Hyperbilirubinemia in the Neonate Guidelines Update and Treatment Recommendations

1
Hyperbilirubinemia in the NeonateGuidelines
Update and Treatment Recommendations

• Lea A. Bonifacio, MD.
• Marquette General Hospital - NICU
• Marquette, MI

2
Objectives

• Summarize the mechanisms of bilirubin production
  and clearance
• Describe a systematic process to assess and
  monitor neonatal hyperbilirubinemia
• Identify prevention strategies for at risk
  infants
• Describe the recommended treatment modalities for
  severe hyperbilirubinemia
• Summarize the current consensus guidelines for
  early prevention, intervention treatment and
  follow-up of neonates at risk for severe
  hyperbilirubinemia

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History of Bilirubin in the Newborn Infant

• It has been over 500 years since Bartholomeus
  Metlinger provided the earliest record of
  jaundice in the newborn in his book Ein Regiment
  der Jungen Kinder
• Michael Ettmuller in 1708 and John Burton in 1751
  expanded on the descriptions of this disorder
• In 1913 Ylppo introduced the idea that neonatal
  icterus was a manifestation of the immaturity of
  the liver
• The central nervous system morbidity in the
  newborn due to hyperbilirubinemia was originally
  described by Schmorl in 1903 and has been well
  recognized for several decades.

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Metabolic Pathway for the Formation of Bilirubin
5
Heme Metabolism
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Physiologic Jaundice
Peak on 3rd day
Drop by 2 mg/dl first week
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Pathologic Jaundice
SBC INCREASING BY gt 5mg/100ml/DAY
SBC gt 12.9 mg/100ml (TERM) or
gt15mg/100ml (PRETERM)
JAUNDICE IN THE
FIRST 24 HRS
DIRECT SBC gt1.5-2.0mg/100ml
JAUNDICE FOR gt 1 WEEK (TERM)
gt 2 WEEKS (PRETER)
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Types of Bilirubin

• Conjugated Direct
• Water soluble
• Easily excreted in urine and stool
• Less toxic form
• Requires O2 and glucose
• Unconjugated Indirect
• Fat or non-water soluble
• Potentially more toxic
• Bound Vs. unbound to albumin

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Increase in Bilirubin ProductionHemolysis

• Genetic factors
• G6PD deficiency erythrocyte enzymatic defects
• Antibody mediated
• Rh/ABO incompatibility
• Acquired hemolytic disorders
• Infection Drugs
• Additional cause
• Polycythemia
• Maternal DM
• Extravasation of Blood

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Decrease in Bilirubin Excretion

• Increase enterohepatic circulation
• Bowel obstructions
• Maternal liver disease
• Hereditary defects
• Crigler-Najjar
• Lucey-Driscoll
• Hypothyroidism
• Hypopituitatism

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Combination of Increase Production and Decrease
Excretion

• Prematurity
• Infection
• Bacterial sepsis, viral, protozoal
• G6PD deficiency

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AAP Practice Parameter Management of
Hyperbilirubinemia in the Healthy Term Newborn

• Measure bilirubin in any infant jaundiced before
  24 hours and, if elevated, evaluate for possible
  hemolysis
• Provide follow-up within 2-3 days for all
  neonates discharged lt 48 hours
• Pay special attention to infants lt 38 weeks
  gestation
• Guidelines for initiation of phototherapy and
  exchange transfusion in the healthy term newborn

Pediatrics 199494558-562
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Problems with 1994 Guideline

• Too aggressive or not aggressive enough
• When should a bilirubin level be obtained?
• .measure TSB if jaundice clinically significant
  by medical judgment
• Restricted to Healthy Term Newborn gt 37 weeks
  without hemolysis
• Hemolytic disease is a risk factor for
  kernicterus
• In absence of Rh disease or classical direct
  Coombs positive ABO hemolytic disease, difficult
  to know whether or not hemolysis is present
• Standard laboratory tests for hemolysis
  (hemoglobin, reticulocyte count, peripheral
  smear, Coombs test) lack sensitivity and
  specificity
• Evidence that many infants who are significantly
  jaundiced before they leave the hospital have an
  increase in bilirubin production (hemolysis)

