia is an incompaDbility between the blood of the mother and her fetus

This can occur due to Rh incompaDbility or ABO blood incompaDbility

Rh IncompaDbility

Rh incompaDbility is when the mother lacks the Rh factor on the surface of her red blood cells and her baby is born with the Rh factor on his or her red blood cells (13)

This occurs in about 15% of the Caucasian populaDon and 7% of the African American populaDon (13)

It does not occur with the rst born child

Rh IncompaDbility

In Rh incompaDbility there is potenDal for the infants blood to enter the mothers system (13)

If this happens the mother will develop an6bodies against the fetal blood cells which may cross the placenta and destroy the infants red blood cells (13)

Increased destrucDon of red blood cells leads to increased bilirubin in the blood; therefore, leading to hyperbilirubinemia

Treatment for Rh IncompaDbility

There is an injecDon called Rh immune globulin (also known as Rhogam) which is given to pregnant women at 28 weeks of pregnancy and within 72 hours of delivering an infant who is born Rh posiDve (13)

This injecDon prevents the mothers body from forming an6bodies against the Rh factor found on fetal red blood cells (13)

If the mother is already sensiDzed, meaning her body has already made anDbodies against the Rh factor, the injecDon will be ineecDve (13)

This injecDon prevents sensiDzaDon in more than 95% of Rh negaDve women (13)

ABO Blood IncompaDbility

ABO incompaDbility occurs with any blood type; however, it is more common if the mother has type O blood and the infant has blood type A, B, or AB

ABO Blood IncompaDbility

Fetal cells cross the placenta and enter the mothers bloodstream (6)

When this occurs the mothers body forms an6bodies against the fetal cells (6)

Those anDbodies are then small enough to cross back through the placenta into the babys circulaDon and cause destrucDon of red blood cells (6)

Increased destrucDon of red blood cells leads to increased bilirubin in the blood; therefore, leading to hyperbilirubinemia

Glucose-6-Phosphate Dehydrogenase G6PD The funcDon of G6PD enzyme is to iniDate an

oxidaDon/reducDon reacDon (3) An oxidaDon/reducDon reacDon is transferring electrons from one molecule to the next (3)

OxidaDon is the loss of electrons and reducDon is the gain of electrons (3)

G6PD

The G6PD enzyme is responsible for reducing NADP+ (nicotinamide adenine dinucleotide phosphate) to NADPH (reduced nicotinamide adenine dinucleotide phosphate) (3)

Retrieved from http://www.malariasite.com/malaria/g6pd.htm

Used with permission (11)

Pentose Phosphate Pathway

G6PD

Without adequate levels of NADPH, red blood cells are more prone to stress and oxidaDon, which leads to hemolysis of red blood cells (3)

If there is a G6PD deciency there will not be adequate levels of NADPH; therefore, leading to increased hemolysis of red blood cells

Increased hemolysis of red blood cells leads to increased levels of bilirubin, which then leads to hyperbilirubinemia

Physiologic Occurs 24 hours after birth Prematurity Polycythemia

Pathologic Occurs less than 24 hours after birth Hemolytic anemia G6PD deficiency

Physiologic Jaundice versus

Pathologic Jaundice

IdenDfy The Causes Of Pathologic Jaundice

HemolyDc anemia ABO incompaDbility Increased uid intake G6PD deciency Prematurity Polycythemia Rh incompaDbility Headache

Kernicterus

Kernicterus is a rare, irreversible complicaDon of hyperbilirubinemia

If bilirubin levels become markedly elevated, the unconjugated bilirubin may cross into the blood brain barrier and stain the brain Dssues (1)

If staining of the brain Dssues occurs there is permanent injury sustained to areas of the brain which leads to neurological damage (10)

Kernicterus

Kernicterus is used to describe the yellow staining of the brain nuclei as seen on autopsy (kern means nuclear region of the brain; icterus means jaundice) (Juretschke, 2005, p. 10)

