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Jurding Anak
Jurding Anak
Rebound Hyperbilirubinemia
Following Inpatient Phototherapy
Pearl W. Chang, MD,a Michael W. Kuzniewicz, MD, MPH,b,c Charles E. McCulloch, PhD,d Thomas B. Newman, MD, MPHb,c,d
OBJECTIVES: The American Academy of Pediatrics provides little guidance on when to abstract
discontinue phototherapy in newborns treated for hyperbilirubinemia. We sought to
develop a prediction rule to estimate the probability of rebound hyperbilirubinemia after
inpatient phototherapy.
METHODS: Subjects for this retrospective cohort study were infants born in 2012 to 2014 at
≥35 weeks’ gestation at 16 Kaiser Permanente Northern California hospitals who received
inpatient phototherapy before age 14 days. We defined rebound as the return of total serum
bilirubin (TSB) to phototherapy threshold within 72 hours of phototherapy termination. We
used stepwise logistic regression to select predictors of rebound hyperbilirubinemia and
devised and validated a prediction score by using split sample validation.
RESULTS: Of the 7048 infants treated with inpatient phototherapy, 4.6% had rebound
hyperbilirubinemia. Our prediction score consisted of 3 variables: gestational age <38
weeks (adjusted odds ratio [aOR] 4.7; 95% confidence interval [CI], 3.0–7.3), younger age
at phototherapy initiation (aOR 0.51 per day; 95% CI, 0.38–0.68), and TSB relative to the
treatment threshold at phototherapy termination (aOR 1.5 per mg/dL; 95% CI, 1.4–1.7).
The model performed well with an area under the receiver operating characteristic curve
of 0.89 (95% CI, 0.86–0.91) in the derivation data set and 0.88 (95% CI, 0.86–0.90) in the
validation data set. Approximately 70% of infants had scores <20, which correspond to a
<4% probability of rebound hyperbilirubinemia.
CONCLUSIONS: The risk of rebound hyperbilirubinemia can be quantified according to an
infant’s gestational age, age at phototherapy initiation, and TSB relative to the treatment
threshold at phototherapy termination.
aDepartment
WHAT’S KNOWN ON THIS SUBJECT: There are no
of Pediatrics, Seattle Children’s Hospital, Seattle, Washington; bDivision of Research, Kaiser
Permanente Northern California, Oakland, California; and Departments of cPediatrics, and dEpidemiology & standards and little evidence to support decisions
Biostatistics, University of California, San Francisco, California about when to discontinue phototherapy in
newborns being treated for hyperbilirubinemia.
Dr Chang conceptualized and designed the study, carried out statistical analysis and
interpretation of data, and drafted the initial manuscript; Drs Kuzniewicz and McCulloch assisted WHAT THIS STUDY ADDS: We describe a model to
with study design; Dr Newman conceptualized and designed the study, obtained funding, and quantify the risk of rebound hyperbilirubinemia.
guided statistical analysis and interpretation of data; and all authors revised and reviewed the This model will enable clinicians to discontinue
manuscript and approved the final manuscript as submitted. phototherapy when the risk of rebound
DOI: 10.1542/peds.2016-2896 hyperbilirubinemia reaches a suitably low level.
Accepted for publication Dec 19, 2016
Address correspondence to Pearl W. Chang, MD, Seattle Children’s Hospital, M/S FA.2.115, PO Box
5371, Seattle, WA 98145-5005. E-mail: pearlchangmd@gmail.com To cite: Chang PW, Kuzniewicz MW, McCulloch CE, et al. A
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Clinical Prediction Rule for Rebound Hyperbilirubinemia
Following Inpatient Phototherapy. Pediatrics. 2017;139(3):
Copyright © 2017 by the American Academy of Pediatrics e20162896
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TABLE 1 Cohort Characteristics (N = 7048) 0.895 in the derivation sample.
Characteristic n % Therefore, we elected to include
Gestational age, wk, mean (SD) 38 (1.7)
only the original 3 variables in our
<38 wk 2791 39.6 prediction rule.