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Table vs. Graph for Treatment
Table provided artificial transition from one
time zone to the next e.g., exchange transfusion
recommended if TSB gt20 mg/dl at 48 hours but not
if infant is 49 hours
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Lapses in Management of Neonatal Jaundice

• Perinatal management  
• Failure to adequately educate parents about
  neonatal jaundice
• Failure to educate parents and health care
  providers about the potential for irreversible
  bilirubin toxicity during newborn period
• Pre-discharge bilirubin management
• Failure to recognize the limitations of visual
  assessment of jaundice
• Failure to recognize the significance of jaundice
  within the first 24 hours after birth and its
  relation to increased bilirubin production
  secondary to hemolysis
• Failure to recognize jaundice and document its
  severity by bilirubin measurement before
  discharge from the hospital

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Lapses in Management of Neonatal Jaundice

• Post-discharge bilirubin management (follow-up)
• Failure to ensure follow-up based on the severity
  of pre-discharge hyperbilirubinemia and
  associated risk factors, including race,
  ethnicity, and family history
• Failure to provide ongoing lactational support to
  ensure adequacy of intake
• Failure to respond to parental concerns of
  newborn jaundice poor feeding, lactational
  difficulties, and change in newborns' behavior
  and activity
• Centralized Registry For newborns with dangerous
  hyperbilirubinemia
• Failure to maintain and collect evidence of
  potential kernicterus in healthy term and
  near-term infants with excessive
  hyperbilirubinemia

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Re-emergence of Kernicterus in the United States,
2002
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Reasons for Re-emergence of Kernicterus

• Early Discharge
• Lack of concern about jaundice
• Over-reliance on visual assessment
• Bilirubin test considered as a healthcare cost
• Limited experience with severe jaundice
• Clinicians were not consistently using the AAP
  practice guidelines

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Kernicterus

• Clinical Findings
• Acute Stage Irritability, hypertonia,
  retrocolis, drowsiness, poor feeding, altered
  tone, opisthotonus, failed ABR
• Sequelae
• Extrapyramidal movements Dystonia, athetosis
• Gaze abnormalities Upward gaze
• Auditory disturbances Sensorineural hearing
  loss, auditory neuropathy
• Intellectual deficits
• Enamel dysplasia of deciduous teeth
• Pathologic Findings
• Pigmentation of nuclei (subthalamic, hippocampus,
  globus pallidus)

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Bilirubin Entry into the Brain Free Bilirubin
Theory
Kernicterus
21
The MRI in Kernicterus
T1- and T2-weighted MR images at 38 weeks
postmenstrual age hyperintense signal (arrows)
in globus pallidus on T1 and not T2 sequences.
22
New Guideline

• Focus of the guideline is the prevention of
  kernicterus
• Identifies key root causes as major
  contributors to the reported cases of kernicterus
• Failure to evaluate jaundice in the first 24
  hours
• Failure to recognize risk factors
• Failure to provide timely follow up
• Failure to respond to parental concerns

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AAP Recommendation 1

• Primary Prevention
• Clinicians should advise mothers to nurse their
  infants at least 8 to 12 times per day for the
  first several days
• The AAP recommends against routine
  supplementation of nondehydrated breastfed
  infants with water or dextrose water

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AAP Recommendation 2

• Secondary Prevention
• Clinicians should perform ongoing systematic
  assessments during the neonatal period for the
  risk of an infant developing severe
  hyperbilirubinemia
• Blood Typing
• All pregnant women should be tested for ABO and
  Rh (D) blood types and have a serum screen for
  unusual isoimmune antibodies
• If a mother has not had prenatal blood grouping
  or is Rh-negative, a direct antibody test (or
  Coombs test), blood type, and an Rh (D) type on
  the infants (cord) blood are strongly
  recommended
• If the maternal blood is group O, Rh-positive, it
  is an option to test the cord blood for the
  infants blood type and direct antibody test, but
  it is not required provided that there is
  appropriate surveillance, risk assessment before
  discharge, and follow-up

