Neonatal Hyperbilirubinemia

Objectives

• To understand the pathophysiology of hyperbilirubinemia
• To identify risk factors for hyperbilirubinemia
• To identify signs and symptoms of hyperbilirubinemia
• To understand diagnosing of hyperbilirubinemia in infants
• To understand current treatment recommendations

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

What Is Bilirubin?

• Bilirubin is the product of the breakdown of heme which is found in red blood cells
• Normal red blood cell destruction accounts for 80% of daily bilirubin produced in the newborn
• Infants produce twice as much bilirubin per day than as an adult
• There are two types of bilirubin -unconjugated (indirect) bilirubin and conjugated (direct) bilirubin

Unconjugated Bilirubin

-Unconjugated (indirect) bilirubin

• Fat-soluble
• Not yet metabolized 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

Conjugated Bilirubin

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

Bilirubin Metabolism

 What Is Physiologic Jaundice?

• Physiologic jaundice is an exaggerated normal process seen in 60% of term infants, and 80% of premature infants
• It normally occurs during the first week of life
• It is normally benign and self-limiting
• Associated with a bilirubin level greater than 5-7mg/dL

Factors That Contribute To Physiologic Jaundice

• Prematurity
• Polycythemia

Prematurity & Hyperbilirubinemia

• Premature infants are more susceptible to hyperbilirubinemia due to:
• Immature hepatic system
• Delayed enteral feedings
• Decrease in serum albumin levels

Prematurity & Hyperbilirubinemia

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

Prematurity & Hyperbilirubinemia

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

Prematurity & Hyperbilirubinemia

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)

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 destruction of RBCs, which leads to more bilirubin in the blood, which leads to hyperbilirubinemia

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

Persists for longer than 7 to 10 days

Factors That Contribute To Pathologic Jaundice

Hemolytic anemia

Rh incompatibility

ABO incompatibility

G6PD (glucose-6-phosphate deficiency) deficiency

Hemolytic Anemia & Hyperbilirubinemia

Hemolytic anemia is an incompatibility between the blood of the mother and her fetus

This can occur due to Rh incompatibility or ABO blood incompatibility

Rh Incompatibility

Rh incompatibility 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 population and 7% of the African American population (13) 

It does not occur with the first born child

            Rh Incompatibility

In Rh incompatibility there is potential for the infant’s blood to enter the mother’s system

If this happens the mother will develop antibodies against the fetal blood cells which may cross the placenta and destroy the infant’s red blood cells

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

Treatment for Rh Incompatibility

There is an injection 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 positive

This injection prevents the mother’s body from forming antibodies against the Rh factor found on fetal red blood cells

If the mother is already sensitized, meaning her body has already made antibodies against the Rh factor, the injection will be ineffective

This injection prevents sensitization in more than 95% of Rh negative women

ABO Blood Incompatibility

ABO incompatibility 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 Incompatibility

Fetal cells cross the placenta and enter the mother’s bloodstream (6)

When this occurs the mother’s body forms antibodies against the fetal cells (6)

Those antibodies are then small enough to cross back through the placenta into the baby’s circulation and cause destruction of red blood cells (6)

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

Glucose-6-Phosphate Dehydrogenase
                                         G6PD 

The function of G6PD enzyme is to initiate an oxidation/reduction reaction (3)

An oxidation/reduction reaction is transferring electrons from one molecule to the next (3) 

Oxidation is the loss of electrons and reduction is the gain of electrons (3) 

                                         G6PD

                                G6PD

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

If there is a G6PD deficiency 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 Jaundice
versus
Pathologic Jaundice

Kernicterus

Kernicterus is a rare, irreversible complication of hyperbilirubinemia

If bilirubin levels become markedly elevated, the unconjugated bilirubin may cross into the blood brain barrier and stain the brain tissues

If staining of the brain tissues occurs there is permanent injury sustained to areas of the brain which leads to neurological damage

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

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 effects are: choreoathetoid cerebral palsy, tremerousness, mental retardation, sensorineural hearing loss, dental dysplasia, and upward gaze paresis (10)

Major Risk Factors for Hyperbilirubinemia in Full-Term Newborns

Jaundice within first 24 hours after birth

A sibling who was jaundiced as a neonate

Unrecognized hemolysis such as ABO blood type incompatibility or Rh incompatibility

Nonoptimal sucking/nursing

Deficiency in glucose-6-phosphate dehydrogenase, a genetic disorder

Infection

Cephalohematomas /bruising

East Asian or Mediterranean descent

        Signs & Symptoms

Poor feeding

Increased sleepiness

Increased yellowing of the skin or sclera

Increased bilirubin level

Hypotonia

                        Diagnosis            

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 identified

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)

Reticulocyte Count

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

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

Blood Groups & Types

ABO grouping and Rh types are confirmed by examining RBCs for presence of blood group antigens and RBCs and antibodies against these antigens (4)

Direct Coombs Test

“The direct coombs test is a direct measure of the amount of maternal antibody coating the infant’s red blood cell” If the antibody is present, the test is positive

Indirect Coombs Test

“The indirect coombs test measures the effect of a sample of the infant’s serum (which is thought to contain maternal antibodies) on unrelated adult RBCs”

“If the infant’s serum contains antibodies, they will interact with and coat these adult RBCs (positive test)”

G6PD Level

The G6PD level is done to identify neonates at risk for G6PD deficiency

“The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be false-positive in patients who are actively hemolysing. It can therefore only be done several weeks after a hemolytic episode” (Glucose-6-phosphate-dehydrogenase deficiency, 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 infant’s 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”

Zones Showing Kramer’s 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 infant’s 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

Progression Of Jaundice

Jaundice to the face and part of the trunk above the umbilicus, have the bilirubin less than (12 mg/dL) (less dangerous level).

 Infants whose palms and soles are yellow, have serum bilirubin level over (15 mg/dL) (more serious level)

                           Treatment

Phototherapy is treatment of choice

Encourage frequent feedings

Intravenous hydration

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 converting 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 effectively, however, green light is more deeply absorbed into the skin”

Side effets of PT

Diarrhea

Temperature instability

Increased water loss via the skin

Erythematous rashes

Tanning

Bronze baby syndrome

DNA damage

Oxidative injury

Other rare side effects

Frequent Feedings

Encouraging frequent feedings at least eight times per day helps to stimulate intestinal motility and removal of meconium, thus reducing reabsorption of direct bilirubin into the system (1)

Intravenous Hydration

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

Intravenous Immune Globulin

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

It is thought that IVIG interferes with receptors in the reticulendothelium 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

The process continues until twice the circulating volume has been replaced

The exchange replaces ~ 87% of the circulating blood volume and decreases the bilirubin level by ~ 55%