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2020 Initiatives

Annual Meeting
September 12, 2018
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Evidence-Based Standardization of Phototherapy
Treatment of Neonatal Hyperbilirubinemia in Term
and Late Preterm Infants

Christopher M. Lakin, MD, FAAP
Charlotte / Asheville, NC
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Neonatal hyperbilirubinemia is an extremely prevalent condition which is
screened for in most newborns, and for which treatment with phototherapy is
not infrequently given.
The most serious potential outcome - kernicterus - is extremely rare (with
reported incidence rates of 0.0006 to 0.0015%), while the most common
treatment (UV phototherapy) is not without possibly associated medical risks -
including leukemia (esp. in Down Syndrome), skin cancer, retinal damage,
increased Tumor Necrosis Factor-alpha), and riboflavin deficiency. In addition, it
has the known adverse effects of interference with mother-infant bonding,
prolonged hospital stays, hospital re-admissions, and increased cost.
In addition to the risk-benefit equation, there is the documented issue of
significant inter-hospital variation in management - including adherence to the
2004 AAP Guidelines, and use of available resources such as BiliTool and
nomograms. Furthermore, a new tool has become available in the past year,
but is seemingly not yet in widespread circulation or use:
Risk scoring for rebound hyperbilirubinemia (similar to the Kaiser
Permanente Neonatal Sepsis Calculator)
Initiative Background
-cont.-
PQCNC has a real opportunity to reduce (presumptive) inter-hospital
variability in adherence to phototherapy guidelines - with a primary
desired outcome being reduction of unnecessary phototherapy —->
Possible strategies could include:

+ Standing orders or order sets that incorporate phototherapy
guidelines

+ Embedding BiliTool in EMR - and/or electronic graphing of
baby’s bill levels on the Bhutani and/or AAP treatment nomograms
(if this is not already in place at your institution)

+ Embedding the Clinical Prediction Rule for Rebound
Hyperbilirubinemia in EMR [Note: As of now, a web-based
calculator has not been developed. - and is not planned by Kaiser
Permanente.]
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Promote improved, widespread, and uniform adherence to evidence-based guidelines
and tools for phototherapy treatment of neonatal hyperbilirubinemia with primary goals
of reducing: unnecessary or excessive UV exposure, cost, hospital length of stay and
re-admissions.
Included within this will be the introduction of a new clinical tool: “Rebound Risk
Calculator”
- -> See following slide

Also: Survey institutions & providers regarding current bill mgmt. practices -
including:
- Use of Nomogram, BiliTool - - and are these embedded in EMR or easily
accessible?
- Protocol (if any) for how often to check TSB for babies receiving
phototherapy
- Protocol (if any) used to determine when to stop phototherapy, and if/
when to do
follow-up TSB (or serum bili) to check for rebound
REBOUND RISK CALCULATOR
A Clinical Prediction Rule for Rebound Hyperbilirubinemia Following Inpatient Phototherapy
- Pearl W. Chang, Michael W. Kuzniewicz, Charles E. McCulloch, Thomas B. Newman // [Kaiser
Permanente of Northern California] // http://pediatrics aappublications.org/content/139/3/e20162896

The risk of rebound hyperbilirubinemia can be
quantified according to an infant’s gestational
age, age at phototherapy initiation, and TSB
[Total Serum Bilirubin] *relative to the
treatment threshold* at phototherapy
termination.

Score = 15 (if gestational age < 38 weeks)− [7
× age in days at phototherapy initiation] − [4 ×
(AAP phototherapy threshold − TSB at
phototherapy termination)] + 50
REBOUND RISK CALCULATOR
-cont.-
• If gestational age is >38 weeks, omit the “15”, but leave
the minus sign that comes in front of the next part of the
equation!
• For “age in days”, divide hours of age by 24
• NOTE: Although a score of <20 corresponds to a very low
(<4%) risk of rebound (within 72 hrs.) - - this factor alone
cannot/should not be the sole determinant in the decision
to stop phototherapy (or check further TSB’s). - However,
it can be a very helpful guide within the context of other
clinical factors. [This is an important distinction from the
Kaiser Permanente Neonatal Sepsis Calculator!]
• See commentary article by Paul & Maisels in “Supportive
Materials” (Slides 10-12)
REBOUND RISK CALCULATOR
-cont.-