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• Clinical Assessment
• Clinicians should ensure that all infants are
  routinely monitored for the development of
  jaundice, and nurseries should have established
  protocols for the assessment of jaundice.
  Jaundice should be assessed whenever the infants
  vital signs are measured but no less than every 8
  to 12 hours
• Protocols for the assessment of jaundice should
  include the circumstances in which nursing staff
  can obtain a TcB level or order a TSB measurement
  

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AAP Recommendation 3

• Laboratory Evaluation
• A TcB and/or TSB measurement should be performed
  on every infant who is jaundiced in the first 24
  hours after birth. The need for and timing of a
  repeat TcB or TSB measurement will depend on the
  zone in which the TSB falls, the age of the
  infant, and the evolution of the
  hyperbilirubinemia
• A TcB and/or TSB measurement should be performed
  if the jaundice appears excessive for the
  infants age. If there is any doubt about the
  degree of jaundice, the TSB or TcB should be
  measured. Visual estimation of bilirubin levels
  from the degree of jaundice can lead to errors,
  particularly in darkly pigmented infants
• All bilirubin levels should be interpreted
  according to the infants age in hours

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Transcutaneous Bilirubin
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Laboratory Evaluation of the Jaundiced Infant of
35 or More Weeks Gestation
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AAP Recommendation 4Cause of Jaundice

• The possible cause of jaundice should be sought
  in an infant receiving phototherapy or whose TSB
  level is rising rapidly (ie, crossing
  percentiles) and is not explained by the history
  and physical examination
• Infants who have an elevation of direct-reacting
  or conjugated bilirubin should have a urinalysis
  and urine culture. Additional laboratory
  evaluation for sepsis should be performed if
  indicated by history and physical examination

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• Sick infants and those who are jaundiced at or
  beyond 3 weeks should have a measurement of total
  and direct or conjugated bilirubin to identify
  cholestasis. The results of the newborn thyroid
  and galactosemia screen should also be checked in
  these infants
• If the direct-reacting or conjugated bilirubin
  level is elevated, additional evaluation for the
  causes of cholestasis is recommended
• Measurement of the glucose-6-phosphate
  dehydrogenase (G6PD) level is recommended for a
  jaundiced infant who is receiving phototherapy
  and whose family history or ethnic or geographic
  origin suggest the likelihood of G6PD deficiency
  or for an infant in whom the response to
  phototherapy is poor

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AAP Recommendation 5Risk Assessment Before
Discharge

• Before discharge, every newborn should be
  assessed for the risk of developing severe
  hyperbilirubinemia, and all nurseries should
  establish protocols for assessing this risk. Such
  assessment is particularly important in infants
  who are discharged before the age of 72 hours
• The AAP recommends 2 clinical options used
  individually or in combination for the systematic
  assessment of risk predischarge measurement of
  the bilirubin level using TSB or TcB and/or
  assessment of clinical risk factors. Whether
  either or both options are used, appropriate
  follow-up after discharge is essential

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Major Risk Factors for Development of Severe
Hyperbilirubinemia

• Predischarge TSB or TcB level above the 95th
  percentile for age
• Jaundice observed in the first 24 hours
• Blood group incompatibility with positive direct
  antiglobulin test, positive maternal antibody
  screen,other known hemolytic disease
• Gestational age 34-36 6/7
• Previous sibling received phototherapy
• Cephalohematoma or significant bruising
• Exclusive breast feeding, particularly if
  feedings are infrequent, or nursing is not going
  well and weight loss is excessive
• East Asian race

