1. Neonatal Jaundice Joel Cadrin MD Candidate 2016, French Stream
CHEO ~ Children’s Hospital of Eastern Ontario
Wednesday, June 3, 2015

2. Case Study
A full term male infant, born by Emergency Caesarean section following failed forceps-assisted delivery, is now 4 days old and is ready for discharge. His birth weight was 3.3kg. He is being breastfed every 3 to 4 hours, which seems to be going well. This is the mother’s second child. The family is of Greek origin. You are called, because, on exam, the bedside nurse noticed the baby to be jaundiced. His mother thinks she noticed the jaundice at around 24 hours of life, but isn’t certain. It appears to be worse today. His weight is now 3.1kg. He is alert on exam. You notice a Band-Aid on his right heel. Jaundice is visible on his head, trunk, legs and sclerae. You can palpate his liver 2 cm below the right costal margin, and the spleen seems palpable. How do you approach this program?

3. Reflections
What particular characteristics do you find pertinent in this case?
How you would begin to approach this case?
Remember to keep this case study in mind as we proceed through the presentation

4. Objectives
To review the physiology of bilirubin metabolism and recognize the significance of jaundice in newborn infants.
To explore the differential diagnosis of jaundice according to timing of occurrence.
To review the important clues on history and important physical findings (antenatal, perinatal and postnatal) to assist with diagnosis
To elaborate an appropriate plan of management and discuss the currently available therapies

5. Objective #1
Review the physiology of bilirubin metabolism and recognize the significance of jaundice in newborn infants.

6. Physiological Mechanism of Bilirubin Metabolism
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Extra or intra vascular hemolysisis the main source bilirubin, which is product of heme degradation by the reticuloendothelial system.
It is transported bounded to albumin
Hepatocytes convert unconjugated bilirubin to conjugated bilirubin in part by the enzyme UGT1A1
Conjugated bilirubin is then excreted in the bile, and is mostly excreted in feces

7. Bilirubin What is Bilirubin? A byproduct of normal RBC hemolysis
Derived from hemoglobin through degradation in the reticuloendothelial system
Heme oxygenase degrades heme to biliverdin and CO
Biliverdin reductase reduces biliverdin to unconjugated bilirubin
Unconjugated bilirubin binds to albumin and is transported to the liver
Lauer & Spector (2014) Hyperbilirubinermia in the Newborn.

8. UGT1A1 and Conjugation of Bilirubin
Uridine diphospate glucuronosyl transferase (UGT1A1) conjugates the unconjugated bilirubin in the liver
At weeks’ gestation UGT1A1 is at ~1% of adult levels
At 14 weeks of age, the levels rise to adult concentration
Lauer & Spector (2014) Hyperbilirubinermia in the Newborn.

9. The Pathways of Conjugated Bilirubin
Excreted into the intestine through the gallbladder and bile duct, and follows one of two following paths:
Pathway 1: Bilirubin excreted with the stool
Pathway 2: Bilirubin may be de-conjugated by bacteria and then reabsorbed into the blood via the enterohepatic circulation
Lauer & Spector (2014) Hyperbilirubinermia in the Newborn.

10. Jaundice What is jaundice?
Bilirubin deposition in skin and mucous membrane
Results in yellow color on the skin and mucous membranes
Cephalocaudal progression
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11. Significance of Neonatal Jaundice
May be indicative of physiologic or pathologic origins
Most cases: Bilirubin deposition and according jaundice has little consequence on the neonate
However, there is potential for severe consequences as bilirubin may cross the BBB
Almost all neonates develop som eknind of mild, transient jaundice since the hepatic machinery for conjugating and excreting bilirubin is not fully mature until past the second week of age.
Also, jaundice can be exacebated by breastfeeding as a result of the presence of bilirubin deconjugating enzymes in breast milk.

12. Kernicterus Severe jaundice may lead to kernicterus
Kernicterus is the staining of the basal ganglia with bilirubin
A rare, but preventable cause of athetoid cerebral palsy, and other neurological pathologies
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13. Significance of Neonatal Jaundice
Factors to consider:
Many causes of jaundice
Timing of onset
Rate of rise of bilirubin
Maximum levels of bilirubin
Persistent jaundice
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14. Acute Symptoms of Kernicterus
Lethargy
Hypotonia
Poor Suck
Hypertonia of extensor muscles (retrocolis, opisthotonus)
High-pitched cry
Fever
Seizures
Comas

15. Chronic Symptoms of Kerniterus
Athetoid cerebral palsy
Seizures
Developmental delay
Hearing deficits
Oculomotor disturbances
Dental Dysplasia
Mental deficiency
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16. Objective #2
Explore the differential diagnosis of jaundice according to timing of occurrence.