Picture Of A Brain With Kernicterus

Yellow staining in the brain due to

increased unconjugated

bilirubin passing through the blood brain

barrier

Retrieved April 30, 2006, from

http://www.urmc.rochester.edu/neuroslides/slide156.html


Kernicterus

Early signs of kernicterus are: lethargy, poor feeding, temperature instability, and hypotonia (1)

Symptoms then progress to: hypertonia, opisthotonos and arching, fever, seizures, and high pitched cry (10)

Long term eects are: choreoathetoid cerebral palsy, tremerousness, mental retardaDon, sensorineural hearing loss, dental dysplasia, and upward gaze paresis (10)

True or False

GeneDcs play a part in hyperbilirubinemia

Correct

There are studies that link geneDc mutaDons in enzymes to increased risk for

hyperbilirubinemia

Incorrect

There are studies that link geneDc mutaDons in enzymes to increased risk for

hyperbilirubinemia

GeneDcs & Hyperbilirubinemia

A study done from 2001 to 2003 looked at three enzymes with possible geneDc defects that were linked to increased rates of hyperbilirubinemia in the Asian populaDon (7)


The study was conducted in Taiwan The reason for this is because the Asian populaDon has twice the incidence of hyperbilirubinemia than the Caucasian populaDon (7)

They were looking to idenDfy potenDal geneDc defects that contribute to the higher incidence of hyperbilirubinemia


The three enzymes are: G6PD - glucose-6-phosphate dehydrogenase

OTAP 2 - organic anion transporter 2

UGT1A1 - UDP- glucuronsyltransferase 1A1

G6PD

The G6PD enzyme is responsible for reducing NADP+ (nicotinamide adenine dinucleotide phosphate) to NADPH (reduced nicotinamide adenine dinucleotide phosphate) (3)

Retrieved from http://www.malariasite.com/malaria/g6pd.htm


Pentose Phosphate Pathway

Glucose-6-Phosphate Dehydrogenase G6PD The funcDon of G6PD enzyme is to iniDate an

oxidaDon/reducDon reacDon (3) An oxidaDon/reducDon is transferring electrons from one molecule to the next (3)

OxidaDon is the loss of electrons and reducDon is the gain of electrons (3)

G6PD G6PD is also responsible for maintaining adequate levels of NADPH inside the cells (3)

If there is a G6PD deciency there will not be adequate levels of NADPH

Without adequate levels on NADPH, red blood cells are more prone to stress and oxidaDon, which leads to hemolysis of red blood cells (3)

If there is increased hemolysis of red blood cells, there will be increased levels of bilirubin, which then leads to hyperbilirubinemia

G6PD enzyme

Retrieved April 8, 2006, from http://www.rcsb.org/pdb/explore.do?structureId=1QKI

Used with permission

Organic Anion Transporter 2 OATP 2

The funcDon of the OATP 2 enzyme is involved in the hepa6c uptake of unconjugated bilirubin (7)

Iron Globin

Heme

Biliverdin







Organic Anion Transporter 2 OATP 2

In the study done, the authors idenDed polymorphisms in the OATP 2 enzyme, which led to increased risk for hyperbilirubinemia in the Asian populaDon (7)

If the enzyme acDvity is delayed there will be increased levels of unconjugated bilirubin in the blood, therefore leading to hyperbilirubinemia

UDP - Glucuronsyltransferase 1A1 UGT1A1

The funcDon of UGT1A1 is to convert unconjugated or indirect bilirubin to conjugated or direct bilirubin (7)

Iron

Globin

Heme

Biliverdin







UDP - Glucuronsyltransferase 1A1 UGT1A1

In the study done, the authors idenDed polymorphisms in the UGT1A1 enzyme which, led to increased risk for hyperbilirubinemia in the Asian populaDon (7)

If the enzyme acDvity is delayed there will be increased bilirubin in the blood, therefore leading to hyperbilirubinemia

What enzyme is responsible for converDng unconjugated (indirect) bilirubin to conjugated (direct) bilirubin?

