1. Clinical Case
JR, 7 do hispanic BB, twin B, presented to UCCH ER with jaundice on 5/9/06
DOB – 5/3/06, at OSH in Indiana
NVD, GA 38 weeks, APGARs 9/9
BWt 3.18 kg (7#0oz)
Maternal Hx: 31 yo G2P3 now, good PNC, uncomplicated pregnancy
PNL – B+/RPR NR/R Imm/HepB NR/HIV NR/GBS-

2. Perinatal course Initial PE unremarkable; + some facial bruising noted
Wt 2.9 kg
Feeding BM/E20 – well per GCN records
Voiding and stooling well
Discharged at 48 hrs
D/C Wt – 2.03 kg
Mom told that baby had “borderline” jaundice
To call Pediatrician if she sees baby gets yellow

3. Baby was OK at home, eating well – 10-15 min each breast
Stooling well – per mother
On DOL 5 mother thought babies look yellow and called the PMD
She was told to go to the hospital next day for Bili check

4. Labs
Baby B+/Coombs-
Mom B+

5. Work Up CBC – WBC 13.6, H/H 18.9/54, Plt 301 Diff N26, Bn4
Retic count 0.7%

6. Bilirubin 5/5/06 - @48 hrs (OSH) – 13.0/0.4
5/9/06 – DOL 7 – (OSH) – 30.9/0.6
5/9/04 – UCCH – 31.5/0.8
Sibling’s Bili was 21 – admitted to Peds Floor for phothotherapy

7. ER course VSS, baby was jaundiced and “sleepy”
Placed under phothotherapy
Given IVF
Admitted to PICU for exchange transfusion

8. Here comes the NICU
0230 – NICU fellow received a call from upstairs to help with the exchange transfusion
By 0530 baby was in the PICU
Blood ordered
UVC placed
Double volume exchange transfusion was done
Rpt Bili – 23.8/0.7 half way through the exchange

9. Neonatal Hyperbilirubinemia

10. WHAT IS HYPERBILIRUBINEMIA AND WHY DO WE WORRY ABOUT IT?

11. Jaundice
A visible manifestation in the skin and sclera of elevated bilirubin concentrations
Adults are usually jaundiced when bilirubin levels exceed 2 mg/dL
Neonates appear jaundiced when serum total bilirubin (STB) levels reach 5-7 mg/dL

12. Some degree of jaundice develops in 60-70% of all neonates born on the United States
More than 2.7 million neonates born each year in the United States will develop jaundice
Chemical hyperbilirubinemia, a STB > 2.0 mg/dL, is virtually universal
Although most jaundice is benign, there is a potential for neurological devastation and death and consequently all newborns must be assessed

13. WHY DO INFANTS DEVELOP HYPERBILIRUBINEMIA?

14. Increased Bilirubin Production
Decreased Binding and Transport Capacity
Limited Conjugation and Excretion Capacity
Increased Enterohepatic Circulation of Bilirubin

15. Bilirubin is the breakdown product of hemoglobin
Lysis of red cells releases heme from hemoglobin
Heme is then converted to bilirubin and excreted

16. Bilirubin Synthesis
There is increased production of bilirubin in the newborn because of:
Increased rate of degradation
A shortened circulating erythrocyte life span (70-90 days versus 120 days) of an increased mass
A very large pool of hematopoietic tissue that ceases to function shortly after birth resulting in heme degradation
An increased turnover of cytochromes (nonhemoglobin heme proteins)
An increase in enterohepatic circulation

17. Binding and Transport
Unconjugated bilirubin is quickly bound to albumin in the serum
Newborns have reduced albumin concentrations and consequently a lower plasma binding capacity for bilirubin
There is consequently more free bilirubin in the serum
It is the free bilirubin that is believed to cause neurological damage in newborns

18. Conjugation and Excretion
During fetal life, removal of bilirubin is accomplished by the placenta
In the newborn, bilirubin excretion requires conversion of the nonpolar unconjugated bilirubin into a more polar water-soluble substance, conjugated bilirubin

19. Blood flow through the hepatic artery develops during the first week of life
The ductus venosus allows blood to bypass the liver completely
Conjugation depends on the maturity of the liver cell

20. UDPGT UDPGT in the newborn liver must be induced
UDPGT activity is extremely low in infants born at less than 30 weeks, 0.1% of adult levels
This activity increases to only 1% at term
The activity reaches adult levels by 6-12 weeks of age