17. Differential diagnosis of jaundice according to timing of occurrence
The differential diagnoses in neonatal jaundice has much to do with the timing of the onset of the jaundice.
Timing can indicate physiologic vs. pathologic jaundice
Timing can indicate the presence of unconjugated vs. conjugated bilirubin in the system

18. DDx Hemolytic Disease: Isoimmune: ABO, Rh, Minor group incompatibility
Structural or RBC abnormalities (Spherocytosis, Glucose-6- Phosphate Dehydrogenase Deficiency)
Hereditary of defects in bilirubin conjugation (Gilbert Syndrome, Crogler-Najjar Syndrome)
ABO: 1. about 20% of pregnancies have this type of incompatibility, 10% of these show signs of hemolysis, 0.5% severe enough for treatment
2. most A and B antibodies are IgM (they do not cross placenta)
3. Fetal RBC express A and B antigens poorly
For some reason ABO incompatibility occurs almost exclusively in O mothers
For some reason, these mothers possess IgG antibodies
Rh : rhesus negative mothers with prior rh contact

19. DDx Bacterial Sepsis Breastfeeding jaundice Breast milk jaundice
Congenital biliary atresia
Extrahepatic Biliary Obstruction
Neonatal Hepatitis (Bacterial, Viral, Not Specific)
Breastfeeding = underfeeding jaundice… caloric deprivation,
Breast milk jaundice = later onset, prolonged jaundice

20. Onset of Jaundice Specific Timings of Onset to Consider:
First 24h of life
Between 24h to 2 weeks of age
After 2 weeks of age

21. Reflections
What do you think is significant about timing in the DDx of neonatal jaundice?
How do you think jaundice before 24h of life differs from jaundice after the 24h mark?

22. Requires IMMEDIATE Attention
First 24h of Life
Requires IMMEDIATE Attention
Hemolysis
Rh incompatibility: Identified antenatally. Hydrops, anemia, Hepatosplenomegaly
ABO incompatibility: O women have IgG anti A or B that cross placenta
G6PD Deficiency: Mediterranean, Asian, Middle-Eastern, African American
Hemorrhage and Bruising
Sepsis
Congenital Infection
Bilirubin is conjugated & abnormal clinical signs
Growth restriction
Hepatosplenomegaly,
Thrombocytopenia purpura
G6PD : family hx of persistent jaundice

23. Between 24h to 2 Weeks
Physiological jaundice (usually most noticeable around days 2-5)
Breast milk jaundice
Infection (UTI)
Hemolysis
Bruising
Polycythemia
Crigler-Najjar Syndrome (UTB1A1 deficiency)

24. After 2 Weeks of Age Unconjugated Conjugated Bile duct obstruction
Physiological or breast milk jaundice
Infection (UTI)
Hypothyroidism
Hemolytic Anemia
High GI obstruction (i.e. pyloric stenosis)
Bile duct obstruction
Neonatal hepatitis

25. Objective #3
Review the important clues on history and important physical findings (antenatal, perinatal and postnatal) to assist with diagnosis

26. History Newborn history Delivery history
Risk Factors for Hyperbilirubinemia
PreTerm
Previous sibling with severe hyperbilirubinemia
Bruising
Cephalhematoma
Male
Asian or European background
Dehydration
Maternal blood type
Signs of cholestasis: Acholic stools, dark urine, weight loss
Newborn history:
Feeding hx (dehydration, starvation)
Stool pattern (inadequate breastfeeding, Hirschsprung disease)
Vomiting (intestinal obstruction, pyloric stenosis)
Delivery history:
Type of delivery – was there trauma?
Medications
Prolonged time with rupture of membranes ?
Delay of clamping – polycythemia?
Apgar score – asphyxia?

27. Back to the Case
A full term male infant, born by Emergency Caesarean section following failed forceps- assisted delivery, is now 4 days old and is ready for discharge.
His birth weight was 3.3kg. He is being breastfed every 3 to 4 hours, which seems to be going well. This is the mother’s second child. The family is of Greek origin. You are called, because, on exam, the bedside nurse noticed the baby to be jaundiced. His mother thinks she noticed the jaundice at around 24 hours of life, but isn’t certain. It appears to be worse today. His weight is now 3.1kg. He is alert on exam. You notice a Band-Aid on his right heel. Jaundice is visible on his head, trunk, legs and sclerae. You can palpate his liver 2 cm below the right costal margin, and the spleen seems palpable. How do you approach this program?

