Neonatal Jaundice

07/23/11

Objectives
Review normal bilirubin metabolism and describe how it varies in the neonatal period. Describe the different types and causes of neonatal jaundice including physiologic jaundice, breast milk jaundice, breast feeding jaundice, and pathologic jaundice Discuss treatment options for hyperbilirubinemia including phototherapy, exchange transfusion, and experimental treatments.
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Definition
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Deposition of unconjugated (indirect) bilirubin onto the skin & mucus membranes Caused by increased bilirubin levels
Head to toe progression
Face > 5 mg/dL Upper Chest > 10 mg/dL Abdomen > 12 mg/dL Palms/Soles >15 mg/dL

Neonatal Hyperbilirubinemia
Total Bilirubin (indirect+direct) level > 5 mg/dL
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Neonatal Bilirubin Metabolism

Bilirubin derived from heme
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75% from catabolism of circulating RBC 25% from ineffective erythropoesis and turnover of heme protein and free heme

No known physiologic function. Heme iron + carbon monoxide + biliverdin bilirubin

Heme oxygenase converts heme to biliverdin Biliverdin reductase converts biliverdin to bilirubin

Neonatal Bilirubin Metabolism

Bilirubin is carried bound to albumin to the liver, where in presence of the enzyme uridyldiphosphoglucuronyl transferase (UDPGT), it is taken up by the hepatocyte and conjugated with two glucuronide molecules The conjugated bilirubin is then excreted through the bile to the intestine In the presence of normal intestinal flora, the conjugated bilirubin is metabolized further and excreted in the stool
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Neonatal Bilirubin Metabolism

Enterohepatic circulation
In the absence of gut flora and with slow intestinal motility/delayed feeding (as in the first days of life) - the conjugated bilirubin remains in the intestinal lumen, where a mucosal enzyme (-glucuronidase) can cleave off the glucuronide molecules, leaving unconjugated bilirubin to be reabsorbed
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Bonemarrow
RETICULOEND OTHELIAL SYSTEM (RES)
Hgb hem e oxygena se Biliverdin Biliverdin re ductase Bilirubin Fe Globin

Hgb Globin + He me Fe +

RBCs

SHUNT PATHWAY He precursors me Myoglobulin Non-hgb hem prote e ins

Kid y ne

Porp e hog ns Liver

uptake Cytopla ic sm protein binding

Bilirubin-Albumin Co mple x
ENTEROHEPATIC CIRC

Sm ooth endoplasmic reticulum

Conjuga ted bilirubin

Urine urobilinoge n
excretion Hydrolysis Bilirubin

In tin tes e
Urobilinogen Stercobilin

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Bilirubin Forms
Unconjugated bilirubin
Does not cross blood-brain-barier (BBB) Distruption of this bond by certain drugs (sulfa drugs, ceftriaxone, free fatty acids), hypothermia, hypoxia, acidosis
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Bound to albumin

Free unconjugated bilirubin

Amount of bilirubin exceeds the available binding sites on albumin Readily crosses the BBB

Conjugated bilirubin
Bilirubin glucuronide

Physiologic Jaundice
Clinical jaundice develops in 50%-65% of all newborns
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Jaundice appears after 24 hrs of age Total bilirubin rises by less than 5 mg/dl (86 mmol/l) per day

Contributing factors

UDPGT inactivity at birth Relatively high RBC mass Absence of intestinal flora Slow intestinal motility leading to an active enterohepatic circulation

Physiologic Jaundice
Full term infants
Peak bilirubin occurs at age 3 to 5 days with total bilirubin of no more than 15 mg/dl (258 mmol/l) Only 3% develop serum bilirubin levels > 15 mg/dl Jaundice is resolved by 1 week
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Premature infants
Higher bilirubin levels with later peak (6-7 days) Jaundice is resolved by 2 weeks of age

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Exaggerated Physiologic Jaundice

Prematurity
Poor enteral intake Delayed stooling Increased enterohepatic circulation
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Factors that may enhance or worsen normal physiologic jaundice

Sequestrated blood Delayed establishment of feedings Maternal drugs

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Breast Feeding Jaundice

Also known as lack of breast milk jaundice
Occurs 1st week of life Breast fed infants are more likely to have bilirubin >15 mg/dl than formula fed infants: 2% versus 0.3%
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The pathogenesis appears to be

decreased enteral intake and increased enterohepatic circulation No increase in bilirubirubin production is seen

