Neonatal Jaundice

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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• 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• 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

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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 (β-glucuronidase) can cleave off the glucuronide molecules, leaving unconjugated bilirubin to be reabsorbed

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Bone marrowBone marrow

PorphogensPorphogens

RBCsRBCs

RETICULOENDOTHELIALRETICULOENDOTHELIALSYSTEM (RES)SYSTEM (RES) SHUNT PATHWAYSHUNT PATHWAY

Heme precursorsHeme precursorsMyoglobulinMyoglobulinNon-hgb heme proteinsNon-hgb heme proteins

KidneyKidney

UrineUrineurobilinogenurobilinogen

Bilirubin-Albumin ComplexBilirubin-Albumin Complex

LiverLiver

SmoothSmoothendoplasmicendoplasmicreticulumreticulum

ConjugatedConjugatedbil irubinbil irubin

CytoplasmicCytoplasmicproteinproteinbindingbinding

uptake ENTEROHEPATIC CIRCENTEROHEPATIC CIRC

excretionexcretion

HydrolysisHydrolysisBilirubinBilirubin

UrobilinogenUrobilinogen

IntestineIntestine

StercobilinStercobilin

HgbHgb

GlobinGlobin++

HemeHeme

FeFe++

BiliverdinBiliverdin

HgbHgb

BilirubinBilirubin

BiliverdinBiliverdinreductasereductase

hemehemeoxygenaseoxygenase

FeFe

GlobinGlobin

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Bilirubin Forms• Unconjugated bilirubin• Bound to albumin• Does not cross blood-brain-barier (BBB) • Distruption of this bond by certain drugs (sulfa drugs,

ceftriaxone, free fatty acids), hypothermia, hypoxia, acidosis

• Free unconjugated bilirubin• Amount of bilirubin exceeds the available binding sites on

albumin• Readily crosses the BBB

• Conjugated bilirubin• Bilirubin glucuronide

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Physiologic Jaundice• Clinical jaundice develops in 50%-65% of all

newborns• 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

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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

• 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

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

• 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%

• 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• 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

• 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

• 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

• Polycythemia• Exaggerated enterohepatic circulation of bilirubin• GI tract obstruction (intestinal atresia, Hirschprung’s 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• 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

• Biliary atresia

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Bilirubin Toxicity

• 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• 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

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

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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)

• Visual inspection does not demonstrate good predictive ability

• Cephalocaudal progression

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Physical Exam• Evaluate • Prematurity/SGA

• Polycythemia; congenital infections • Extravascular blood

• Cephalohematoma or other bruising• Pallor

• Hemolysis; extravascular blood• Petechiae

• Congenital infections; sepsis• HSM

• Congenital infection; liver disease

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Indirect Serum Bilirubin ConcentrationIndirect Serum Bilirubin Concentrationand Its Relation To The Progressionand Its Relation To The Progressionof Dermal Icterus in Full-Term Infants*of Dermal Icterus in Full-Term Infants*

11

22

44

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55

55 55

DermalDermalZoneZone

Bilirubin (mg/100 mL)Bilirubin (mg/100 mL)

Mean ± SD Range Observations Mean ± SD Range Observations

5.9 ± 0.35.9 ± 0.38.9 ± 1.78.9 ± 1.7

11.8 ± 1.811.8 ± 1.815 ± 1.715 ± 1.7

4.3 ± 7.9 4.3 ± 7.9 5.4 ± 12.25.4 ± 12.28.1 ± 16.58.1 ± 16.5

11.1 ± 18.3711.1 ± 18.37>15 >15

13134949525245452929

1122334455

*Includes all infants whose rate of serum bilirubin rise was 0.7*Includes all infants whose rate of serum bilirubin rise was 0.7 mg/dL/h or less. mg/dL/h or less.

Dermal Zones of J aundiceDermal Zones of J aundice

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Studies

• Bilirubin level• Total and direct

• Infant’s 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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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

• 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• 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 5-10%

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Management • Exchange transfusion• 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 0

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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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