12. neonatal hyperbilirubinemia

Module: Neonatal Hyperbilirubinemia - Session 1

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Competency Based Training Module for Physicians

Neonatal Health Care Modules

Neonatal Hyperbilirubinemia

Jayashree Ramasethu, M.D.

Georgetown University Hospital


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Module Overview: Purpose

• To introduce to the participants the knowledge, competencies and skills required to identify the etiology, diagnose and manage both unconjugated and conjugated hyperbilirubinemia in full term and preterm infants.


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Module Overview: Story

• Neonatal hyperbilirubinemia is an elevated serum bilirubin level in the neonate.

• The most common type is unconjugated hyperbilirubinemia, which is visible as jaundice in the first week of life.

• Although 60% of babies will develop jaundice, and most jaundice is benign, severe hyperbilirubinemia can cause serious permanent brain damage.

• The goal of this module is to teach physicians to identify,

assess and manage neonatal hyperbilirubinemia.


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Module Overview: Learning ObjectivesBroad Outline

Physicians must:• Understand the physiology of bilirubin metabolism in the

neonate, and the difference between unconjugated and conjugated hyperbilirubinemia

• Identify neonatal hyperbilirubinemia and decide whether it is physiological or pathological.

• Obtain an accurate history and perform a physical examination in order to diagnose the etiology of hyperbilirubinemia.

• Identify laboratory tests needed for investigation.• Manage unconjugated hyperbilirubinemia• Diagnose conjugated hyperbilirubinemia.


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CLINICAL JAUNDICE

• 60% of newborn• Visible jaundice: serum bilirubin > 5 mg/ dl


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Neonatal Jaundice: WHY WE WORRY

bilirubin bilirubin encephalopathy

KernicterusStage 1: lethargy, hypotonia, poor suck

Stage 2: fever, hypertonia, opisthotonus

Stage 3: apparent improvement

Sequelae: Sensorineural hearing loss Choreoathetoid cerebral palsy

Gaze abnormalities


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Kernicterus Neuropathology

yellow staining and neuronal necrosis• basal ganglia:

globus pallidus subthalamic nucleus

• cranial nerve nuclei:

vestibulocochlear oculomotor facial

• cerebellar nuclei


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• 1970s - KERNICTERUS ELIMINATED • 1990s - 125 CASES OF KERNICTERUS in the United States

• 2000s - ? Cases of kernicterus in Indonesia

A preventable tragedy


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NEONATAL JAUNDICE

• Mechanism

Physiologic vs Pathologic

• Non- physiologic jaundice:

differential diagnosis

• Management


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Bilirubin metabolism

HEME + Globin

BILIVERDIN

BILIRUBIN

Alb

UCBLIVER

CO(Heme Oxygenase)

Conjugated bilirubin

Free unconjugatedbilirubin


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BILIRUBIN

UNCONJUGATED • Indirect bilirubin• Water- insoluble• Bound to albumin for

transport• Free component

fat - soluble• Free component

TOXIC to brain

CONJUGATED • Direct bilirubin• Water soluble

• Not fat soluble

• Not toxic to brain


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BILIRUBIN TOXICITY

Unconjugated bilirubin level > 20 mg/ dL? >25 mg/ dl? > 30 mg/ dL?

• Gestational age• Hemolysis• Other illness: asphyxia, hypoglycemia,

acidosis, sepsis• Drugs displacing bilirubin from albumin

binding sites


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CLINICAL JAUNDICE

• 60% of newborn• Visible jaundice: serum bilirubin > 5 mg/ dl


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Why do babies have jaundice in the

first week of life? • Increased bilirubin production

– Higher turnover of red blood cells– Decreased life span of red blood cells

• Decreased excretion of bilirubin– Decreased uptake in the liver– Decreased conjugation by the liver– Increased enterohepatic circulation of bilirubin

Bilirubin excretion improves after 1 week


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PHYSIOLOGICAL JAUNDICE

0

2

4

6

8

10

12

14

DAY 1 DAY 3 DAY 5 DAY 7

S.Bili mg/dl


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Physiological Jaundice

• Note the natural history of physiologic jaundice in the full term newborn- – onset after 24 hours– peaks at 3 to 5 days– decreases by 7 days.