21. Conjugation
Bilirubin dissociates from circulating albumin before its entry into the liver cell
Bilirubin enters the liver by a process of carrier-mediated diffusion
It is carried by hepatic ligandin (Y protein) and Z protein
Bilirubin is presumed to be transported from the liver cell membrane to the endoplasmic reticulum, the site of the conjugating enzyme uridine diphosphate glucuronyl transferase (UDPGT)
After conjugation, bilirubin is then excreted into bile in the intestine

23. Increased Enterohepatic Circulation
Conjugated bilirubin is unstable and can be easily hydrolyzed back to unconjugated bilirubin and reabsorbed through the intestinal mucosa
High mucosal beta-glucuronidase activity leads to increased hydrolysis
An alkaline environment also facilitates hydrolysis
In the newborn, the relative lack of intestinal bacterial flora to reduce bilirubin to urobilinogen further increases the bilirubin pool

25. Neonatal Hyperbilirubinemia
Physiologic Jaundice
A progressive rise in unconjugated bilirubin to a peak of 5-6 mg/dL between 60 and 72 hours of life in white and African-American babies and mg/dL between hours of life in Asian babies
A rapid decline in TSBs occurs by the 5th or 7-10th day respectively

26. Pathologic Unconjugated Hyperbilirubinemia
Pathologic hyperbilirubinemia is defined as a prolonged or exaggerated hyperbilirubinemia
Occurs because of disorders of:
Production
Hepatic Uptake
Conjugation
Enterohepatic Circulation

27. Disorders of Production
Isoimmunization
Erythrocyte Enzymatic Defects
Erythrocyte Structural Defects
Infection
Sequestration
Polycythemia

28. Isoimmunization Rh Incompatibility ABO Incompatibility
Other Blood Group Incompatibilities

29. Rh Incompatibility
This is a blood group incompatibility between the mother and newborn that can cause severe hemolytic anemia in the fetus and newborn
The Rh antibody is produced by a Rh negative mother after being exposed to a Rh antigen from fetal blood
The initial response is to make IgM antibodies
Later IgG are produced which cross the placenta and bind to fetal red blood cells which are consequently destroyed
Infants do not appear jaundiced at birth, but severe anemia can lead to hydrops and death
After birth, infants may develop hyperbilirubinemia rapidly

30. The D antigen may produce sensitization with a fetomaternal hemorrhage as small as 0.1 mL
At one time this was the most common cause of kernicterus; but with the use of RhoGAM (anti-D immunoglobulin G) and careful fetal monitoring, the incidence and severity have decreased

31. ABO Incompatibility
This is a hemolytic disease caused by a reaction of maternal anti-A or anti-B antibodies with fetal A or B antigens
Usually milder than Rh
Almost exclusively in type O mothers
Jaundice appears at hours
Half of infants with a positive Coombs show hemolysis and some with a negative Coombs have hemolysis

32. Minor Blood Groups Kell, Kidd, Duffy, Lutheran
< 2 % of hemolysis from isoimmunization

33. Erythrocyte Enzymatic Defects
Glucose-6-Phosphate Dehydrogenase Deficiency
Pyruvate Kinase Deficiency
These defects may have profound effects on erythrocyte function and life span

34. Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common disease, especially in people of Mediterranean; African; and Asian decent
G6PD deficiency occurs in 11-13% of African Americans
Estimated million people carry the gene
X-linked
Presentation is heterogeneous
Hemolysis occurs, but can be absent
Hyperbilirubinemia occurs between 24 and 72 hours of life

35. RBCs are unable to activate the pentose phosphate metabolic pathway
And consequently cannot defend against oxidative stress
Sepsis and Vitamin K analogues
Severity of disease depends on type and amount of stress

36. Pyruvate Kinase Deficiency
This is the second most common cause of enzymatic-related hemolytic anemia
Autosomal recessive
It is common in people of Northern European decent
It is an enzyme required for production of ATP in RBCs

37. Its deficiency leads to decreased RBC life span and hemolysis

38. Erythrocyte Structural Defects
Hereditary Spherocytosis
Hereditary Elliptocytosis
These defects alter RBC structure and cause sequestration

39. Hereditary Elliptocytosis
Incidence of 1:4000
Autosomal dominant
Abnormality in spectrin or glycophorin C
Hemolysis and hyperbilirubinemia are unusual in the newborn period

40. Hereditary Spherocytosis
Incidence of 1:5000
Autosomal dominant
Heterogeneous presentation
Fifty percent present with hemolytic anemia, hyperbilirubinemia, reticulocytosis, and increased erythrocyte osmotic fragility

41. Infection Hyperbilirubinemia is believed to be secondary to hemolysis
Sepsis may impair conjugation also leading to increased bilirubin levels

