neonatal hyperbilirubinemia

50
Review 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 contain discussions 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) Definition Jaundice 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: 4

Upload: mahmmoudeltaweel

Post on 30-Oct-2014

321 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: Neonatal Hyperbilirubinemia

Review

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 contain discussions 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)

Definition Jaundice 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. This condition can easily be treated; contact your doctor

if you think your baby may have newborn jaundice. (J. Thomas

Megerian, 2011)

4

Page 2: Neonatal Hyperbilirubinemia

Review

Incidence

Hyperbilirubinemia 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)

Pathophysiology of hyperbilirubinemia

Bilirubin Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal 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)

5

Page 3: Neonatal Hyperbilirubinemia

Review

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

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 is 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)

6

Page 4: Neonatal Hyperbilirubinemia

Review

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 the total bilirubin in

patients with cholestatic jaundice. (Chung et al., 2004)

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 up to 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. Conditions 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)

7

Page 5: Neonatal Hyperbilirubinemia

Review

4-Conjugation of Bilirubin:

In the liver it is conjugated with glucuronic acid by the enzyme glucuronyltransferase, 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 to urobilinogen, which is further metabolized to stercobilinogen, and finally oxidised to stercobilin. 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 unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and delta bilirubin which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease). (Kliegman & Behrman, 2007)

5-Bilirubin Secretion and Excretion

Conjugation 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 is 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)

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)

8

Page 6: Neonatal Hyperbilirubinemia

Review

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 fetus does not normally pass stool. The enzyme β-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)

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 well as vasodilator properties (Morita, 2005).

9

Page 7: Neonatal Hyperbilirubinemia

Review

Pathophysiology of neonatal hyperbilirubinemia

Fig.

(1):

The

pathophysiology of neonatal hyperbilirubinemia (Maisels,

2005).

10

Page 8: Neonatal Hyperbilirubinemia

Review

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.

11

Page 9: Neonatal Hyperbilirubinemia

Review

(Camilla and Clohert, 2003)

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/dl (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, A. F.; 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).

12

Page 10: Neonatal Hyperbilirubinemia

Review

4. Direct bilirubin more than 34 umol/l (2.0 mg/dL).

(Miguel Helft, 2007)Neonatal hyperbilirubinaemia can also be classified into:** Unconjugated hyperbilirubinemia:

** Conjugated hyperbilirubinemia:

Unconjugated hyperbilirubinemia:Causes of unconjugated hyperbilirubinemia in neonatal period

are listed in the following table:

Table (1) Causes of Unconjugated Hyperbilirubinemia

Haemolytic disease (hereditary 0r acquired)-lsoimmune hemolysis (neonatal; acute or delayed transfusion reaction; autoimmune)-Rh incompatibility, AB0 lncompatibility and other blood group incompatibilities-Congenital spherocytosis -Hereditary elliptocytosis -Infantile pyknocytosisErythrocyte enzyme defects-G6PD deficiency -Pyruvate kinase deficiencyHemoglobinopathy-Sickle cell anemia -ThalassemiaOthers-Sepsis -Hemolytic Uremic syndrome-Hemangioma -MechanicaL trauma (heart valve)-Drugs as vitamin K and maternal oxytocin-lnfection -Enclosed hematoma-Polycythemia as in Diabetic mother, Fetal transfusion (recipient) and Delayed cord clampingDecreased delivery of UCB (in plasma) to hepatocytes:-Right-sided congestive heart failure-Portacaval shuntDecreased bilirubin uptake by hepatocytes membrane:-Breast milk jaundice -Lucey- Driscoll syndrome-Hypothyroidism -Hypoxia -AcidosisDecreased storage of UCB in cytosol:-Competitive inhibition -Fever Decreased conjugation:-Neonatal jaundice (physiologic) -lnhibition (drugs)-Hereditary (Crigler-Najjar) Type I (complete enzyme deficiency) and Type Il (partial deficiency)-Gilbert disease -Hepatocellular dysfunctionINCREASED ENTEROHEPATIC CIRCULATION-Breast milk Jaundice -lntestinal obstruction-Ilea atresia -Hirsch sprung disease

