Neonatal Hyperbilirubinemia

DR. Mahmoud Mohamed OsmanMBBCh, MSc (Pedia), MRCPCH (UK), FRCP

(Edinburgh)

Consultant Pediatrician & Neonatologist

Al Yammamah Hospital , MOH

Lecture objectives: Discuss bilirubin metabolism. Understand clinical significance of

hyperbilirubinemia . Learn diagnostic approach and work-up. Distinguish indirect vs. direct hyperbilirubinemia. Develop differential diagnoses. Understand management options.

I. INTRODUCTION

1) Definition: Hyperbilirubinemia refers to an excessive level of bilirubin in the blood

and is characterized by jaundice, a yellowish discoloration of the skin,

sclerae, mucous membranes and nails.

Adult serum bilirubin level is <1 mg/dL; and adults appear jaundiced

when the level is >2 mg/dL.

Newborns appear jaundiced when it is >7 mg/dL.

2) Incidence: About 60% of all term newborns and up to 80% of premature infants

develop clinical jaundice.

In well term newborns 6 % have serum bilirubin level >13 mg/dL; and

3% have a serum bilirubin level >15 mg/dL.

3) Bilirubin Sources: Bilirubin is derived from the breakdown of heme- containing proteins in

the reticuloendothelial system.

The major heme-containing protein is hemoglobin, It is the source of 75% of all bilirubin production.

One gram of hemoglobin produces 34 mg of bilirubin.

Normal newborn produces 6 to 10 mg of bilirubin/kg/day.

Accelerated release of hemoglobin from RBCs is the cause of hyperbilirubinemia in heamolytic aneamias, sequestered blood (Cephalohematoma), and polycythemia.

The other 25% of bilirubin is derived from ineffective erythropoiesis in the bone marrow, and other heme-containing proteins in tissues (Myoglobin, Cytochromes).

4) Bilirubin metabolism. The heme ring from heme-containing proteins is

oxidized in reticuloendothelial cells to biliverdin by the enzyme heme-oxygenase.

This reaction releases carbon monoxide (CO) (excreted from the lung) and iron (reutilized).

Biliverdin is then reduced to bilirubin by the enzyme biliverdin reductase.

Catabolism of 1 mol of hemoglobin produces 1 mol each of CO and bilirubin

1. Transport.

Bilirubin is nonpolar, insoluble in water, and is transported to liver cells bound to serum albumin. Bilirubin bound to albumin does not usually enter the CNS and is thought to be nontoxic.

2. Uptake.

Bilirubin dissociated from albumin crosses the hepatocyte plasma membrane and is bound mainly to cytoplasmic ligandin (Y protein) for transport to the smooth endoplasmic reticulum.

3. Conjugation.

Unconjugated (indirect) bilirubin is converted to water-soluble conjugated (direct) bilirubin in the smooth endoplasmic reticulum by uridine diphosphate glucuronyl-transferase (UDPG-T).

4. Excretion.

Conjugated bilirubin enters the gastrointestinal tract and is then eliminated from the body in the stool. It may be resorbed from the bowel after converted back to UCB by the enzyme β-glucuronidase.

8Bilirubin Production

and Hepatic Bilirubin Clearance

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Diagram of bilirubin metabolism. Fe2+, iron; CO, carbon monoxide; UDPGT (UGT), uridine diphosphoglucuronyl

transferase.

Stercobilinogen & Urobilinogen

Urobilinogen

II. Classification and Differential Diagnosis

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Classification and Differential Diagnosis:

A. Physiologic Hyperbilirubinemia

B. Unconjugated Hyperbilirubinemia

A. Disorders of Production

B. Disorders of Hepatic Uptake

C. Disorders of Conjugation

D. Other Causes

C. Conjugated Hyperbilirubinemia

Classification and Differential Diagnosis:

A. Physiologic Hyperbilirubinemia

B. Unconjugated Hyperbilirubinemia

A. Disorders of Production

B. Disorders of Hepatic Uptake

C. Disorders of Conjugation

D. Other Causes

C. Conjugated Hyperbilirubinemia

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III. PHYSIOLOGIC HYPERBILIRUBINEMIA

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PHYSIOLOGIC HYPERBILIRUBINEMIA. It is a term used by clinicians to describe jaundice

for which no underlying cause is identified and is therefore a diagnosis of exclusion.