A. G6PD B. UGT1A1 C. OATP 2

Correct

The UGT1A1 is responsible for converting unconjugated (indirect)

bilirubin to conjugated (direct) bilirubin

Incorrect

Please try again!

The G6PD enzyme is responsible for

maintaining adequate levels of NADPH in the red blood cells

which helps prevent hemolysis of red

blood cells

Incorrect

Please try again!

The OATP 2 enzyme is involved in the hepa6c

uptake of unconjugated bilirubin

What enzyme is responsible for maintaining adequate levels of NADPH in the red blood cells which helps

prevent hemolysis of red blood cells?

A. G6PD B. OATP 2 C. UGT1A1

Correct

The G6PD enzyme is responsible for maintaining adequate levels of NADPH in the red blood cells which helps prevent hemolysis of

red blood cells

Incorrect

Please try again!

The OATP 2 enzyme is involved in the hepa6c

uptake of unconjugated bilirubin

Incorrect

Please try again! The UGT1A1 is responsible for converDng

unconjugated (indirect) bilirubin to conjugated

(direct) bilirubin

What enzyme is involved in the hepa6c uptake of unconjugated bilirubin?

A. G6PD B. OATP 2 C. UGT1A1

Correct

The OATP 2 enzyme is involved in the hepatic uptake of unconjugated

bilirubin

Incorrect

Please try again!

The G6PD enzyme is responsible for

maintaining adequate levels of NADPH in the red blood cells which

helps prevent hemolysis of red blood

cells

Incorrect

Please try again!

The UGT1A1 is responsible for converDng

unconjugated (indirect) bilirubin to conjugated

(direct) bilirubin

Major Risk Factors for Hyperbilirubinemia in Full-Term Newborns

Jaundice within rst 24 hours aFer birth A sibling who was jaundiced as a neonate Unrecognized hemolysis such as ABO blood type incompaDbility or Rh

incompaDbility

NonopDmal sucking/nursing Deciency in glucose-6-phosphate dehydrogenase, a geneDc disorder InfecDon Cephalohematomas /bruising East Asian or Mediterranean descent

Retrieved April 18, 2006, from http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5023a4.htm


Signs & Symptoms

Poor feeding Increased sleepiness Increased yellowing of the skin or sclera Increased bilirubin level Hypotonia

Diagnosis

Check bilirubin level Check complete blood count Check reticulocyte count Coombs test Blood groups & types G6PD level Albumin level Visual assessment (least reliable)

Bilirubin Level

This test is to measure the amount of bilirubin in the blood

Increased bilirubin = hyperbilirubinemia In term infants a normal bilirubin level is between 1.0 - 10.0 mg/dL (4)

There is NO safe bilirubin level idenDed

Complete Blood Count

This test will determine if the infant has increased red blood cells in the circulatory system (polycythemia)

If an infant has a hematocrit greater than 65% this places that infant at risk for hyperbilirubinemia (16)

ReDculocyte Count

This test measures young non-nucleated red blood cells (4)

If the reDculocyte count is greater than 5% in the rst week of life, this idenDes the infant as trying to replace destroyed red blood cells (16)

Blood Groups & Types

ABO grouping and Rh types are conrmed by examining RBCs for presence of blood group an6gens and RBCs and an6bodies against these anDgens (4)

Direct Coombs Test

The direct coombs test is a direct measure of the amount of maternal an#body coaFng the infants red blood cell (Blackburn, 1995, p. 21)

If the anFbody is present, the test is posiFve


http://en.wikipedia.org/wiki/Image:Coombs_test_schematic.png

Used with Permission (15)

Indirect Coombs Test

The indirect coombs test measures the eect of a sample of the infants serum (which is thought to contain maternal an#bodies) on unrelated adult RBCs (Blackburn, 1995, p. 21)