• Average full term newborn has peak serum bilirubin level of 5 to 6 mg/ dl.

• Exaggerated physiologic jaundice- when peak serum bilirubin is 7 to 15 mg/ dl in full term neonates.

• Always consider age of the baby and bilirubin level


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Hour- specific bilirubin level

• Bilirubin level of 10 mg/ dl at 72 hours of age in a term newborn is probably physiological.

• Bilirubin level of 10 mg/ dl at 10 hours of age is NOT physiological, and needs immediate attention.

(see natural history of physiological jaundice)


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Serum Bilirubin levels

in term and preterm infants

0

2

4

6

8

10

12

14

16

day 1 day 2 day 3 day 4 day 5 day 6 day 7

Normal term

Preterm


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Jaundice in preterm neonates

• Onset earlier

• Peaks later

• Higher peak

• Takes longer to resolve- up to 2 weeks

• What level is physiologic?


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Physiologic vs Non- physiologic

hyperbilirubinemia

02468

101214161820

day 1 day 2 day 3 day 4 day 5 day 6 day 7

physiologic

non- physiologic


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NON- PHYSIOLOGIC JAUNDICE

• Onset before 24 hours of age• Rate of rise > 0.5 mg/ dl/ hour• Cutoff levels

> 15 mg/ dl in term infant?

> ? mg/ dl in preterm infant?

• Jaundice persisting

> 8 days in term infant

> 14 days in preterm infant

• Other signs of illness


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HYPERBILIRUBINEMIA - CAUSES OVERPRODUCTION ( HEMOLYSIS)

• Extravascular blood- hematomas, bruises• Feto- maternal blood group incompatibility

Rh- mom / baby Rh+

O group mom / baby A or B

• Intrinsic red cell defects

G-6-PD deficiency

hereditary spherocytosis

• Polycythemia


NEONATAL JAUNDICE - case ( ref. MacDonald MG. Pediatrics 1995)

African- American male infant, birth weight 3.47kg

Normal delivery 39 w gestation

Discharged home at 24 hrs of age

Jaundice and lethargy noted at 5 days of age

LABS: Total serum bilirubin 37mg/ dL

Peripheral blood smear normal, retic count 3.6%

Mom O+, Baby O +, Coomb’s test negative

Seizures, apnea, opisthotonus during Exchange Tx

13 months of age: profound hearing loss and hypotonia


G6PD DEFICIENCY

• X- Linked disorder (2- 6% carrier rate in Indonesia)• enzyme protects red cell from oxidative damage• >150 mutations• Onset of jaundice usually day 2- 3, peaks day 4 - 5• Hyperbilirubinemia may be out of proportion to

anemia• microspherocytes/ bite cells/ normal blood picture• Diagnosis- enzyme assay baby and mother• False negative test with reticulocytosis• DNA analysis


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HYPERBILIRUBINEMIA CAUSESUNDERSECRETION

• Prematurity• Hypothyroidism• Infants of diabetic mothers• Inherited deficiency of conjugating enzyme

uridine diphosphate glucuronyl transferase• Other metabolic disorders


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HYPERBILIRUBINEMIA CAUSESSecreted but reabsorbed from gut

ENTEROHEPATIC CIRCULATION

• Decreased enteral intake• Pyloric stenosis• Intestinal atresia/ stenosis• Meconium ileus• Meconium plug• Hirschsprung’s disease


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OBSTRUCTIVE DISORDERS - direct hyperbilirubinemia

• Cholestasis• Biliary atresia• Choledochal cyst

# Direct bilirubin > 2 mg/ dL# Time of appearance# Color of stools# Color of urine


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HYPERBILIRUBINEMIA CAUSESMIXED