It occurs in virtually every newborn to some degree. In full-term infants serum UCB level rises to >2 mg/dL

in the first week of life; with peak of 6 to 8 mg/dL by 3 days of age and then falls. (Up to 12 mg/dL is physiologic range)

In premature infants, the peak may be 10 to12 mg/dL on the fifth day of life, possibly rising >15 mg/dL.

Levels <2 mg/dL may not be seen until 1 month of age in both full-term and premature infants.

This “Physiologic Jaundice” is attributed to the following mechanisms:

Increased bilirubin production

Defective uptake of bilirubin from plasma

Defective conjugation due to decreased UDPG-T activity

Decreased hepatic excretion of bilirubin.

Increased enterohepatic circulation

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IV. Unconjugated Hyperbilirubinemia

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A. CAUSES OF UNCONJUGATED HYPERBILIRUBINEMIA

1. Disorders of Production: (Increased RBC destruction)

1) Isoimmunization: Rh, ABO, other incompatibilities

2) RBC Biochemical defects: G6PD, pyruvate kinase deficiency

3) RBC Structural Abnormalities: Spherocytosis, elliptocytosis, infantile pyknocytosis

4) Infections: Bacterial, viral, protozoal

5) Sequestration: Bruising, cephalohematomas, hematomas

6) Polycythemia: IDM, delayed cord clamping

7) Hemoglobinopathy: Alpha thalathemia

1. Disorders of Hepatic Uptake:

1. Gilbert Syndrome

2. Disorders of Conjugation:

1. Crigler-Najjar Syndrome Type I

2. Crigler-Najjar Syndrome Type II

3. Lucey-Driscoll Syndrome (Transient familial neonatal hyperbilirubinemia)

4. Hypothyroidism

3. Other Causes:

1. Breast-feeding Jaundice (Lack of volume)

2. Breast Milk Jaundice (Unknown mechanism)

3. Infant of Diabetic Mother

1. Disorders of Hepatic Uptake:

1. Gilbert Syndrome

2. Disorders of Conjugation:

1. Crigler-Najjar Syndrome Type I

2. Crigler-Najjar Syndrome Type II

3. Lucey-Driscoll Syndrome (Transient familial neonatal hyperbilirubinemia)

4. Hypothyroidism

3. Other Causes:

1. Breast-feeding Jaundice (Lack of volume)

2. Breast Milk Jaundice (Unknown mechanism)

3. Infant of Diabetic Mother

B. CLINICAL & LABORATORY EVALUATION

1- General considerations: The following situations suggest nonphysiologic

hyperbilirubinemia and require investigation:

1. Onset of jaundice before 24 hours of age.

2. Any elevation of bilirubin that requires phototherapy

3. A rise in serum bilirubin levels of > 0.5 mg/dL/hour.

4. Signs of underlying illness in any infant. (vomiting, lethargy, poor feeding, excessive weight loss, apnea, tachypnea, or temperature instability).

5. Jaundice persisting after 8 days in a term infant or after 14 days in a premature infant.

2- History: 1. A family history of jaundice, anemia, splenectomy,

. or gallbladder disease may suggest: Hereditary hemolytic anemia.

2. A family history of liver disease and jaundice suggest: Galactosemia, α1-

antitrypsin deficiency, cystic fibrosis.

3. A sibling with jaundice or anemia may suggest: Blood group incompatibility, breast-milk jaundice.

4. Maternal illness during pregnancy may suggest: Congenital viral or toxoplasmosis infection.

5. Infants of diabetic mothers tend to develop jaundice.

6. Ethnic or geographic origin associated with jaundice: East Asian, Greek.

2- History: 1. A family history of jaundice, anemia, splenectomy,

. or gallbladder disease may suggest: Hereditary hemolytic anemia.