42. Sequestration
Sequestration of blood in body cavities may lead to hyperbilirubinemia as the body metabolizes hemoglobin
Cephalohematomas, subdural hematomas, subgaleal hematomas
Excessive bruising

43. Polycythemia
The increase in red blood cell mass has the potential to overload the newborn hemoglobin metabolism capacities

44. Disorders of Hepatic Uptake
Gilberts Syndrome
This is a benign disorder producing persistent unconjugated hyperbilirubinemia
There is defective hepatic uptake and decreased UDPGT activity
It usually occurs in the second decade of life, but can present in neonates

45. Disorders of Conjugation
Crigler-Najjar Syndrome
Transient Familial Neonatal Hyperbilirubinemia (Lucey-Driscoll Syndrome)
Pyloric Stenosis
Hypothyroidism

46. Crigler-Najjar Syndrome
Type I
There is absence of UDPGT activity
Autosomal recessive
1:1,000,000
Severe unconjugated hyperbilirubinemia develops and persists beyond the first week of life
No hemolysis
Lifelong risk of kernicterus
Lifelong phototherapy is needed

47. Type II There is various degree of decrease of UDPGT activity
Typically benign
There is unconjugated hyperbilirubinemia in the first few days of life that does not exceed 20 mg/dL
Hyperbilirubinemia persists into adulthood
The treatment is phenobarbital

48. Transient Familial Neonatal Hyperbilirubinemia
Neonates develop severe nonhemolytic hyperbilirubinemia
Their serum contains high concentrations of glucuronyl transferase inhibitors
This inhibitor decreases by about 14 days of life and consequently hyperbilirubinemia resolves

49. Pyloric Stenosis
10-25% of babies with pyloric stenosis have hyperbilirubinemia at the time of presentation
Hepatic glucuronyl tranferase activity is reduced
Surgical correction improves bilirubin levels

50. Hypothyroidism
UDPGT activity is deficient and remains low for weeks with hypothyroidism

51. Disorders of Enterohepatic Circulation
Breast Feeding Jaundice
Breast Milk Jaundice

52. Breast Feeding Jaundice
Unconjugated hyperbilirubinemia is secondary to a suboptimal establishment of breastfeeding
Newborns are under-hydrated and in a state of starvation.
They also have delayed passage of meconium
Enterohepatic reuptake of bilirubin is consequently increased, leading to hyperbilirubinemia
Treatment and prevention include frequent feedings (8-12/day)

53. Breast Milk Jaundice
Occurs after 3-5 days of life, typically at 2-3 weeks of life
The etiology is unknown, but believed to be a factor in breast milk or an altered chemistry in breast milk that enhances intestinal reabsorption of bilirubin
No need to stop breastfeeding unless bilirubin levels are dangerously high

54. WHY DO WE WORRY ABOUT HYPERBILIRUBINEMIA?

55. Sequelae
Bilirubin may penetrate the brain cell and cause neuronal dysfunction or death if not carefully managed
Bilirubin causes staining and necrosis of neurons in the basal ganglia, hippocampal cortex, subthalamic nuclei, and cerebellum which is followed by gliosis
50%of patients with kernicterus die

56. Acute Bilirubin Encephalopathy
Phase 1 - poor suck, hypotonia, and depressed sensorium
Phase 2 - fever and hypertonia or opisthotonos
Phase 3 - less hypertonia, high pitched cry, hearing and visual abnormalities, poor feeding, athetosis

57. Kernicterus Long term sequelae: Chorioathetoid cerebral palsy
Sensorineural hearing loss
Upward gaze palsy
Dental-enamel dysplasia
Mental retardation

58. SO, WHAT CAN WE DO?

59. Diagnosis and Management
There has been evidence that neonatal jaundice can be treated less aggressively, but there is not a consensus yet and until then it should be managed conservatively

60. Diagnosis
All neonates are entitled to a thorough physical examination and evaluation to determine which neonates are at an increased risk for becoming abnormally jaundiced and developing sequelae

61. Risk Assessment
Every newborn should be assessed, especially if discharged before 72 hours of life
2 options:
TSB or TcB before discharge and plot results on the nomogram

62. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with birth weight of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

63. Assessment of risk Major Predischarge TSB or TcB in the high-risk zone
Jaundice in the first 24h
Hemolytic disease
Gestational age weeks
Sibling received phototherapy
Cephalohematoma or bruising
Poor breastfeeding
East Asian descent

64. Carbon Monoxide
End Tidal Carbon Monoxide detection allows rapid noninvasive detection of infants at risk for hemolytic disease and consequently at high risk for neurological sequelae