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Breast Feeding Jaundice

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Jaundice should be considered a possible sign of failure to establish an adequate milk supply and should prompt specific inquires into this possibilty
Weight loss >10% from birth Fewer than 6 wet diapers by day 3-4 Fewer than 4 stools per day Nursing fewer than 8 times per 24 hrs for at least 10 min each feed

If intake is inadequate, the infant should receive supplementation with formula, and mother should be instructed to nurse more frequently

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Breast Milk Jaundice

Incidence 1/200 Reason unknown
Believed to be caused by a prolonged increased enterohepatic circulation of bilirubin
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Breast Milk Jaundice

High levels of unconjugated bilirubin over longer period of time
Can reach 20 mg/dl (344 mmol/l) by age 2 weeks and then begin to fall and normalize over age 8 to 12 weeks Presence of unconjugated hyperbilirubinemia for 6-8 weeks in thriving breast fed infant without evidence of hemolysis, hypothyroidism or other disease strongly suggest this diagnosis
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Pathological Jaundice
Characteristics
Onest is usually within the first 24 hrs of life. Rate of increase > 0.5 mg/dl/hr (8.6 mmol/l/hr) Evidence of underlying illness
Gastrointestinal Hematologic Infectious
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Jaundice that persists greater than 8 days in term infants and 14 days in preterm infants

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Pathologic Jaundice - Causes

Overproduction of bilirubin
Increased rate of hemolysis
Patients with a positive Coombs test
ABO/Rh blood group incompatibility
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Patients with a negative Coombs test

Abnormal RBC shapes spherocytosis RBC enzyme abnormalities G6PD Infants with bacterial or viral sepsis (increased hemolysis, decreased uptake, decreased excretion)

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Pathologic Jaundice - Causes

Nonhemolytic causes of increased bilirubin load
Extravascular hemorrhage
Cephalohematoma Extensive bruising CNS hemorrhage
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Polycythemia Exaggerated enterohepatic circulation of bilirubin

GI tract obstruction (intestinal atresia, Hirschprungs disease) Ileus (meconium ileus, septic ileus)

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Pathologic Jaundice - Causes

Deceased rate of conjugation
Crigler-Najjar syndrome UDPGT deficiency
Type I complete deficiency; autosomal recessive
Severe hyperbilirubinemia, bilirubin encephalopathy, and death without therapy
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Type II partial defficiency; autosomal dominant

The enzyme can be induced with phenobarbital, which may lower bilirubin levels by 30-80%

Gilbert syndrome
Mild autosomal dominant disorder Decreased hepatic UDPGT levels
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Pathologic Jaundice - Causes

Other
Congenital hypothyroidism Inborn error of metabolism Hepatitis (A, B, C, autoimmune, TORCH) Liver failure Prolonged TPN Neonatal hypoxic-ischemic event
Hypoperfusion of GI tract
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Biliary atresia

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Bilirubin Toxicity
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Kernicterus acute bilirubin encephalopathy

Amount of unconjugated bilirubin exceeds the available binding sites on albumin, unbound bilirubin crosses BBB Yellow staining of the brain generally involving basal ganglia, cranial nerve nuclei, hippocampus Staining correlates microscopically with necrosis, neuronal loss, and gliosis

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Bilirubin Toxicity
Three phases
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Jaundice, hypotonia, lethargy, poor feeding, poor suck After few days: hypertonia, high-pitched cry, fever, seizures After about one week: hypertonia replaced by hypotonia, long-term neuronal injury

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Bilirubin Toxicity
Extrapyramidal disturbances (choreoathetosis) Hearing loss Limitation of upward gaze Dental dysplasia Mild intellectual deficits
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Surviving children develop

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Diagnosis History
Family hx
Previous sibling with jaundice in the neonatal period, particularly if the jaundice required treatment ABO or Rh incompartibility, hereditary sphirocytosis etc Other family members with jaundice or known family history of Gilbert syndrome Anemia, splenectomy, or bile stones in family members or known heredity for hemolytic disorders Liver disease
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 History of pregnancy and delivery

Maternal illness suggestive of viral or other infection e.g. TORCH Maternal drug intake Delayed cord clamping Birth trauma with bruising e.g. cephalohematoma
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 Postnatal history
Loss of stool color Breastfeeding Greater than average weight loss Symptoms or signs of hypothyroidism Symptoms or signs of metabolic disease (eg, galactosemia) Exposure to total parental nutrition
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Physical Examination
Jaundice is visible when bilirubin > 7 mg/dl (120 mmol/l)
In adults >2 mg/dl (35 mmol/l)
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Visual inspection does not demonstrate good predictive ability Cephalocaudal progression