2. A family history of liver disease and jaundice suggest: Galactosemia, α1-

antitrypsin deficiency, cystic fibrosis.

3. A sibling with jaundice or anemia may suggest: Blood group incompatibility, breast-milk jaundice.

4. Maternal illness during pregnancy may suggest: Congenital viral or toxoplasmosis infection.

5. Infants of diabetic mothers tend to develop jaundice.

6. Ethnic or geographic origin associated with jaundice: East Asian, Greek.

7. Maternal drugs may interfere with bilirubin binding to albumin, or cause hemolysis in a G6PD-deficient infant

8. The labor and delivery history may show : Trauma associated with extravascular bleeding and hemolysis.

Oxytocin use may be associated with hyperbilirubinemia

Asphyxiated infants may have elevated bilirubin

Delayed cord clamping may be associated with polycythemia.

9. The infant's history may show delayed or infrequent stooling, caused by poor caloric intake or intestinal obstruction and lead to increased enterohepatic circulation.

10. Vomiting can be due to sepsis, pyloric stenosis, or Galactosemia.

7. Maternal drugs may interfere with bilirubin binding to albumin, or cause hemolysis in a G6PD-deficient infant

8. The labor and delivery history may show : Trauma associated with extravascular bleeding and hemolysis.

Oxytocin use may be associated with hyperbilirubinemia

Asphyxiated infants may have elevated bilirubin

Delayed cord clamping may be associated with polycythemia.

9. The infant's history may show delayed or infrequent stooling, caused by poor caloric intake or intestinal obstruction and lead to increased enterohepatic circulation.

10. Vomiting can be due to sepsis, pyloric stenosis, or Galactosemia.

11. Breast-feeding: A. Breast-feeding jaundice:

Infants who are breast-fed have higher bilirubin levels after day 3 compared to formula-fed infants. The main responsible factor is a decreased intake of milk.

B. Breast-milk jaundice:

It is of late onset and has an incidence in term infants of 2% to 4%. By day 4, instead of the usual fall in the serum bilirubin level, the bilirubin level continues to rise and may reach 20 to 30 mg/dL by 14 days of age.

3- The physical examination: Jaundice is detected by blanching the skin with finger pressure

Jaundiced infants should be examined for: 1. Prematurity.

2. Small for gestational age (SGA), which may be associated with polycythemia and in utero infections.

3. Microcephaly, which may be associated with in utero infections.

4. Extravascular blood bruising, cephalohematoma, or others.

5. Pallor due to hemolytic anemia or extravascular blood loss.

6. Petechiae associated with congenital infection, sepsis.

7. Hepatosplenomegaly associated with hemolytic anemia, congenital infection, or liver disease.

8. Omphalitis.

9. Chorioretinitis associated with congenital infection.

10. Evidence of hypothyroidism.

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4- Prediction of hyperbilirubinemia:

1. Visual inspection is not a reliable

indicator of S. bilirubin levels.

2. A screening total serum bilirubin

(TSB) collected pre-discharge

and plotted on an “hour-specific

bilirubin nomogram”.

3. In infants >30 weeks' gestation, transcutaneous bilirubin

(TCB) can reliably estimate serum bilirubin levels: If the

TCB is >8, we check a TSB.

4. TCB is unreliable after phototherapy.

4- Prediction of hyperbilirubinemia:

1. Visual inspection is not a reliable

indicator of S. bilirubin levels.

2. A screening total serum bilirubin

(TSB) collected pre-discharge

and plotted on an “hour-specific

bilirubin nomogram”.

3. In infants >30 weeks' gestation, transcutaneous bilirubin

(TCB) can reliably estimate serum bilirubin levels: If the

TCB is >8, we check a TSB.