Estimated relative risk 3 or more
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Minor Risk Factors for Development of Severe
Hyperbilirubinemia

• Predischarge TSB or TcB between 75th and 95th
  percentile
• Gestational age 37-38 weeks
• Previous sibling with jaundice
• Macrosomic infant of a diabetic mother
• Maternal age gt 25 years
• Male sex

Estimated relative risk 1.5-3
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Decreased Risk for Development of Severe
Hyperbilirubinemia

• TSB or TcB lt 40th percentile
• Gestational age gt 41 weeks
• Exclusive bottle feeding
• Black race
• Discharge from hospital after 72 hours

Estimated relative risk lt 0.5
35
Risk Assignment for Hyperbilirubinemia
Nomogram for designation of risk in 2840 well
newborns . Bhutani et al.
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AAP Recommendation 6Follow-up

• All hospitals should provide written and verbal
  information for parents at the time of discharge,
  which should include an explanation of jaundice,
  the need to monitor infants for jaundice, and
  advice on how monitoring should be done

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AAP Recommendation 6Follow-up cont.

• All infants should be examined by a qualified
  health care professional in the first few days
  after discharge to assess infant well-being and
  the presence or absence of jaundice. The timing
  and location of this assessment will be
  determined by the length of stay in the nursery,
  presence or absence of risk factors for
  hyperbilirubinemia, and risk of other neonatal
  problems

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AAP Recommendation 6Follow-up cont.

• Follow-up should be provided as follows
• Infant Discharged Should Be
• Seen
  by Age
• Before age 24 h 72 h
• Between 24 and 47.9 h 96 h
• Between 48 and 72 h 120 h

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• For some newborns discharged before 48 hours, 2
  follow-up visits may be required, the first visit
  between 24 and 72 hours and the second between 72
  and 120 hours. Clinical judgment should be used
  in determining follow-up. Earlier or more
  frequent follow-up should be provided for those
  who have risk factors for hyperbilirubinemia,
  whereas those discharged with few or no risk
  factors can be seen after longer intervals.

40

• If appropriate follow-up cannot be ensured in the
  presence of elevated risk for developing severe
  hyperbilirubinemia, it may be necessary to delay
  discharge either until appropriate follow-up can
  be ensured or the period of greatest risk has
  passed (72-96 hours).

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• The follow-up assessment should include the
  infants weight and percent change from birth
  weight, adequacy of intake, the pattern of
  voiding and stooling, and the presence or absence
  of jaundice. Clinical judgment should be used to
  determine the need for a bilirubin measurement.
  If there is any doubt about the degree of
  jaundice, the TSB or TcB level should be
  measured. Visual estimation of bilirubin levels
  can lead to errors, particularly in darkly
  pigmented infants.

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AAP Recommendation 7Treatment - Phototherapy
43
When people allow the sun to paint their faces
brown, torpid livers are less liable to paint
them yellow
44
Complications of Phototherapy

• Syndrome
• Bronze Baby Syndrome

• Adverse Effects
• Dehydration
• Watery diarrhea
• Skin rashes
• Hyperthermmia
• Decrease maternal-infant interaction

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AAP Recommendation 7Treatment Exchange
Transfusion
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AAP Recommendation 7 (contd)

• In using the guidelines for phototherapy and
  exchange transfusion, the direct-reacting (or
  conjugated) bilirubin level should not be
  subtracted from the total
• If the TSB is at a level at which exchange
  transfusion is recommended or if the TSB level is
  25 mg/dL (428 µmol/L) or higher at any time, it
  is a medical emergency and the infant should be
  admitted immediately and directly to a hospital
  pediatric service for intensive phototherapy.
  These infants should not be referred to the
  emergency department, because it delays the
  initiation of treatment

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AAP Recommendation 7 (contd)