Birth wt, g, mean (SD) 3237 (577)
We also performed sensitivity
Male sex 3830 54.3
Infant race and ethnicity analyses with inclusion of gestational
White 2106 29.9 age as a categorical variable in the
Asian 2357 33.4 predictive model, which minimally
Hispanic 1607 22.8 affected the AUROC (0.891 as
African American 356 5.1
a categorical versus 0.887 as a
Other 453 6.4
Unknown 169 2.4 dichotomous variable). Inclusion
DAT of the 34 infants who underwent
Positive 1019 14.5 recurrent phototherapy below
Negative 3340 47.4 treatment threshold did not alter
Not done 2689 38.2
Feeding during phototherapy hospitalization
the predictors selected by stepwise
Breast milk only 2051 29.1 regression or the equation or have
1–3 formula feedings 994 14.1 a marked effect on the Hosmer–
4–10 formula feedings 2605 37.0 Lemeshow goodness of fit (P = .22)
≥11 formula feedings 1107 15.7 and AUROC (0.877) in the derivation
Unknown 291 4.1
Phototherapy during birth hospitalization 4364 61.9
data set. In the subset of infants
Initiation of phototherapy with measured TSB at phototherapy
Age, d, mean (SD) 2.3 (1.3) — termination (n = 1737), AUROC was
Relative TSB, mg/dL, mean (SD) 0.1 (2.0) — slightly higher at 0.901 (95% CI,
Termination of phototherapy 0.871–0.930). For our secondary
Age, d, mean (SD) 3.6 (1.3) —
Estimated TSB, mg/dL, mean (SD) 9.8 (2.7) —
outcome of TSB rebound to ≥1
Estimated relative TSB, mg/dL mg/dL above treatment threshold,
<−13 197 2.8 application of the above score gave
−13 to <−10 1153 16.4 an AUROC of 0.888 (95% CI, 0.866–
−10 to <−7 2677 38.0 0.909), and for TSB rebound to ≥2
−7 to <−4 2114 30.0
−4 to <0 839 11.9
mg/dL above treatment threshold,
≥0 68 1.0 the AUROC was 0.901 (95% CI,
Home phototherapy order 0.869–0.932).
During inpatient phototherapy 310 4.4
After inpatient phototherapy termination 462 6.6 The probability of rebound
Rebound hyperbilirubinemia within 72 h 324 4.6 hyperbilirubinemia was <10% with
≥0 to <1 above AAP phototherapy threshold 159 2.3 a prediction score of <30 (87% of
≥1 to <2 above AAP phototherapy threshold 86 1.2 the derivation group, 86% of the
≥2 above AAP phototherapy threshold 79 1.1
validation group) and <4% with
Recurrent inpatient phototherapy below threshold 34 0.5
a prediction score of <20 (71% of
—, not applicable.
the derivation group, 69% of the
validation group) (Table 4 and Fig 2).
days (60 hours) old at phototherapy of freedom) was 7.7 (P = .47) and There were 3023 infants who had
initiation and whose TSB was 6 mg/ the AUROC was 0.887 (95% CI, ≥2 measured TSBs after the start
dL below the treatment threshold at 0.864–0.910). The validation data of phototherapy. Of these infants,
phototherapy termination (eg, TSB set (n = 3530) had a similar AUROC 1025 (34%) had a score of <20 at
11.5 mg/dL at 96 hours) would have (0.881) and 95% CI (0.859–0.903) the penultimate TSB measurement
a score of 15 − (7 × 2.5) − (4 × 6) + (Fig 1). With the best subsets variable and were continued on inpatient
50 = 23.5, whereas a score for the selection, the best model by Bayesian phototherapy for another average
same baby at ≥38 weeks’ gestation information criterion consisted of the 23 ± 9 hours.