28. Pertinent points in the history
Full term : lower risk
Male sex: increased risk
Emergency C-Section following failed forceps: Trauma (cephalhematoma?)
4 days old and ready for discharge: 96 hours old
Breastfed every 3-4 hours, going well: exclusive breastfeeding
Greek origin: higher risk for G6PD deficiency in people of Mediterranean descent
Risk factors for Hyperbilirubinemia: hh

29. Physical Exam What should we be examining for?
Where would you start your physical exam in neonatal jaundice?

30. Physical Exam Vital Signs General appearance Measurements
Respiratory, CVS
Abdo
Neuro
General Appearance: Color (plethora, pallor, jaundice) , bruising (cephalhematoma, bruising), wellness (behavior, alertness)
Measurements: large or small babies, babies of dm mothers
Abdo: umbilical hernia in hypothyroidism, hepatosplenomegaly (infection or hemolysis)Neuro: Lethargy, Hypotonus, hypertonus, Poor feeding ,High pitched cry

31. Findings on Physical Exam
Vital Signs are normal
Birth Weight was 3.3 kg, now 3.1 kg: Weight loss <10%
At Day 4, nurse finds baby to be jaundiced: 96 hours
Mother thinks it began at 24 h of life: Significance of 24h
Baby is on alert on exam, no abnormal neurological signs
Jaundice visible on head, trunk, legs, sclera: Moves in cephalocaudal direction
Band-Aid on right heel: metabolic screening underway
Hepatosplenomegaly : sign of possible intrauterine infection, Rh incompatibility (extravascular hemolysis)

32. Objective #4
To elaborate an appropriate plan of management and discuss the currently available therapies

33. Plan of Management When to measure bilirubin concentration?
CPS recommendations
How do we predict hyperbilirubinemia?
How does phototherapy lower unconjugated bilirubin levels?
When should we consider exchange transfusions?

34. Investigations TSB (or Transcutaneous measurement if available)
Universal screening
CBC, Reticulocytes, Film, LDH, Haptoglobuline, DAT, Blood type
Electrolytes, Urea, Creatinine LP
LFTs
Ultrasound (hepatobiliary anatomy)
CXR
Metabolic screen
TSB (or Transcutaneous measurement if available)
Conjugated vs non-conjugated
CBC, Reticulocytes, Film, LDH, Haptoglobuline, DAT, Blood type (haemolysis?)
Electrolytes, Urea, Creatinine (dehydration?)
LP (Sepsis?)
LFTs (Cholestatic Jaundice, hepatitis)
Ultrasound (biliary tree anatomy)
CXR (chf)
Metabolic screen (endocrine and metabolic causes)

35. Guideline 1
To be used to determine if phototherapy , follow up or if routine care is required.
Direct antiglobulin test (Coombs test) should be performed in infants with early jaundice and mother of blood group O in order to identify risk group (presently, in Ottawa this is done for all O mothers)

36. Guideline 2
To be used to determine if intensive phototherapy is required.

37. Guideline 3 Used to determine if exchange transfusion required
Immediate exchange tranfusion is recommended if signs of acute bilirubin encephalopathy (hypertonia, arching, retrocolis, fever, high pitched cry)

38. Available Therapies Breastfeeding support programs Phototherapy
Supplemental fluids (PO,IV)
IVIg
Exchange transfusion
Phototherapy: makes bilirubin water soluble, excreted by kidneys
light in blue-green part most effective
fibre optic blanket can be used
conventional phototherapy is an option at TSB concentration below guidelines (fig2)
Supplemental fluids (PO,IV) in infants receiving phototherapy that are at risk of progressing to exchange transfusion.
IVIg for infants with positive DAT who have predicted severe disease
Exchange transfusion for infants with acute clinical signs of bilirubin encephalopathy (immediate exchange)

39. Management of this case
If our patient’s bilirubin was measured to be 300 micromol/L, with a negative DAT (DAT performed since mother was O+), and no other risk factors
If our patient’s bilirubin was measured to be 400 micromol/L, with a positive DAT.
If our patient’s bilirubin was measured to be 350 micromol/L, with a positive DAT
Conventional phototherapy or possibly retesting in 24h
exchange
Intensive

40. Case 2 Female infant born at 39 weeks. Mother AB+
Spontaneous vaginal delivery, no complications
At 36 hours, weight is stable, baby is feeding well, she is alert on exam, she is ready for discharge.
No jaundice at present time, bilirubin at 96 micromol/L
What action is to be taken?