13

Page 11: Neonatal Hyperbilirubinemia

Review

-Cystic fibrosis -Pyloric stenosis-Antibiotic administration

Balistreri, 2008((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. TOXICParenteral nutrition related, sepsis (urinary tract) with end-toxemia and drug relatedMETABOLICDisorders of amino acid metabolismTyrosinemia, Wolman disease, Niemann- Pick disease&Gaucher disease,Disorders of carbohydrate metabolismGalactosemia, fructosemia and glycogenesis lVDisorders of bile acid biosynthesisOther metabolic defectsα1-Antitrypsin deficiency, cystic fibrosis, idiopathic hypopituitarism, hypothyroidism and childhood cirrhosis.GENETIC/CHROMOSOMAL.Trisomy E and Down syndromeINTRAHEPATIC CHOLESTATIC SYNDROME"ldiopathic neonatal hepatitis, familial intrahepatic cholestasis and congenital hepatic fibrosisEXTRAHEPATIC DISEASESBiliary 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(

14

Page 12: Neonatal Hyperbilirubinemia

Review

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 bilirubin encephalopathy 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)

** Kernicterus

Causes

Kernicterus is caused by very high levels of bilirubin. Bilirubin is a yellow pigment that is created in the body during the normal recycling of old red blood cells. In some cases when there are extremely high levels of bilirubin in the body or the baby is extremely ill, the substance will move out of the blood and collect in the brain tissue. (Milton S. Hershey, 2011)

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

(Kimberly G, 2011)

15

Page 13: Neonatal Hyperbilirubinemia

Review

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 viral infection or toxoplasmosis, and maternal medications should be reviewed. History of instrumental delivery, oxytocin induced labor, delayed cord clamping, and Apgar score should be 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, or 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 well 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 for jaundice. Look for cephalohematoma or bruising. Cardiovascular: Heart rate, pulse, blood pressure, apex site, perfusion. Severe haemolytic processes can result in heart failure.

16

Page 14: Neonatal Hyperbilirubinemia

Review

Respiratory: Respiration rate and rhythm and oxygen saturation.  If the neonate is in heart failure, there may be respiratory signs.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).

(Quoted from Maisels, 2006)

Differential DiagnosisThe 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).

17

Page 15: Neonatal Hyperbilirubinemia

Review

(Stoll and Kliegman, 2004)

C- Laboratory Evaluation of Neonatal Hyperbilirubinemia:

Laboratory Studies A. 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 δ-bilirubin.

B. Complete blood count: Useful in detecting hemolysis, indicated by the presence of anemia 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)

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

18

Page 16: Neonatal Hyperbilirubinemia

Review

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 Complicated1000 12-13 10-12

1000-1250 12-14 10-121251-1499 14-16 12-141500-1999 16-20 15-172000-2500 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 bilirubin measurement in 6–12 hours

Consider phototherapy and repeat bilirubin measurement in 6 hours

Start phototherapy

Perform an exchange transfusion unless the bilirubin level falls below threshold while the treatment is being prepared

19

Page 17: Neonatal Hyperbilirubinemia

Review

(Neonatal jaundice. NICE clinical guideline 2010)The management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation is summarized in Figure (5).

20

Page 18: Neonatal Hyperbilirubinemia

Review

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).

Lifestyle and home remedies When infant jaundice isn't severe, your doctor may recommend changes in feeding habits that can lower levels of bilirubin. Talk to your doctor if you have any questions or concerns about how much or how often your baby is feeding or if you're having trouble breast-feeding. The following steps may lessen jaundice: More frequent feedings. Feeding more frequently will provide your baby with more milk and cause more bowel movements, increasing the amount of bilirubin eliminated in your baby's stool. Breast-fed infants should have eight to 12 feedings a day for the first several days of life. Formula-fed infants usually should have 1 to 2 ounces (about 30 to 60 milliliters) of formula every two to three hours for the first week.Supplemental feedings. If your baby is having trouble breast-feeding, is losing weight or is dehydrated, your doctor may suggest giving your baby formula or expressed milk to supplement breast-feeding. In some cases, your doctor may recommend using formula alone for a couple of days and then resuming breast-feeding. Ask your doctor what feeding options are right for your baby.) Mayo, 2011.(

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

21

Page 19: Neonatal Hyperbilirubinemia

Review

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, sepsis, acidosis, and hypoalbuminemia.

