1. family and parenting
2. babies and toddlers

Hyperbilirubinemia
and Kernicterus: Not Gone
and Not Forgotten
M.Jeffrey Maisels, MD, DSc
Beaumont Children’s Hospital
Royal Oak, MI
jmaisels@beaumont.edu
Why worry about jaundice?
• Occurs in almost all babies
• Source of anxiety and
aggravation to families and
doctors
• Can lead to kernicterus
1
Kernicterus Registry
• 125 cases in USA of infants born between
1979 - 2002 and discharged as “healthy
newborns”
• Sources - parents, physicians, nurses,
literature, medico-legal
• 69% male
• Nearly all breastfed
• 97% discharged <72 hr (57.5% <48hr)
• 40% <38 weeks
Bhutani et al, J Perinatol 2004;24:650
Kernicterus in Healthy Breastfed
Term Infants
Case
Sex
BW (g)
Gestation
(wk)
Peak serum
bilirubin
(mg/dL)
1
M
2820
37
49.7
2
M
3771
37
39.0
5
3
M
4280
39
40.3
10
4
F
4026
37
44.7
7
5
F
3375
38
44.7
4
6
M
3175
37
41.4
6
Age at
peek
bilirubin
(days)
7
Causes of Hyperbilirubinemia in
Kernicterus Registry
•Idiopathic
37%
•Hemolysis
14%
•G6PD deficiency
25%
•Other
23%
Bhutani et al, Pediatr Res 2004;24:650
Kernicterus
• Still occurring and can occur in a
healthy breastfed infant
• Relatively rare disease (8,000 new
cases of CP/yr in the US)
• But, unlike other causes of CP,
almost always preventable
Maisels MJ. Pediatrics 1995;96:730
2
Why is this happening?
Natural History of Bilirubinemia
Have a high degree of humility
when you do a visual estimate
of the bilirubin level
Newsweek Aug 4, 1997
3
RISK OF BEING READMITTED
FOR PHOTOTHERAPY
30,000 discharges from well baby nursery 1988-94
4.2/1,000 readmitted for phototherapy
RISK FACTOR
ODDS RATIO
35 - 36 wks
13.2
36 – 38 wks
7.5
Breast feeding
4.2
Jaundice in nursery
7.8
LOS < 72 h
3.2
Newsweek Aug 4, 1997
Maisels MJ, Pediatrics 1998;101:995
Kernicterus Registry
Practitioners do not assess
jaundice risks the way they
assess other risks
• 69% male
• Nearly all breastfed
• 97% discharged <72 hr (57.5%
<48hr)
• 40% <38 weeks
Bhutani et al, J Perinatol 2004;24:650
Other important risk factors
• Jaundice in first 24 hours
• Previous sibling jaundiced/phototherapy
• Cephalhematoma or bruising (vacuum
extraction)
• ABO incompatibility with positive DAT
• Predischarge bilirubin >95th percentile
4
Effect of Breastfeeding Frequency in First 24 Hours and
Bilirubin > 15mg/dL on Day 6 in Japanese Newborns
Percent > 15 mg/dL Day 6
Modified from Yamauchi, Pediatrics 1990; 86: 171
Effective breastfeeding is one
intervention that could
significantly reduce the risk of
severe hyperbilirubinemia
30
25
20
15
10
5
0
0-2
3-4
5-6
7-8
Feedings in first 24 hours
9-11
Should you supplement breastfed
newborns with water?
5
AMERICAN ACADEMY OF
PEDIATRICS
Subcommittee on Hyperbilirubinemia
Clinical Practice Guideline: Management
of Hyperbilirubinemia in the Newborn
Infant > 35 Weeks of Gestation
Pediatrics 2004 (July);114:297
AAP Jaundice Guideline
The 10 Key Elements
1. Promote and support successful
breastfeeding.
2. Establish nursery protocols – include
circumstances in which nurses can
order a bilirubin.
3. Measure TSB or TcB if jaundiced in the
first 24 hours.
4. Visual estimation of jaundice can lead to
errors, particularly in darkly pigmented
infants.
5. Interpret bilirubin levels according to the
infant’s age in hours.
Risk Assessment
New Recommendation by
Advisory Group
• Do this on every baby
-Clinical risk factors (gestation
most important)
-Measure TcB or TSB
AAP Jaundice Guideline
The 10 Key Elements (cont)
6. Infants <38 weeks, particularly if breastfed,
are high risk
7. Perform risk assessment prior to
discharge.
8. Give parents written and oral information .
9. Provide appropriate follow-up based on
time of discharge and risk assessment.
10. Treat newborns, when indicated, with
phototherapy or exchange transfusion.