If the infants serum contains anFbodies, they will interact with and coat these adult RBCs (posiFve test) (Blackburn, 1995, p. 21)


http://en.wikipedia.org/wiki/Image:Coombs_test_schematic.png

Used with Permission (15)

G6PD Level

The G6PD level is done to idenDfy neonates at risk for G6PD deciency

The Beutler uorescent spot test is a rapid and inexpensive test that visually idenDes NADPH produced by G6PD under ultraviolet light. When the blood spot does not uoresce, the test is posiDve; it can be false-posiDve in paDents who are acDvely hemolysing. It can therefore only be done several weeks aFer a hemolyDc episode (Glucose-6-phosphate-dehydrogenase deciency, n.d., 16)

Albumin Level

This test indicates the reserve amount of serum albumin available for binding indirect bilirubin (16)

A normal albumin level in a term infant is between 2.6 - 3.6 g/dL (4)

Visual Assessment Visual assessment of jaundice is most accurate when the infants skin is blanched with light digital pressure in a well-lit room (Juretschke, 2005, p. 11)

As bilirubin levels rise, the accuracy of visual assessment decreases (Juretschke, 2005, p. 11)

Zones Showing Kramers Progression Of Jaundice

Jaundice proceeds in a cephalopedal progression, meaning jaundice progresses from the head down to the toes (10)

This diagram demonstrates what level the bilirubin is at depending on what areas of the infants body is jaundiced

For example, if the infant was noted to be jaundiced from the head to the neck that would be zone 1 and the bilirubin level would be between 4 8 mg/dL

After Kramer, 1969 (12)

Zone 1 2 3 4 5

Bilirubin 4-8 5-12 8-16 11-18 >15

Level (mg/dL)

Treatment

Phototherapy is treatment of choice Encourage frequent feedings Intravenous hydraDon Intravenous immune globulin Exchange transfusion

Phototherapy

In the mid-1950s, Sister Jean at Rochford General Hospital in England noted that infants exposed to sunlight were less jaundiced in the uncovered skin areas than their nonexposed counterparts (17)

Phototherapy works by converDng indirect bilirubin to lumirubin, a water-soluble compound that is a more excretable form of bilirubin (10)

Phototherapy Only certain wavelengths (colors) of light are absorbed by bilirubin; as bilirubin is a yellow pigment, blue is absorbed more eecDvely, however, green light is more deeply absorbed into the skin (17)

Retrieved April 24, 2006, from http://en.wikipedia.org/wiki/Image:Infant_jaundice_treatment.jpg

Used with permission

An infant undergoing phototherapy

Frequent Feedings

Encouraging frequent feedings at least eight Dmes per day helps to sDmulate intesDnal moDlity and removal of meconium, thus reducing reabsorpDon of direct bilirubin into the system (1)

Intravenous HydraDon

Intravenous hydraDon of infants with hyperbilirubinemia was thought to decrease bilirubin levels, however, unless an infant is dehydrated intravenous hydraDon is not indicated (17)

Intravenous Immune Globulin

Intravenous immune globulin (IVIG) has been used to decrease bilirubin levels due to hemolyDc anemia

It is thought that IVIG interferes with receptors in the re6culendothelium that are necessary for hemolysis to occur (10)

Exchange Transfusion

An exchange transfusion is used only in extreme cases when phototherapy has failed

The process for an exchange transfusion involves small amounts of blood being removed from the infant and then replaced with the same amount of donor RBCs and plasma (1)

The process conDnues unDl twice the circulaDng volume has been replaced (1)

The exchange replaces ~ 87% of the circulaDng blood volume and decreases the bilirubin level by ~ 55% (1)

Links For informaDon on kernicterus there is a website enDtled Parents of Infants and children with Kernicterus. Their website is h6p://www.pickonline.org/

A SenDnel Alert was issued in April 2001 by the Joint Commission on AccreditaDon of Healthcare OrganizaDons on Kernicterus. The website address is h6p://www.jointcommission.org/SenDnelEvents/SenDnelEventAlert/sea_18.htm