4. TCB is unreliable after phototherapy.

5- Laboratory tests:

1. Mother blood group, Rh, and antibody screen during pregnancy and repeated at delivery.

2. Baby blood group, Rh, and direct Coombs test for isoimmune hemolytic disease (Rh-negative, or O-positive mothers).

3. TSB and/or TcB ( transcutaneous bilirubin) .

4. Peripheral blood smear for RBC morphology and reticulocyte count.

5. Hematocrit will detect polycythemia or blood loss.

6. A G6PD screen may be helpful.

7. Direct bilirubin determination is necessary when:

Jaundice persists beyond the first 2 weeks of life.

Signs of cholestasis. (Light-colored stools and bilirubin in urine).

8. In prolonged jaundice:

Tests for liver disease

Congenital infection, or sepsis

Metabolic defects

Hypothyroidism

Urinalysis and a urine culture.

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V. BILIRUBIN TOXICITY

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Currently, there is major debate surrounds the toxicity of bilirubin in otherwise healthy full-term and premature infants.

A. Bilirubin entry into the brain:

It occurs as free (unbound) bilirubin or as bilirubin bound to albumin in the presence of a disrupted blood-brain barrier.

Certain drugs interfere with bilirubin binding to albumin.

Factors that disrupt the blood-brain barrier include hyperosmolarity, anoxia, and hypercapnia.

The barrier may be more permeable in premature infants.

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B. Acute bilirubin encephalopathy

It can be divided into three phases:

1. Early phase.

• Hypotonia, lethargy, high-pitched cry, and poor suck.

2. Intermediate phase.

• Hypertonia of extensor muscles with opisthotonus, rigidity, irritability, fever, and seizures.

• Many infants die in this phase; and who survive develop chronic bilirubin encephalopathy.

3. Advanced phase.

• Pronounced opisthotonus (although hypotonia replaces

hypertonia after approximately 1 week), shrill cry, apnea, seizures, coma, and death.

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Acute bilirubin encephalopathy

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Infant with acute advanced bilirubin encephalopathy

(post-exchange transfusion). Note the classic facies, hypertonia with retrocollis, opisthotonus, and cephalohematoma.

C. Kernicterus:

It is a pathologic diagnosis and refers to yellow staining of the brain by bilirubin together with evidence of neuronal injury.

Bilirubin staining is most commonly seen in the basal ganglia, hippocampus, various cranial nerve nuclei, brainstem nuclei, cerebellar nuclei, and anterior horn cells of the spinal cord.

Microscopically, there is necrosis, neuronal loss, and gliosis.

C. Kernicterus:

It is a pathologic diagnosis and refers to yellow staining of the brain by bilirubin together with evidence of neuronal injury.

Bilirubin staining is most commonly seen in the basal ganglia, hippocampus, various cranial nerve nuclei, brainstem nuclei, cerebellar nuclei, and anterior horn cells of the spinal cord.

Microscopically, there is necrosis, neuronal loss, and gliosis.

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A, Coronal T1-weighted MRI at the level of the basal ganglia, demonstrating bilateral, symmetric high-intensity globus pallidus (GP) signals (arrows). B, Deep orange-yellow staining of the globus pallidus (GP) of the coronal section at postmortem in another neonate.

D. Chronic bilirubin encephalopathy : It is marked by athetosis, partial or complete sensorineural deafness,

limitation of upward gaze, dental dysplasia, and intellectual deficits.

(chorioathetotic cerebral palsy).

NB: The use of the term kernicterus in the clinical setting should be used to denote the chronic and permanent sequelae of bilirubin toxicity.

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E. Bilirubin toxicity and hemolytic disease.

There is general agreement that in Rh hemolytic

disease there is a direct association between marked

elevations of bilirubin and signs of bilirubin

encephalopathy with kernicterus at autopsy.

Studies and clinical experience have shown that in

full-term infants with hemolytic disease, if the total

bilirubin level is kept <20 mg/dL, bilirubin

encephalopathy is unlikely to occur.

This should apply to other causes of isoimmune

hemolytic, and hereditary hemolytic diseases.

E. Bilirubin toxicity and hemolytic disease.

There is general agreement that in Rh hemolytic

disease there is a direct association between marked

elevations of bilirubin and signs of bilirubin

encephalopathy with kernicterus at autopsy.