• Bacterial sepsis• Intrauterine infections: TORCH• Asphyxia


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Hyperbilirubinemia- diagnosis

• History• Physical exam:

– gestational age– activity/ feeding– level of icterus– pallor– hepatosplenomegaly– bruising, cephalhematoma


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Rapidly developing jaundice on Day 1

Likely– Rhesus, ABO, or other hemolytic disease– Spherocytosis

Less likely– Congenital infection– G-6-P-D deficiency


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Rapid Onset jaundice after 48 hours of age

• Likely– Infection– G-6-P-D deficiency

• Unlikely

– Rh, ABO, spherocytosis


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Hyperbilirubinemia- diagnosis

• Laboratory tests– Bilirubin levels: total and direct– Mother’s blood group and Rh type– Baby’s blood group and Rh type– Direct Coomb’s test on baby– Hemoglobin– Blood smear– Reticulocyte count


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NEONATAL HYPERBILIRUBINEMIA MANAGEMENT

• HYDRATION - FEEDING

• PHOTOTHERAPY

• EXCHANGE TRANSFUSION

• Phenobarbital• Tin protoporphyrin


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American Academy of PediatricsSubcommittee on Hyperbilirubinemia

Clinical Practice Guideline

Management of Hyperbilirubinemia

in the Newborn Infant

35 or more weeks of gestation

Pediatrics July 2004


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Management of Hyperbilirubinemia in the Newborn Infant

35 or more weeks of gestation

• Promote and support successful breast-feeding• Perform a systematic assessment before discharge

for the risk of severe hyperbilirubinemia• Provide early and focussed follow-up based on risk

assessment• When indicated, treat newborns with phototherapy or

exchange transfusion to prevent the development of severe jaundice and possibly, kernicterus.


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Feeding to Prevent and Treat Neonatal Jaundice

Mothers should breast feed their babies

at least 8 to 12 times per day

for the first several days

caloric intake / dehydration Jaundice

• Supplementation with water or dextrose water will not prevent prevent or treat hyperbilirubinemia


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Systematic Assessment for Neonatal Jaundice

• Pregnant women - Blood group and Rh type • If mom is Rh negative or O group: Baby’s cord blood

group/ Rh type/ DAT• Monitor infant for jaundice at least every 8 to 12

hours• If level of jaundice appears excessive for age,

perform transcutaneous bilirubin or total serum bilirubin measurement


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Clinical assessmentof severity of jaundice

• Cephalocaudal progression– face 5 mg/ dl (approximately)– upper chest 10 mg/ dl (approx)– abdomen and upper thighs 15 mg/ dl ( approx)– soles of feet 20 mg/ dl ( approx)

• Visual inspection may be misleading


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Transcutaneous Bilirubinometers•Useful as screening device •TcB measurement fairly accurate in most infants with TSB< 15mg/ dL.•Independent of age, race and weight of newborn

•Not accurate after phototherapy


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Assess risk factors for significant jaundice

• Blood group incompatibility with positive DAT • Gestational age 35- 36 weeks• Exclusive breast feeding - first time mom• Cephalhematoma or significant bruising • Asian race • Previous sibling had significant jaundice • Jaundice in the first 24 hours of life• Predischarge bilirubin in the high risk zone


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Hour Specific Serum BilirubinBhutani et al, Pediatrics 1999

Predictive Ability of a Predischarge Hour Specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near - term Newborns.

Serum Bilirubin levels predischarge in 13,003 babies

Serum Bilirubin levels post- discharge in 2840 babies

Racially diverse - 5% Asian

Nomogram- 95th percentile for serum bilirubin level

24 hours: 8 mg/ dl (137 M/ L)

48 hours: 14 mg/ dl (239 M/ L)

72 hours: 16 mg/ dl ( M/ L)

84 hours: 17 mg/ dl (290 M/ L)


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Nomogram for designation of risk based on hour specific serum bilirubin levels at discharge

Bhutani et al., Pediatrics 1999


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Guidelines for phototherapy in infants 35 or more weeks gestationAmerican Academy of Pediatrics, July 2004


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PHOTOTHERAPY

NOT UV LIGHT @#$%*!