References 1. Blackburn, S. (1995). Hyperbilirubinemia and neonatal jaundice. Neonatal

Network, 14(7), 15-29. 2. Center for Disease Control and PrevenDon. (2001). Kernicterus in full-term

infants-United States, 1994-1998. Morbidity and Mortality Weekly Report, 50(23), p. 494. Retrieved April 18, 2006, from h6p://www.cdc.gov/mmwr/preview/mmwrhtml/mm5023a4.htm

3. Ethnasios, R. (2003). Physiology of G6PD. Retrieved March 2, 2006, from

h6p://www.rialto.com/g6pd/physiolo.htm 4. Fischbach, F. Nurses quick reference to common laboratory and diagnosDc

tests (2nd ed.). Philadelphia: Lippinco6-Raven. 5. Glucose-6-phosphate dehydrogenase deciency. (n.d.). Wikipedia. Retrieved

May 1, 2006, from Answers.com Web site: h6p://www.answers.com/topic/glucose-6-phosphate-dehydrogenase-deciency

6. Hull, J. (2006). ABO incompaDbility. Retrieved March 31, 2006, from

h6p://www.drhull.com/EncyMaster/A/ABO_incompaDbility.html

References 7. Huang, M., Kua, K., Teng, H., Tang, K., Weng, H., & Huang, C. (2004). Risk

factors for severe hyperbilirubinemia in neonates. Pediatric Research, 56(5), 682-89.

8. Infant undergoing home phototherapy for jaundice. (2005). Retrieved April

25, 2006, from h6p://en.wikipedia.org/wiki/Image:Infant_jaundice_treatment.jpg

9. Jzefowicz, R., Miller, J., & Powers, J. (2000). Neuropathy and neuroimaging

laboratory: Mind, brain, and behavior course. University of Rochester School of Medicine and DenDstry. Retrieved April 30, 2006 from h6p://www.urmc.rochester.edu/neuroslides/slide156.html

10. Juretschke, L. (2005). Kernicterus: SDll a concern. Neonatal Network, 24(2),

7-19. 11. Kakkilaya, B., M.D. (2005). Glucose 6 phosphate dehydrogenase deciency.

Retrieved March 18, 2006, from h6p://www.malariasite.com/malaria/g6pd.htm

12. Kramer, L. (1969). Advancement of dermal icterus in the jaundiced

newborn. American Journal of Diseases of Children, 118(3), 454-458. Copyright (1969), American Medical AssociaDon, All Rights Reserved.

References 13. March of Dimes Birth Defects FoundaDon. (2001). Quick reference

and fact sheets: Rh disease. Retrieved February 28, 2006, from h6p://www.marchofdimes.com/printableArDcles/681_1220.asp?printable=true

14. PDB ID: 1QKI (IdenDcaDon of the enzyme in the database)

Au, S.W.N., Gover, S., Lam, V.M.S., & Adams, M.J. Human Glucose-6-Phosphate Dehydrogenase: The Crystal Structure Reveals a Structural Nadp+ Molecule and Provides Insights Into Enzyme Deciency. Stucture v8 pp. 293 (2000). Retrieved April 8, 2006, from h6p://www.rcsb.org/pdb/explore.do?structureId=1QKI

15. Rad, A. (2006). Coombs test. Retrieved May 1, 2006, from

h6p://en.wikipedia.org/wiki/Coombs_test 16. Schwobel, A. & Sakraida, S. (1997). Hyperbilirubinemia: new approaches to

an old problem. Journal of Perinatal & Neonatal Nursing, 11(3), 78-98. 17. Steensrud, S. (2004). Hyperbilirubinemia in term and near term infants:

Kernicterus on the rise? Newborn and Infant Nursing Reviews, 4(4), 191-200.

References 18. Venes, D. (Ed.). (2005). Tabers cyclopedic medical dicDonary (20th ed.),

Philadelphia: F.A. Davis Company.

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Documents

HyperbilirubinemiaMSN 621