Studies and clinical experience have shown that in

full-term infants with hemolytic disease, if the total

bilirubin level is kept <20 mg/dL, bilirubin

encephalopathy is unlikely to occur.

This should apply to other causes of isoimmune

hemolytic, and hereditary hemolytic diseases.

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VI. MANAGEMENT OF UNCONJUGATED

HYPERBILIRUBINEMIA

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A. General principles:

Early identification of known causes should prompt close observation, appropriate laboratory investigations, and timely intervention.

Any medication or factor that may interfere with bilirubin metabolism, binding to albumin, or the integrity of the blood-brain barrier should be discontinued or corrected.

Infants who are receiving inadequate feedings, or have decreased urine and stool output, need to increase feedings to reduce bilirubin enterohepatic circulation.

Infants with hypothyroidism need adequate replacement of the thyroid hormone.

A. General principles:

Early identification of known causes should prompt close observation, appropriate laboratory investigations, and timely intervention.

Any medication or factor that may interfere with bilirubin metabolism, binding to albumin, or the integrity of the blood-brain barrier should be discontinued or corrected.

Infants who are receiving inadequate feedings, or have decreased urine and stool output, need to increase feedings to reduce bilirubin enterohepatic circulation.

Infants with hypothyroidism need adequate replacement of the thyroid hormone.

B. Infants with hemolytic disease: In Rh disease:

- Intensive phototherapy immediately.

- An exchange transfusion is performed if the bilirubin level is predicted to reach 20 mg/dL .

In ABO hemolytic disease: Phototherapy if the bilirubin level exceeds:

10 mg/dL at 12 hours,

12 mg/dL at 18 hours,

14 mg/dL at 24 hours,

15 mg/dL at any time.

In hemolytic disease of other causes:

- Treatment as if it is Rh disease.

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An exchange transfusion to be done at 20 mg/dL.

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Serum bilirubin levels plotted against age in term infants (A) and premature infants (B) with

erythroblastosis. Infants with levels plotting below the bottom line require no action, those with levels between the two lines should receive phototherapy, and those with levels above the top line should undergo exchange transfusion.

C. Healthy late-preterm and term infants: Bilirubin measurments are used in conjunction with

an hour-specific bilirubin nomogram to identify infants at risk for significant hyperbilirubinemia.

Most are sent home by 24 to 48 hours of age; parents should be informed about neonatal jaundice.

Follow-up is within 1 or 2 days, especially if the infant is < 38 weeks' gestation, is the first child, has breast-feeding, or has any other risk factors.

In healthy late-preterm and term infants who are jaundiced, we follow the guidelines.

C. Healthy late-preterm and term infants: Bilirubin measurments are used in conjunction with

an hour-specific bilirubin nomogram to identify infants at risk for significant hyperbilirubinemia.

Most are sent home by 24 to 48 hours of age; parents should be informed about neonatal jaundice.

Follow-up is within 1 or 2 days, especially if the infant is < 38 weeks' gestation, is the first child, has breast-feeding, or has any other risk factors.

In healthy late-preterm and term infants who are jaundiced, we follow the guidelines.

Treatment threshold for babies with neonatal jaundice ≥38 weeks’ gestation.

D- Breast-fed & Breast milk jaundice: Preventive measures are the best approach

and include encouragement of frequent nursing (every 2-3 hours) and, supplementation with expressed breast milk or formula.

If the bilirubin reaches a level that would require phototherapy and is predicted to exceed 20 mg/dL, we will start phototherapy, and discontinue breast-feeding for 48 hours and supplement with formula.

Failure of bilirubin levels to fall after the interruption of breast-feeding may indicate other causes, such as hemolytic disease, hypothyroidism, and Crigler-Najjar syndrome.

D- Breast-fed & Breast milk jaundice: Preventive measures are the best approach

and include encouragement of frequent nursing (every 2-3 hours) and, supplementation with expressed breast milk or formula.