65. Carbon Monoxide
The breakdown of hemoglobin by heme oxygenase produces free iron and carbon monoxide in equimolar amounts
The carbon monoxide formed by heme degradation is excreted unchanged by the lungs.
Although there are other endogenous and exogenous sources of CO, quantitative estimation of its excretion or synthesis offers a reasonably accurate assessment of bilirubin synthesis

66. Physical Examination
Detection of clinical jaundice requires digital pressure and the proper lighting, preferably daylight
If clinical jaundice is detected, a total and direct serum bilirubin or transcutaneous bilirubin (TcB) should be measured and plotted on the nomogram

67. When should I do more? If: Cord bilirubin is greater than 4 mg/dL
A rate of rise greater than or equal to 0.5 mg/dL/hour over a 4-8 hour period
An increase of 5 mg/dL per day
13-15 mg/dL in a term infant
10 mg/dL in a preterm infant
If jaundice persist greater than 10 days

68. Then what? Determination of maternal blood group and Rh type
Screen for antibodies directed against minor erythrocyte antigens
Determination of newborns blood type and Rh type
Direct Coombs test
Hemoglobin and Hematocrit
Peripheral blood smear
Reticulocyte count
G6PD level

69. Algorithm for the management of jaundice in the newborn nursery
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

70. Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

71. Helpful resources
Bili-Aid

72. Phototherapy The main mechanism of action
Geometric photoisomerization of unconjugated bilirubin that can then be excreted without conjugation

73. Technique
Wavelength
Bilirubin absorbs light maximally in the blue range ( nm), with a peak at 460 nm for albumin-bound bilirubin and 440 nm for free bilirubin
Special blue lamps have a spectrum between

74. Irradiance
The energy output measured in microwatts per square centimeter per nanometer
Optimal level is 11 microwatts per square centimeter per nanometer
Intensive phototherapy is 30 microwatts per square centimeter per nanometer

75. Positioning Surface area
Within 10 cm of the patient for fluorescent tubes
Surface area
The greater the surface area exposed, the more effective the phototherapy

76. Hydration
There is no evidence that excessive fluid administration affects the serum bilirubin concentration
If admitted with dehydration, babies will need to be rehydrated and then fed
Feeding inhibits enterohepatic circulation of bilirubin
Important to watch fluid status for excretion of bilirubin

77. The TSB level for discontinuing phototherapy depends on the age at which phototherapy was started and the etiology
For infants readmitted after birth admission, you can discontinue usually at mg/dL with a follow up visit 24 hours after discharge
There is no need for a rebound bilirubin, unless there is hemolytic disease

78. Pharmacological Therapy
Phenobarbital
Albumin
Tin-mesoporphyrin
Inhibits heme oxygenase
Intravenous gamma-globulin
Shown to reduce the need for exchange transfusions in isoimmune hemolytic disease

79. Guidelines for exchange transfusion in infants 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

80. Exchange transfusions are recommended if TSB is greater than or equal to 25 mg/dL in a healthy full term infant
If rate of rise is greater than or equal to 0.5 mg/dL/hour
If there is active hemolysis or other risk factors, then an exchange transfusion may be warranted at a lower bilirubin level

81. Exchange Transfusion
With a exchange transfusion, approximately 85% of erythrocytes will be replaced
Serum bilirubin levels should decrease by 50%

82. American Academy of Pediatrics
In 1994 the AAP established practice parameters for the management of hyperbilirubinemia
Revised in 2004

83. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation
Goals:
Promote and support successful breastfeeding
Establish nursery protocols for the identification and evaluation of hyperbilirubinemia
Measure the total serum bilirubin or transcutaneous bilirubin levels on infants jaundiced in the first24 hours

84. Recognize that visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented infants
Interpret all bilirubin levels according to the infant’s age in hours
Recognize that infants less than 38 weeks’ gestation, particularly those who are breast fed, are at higher risk of developing hyperbilirubinemai and require closer surveillance and monitoring
Perform a systematic assessment on all infants before discharge for the risk of severe hyperbilirubinemia

85. Provide parents with written and verbal information about newborn jaundice
Provide appropriate follow-up based on the time of discharge and the risk assessment
Treat infants, when indicated, with phototherapy or exchange transfusion

86. Follow Up Infant Discharged Should Be Seen By Age < 24 hours
24 to 47.9 hours
48 to 72 hours
Should Be Seen By Age
72 hours
96 hours
120 hours

87. Fanaroff, Martin. Neonatal-Perinatal Medicine, 7th Edition.
Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, Pediatrics 2004;114;
Taeusch, Ballard, Gleason. Avery’s Diseases of the Newborn, 8th Edition