• Light wavelength 450 to 460 nm• Blue lamps: 425 to 475 nm• Cool white lamps: 380 to 700 nm

• Spectral irradiance: 30 W / cm2 / nm


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PHOTOTHERAPY

Natural unconjugated bilirubin isomer: ZZZZ ZE( toxic, no conjugation need)

ZZ lumibilirubin

ZZ photooxidation products

Photoisomerization

Structural isomerization

photooxidation


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Measuring Adequacy of Phototherapy


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Intensive Phototherapy

• Light source: daylight, cool white, blue, special blue fluorescent tubes,tungten halogen lamps, fiberoptic blanket, gallium nitride light emitting diode.

• Distance from light: florescent lights should be as close as possible ( up to 10 cms from baby), halogen lights can cause overheating

• Surface area: maximal, remove all clothes except diaper, may remove diaper too

• Intermittent versus Continuous• Hydration


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Complications of phototherapy

• Significant complications very rare– separation of mother and baby– increased insensible water loss and

dehydration in premature baby– Bronze- baby syndrome (in babies with

cholestatic jaundice)


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What decline in serum bilirubin can you expect with phototherapy?

• Rate of decline depends on effectiveness of phototherapy and underlying cause of jaundice.

• With intensive phototherapy, the initial decline can be 0.5 to 1.0 mg/ dl/ hour in the first 4 to 8 hours, then slower.

• With standard phototherapy, expect decrease of 6% to 20% of the initial bilirubin level in the first 24 hours.


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When should phototherapy be stopped?

• Depends on the age of the baby

• Cause of the hyperbilirubinemia


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Exchange Transfusion


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Guidelines for Exchange Transfusion in Infants 35 or more weeks gestation

American Academy of Pediatrics, July 2004


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Exchange Transfusion

waste

Partially packedRed Blood Cells

Double volume Exchange Transfusion2 X 85 mL/ kg


EXCHANGE TRANSFUSION - COMPLICATIONS

• cardiac failure

• metabolic- hypoglycemia, hyperkalemia, hypocalcemia, citrate toxicity,

• air embolism

• thrombocytopenia

• bacterial sepsis

• transfusion transmitted viral disease

• necrotizing enterocolitis

• portal vein thrombosis

Mortality / permanent sequelae 1-12%


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Phototherapy and Exchange Transfusion in VLBW infants (Cashore WJ, Clin Pediatr 2000)

Weight (g) Start phototherapy(mg/ dl)

Consider exchangetransfusion (mg/ dl)

500 - 750 5- 8 12- 15

750 - 1000 6 - 10 > 15

1000 - 1250 8 - 10 15 - 18

1250 – 1500 10 - 12 17 - 20

???


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LAB REPORT

Baby Boy Mango

Total Bilirubin: 13.0 mg / dl

(36 hours age)


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Baby Boy Mango

• Mother O Rh positive • Baby A Rh positive• Total serum bilirubin 13 mg/ dl at 36 hours age• Direct serum bilirubin 0.7 mg/ dl• Hematocrit 38 %• Reticulocyte count: 8%• Blood picture: microspherocytes present

DIAGNOSIS?


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Laboratory ReportBaby Girl Lemon

• Total bilirubin 13 mg/ dL

• Direct bilirubin 0.3 mg/ dL


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Baby Girl Lemon

• Bilirubin 13 mg/ dL at 72 hours age

• Baby breast fed

• Mom A Rh positive


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BREAST MILK JAUNDICE

0

5

10

15

20

25

day 4 day 8 day 12 day 16 day 20 day 24

normalB.M. jaundiceBMJ- stop BM

12. neonatal hyperbilirubinemia

Documents

etiology of hyperbilirubinemia

severe hyperbilirubinemia

module overview

training module

preventable tragedy

newbornvisible jaundice

elevated serum bilirubin

s kernicterus