If the bilirubin reaches a level that would require phototherapy and is predicted to exceed 20 mg/dL, we will start phototherapy, and discontinue breast-feeding for 48 hours and supplement with formula.

Failure of bilirubin levels to fall after the interruption of breast-feeding may indicate other causes, such as hemolytic disease, hypothyroidism, and Crigler-Najjar syndrome.

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E. Premature infants: Current practice for treating premature is as follows: 1. Infants <1,000 gm: - Phototherapy is started within 24 hours, - Exchange transfusion at levels of 10 to 12 mg/dL. 2. Infants 1,000 to 1,500 gm: - Phototherapy at bilirubin levels of 7 to 9 mg/dL - Exchange transfusion at levels of 12 to 15 mg/dL. 3. Infants 1,500 to 2,000 gm : - Phototherapy at bilirubin levels of 10 to 12 mg/dL - Exchange transfusion at levels of 15 to 18 mg/dL. 4. Infants 2,000 to 2,500 gm: - Phototherapy at bilirubin levels of 13 to 15 mg/dL - Exchange transfusion at levels of 18 to 20 mg/dL.

1- Phototherapy: Phototherapy causes isomerization in the skin of the bilirubin to

lumirubin which is water soluble and can be excreted in the urine.

The conversion process is rapid, but the excretion of the molecule out of the skin is slow.

Phototherapy is the standard of treatment and has resulted in a decline in the number of exchange transfusions being performed.

Phototherapy can be delivered from either overhead or underneath the baby (or both).

A number of different types of phototherapy devices have been studied including fluorescent, quartz halogen, light-emitting diode.

Factors that might influence the effectiveness of phototherapy include the number of lights, the distance from the light source to the infant, the time spent in phototherapy and the surface area of skin exposed.

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The Neo-blue Blanket Light-emitting Diode [LED] Phototherapy System

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Important Factors in the Efficacy of Phototherapy.

Guidelines for phototherapy: Use total bilirubin: (do not subtract conjugated bilirubin). Once therapy has been commenced serum bilirubin estimates

will be necessary to assess the severity of jaundice because the skin color becomes unreliable.

In cases of severe jaundice, the TSB will need to be repeated 4–6 h after initiating phototherapy and then every 6–12 h once it is stable or falling.

Phototherapy can be stopped once the TSB has fallen below the phototherapy threshold.

A rebound TSB should be collected (12–24 h) after stopping phototherapy.

General care of the baby during phototherapy includes eye protection, monitoring the baby’s temperature and fluid balance.

Supporting the parents by educating them and encouraging them to interact with their baby.

Some complications of phototherapy: Temperature instability:

Dehydration: Regular assessment of the baby’s fluid balance (weight and urine output) and early management.

Diarrhoea: Phototherapy decreases bowel transit time and induces lactose intolerance; causes of diarrhoea and consequent fluid loss

Retinal damage: The eyes are thought to be vulnerable to phototherapy but this has never been proved (Use suitable eye shield).

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2- Exchange transfusion: The exchange transfusion allows:

• Removal of unconjugated bilirubin

• Removal of the antibody causing haemolysis.

• Replacement of sensitized red cells with normal cells

• Restoration of blood volume and correction of anaemia

• Provision of free albumin for bilirubin binding.

Exchange transfusions may be required in conjunction with phototherapy for infants with severe jaundice.

The indications for exchange transfusion depend on the infant’s gestational age, postnatal age and state of health.

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Technique of exchange transfusion: The blood should be less than 48 h old, ABO compatible with

mother and infant and rhesus negative.

The volume to be exchanged is usually 160 mL/kg for a double- volume exchange.

Commonlly single umbilical vein catheter is used.

1. Donor blood is warmed via a heating coil in a water bath.

2. Generally, 10 mL aliquots are used. (remove 10 mL of infant’s blood then replace).

3. The first 10 mL aliquot is used to sent for laboratory.

4. The heart rate, blood pressure, temperature and respirations should be monitored continuously throughout the exchange transfusion.