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Physical Exam
Evaluate
Prematurity/SGA Extravascular blood
Cephalohematoma or other bruising
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Polycythemia; congenital infections

Pallor
Hemolysis; extravascular blood

Petechiae
Congenital infections; sepsis

HSM
Congenital infection; liver disease

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1
Indire Se ct rum Bilirubin Conce ntratio n and It Re io To The Prog ss s lat n re ion of De rmal Icte in Full-Te Infants rus rm *
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Bilirubin (m /1 m g 00 L) De al rm Zo ne Me n SD a 5 0 .9 .3 8 1 .9 .7 1 1.8 1.8 1 1 5 .7 Ra e ng 4 7 .3 .9 5 1 .4 2.2 8 1 .1 6.5 1 18 7 1.1 .3 >5 1 Obs rv tio e a ns 1 3 4 9 5 2 4 5 2 9

1 2 3 4 5

4
*Inc esall in tswh e rate of s lud fan os erum b ilirub ris was0.7 in e mg L /h or les . /d s

5 De a Zone o J a rm l s f undice

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Studies
Bilirubin level Infants blood type and direct Coombs test Mothers blood type and antibody screening Peripheral smear for RBC morphology Hematocrit level (polycythemia or anemia) Reticulocyte count Others depending on course
LFTs, sepsis evaluation
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Total and direct

Management
Management of jaundice is directed towards: - reducing the level of bilirubin and - preventing CNS toxicity. 1.Prevention of hyperbilirubinemia i.Early and frequent feeding ii.Adequate hydration 2.Reduction of bilirubin:This is achieved by - phototherapy or/and - exchange transfusion.
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Management cont
Phototherapy
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This involves exposure of the naked baby to blue,cool white or green light ofwave length 425-475 nm. The light waves convert the bilirubin to water soluble nontoxic forms which are then easily excreted. Every attempt should be made to find out the cause of jaundice. The advantages of phototherapy are that it is noninvasive,effective,inexpensive and easy to use.

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Management
Clinical assessment of bilirubin level should not be relied upon in an infant under phototherapy. Frequent feeding every 2 hrly and change of posture should be promoted in an infant receiving phototherapy. Eye shades should be fixed. External genitalia may be covered as long as the infant is receiving phototherapy. Additional oral intake of plain water or glucose water is neither recommended nor necessary.
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 Baby is turned every two hours or after each feed. Temperature is monitored every two to four hours. Weight is taken at least once a day. More frequent breastfeeding or 10-20%extra fluid is provided. .Urine frequency is monitored daily. Serum bilirubin is monitored at least every 12 hours. Phototherapy is discontinued if two serum bilirubin values are <10 mg/dl.

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Side effects of phototherapy - Increased insensible water loss:Provide more frequent and for longer duration extra breast feeding. - Loose green stools:weigh often and compensate with breast milk. - Skin rashes:Harmless,no need to discontinue phototherapy; - Bronze baby syndrome:occurs if baby has conjugated hyperbilirubinemia.If so,discontinue phototherapy; - Hypo or hyperthermia:monitor temperature frequently.

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Management
Exchange transfusion
Exchange transfusion (approximately 160-200 ml/kg body weight) remains necessary in some cases of hemolysis resulting from Rh isoimmunization, ABO incompatibility, or hereditary spherocytosis Used when bilirubin level is more than 25g/dl total bilirubin In addition to decreasing the bilirubin level by approximately 50% acutely, the exchange transfusion also removes nearly 80% of the sensitized or abnormal RBC and offending antibodies so that ongoing hemolysis will be deceased
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Management
Exchange transfusion
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Procedure is invasive and not without risk The risk of mortality is 1-5%
Risk is greatest in the smallest, most immature, and otherwise unstable infants, but sudden death during the procedure can occur in any infant

Risk of serious complications such as NEC, infection, electolyte disturbances, or thrombocytopenia is 510%

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Management
Exchange transfusion
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Fresh irradiated whole blood Performed in 5ml to 20 ml aliquots

Monitor HR, BP, pH, glucose, potassium, calcium, magnesium

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Management
Experimental pharmacotherapy
Phenobarbital
Increases uptake Increases bile flow
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Summary
Bilirubin is a normal product of heme metabolism. In newborns, various factors lead to increased levels of bilirubin due to either increased production of bilirubin or decreased elimination of bilirubin. Maternal history and careful examination of the infant are important in diagnosing the cause of pathologic jaundice. Phototherapy is the hallmark of treatment of unconjugated hyperbilirubinemia with exchange transfusion being reserved for the most severe or refractory cases.
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THANK YOU !
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