RISK PROBABILITY BASED ON CALCULATOR SCORE

[The numbers on the x-axis represent percent probability (10%, 20%, etc.) ]
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All hospitals and providers caring for term
and late-preterm newborns.
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• Assurance of more appropriate use of
phototherapy
• Increased awareness of the extremely low risk of
kernicterus
• Minimization of possible long-term risks from UV
exposure
• Improved mother-infant bonding and hospital
experience
• Reduction of cost, hospital length-of-stay, re-
admissions for phototherapy
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• A Clinical Prediction Rule for Rebound
Hyperbilirubinemia Following Inpatient
Phototherapy - Pearl W. Chang, Michael
W. Kuzniewicz, Charles E. McCulloch,
Thomas B. Newman - - http://pediatrics
aappublications.org/content/139/3/
e20162896
Can I Stop Phototherapy for This Baby?
Ian M. Paul, MD, MSc,a,b M. Jeffrey Maisels, MB, BCh, DScc Departments of aPediatrics, and bPublic Health Sciences, Penn State College of Medicine, Hershey,
Pennsylvania; and cDepartment of Pediatrics, Beaumont Children’s Hospital and Oakland University William Beaumont School of Medicine, Royal Oak, Michigan

Pediatrics.2017;139(3): e20163832

The American Academy of Pediatrics (AAP) consensus-based guidelines for the initiation of
phototherapy1,2 have been universally adopted in the United States and even applied in other
countries,3,4 whereas several countries have developed their own phototherapy guidelines.5–8
Substantially less guidance, however, has been provided on when to stop birth hospitalization
phototherapy to avoid retreatment. In fact, the AAP Subcommittee on Hyperbilirubinemia has
acknowledged that there is no standard for discontinuation.2 Evidence-based answers to this
common clinical question are now provided by Chang et al9 …
From 105 808 neonates born at ≥35 weeks’ gestation at 1 of 17 Kaiser Permanente Northern
California hospitals between 2012 and 2014, Chang et al9 identified a cohort of 7048 newborns
treated with phototherapy. The objective of the study was to identify predictors of “rebound,”
defined as a return to treatment threshold levels within 72 hours of discontinuation of a neonate’s
first round of phototherapy treatment. These data were then used to create a score that could
predict the probability of rebound and help clinicians decide when to discontinue phototherapy.
The rich electronic dataset available to the researchers included a number of key variables,
including gestational age, sex, birth weight, feeding type, direct antiglobulin test results, and
details regarding the initiation, course, and termination of phototherapy. Total serum and direct
bilirubin data were also included. With 4.6% of the sample experiencing a return to treatment
threshold after cessation of phototherapy, Chang et al9 identified multiple significant predictors of
rebound hyperbilirubinemia, including Asian race and exclusive breastfeeding, but their
parsimonious prediction score was formulated using only 3 variables: gestational age, age at
phototherapy initiation, and “relative” total serum bilirubin (level at cessation minus the AAP
phototherapy threshold).
-cont.-
Specifically, a gestational age of <38 weeks and higher relative serum bilirubin were associated
with an increased likelihood of rebound hyperbilirubinemia, whereas older age at phototherapy
initiation was protective. These observations are consistent with those of other studies,10,11
and the fact that infants with hemolytic disease–associated hyperbilirubinemia are much more
likely to both require early phototherapy and experience a rebound. The prediction score
calculated from these variables generated thresholds where rebound hyperbilirubinemia was
highly unlikely, something that can easily be included in the clinical care of such neonates.
Importantly, use of this score could have resulted in a 1-day shorter hospital stay for roughly
one-third of those treated with phototherapy, something that would be desirable for all
stakeholders.