5. A careful record is kept of all blood sampled and transfused.

6. At the end of the exchange transfusion, blood is sent to the laboratory.

7. Do not feed the infant for at least 2h before and at least 4h after exchange transfusion. Instead give maintenance IV fluids.

Exchange transfusion through a special four-way stopcock. (1) Male adapter to umbilical venous line; (2) female adapter to waste container;

and (3) attachment to blood bag and warmer.

Complications associated with exchange transfusions: Death (reported mortality rates between 5 and 10%)

Electrolyte disturbance (hypocalcaemia, hyperkalaemia)

Blood glucose disturbance – initially hyperglycaemia followed by rebound hypoglycaemia, especially in rhesus immunization

Infection: viral (CMV, hepatitis B, HIV) or bacterial (Staph. aureus and streptococcus) due to contaminated blood

Embolism of either air or thrombosed blood

Necrotizing enterocolitis (NEC)

Fluid overload or rarely hypovolaemia

Acidosis, hypoxia, bradycardia, cardiac arrest

Benign intrahepatic cholestasis.

Haemorrhage

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3- OTHER TREATMENT MODALITIES

A. Phenobarbital:

In a dose of 5 to 8 mg/kg every 24 hours, induces microsomal enzymes, increases bilirubin conjugation and excretion, and increases bile flow.

It is useful in treating of Crigler-Najjar syndrome type II (but not type I) and in the treatment of the direct hyperbilirubinemia associated with hyperalimentation.

Phenobarbital given antenatally to the mother is effective in lowering bilirubin levels in erythroblastotic infants

Phenobarbital does not augment the effects of phototherapy.

B. Intravenous Immune Globulin:

High-dose intravenous immune globulin (0.5 -1,0 gm/kg IV in 4 hours) has been used to reduce bilirubin levels in infants with isoimmune hemolytic disease.

The mechanism is unknown, but theoretically the immune globulin acts by occupying the Fc receptors of reticuloendothelial cells, thereby preventing hemolysis.

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VI. CONJUGATED HYPERBILIRUBINAEMIA

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1- Introduction: Conjugated hyperbilirubinaemia is much less common

than unconjugated hyperbilirubinaemia in the newborn, but has a much more serious prognosis.

It usually presents in the second week of life or later and is associated with greenish skin discoloration, dark bile-stained urine and pale acholic stools.

Occasionally, presents at birth as a result of TORCH infections or rhesus isoimmunization.

Hepatosplenomegaly is commonly present and the infant often fails to thrive.

The preferred term to describe it is cholestasis, which includes retention of CB, bile acids, and others.

Conjugated hyperbilirubinaemia

2- Common Causes of Neonatal Cholestasis:

Obstructive Biliary atresia Choledochal cyst Gallstones/ biliary sludge Inspissated bile (due to hemolysis) Alagille syndrome (biliary hypoplasia)

Cystic fibrosis

Hepatocellular Idiopathic “neonatal hepatitis” Viral (CMV, HIV) Bacterial Urinary tract infection Sepsis Syphilis

Genetic/Metabolic Alpha-1-Antitrypsin deficiency Hypothyroidism, hypopituitarism Tyrosinemia ; Galactosemia Progressive familial cholestasis

Toxic Total parenteral nutrition Drugs

In term infants Biliary atresia and Neonatal hepatitis account for 80% of cases. In preterm infants cholestasis secondary to prolonged TPN is the most common.

3- Investigations for conjugated hyperbilirubinaemia: Serial bilirubin levels

Liver enzymes (Transaminases - Alkaline phosphatase)

Prothrombin time (PT), Partial thromboplastin time (PTT), and serum albumin level.

Alpha-Fetoprotein

Alpha-1-antitrypsin screen and phenotype

Abdominal ultrasound

Sweat test

TORCH serology

Eye examination (cataract; chorioretinitis)

Amino acid screen

Percutaneous liver biopsy

Urinalysis for glucose and reducing substances

Radionuclide (HIDA) scan.