• Exchange transfusions should be performed only by
  trained personnel in a neonatal intensive care
  unit with full monitoring and resuscitation
  capabilities
• In isoimmune hemolytic disease, administration of
  intravenous gamma-globulin (0.5-1 g/kg over 2
  hours) is recommended if the TSB is rising
  despite intensive phototherapy or the TSB level
  is within 2 to 3 mg/dL (34-51 µmol/L) of the
  exchange level. If necessary, this dose can be
  repeated in 12 hours

48

• It is an option to measure the serum albumin
  level and consider an albumin level of less than
  3.0 g/dL as one risk factor for lowering the
  threshold for phototherapy use.
• If an exchange transfusion is being considered,
  the serum albumin level should be measured and
  the bilirubin/albumin (B/A) ratio used in
  conjunction with the TSB level and other factors
  in determining the need for exchange transfusion

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AAP Recommendation 7. cont

• Immediate exchange transfusion is recommended in
  any infant who is jaundiced and manifests the
  signs of the intermediate to advanced stages of
  acute bilurbin encephalopathy (hypertonia,
  arching, retrocollis, opisthotomos, fever,
  high-pitched cry) even if the TSB is falling

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• B/A Ratio at Which Exchange Transfusion
  Should be Considered
• TSB mg/dL/ Alb, g/dL TSB µmol/L/Alb,
  µmol/L

Risk Category
The following B/A ratios can be used together
with but not in lieu of the TSB level as an
additional factor in determining the need for
exchange transfusion.
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AAP Recommendation 7 (contd)

• All nurseries and services treating infants
  should have the necessary equipment to provide
  intensive phototherapy
• In breastfed infants who require phototherapy,
  the AAP recommends that, if possible,
  breastfeeding should be continued. It is also an
  option to interrupt temporarily breastfeeding and
  substitute formula. This can reduce bilirubin
  levels and/or enhance the efficacy of
  phototherapy. In breastfed infants receiving
  phototherapy, supplementation with expressed
  breast milk or formula is appropriate if the
  infants intake seems inadequate, weight loss is
  excessive, or the infant seems dehydrated.

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Therapies Under Investigation
53
A Single Dose of Sn-MP in G-6-PD Deficient
Newborns
Frequency distribution of peak PBC. Group A
(N  172) preventive SnMP in G-6-PD-deficient
neonates group B (N  168) therapeutic
phototherapy in G-6-PD-normal neonates group C (
N  58) therapeutic phototherapy in
G-6-PD-deficient neonates
Kappas, Pediatrics 2001108 25-30
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Sn-MP in a Jehovahs Witness Newborn as an
Alternative to Exchange Transfusion
Kappas, Pediatrics 2001108 25-30
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Key Elements of Guidelines

• Establish standing nursery protocol for
  assessment of jaundice. Includes circumstances in
  which nurses can obtain TSB without physician
  order
• Measure TSB on every baby jaundiced in the first
  24 hours
• If any doubt about level of jaundice obtain TSB
  or TcB level. Clinical assessment of jaundice can
  be unreliable, particularly in darkly pigmented
  newborns
• Perform systematic assessment on all infants,
  prior to discharge, for the risk of subsequent
  hyperbilirubinemia. This is best done by
  measuring the TSB or TcB, by using risk factors,
  or, ideally, a combination of both

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Key Elements

• 5. Interpret all TSB levels according to infants
  age in hours.
• 6. Do not manage infants lt 38 0/7 weeks like
  infants gt 39 weeks. Infants lt 38 0/7 weeks,
  particularly those who are breastfed, are at much
  higher risk of hyperbilirubinemia
• 7. Follow guidelines in tables and figures for
  phototherapy and exchange transfusion
• 8. Provide appropriate follow-up for all infants,
  particularly those discharged before age 72
  hours
• 9. If follow-up cannot be assured, assess risk
  for severe hyperbilirubinemia and obtain TSB or
  TcB level. It may be necessary to delay discharge
• 10. Infants with TSB gt 25 mg/dl should be treated
  immediately