Numerous previous studies have analyzed the bilirubin rebound after phototherapy,10–15 but
none have approached the sample size studied by Chang et al.9 In addition, comparisons with
these studies are difficult because of differences in the populations studied, the bilirubin levels
chosen for phototherapy termination, and the criteria used to define rebound. In some
ilnstitutions, about half of the infants receiving phototherapy for the first time are those who are
readmitted,10 a population in whom the primary cause for hyperbilirubinemia is much less likely
-cont.-
to be active hemolysis and in whom the risk of rebound is much lower.10 In the Chang
et al study,9 62% of infants received their phototherapy during their birth
hospitalization. Because of the strong association between older age and less
rebound, we assume that many of the older infants were those readmitted for their first
course of phototherapy, although the authors do not specifically address this issue.
This prediction rule for rebound hyperbilirubinemia comes at a

time when innovation around well newborn care has been increasing, providing
evidence-based and guideline-based tools to improve patient care. After publication of
the Bhutani nomogram for neonatal hyperbilirubinemia,16 Web-based tools, such as
Bilitool (www.bilitool. org), became routinely used in daily clinical care. More recently,
the Newborn Sepsis calculator17,18 (https://neonatalsepsiscalculator.
kaiserpermanente.org/) and Newborn Weight Tool19,20 (www. newbornweight.org)
have helped clinicians adapt evidence on sepsis risk and newborn weight loss into
mobile platforms that can inform clinical care in real-time. The formula used in the new
prediction rule for rebound hyperbilirubinemia is simple and easy to use, and has
similar potential to influence clinical care for those newborns receiving phototherapy.

Pediatrics Nov. 1, 2016 - - Janelle L Aby, MD, FAAP (Stanford Univ. School of
Medicine) - at the 2016 American Academy of Pediatrics (AAP) National
Conference

“To think through a clinical scenario in a stepwise fashion, remember the
RAINBOW acronym:

· Risk of bilirubin toxicity.

· Assess rate of bilirubin rise.

· Investigate causes of hyperbilirubinemia.

· Number (total bilirubin/TB) at which to treat.

· Breastfeeds to continue.

· Outcome.
-cont.-
Another invaluable tool is available at www.bilitool.org. Plugging in information such as the baby's
age and bilirubin level calls up published nomograms and AAP treatment guidelines for that case.
Not every baby with the same numeric bilirubin level is the same. Say a preterm baby's bilirubin
level falls into the Bhutani nomogram low-intermediate risk category. If the baby is late preterm

It's a 2-step process—the Bhutani nomogram provides a general picture of risk, while AAP
guidelines drill down into actual treatment recommendations. Using these guidelines is somewhat
tricky because the AAP uses slightly different risk categories. Consider a bilirubin level of 15 mg/
dL at 60 hours. For a term neonate without risk factors, the AAP does not recommend
phototherapy until 16 mg/dL or higher. However, if a baby has hemolysis, AAP guidelines
recommend phototherapy at 15 mg/dL. There's no specific number that drives treatment
decisions because every hour the threshold changes, for all categories.

Ultimately, said Aby, we are trying to identify the babies who really need to start phototherapy at a
lower TB level, versus those who perhaps do not.”

————————————-

“Additional emphasis also should be placed on determining prior to hospital discharge which
infants are at highest risk of requiring phototherapy. Bhutani et al reported that a combination of
predischarge bilirubin level and specific clinical factors is highly predictive of subsequent
phototherapy use. Recent and evolving work on genetic factors affecting bilirubin metabolism also
may give clinicians insight into which infants may require extra vigilance for progressive jaundice
during the early neonatal period.”
- W. Christopher Golden, MD, FAAP
(Medical Director of Newborn Nursery, Johns
Hopkins School of Medicine)
Regarding cancer risk/overuse of phototherapy -
(1) Kaiser Permanente of Northern California Study / Pediatrics - June 2016/Vol.
137, Issue 6:
“…[E]ven if the HRs [Hazard Ratios] for any phototherapy were at the top of the 95% CIs reported in this
study, absolute risk of cancer from phototherapy would be low, at least in childhood (<1/1000 over 10 years).

Is that potential risk worth taking? Phototherapy is often given at TSB levels at which the number needed to
treat to prevent 1 infant from reaching exchange levels is in the hundreds or thousands. Recent data suggest
that unless exchange transfusion thresholds are exceeded by at least 10 mg/dL, there is little or no
increased risk of cerebral palsy or hearing loss. Thus, even the low upper limit of risk of cancer may
exceed the likely benefits of treatment in many infants. The likelihood of harms exceeding benefits is
greatest in children with Down syndrome, whose much higher baseline risk of leukemia might lead
cautious clinicians to increase the treatment threshold for initiation of phototherapy in these infants, despite
the fact that the association between phototherapy and cancer has not yet been proven to be causal.

