Competency Based Training Module for Physicians

Neonatal Health Care Modules

Neonatal Hyperbilirubinemia
Jayashree Ramasethu, M.D. Georgetown University Hospital
Module: Neonatal Hyperbilirubinemia - Session 1 1

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.

Module: Neonatal Hyperbilirubinemia - Session 1

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.
Module: Neonatal Hyperbilirubinemia - Session 1 3

Module Overview: Learning Objectives Broad 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

Module: Neonatal Hyperbilirubinemia - Session 1

Neonatal Jaundice:
WHY WE WORRY
bilirubin bilirubin encephalopathy

Kernicterus
Stage 1: Stage 2: Stage 3: Sequelae: lethargy, hypotonia, poor suck fever, hypertonia, opisthotonus apparent improvement 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

Module: Neonatal Hyperbilirubinemia - Session 1

NEONATAL JAUNDICE
Mechanism

Physiologic vs Pathologic
Non- physiologic jaundice:
differential diagnosis

Management
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Bilirubin metabolism
HEME + Globin
BILIVERDIN

CO

LIVER UCB
BILIRUBIN

Alb

Module: Neonatal Conjugated bilirubin Hyperbilirubinemia - Session 1

Free unconjugated 10 bilirubin

BILIRUBIN
UNCONJUGATED CONJUGATED Indirect bilirubin Direct bilirubin Water- insoluble Water soluble Bound to albumin for transport Free component Not fat soluble fat - soluble Free component Not toxic to brain TOXIC to brain Module: Neonatal
Hyperbilirubinemia - Session 1

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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
14 12 10 8 S.Bili mg/dl 6 4 2 0 DAY 1 DAY 3 DAY 5 DAY 7
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Module: Neonatal Hyperbilirubinemia - Session 1

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
16 14 12 10 8 6 4 2 0 day 1 day 2 day 3 day 4 day 5 day 6 day 7
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Normal term Preterm

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
20 18 16 14 12 10 8 6 4 2 0 day 1 day 2 day 3 day 4 day 5 day 6 day 7
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physiologic non- physiologic

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 Module: illness Neonatal

Hyperbilirubinemia - Session 1

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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
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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 +, Coombs 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

HYPERBILIRUBINEMIA CAUSES UNDERSECRETION

Prematurity Hypothyroidism Infants of diabetic mothers Inherited deficiency of conjugating enzyme uridine diphosphate glucuronyl transferase Other metabolic disorders

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HYPERBILIRUBINEMIA CAUSES Secreted but reabsorbed from gut

ENTEROHEPATIC CIRCULATION
Decreased enteral intake Pyloric stenosis Intestinal atresia/ stenosis Meconium ileus Meconium plug Hirschsprungs 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 CAUSES MIXED

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 Mothers blood group and Rh type Babys blood group and Rh type Direct Coombs 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 Pediatrics

Subcommittee 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: Babys 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 assessment of 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 Bilirubin

Bhutani 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 pre- discharge 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 gestation

American 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: ZZ

ZZ ZZ
ZZ

Photo isomerization

ZE( toxic, no conjugation need)

lumibilirubin
Structural isomerization

photooxidation products
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
Double volume Exchange Transfusion 2 X 85 mL/ kg

Partially packed Red Blood Cells

waste

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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%

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

???

Weight (g) 500 - 750 750 - 1000 1000 - 1250 1250 1500

Start phototherapy (mg/ dl) 5- 8 6 - 10 8 - 10 10 - 12

Consider exchange transfusion (mg/ dl) 12- 15 > 15 15 - 18 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 Report Baby 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

25 20 15 10 5 0 day 4 day 8 day 12 day 16 day 20 day 24
63

normal B.M. jaundice BMJ- stop BM

Module: Neonatal Hyperbilirubinemia - Session 1