(M. Jeffrey Maisels et al;2008)

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 as 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.

D) Mechanism of Action Phototherapy uses light energy to change the shape and structure of bilirubin, converting it to molecules that can be excreted even when normal conjugation is deficient. Absorption of 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 or urine without the need for conjugation. Bilirubin elimination depends on the rates of formation as well as the rates of clearance of

22

Page 20: Neonatal Hyperbilirubinemia

Review

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 output predominantly in the 460-to-490-nm blue region of the spectrum are probably the most effective for treating hyperbilirubinemia. A common misconception is that ultraviolet (UV) light (<400 nm) is used for phototherapy. Phototherapy lights in current use do not emit significant erythemal UV radiation. In addition, the plastic covers of the lamp and, in the case of preterm infants, the incubator, filter out UV light (Maisels and McDonagh, 2008).The dose and efficacy of phototherapy are also affected by the infant's distance from the light (the nearer the light source, the greater the irradiance) and the area of skin exposed, hence the need for a light source beneath the infant for intensive phototherapy. Although controlled trials have demonstrated that the more surface area exposed, the greater the reduction in the total demonstrated that the more surface area exposed, the greater the reduction in the total serum bilirubin level, it is usually unnecessary to remove the infant's diaper. If, however, the total serum bilirubin level continues to rise despite treatment, the diaper should be removed until there is a clinically significant decline. Aluminum foil or white cloth placed on either side of the infant to reflect light will also improve the efficacy of phototherapy. Because light can be toxic to the immature retina, the infant's eyes should always be protected with opaque eye patches (Maisels and McDonagh, 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 tailored to 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 birthweight receiving aggressive phototherapy.[ Morris BH, Oh W, Tyson JE, 2008]

23

Page 21: Neonatal Hyperbilirubinemia

Review

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 may create 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, because most 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 servocontrolled 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.

Hypocalcemia 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., ect. 2009(

F) Methods of administration :

24

Page 22: Neonatal Hyperbilirubinemia

Review

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 rountinely measure irradiance when administering phototherapy, but units should be checked periodically to ensure that the lamps are providing adequate irradiance, according to the manufacturer's guidelines. ( JAbyMD, 2012 Stanford School of Medicine)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, Chawla D, ect 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, Roislien J, ect 2008)

v-Home phototherapy:Home phototherapy for a term infant with neonatal jaundice is considered medically appropriate if ALL of the following criteria are met:

25

Page 23: Neonatal Hyperbilirubinemia

Review

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(National Guideline Clearinghouse. National Center for Primary Care. 2008)

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 of Carbon 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 reflects 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

LASER photo radiation therapy in neonatal hyperbilirubinemia:The conventional light therapy for neonatal hyperbilirubinemia supply not only the desired radiation at the effective band of

26

Page 24: Neonatal Hyperbilirubinemia

Review

wavelength, but also light at different wavelengths between 300 - 700 nm, which might cause undesired and sometime harmful effects. LASER light is unique in that it is all of one color (monochromatic), and the photons emitted from LASER source are of the same wavelength which is important in tissue reaction. If LASER irradiation is used instead of fluorescent irradiation maximum efficiency and minimal morbidity can be achieved, since it provides light source with much narrower wave band that can optimally excite the photo decomposition of bilirubin (Hansen.,2002).

27

Page 25: Neonatal Hyperbilirubinemia

Review

28

Page 26: Neonatal Hyperbilirubinemia

Review

29

Page 27: Neonatal Hyperbilirubinemia

Review

30

Page 28: Neonatal Hyperbilirubinemia

Review

31

Page 29: Neonatal Hyperbilirubinemia

Review

32

Page 30: Neonatal Hyperbilirubinemia

Review

33

Page 31: Neonatal Hyperbilirubinemia

Review

Figure (6) :Guidelines for phototherapy in infants of 35 or more weeks’ gestation

(AAP.,2005)

34

Page 32: Neonatal Hyperbilirubinemia

Review

III. Exchange transfusion: AIMTo modify abnormal values of the circulating bloods composition, by removing one or more components whilst maintaining a close to constant blood volume.