Predictive Ability of a Predischarge
Hour-specific Serum Bilirubin for
Subsequent Significant
Hyperbilirubinemia in Healthy Term
and Near-Term Newborns
Bhutani VK, Johnson L, Sivieri EM.
Pediatrics 1999;103:6-14
6
25
Serum Bilirubin (mg/dl)
20
95 th%ile
High Risk Zone
75 th%ile
e
Zon
Risk
diate
rme
Inte
one
Z
High
k
Ris
diate
rme
Inte
Low
15
10
40 th%ile
Low Risk Zone
5
0
0
12
24
36
48
60
72
84
96
108
120
132
144
Postnatal Age (hours)
Bhutani, Pediatrics 1999; 103: 6-14
Newman, Arch Ped Adolesc Med 2005;159:113
Conclusion
Risk of developing hyperbilirubinemia
can be accurately assessed by measuring
predischarge TSB or TcB and gestational
age
25
Serum Bilirubin (mg/dl)
20
95 th%ile
High Risk Zone
75 th%ile
e
Zon
Risk
diate
rme
Inte
e
High
Zon
Risk
diate
rme
Inte
15
40 th%ile
Low
10
Low Risk Zone
5
0
0
12
24
36
48
60
72
84
96
108
120
132
144
Postnatal Age (hours)
Keren. Pediatrics 2008; 121: e170-e179
Follow-up
• Provide appropriate follow-up ,
according to time of discharge and
risk factors
• If cannot do this, assess risk and do
TcB or TSB level, get outpatient
TSB prn.
If you discharge an infant before
age 72 hours, you or a nurse
should see the infant within 2 days
of discharge
7
Implementation
Give Physicians the Tools to
Implement the Guidelines
Give Physicians the Tools to
Implement the Guidelines
Risk assessment tool at bedside
Wallet-sized nomogram and guidelines
PDA
Hospital computer access and website
Lab reports of bilirubin to include age in
hours and percentile with
recommendations for follow up and
phototherapy
Risk assessment tool at bedside
Predischarge Assessment for the Risk of Hyperbilirubinemia in
Infants >35 wk Gestation (Pediatrics 2004;114:257-313)
Phototherapy Guidelines for Infants >35 wks Gestation
25
ƒGuidelines refer to use of intensive phototherapy.
ƒUse total bilirubin. Do not subtract direct reacting or conjugated bilirubin
ƒRisk factors*= isoimmune hemolytic disease, G6PD deficiency, asphyxia,
25
Time
Age
(hrs)
TcB
TSB
Initials
Total Serum Bilirubin (mg/dL0
Date
20
Serum Bilirubin (mg/dl)
95 th %ile
High Risk Zone
15
Hig
h Inte
Lo w
10
rm edi
Interm
ate
ed iate
ne
75 th%ile
ne
k Zo
Ris
40 th %ile
Ris
k Zo
Low Risk Zone
5
20
respiratory distress, significant lethargy, temperature instability, sepsis,
acidosis, or albumin < 3.0 g/dL (if measured)
ƒFor well infants 35-36 6/7 wk can adjust TSB levels for intervention around
the medium risk line. It is an option to intervene at lower TSB levels for
infants closer to 35 wks and at higher TSB levels for those closer to 37 6/7
wks.
15
ƒIt is an option to provide conventional phototherapy in hospital or at home
at TSB levels 2-3 mg/dL below those shown but home phototherapy should
not be used in any infant with risk factors.
10
*The risk factors listed above are conditions that might affect the likelihood
of brain damage at different bilirubin levels. These factors increase the risk
of brain damage because of their negative effects on albumin binding of
bilirubin, the integrity of the blood brain barrier, and the susceptibility of the
brain cells to damage by bilirubin.
5
Infants at lower risk = > 38 wk. and well
Infants at medium risk= > 38 wk. +risk factors or 35 – 37 6/7 wk. & well
Bhutani, Pediatrics1999;103:6
Infants at higher risk= 35-37 6/7 wk. + risk factors
0
TcB – Transcutaneous Bilirubin
TSB – Total Serum Biilirubin/Direct
0
12
24
36
48
60
72
84
96
108
120
132
0
144
B irth
Postnatal Age (hours)
24 h
48 h
72 h
96 h
5 Days
6 Day s
7 Days
Age
Risk Factors
3
Risk Factors
forRisk
Development3of Severe Hyperbilirubinemia
Major
Minor Risk
Predischarge TSB or TcB
(see nomogram above)
In high zone (>95%)
In high intermediate zone
(>75%)
Visible Jaundice
First 24 hrs.