Conclusions
Although we confirmed a crude association between phototherapy and childhood cancer, particularly
nonlymphocytic leukemia, associations were diminished and no longer statistically significant after we
controlled for confounding variables. Nonetheless, consistent crude associations, clinically relevant upper
limits of adjusted 95% CIs, and the statistically significant adjusted association between multiple
phototherapy admissions and myelogenous leukemia suggest that avoiding unnecessary phototherapy
would be prudent, especially in children with Down syndrome.”
(2) Update on Pediatric Overuse
Eric R. Coon, et.al. - Pediatrics January, 2017

Current Thresholds for Treating Hyperbilirubinemia Are Probably Too Low

“Background: Because of an association between infant hyperbilirubinemia and
neurodevelopmental abnormalities, the American Academy of Pediatrics recommends treatment
of hyperbilirubinemia, including exchange transfusion, when serum levels reach certain
thresholds in the context of patient risk factors.

Findings: A multicenter study evaluating 525 409 infants born within an integrated health care
system in Northern California between 1995 and 2011 found small increases in the absolute risk
of cerebral palsy for hyperbilirubinemia in excess of recommended exchange transfusion
thresholds. Compared with infants whose total serum bilirubin levels were never above the
exchange transfusion threshold (ETT), infants with peak bilirubin values of 0 to 4.9 mg/dL above
the ETT had a slightly increased risk of cerebral palsy (absolute risk difference, 0.2%; 95% CI,
0%–0.5%). Of the 3/525 409 [< 0.0006%]* patients who developed kernicterus, all had ≥2
neurotoxicity risk factors and peak bilirubin levels >5 mg/dL higher than the currently
recommended ETT.”
[*This is lower than the incidence of 0.0015% during the period 1994-2005, as reported by B.L.
Burke et. al. in Trends in hospitalizations for neonatal jaundice and kernicterus in the United
States, 1988-2005 - Pediatrics, Feb. 2009 (Vol. 123, Issue 2)]
-cont.-
Implications: Risk of cerebral palsy and kernicterus is extremely low among infants
with modest elevations in peak serum bilirubin values beyond the current ETT.
Current treatment thresholds for hyperbilirubinemia can likely be raised without
putting infants at greater risk of brain injury.”

[29] Wu YW, Kuzniewicz MW, Wickremasinghe AC, et al. Risk for cerebral palsy in
infants with total serum bilirubin levels at or above the exchange transfusion
threshold: a population-based study. JAMA Pediatr. 2015;169(3):239–246pmid:
25560920

>> Evidence quality: 2b [Individual cohort study or low quality randomized controlled
trials (e.g. <80% follow-up) ] <<
Clinician Adherence to Guideline for Phototherapy Use in Newborns
- Diane J. Madlon-Kay, MD, MS - Journal of the American Board of Family
Practice, July-Aug. 2012 / Vol. 25, No. 4

Retrospective review of medical records of 1160 newborns receiving care
at the normal newborn nurseries at 2 Twin City, MN, hospitals. —>
436 babies received phototherapy - - Of these, phototherapy “was
indicated [per 2004 AAP guideline] in 37% of cases and not indicated in
8%. In 56% of cases it was considered sub-threshold [<3 mg/dL below
treatment threshold]. When phototherapy was not administered, it was
appropriate in 99% of cases but was inappropriate or missed in 1% of
cases.
There was a significant difference in clinician adherence to the
phototherapy guidelines between the hospitals. The addition of the
phototherapy nomogram to the newborn charts did not change adherence
to the guideline.”
TAKE-AWAY POINTS:

(1) More potential risk from over-treatment than from under-treatment

(2) One of - if not the - most important factor(s) in adherence to
phototherapy guidelines is hospital of birth

(3) Having the phototherapy nomogram available in the chart does not likely
influence guideline adherence [? No studies evaluating the effectiveness of
BiliTool.]

(4) Use of Rebound Risk scoring should aid in making the decision on
whether/when to stop phototherapy, and on the advisability/relative
importance of follow-up bilirubin assessment within the following 72 hrs.