INDICATIONS Hyperbilirubinaemia – to lower serum bilirubin (SBR) levels

and prevent Kernicterus Rhesus/ABO incompatibility – removal of red blood cells with

antibodies or free circulating antigens to reduce degree of red cell destruction

Severe Anaemia – replace volume with that containing a higher red blood cell mass

Hydrops Foetalis – to regulate blood volume and allay potential heart failure

Other rare indications – Hyperkalaemia, Drug toxicity, Disseminated Intravascular Coagulation (DIC) (NICU 2011, Jennifer Ormsby CNC Newborn Services)

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, Carlo WA.  2011)(Saunthararajah S,2008.)

Fig. (7): Guidelines for exchange transfusion in infants 35 or more weeks’ gestation.

35

Page 33: Neonatal Hyperbilirubinemia

Review

The following B/A 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 (8): Bilirubin / Albumin ratio as an additional factor in determining the need for exchange transfusion.

Risk CategoryB/A Ratio at Which Exchange Transfusion

Should be ConsideredTSB mg/dL/Alb, g/dL TSB _mol/L/Alb, _mol/L

Infants _38 0/7 wk Infants 35 0/7–36 6/7 wk and well or _38 0/7 wk if higher risk or isoimmune hemolytic disease or G6PD deficiencyInfants 35 0/7–37 6/7 wk if higher risk or isoimmune hemolytic disease or G6PD deficiency

8.07.2

6.8

0.94

0.84

0.80

If the TsB is at or approaching the exchange level, send blood for immediate type and cross match. Blood for exchange transfusion is modified whole blood (red cells and plasma) cross matched against the mother and compatible with the infant (A.A.P.,2004)a.

• Pharmacological Treatments:

Phenobarbitone. Intravenous immunoglobins. Ursodeoxycholate therapy. 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 administered prenatally in the mother or postnatally 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, MD, PhD, MHA, FAAP 2012)

* Intravenous Immunoglobulin: The  American Academy of Pediatrics routinely uses 500 mg/kg infused intravenously over a period of 2 hours for Rh or ABO

36

Page 34: Neonatal Hyperbilirubinemia

Review

incompatibility when the total serum bilirubin levels 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 year following the implementation of IVIG therapy for Rh and ABO isoimmunization. (Huizing K, Roislien J, 2008)

*Albumin:Bilirubin in circulation is predominantly bound to albumin. Although the binding ratio is 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 transfusion albumin 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 protocol probably is proscribed in many countries (Hansen, 2003).• 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 (A.A.P., 2004)b.

Consultations: For infants with physiologic neonatal jaundice, no consultation is required. Gastroenterologists and surgeons may be consulted regarding infants with jaundice resulting from hepatobiliary or bowel disease (A.A.P., 2004)b.When to discharge from hospital?In the era of early discharge, newborns released within the first 48 hours of life need to be reassessed for jaundice within 1-2 days. Use of the hour-specific bilirubin nomogram . May assist in selecting infants with a high likelihood of developing significant hyperbilirubinemia. The American Academy of Pediatrics "Clinical Practice Guideline for Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation" emphasizes the importance of universal systematic assessment for the risk of severe hyperbilirubinemia

37

Page 35: Neonatal Hyperbilirubinemia

Review

(A.A.P., 2004)b.Infants who have been treated for jaundice can be discharged when they are feeding adequately and have had 2 successive serum bilirubin levels demonstrating a trend towards lower value (Newman et al., 2006).

Outcome: When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae. This was illustrated in a prospective cohort control study of 140 infants with TSB levels 25mg/dL (428 micromol/L) identified from a cohort of 106, 627 term or nearterm infants (Newman et al., 2006).

Mortality and Morbidity Death 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).

38