Before discharge
Gestational age
35-36 wks
37-38 wks.
Previous sibling
Received phototherapy
Jaundiced, no phototherapy
Blood Groups
Hemolytic disease
Blood grp. incompatibility with
+DAT. Other known hemolytic disease
Feeding
Exclusive breast (↑risk if poor feeder
or ↑ wt. loss )
East Asian
Breast fed, nursing well
Cephalhematoma or significant
bruising
Macrosomic infant of IDM,male
gender, maternal age >25 yr.
Decreased Risk
Hispanic (Mexican)?
Exclusive formula
feeding.
African American
*unless G^PD def.~12% are
G6PD deficient
Other factors
ƒ
ƒ
25
20
15
Infants at lower risk = > 38 wk. and well
Infants at medium risk= > 38 wk. +risk factors or 35 – 37 6/7 wk. & well
Follow-up should be provided as follows
Any infant discharged before age 72 hours should be seen
within 2 days of discharge.
*If an infant is discharged before age 72 hours AND if you plan to follow up in more than 2 days, please document your reasons in the chart.
The dashed lines for the first 24 hours indicate uncertainty due to a wide range of clinical
circumstances and a range of responses to phototherapy
Perform immediate exchange if infant shows signs of acute bilirubin encephalopathy, (
hypertonia, arching, retrocollis, opisthotonos, fever, high pitched cry)or if TSB is >5 mg/dL
above these lines.
Risk factors = isoimmune hemolytic disease, G6PD deficiency, asphyxia, respiratory
distress, significant lethargy, temperature instability, sepsis, acidosis.
Measure serum albumin and evaluate B/A ratio = bilirubin ( mg/dL) / albumin (g/dL). See
the table below.
Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin
If TSB above exchange transfusion line, repeat every 2-3 hrs until TSB decreases for 2
consecutive measurements.
In isoimmune hemolytic disease give IVIG 0.5 – 1g/kg over 2-3 hours if TSB is rising and
within 2-3 mg/dL of exchange level. This can be repeated in 12 hr.
If infant is well and 35-36 6/7 wk (medium risk) can individualize TSB levels for
exchange based on actual gestational age
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
Infants at higher risk= 35-37 6/7 wk. + risk factors
10
Birth
24 h
Discharged from hospital
after 72 hrs.
*The more risk factors present, the greater the risk of developing severe hyperbilirubinemia
**If considering phototherapy or exchange transfusion please refer to the back of this page for guidelines and information.
Guidelines for Exchange Transfusion in infants > 35 wk Gestation
30
>41 wk
(eg. G^PD deficiency)
Race
3
Low risk zone (<40%)
Total Serum Bilirubin (mg/dL)
•
•
•
•
•
If many risk factors, see earlier. If
few risk factors, can see later but
document your reasons in chart
48 h
72 h
96 h
5 Days
6 Days
7 Days
Age
The risk factors listed above are conditions that might affect the likelihood of brain damage
at different bilirubin levels. These factors increase the risk of brain damage because of their
negative effects on albumin binding of bilirubin, the integrity of the blood brain barrier, and
the susceptibility of the brain cells to damage by bilirubin
During birth hospitalization, exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. For readmitted
infants, if the TSB level is above the exchange level, repeat TSB measurement every 2 to 3 hours and consider exchange, if the TSB remains above
the levels indicated after intensive phototherapy for 6 hours. 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.
Risk Category
B/A Ratio at Which exchange Transfusion Should
be considered
Lower Risk
Medium Risk
Higher Risk
TSB mg/dL
8.0
7.2
6.8
If the TSB is at or approaching the exchange level, send blood for
immediate type and cross match. Blood for exchange transfusion is
modified whole blood. (red cells and plasma) cross matched against
the mother and compatible with the infant.
8
Give Physicians the Tools to
Implement the Guidelines
Wallet-sized nomogram and guidelines
Quality improvement programs
Tony Burgos, MD, MPH
Stanford University and
Packard Children’s Hospital
Chris Longhurst, MD, MS
Stanford University and
Packard Children’s Hospital
Stuart Turner, DVM
University of California Davis
9
% infants
Scheduled follow up < 3 days after discharge
William Beaumont Hospital
100
90
80
70
60
50
40
30
20
10
0
Length of Stay
< 48 hrs
>48 hrs
1994
Chart review &
letter to
pediatricians re:
guidelines
1995
Data
presented to
MD’s.