Full septic screening

4- Neonatal hepatitis: This is a non-specific condition with a variety of

causes, the prognosis depends on the underlying cause.

In general, approximately one-third of cases deteriorate and develop hepatic cirrhosis, one-third have evidence of chronic liver disease and one-third recover fully.

The prognosis for idiopathic neonatal hepatitis is good and more than 90% resolve by 1 year of age.

The main causes of neonatal hepatitis: Infection:

- Most commonly due to TORCH infections, and other viruses.

Metabolic causes:

- Fructosaemia and tyrosinaemia - Galactosaemia (later)

Alpha-1-antitrypsin deficiency:

- This is an autosomal recessive condition.

- There is no specific treatment, up to 50% of affected children improve; others developed liver failure.

Severe intrauterine growth restriction:

- This results in a benign intrahepatic cholestasis

Long-term TPN use:

- As in gastroschisis, short gut syndrome

Chronic hypoxic–ischaemic damage to liver:

- Recovery from multiorgan failure but liver failure persists

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5- Biliary atresia: At birth these infants have absent or atretic bile

ductules involving the main bile ducts or the main branches of the bile ducts.

The commonest variety is extrahepatic biliary atresia.

The pathogenesis is unknown. In up to 30% of cases, biliary atresia may be associated with other malformations including renal anomalies, heart malformations, asplenia, polysplenia, malrotation and situs inversus.

The onset of jaundice may be delayed by up to 4 weeks from birth.

5- Biliary atresia: At birth these infants have absent or atretic bile

ductules involving the main bile ducts or the main branches of the bile ducts.

The commonest variety is extrahepatic biliary atresia.

The pathogenesis is unknown. In up to 30% of cases, biliary atresia may be associated with other malformations including renal anomalies, heart malformations, asplenia, polysplenia, malrotation and situs inversus.

The onset of jaundice may be delayed by up to 4 weeks from birth.

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If surgery is attempted before 60 days of age, there is an 80% chance of achieving biliary drainage by the portoenterostomy operation( Kasai procedure).

Serum bilirubin falls rapidly after successful surgery, but many children develop ascending cholangitis, which is the most serious postoperative complication.

The Kasai procedure is palliative, not curative, and approximately two-thirds of survivors will require liver transplantation by 10 years of age.

If surgery is attempted before 60 days of age, there is an 80% chance of achieving biliary drainage by the portoenterostomy operation( Kasai procedure).

Serum bilirubin falls rapidly after successful surgery, but many children develop ascending cholangitis, which is the most serious postoperative complication.

The Kasai procedure is palliative, not curative, and approximately two-thirds of survivors will require liver transplantation by 10 years of age.

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IN SUMMARY: Jaundice is the most common clinical condition presenting in

the newborn period.

In most infants the jaundice is physiological as there is no underlying disease; commonly presents between 2-5 day of life.

Jaundice presenting in the first 24h may be due to haemolysis and always requires investigation.Unconjugated bilirubin is neurotoxic in high levels

Conjugated hyperbilirubinaemia is much less common than unconjugated.

Infants with obstructive causes of neonatal cholestasis (extrahepatic biliary atresia, choledochal cyst, and many of the intrahepatic) look remarkably well despite the jaundice.

On the other hand, infants with infectious or metabolic causes, appear toxic and ill.

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BEST WISHES

Gilbert’s syndrome This is a common cause of unconjugated

hyperbilirubinaemia in young adults, but rarely causes problems in the neonatal period.

It is due to a single gene mutation affecting a hepatic bilirubin enzyme uridine diphosphate glucuronyl transferase (UDPGT).

In the newborn it is associated with mild unconjugated hyperbilirubinaemia <85 μmol/L.

The prognosis is excellent.

Crigler–Najjar syndrome It is due to multiple gene defects and causes very

severe hyperbilirubinaemia potentially leading to

kernicterus.

There is little effective treatment other than prolonged

phototherapy.

Liver transplantation has been successful in some

severe cases; in milder cases phenobarbitone may

lower the bilirubin.