Follow up
letter
1998
QI monitor
1999
Presentation
to MD’s/
Memo to all
MD’s. QI
monitor and
letter to MD if
noncompliant
2000
If have a very jaundiced baby,
send baby to pediatric floor or
NICU not to emergency
department
2003
Continue QI monitor and letters to
MD’s if not compliant
Jaundice is now
predominantly an outpatient
problem
Newborn follow up in one to
two weeks is abandonment
Drive through deliveries should not
be a problem as long as you don’t
abandon the baby
Need a high degree of
humility when assessing
jaundice clinically.
10
Follow The AAP Guidelines
“This is an age in which one
cannot find common sense
without a search warrant”
No system is perfect,
use common sense
References:
•
•
•
•
•
•
Maisels MJ, Baltz RD, Bhutani VK, et al: Neonatal jaundice and
kernicterus. Pediatrics 2001; 108:763
Bhutani VK, Johnson LH, Maisels MJ, et al: Kernicterus:
Epidemiological strategies for its prevention through systems-based
approaches. J Perinatol 2004;24:650.
Johnson LH, Bhutani VK, Brown AK: System-based approach to
management of neonatal jaundice and prevention of kernicterus. J Pediatr
2002;140:396
Maisels MJ, Baltz RD, Bhutani V, et al: Management of
hyperbilirubinemia in the newborn infant 35 or more weeks of gestation.
Pediatrics 2004;114:297.
Bhutani VK, Johnson L, Sivieri EM: Predictive ability of a predischarge
hour-specific serum bilirubin for subsequent significant
hyperbilirubinemia in healthy-term and near-term newborns. Pediatrics
1999;103:6
Newman TB, Liljestrand P, Escobar GJ: Jaundice noted in the first 24
hours after birth in a managed care organization. Arch Pediatr Adolesc
Med 2002;156:1244
George Will
•
•
•
•
•
•
References:
Moyer VA, Ahn C, Sneed S: Accuracy of clinical judgment in neonatal
jaundice. Arch Pediatr Adolesc Med 2000;154:391
Maisels MJ, Ostrea EJ Jr, Touch S, et al: Evaluation of a new
transcutaneous bilirubinometer. Pediatrics 2004;113:1628
Rubaltelli FF, Gourley GR, Loskamp N, et al: Transcutaneous bilirubin
measurement: A multicenter evaluation of a new device. Pediatrics
2001;107:1264
Newman TB, Escobar GJ, Gonzales VM, et al: Frequency of neonatal
bilirubin testing and hyperbilirubinemia in a large health maintenance
organization. Pediatrics 1999;104:1198
Newman TB, Liljestrand P, Escobar GJ: Combining clinical risk factors
with bilirubin levels to predict hyperbilirubinemia in newborns. Arch
Pediatr Adolesc Med 2005;159:113
Ip S, Chung M, Kulig J, O’Brien R, et al: An evidence-based review of
important issues concerning neonatal hyperbilirubinemia. Pediatrics
2004;114:e130
References
•
•
•
•
•
•
•
Huang M-J, Kua K-E, Teng H-C, Tang K-S, Weng H-W, Huang
C-S. Risk factors for severe hyperbilirubinemia in neonates.
Pediatr Res 2004; 56:682-689.
Kaplan M., Hammerman C., Maisels M.J. Bilirubin genetics for
the nongeneticist: hereditary defects of neonatal bilirubin
conjugation. Pediatrics 2003; 111:886-893.
Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E.
Gilbert's syndrome and hyperbilirubinaemia in ABOincompatible neonates. Lancet 2000; 356:652-653.
Watchko J.F. Vigintiphobia revisited. Pediatrics 2005;
115:1747-1753.
Maisels M.J., Watchko J.F. Treatment of jaundice in low
birthweight infants. Arch Dis Child Fetal Neonatol Ed 2003;
88:F459-F463.
Watchko J.F., Maisels M.J. Jaundice in low birth weight infants pathobiology and outcome. Arch Dis Child Fetal Neonatol Ed
2003; 88:F456-F459.
Kaplan M., Hammerman C. Glucose-6-phosphate
dehydrogenase-deficient neonates: A potential cause for concern
in North America. Pediatrics 2000; 106:1478-1480.
References
• Sgro M, Campbell D, Shah V. Incidence and causes of
severe hyperbilirubinemia in Canada. CMAJ 2006; 175:
587-90
• Canadian Pediatric Society. Guidelines for detection,
management and prevention of hyperbilirubinemia in term
and late preterm newborn infants (35 or more weeks’
gestation) Pediatr Child Health 2007; 12: 1B-112B (suppl).
• Manning D et al Prospective surveillance of severe
hyperbilirubinemia in the newborn in the UK and Ireland.
Arch Dis Child Fetal Neonatal Ed 2007; 92: 342-346
11