would be 15 fewer, or 8.5. same 3 predictors. The best model
The discrimination and fit of by Akaike’s information criterion
the predictive model using the consisted of the same 3 predictors DISCUSSION
generated score were excellent. In plus formula use and race and We used a large cohort to
the derivation data set (n = 3518), ethnicity. With a 5-variable model, examine predictors of rebound
the Hosmer–Lemeshow χ2 (8 degrees the AUROC minimal improved to hyperbilirubinemia, defined
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TABLE 3 Multivariate Predictors of Rebound Hyperbilirubinemia supplementing with formula,
Variable OR 95% CI P discharging an infant
Male sex 1.19 0.95–1.49 .124 with home phototherapy (if
Gestational age, wk <.001 available), or lowering the relative
35 10.63 5.48–20.62 — TSB by an additional 1 mg/dL at
36 11.39 6.51–19.92 — phototherapy termination with
37 11.68 6.95–19.64 —
similar efficacy.
38 2.70 1.88–3.89 —
39 1.91 1.34–2.74 — Although the OR for a positive
40 Reference direct antiglobulin test (DAT) was
41 0.76 0.34–1.70 —
significant in unadjusted analyses,
Birth wt, g <.001
<2000 0.12 0.04–0.37 — the adjusted OR was only 1.37
2000–2499 0.33 0.19–0.56 — (95% CI, 0.90–2.07), probably
2500–2999 0.83 0.57–1.20 — because a positive DAT moves a
3000–3499 Reference baby to a higher risk group, with
3500–3999 1.40 0.99–1.97 —
a lower phototherapy threshold.
4000–4499 1.43 0.63–3.25 —
≥4500 1.74 0.60–5.01 — This change in turn reduces
Infant race and ethnicity <.001 the difference between the last
White Reference measured TSB and the threshold.
Asian 1.62 1.11–2.36 — Thus, the effect of the DAT is
Hispanic 1.02 0.67–1.54 —
captured by the difference between
African American 0.46 0.26–0.81 —
Other 0.53 0.25–1.12 — the last TSB and the phototherapy
DAT .34 threshold.
Negative Reference
Positive 1.37 0.90–2.07 —
Not done 0.86 0.59–1.27 — In our cohort, 34% of infants may
Feeding during phototherapy .001 have been able to discontinue
hospitalization
Breast milk only Reference
inpatient phototherapy a day
1–3 formula feedings 0.92 0.62–1.36 — earlier with <4% risk of rebound
4–10 formula feedings 0.63 0.48–0.83 — hyperbilirubinemia. The decision to
≥11 formula feedings 0.43 0.27–0.68 — discontinue phototherapy is based
Age at phototherapy initiation, 0.38 0.33–0.44 <.001 on balancing the risks and costs
per day
Age at phototherapy termination, 1.15 0.83–1.57 .40
of prolonging treatment against
per day the benefit of reducing the risk
Relative TSB at phototherapy 1.48 1.32–1.66 <.001 of rebound hyperbilirubinemia.
termination, per mg/dL Hospitalization is burdensome
Home phototherapy at discharge 0.62 0.41–0.94 .02 for families, and phototherapy
—, not applicable. can disrupt breastfeeding and
infant bonding. In addition,
for rebound hyperbilirubinemia. were formula feeding during the there is emerging evidence
In the aforementioned Bansal phototherapy hospitalization and that phototherapy may have
et al9 trial, there was no significant continuing on home phototherapy potential associations with
difference in the occurrence of after discharge. A higher number melanocytic nevi14 and infantile
repeat phototherapy between of formula feeds was associated cancer, especially acute myeloid
infants randomly assigned to with lower odds of rebound leukemia.15,16 Our prediction
discontinue phototherapy at a TSB hyperbilirubinemia. Interestingly, score quantifies the probability
of ≥1 mg/dL versus ≥3 mg/dL the OR for 4 to 10 formula of rebound hyperbilirubinemia
below the AAP phototherapy feedings (0.63) was similar to to help physicians and parents
threshold (5 out of 25 vs 5 out that for continuation on home decide, based on their level of
of 27, respectively, P = .58), but phototherapy (OR = 0.62) and for acceptable risk for rebound
the trial was small, consisting of a 1mg/dL decrease in relative TSB hyperbilirubinemia, when to
52 infants born at >36 weeks’ at phototherapy termination (OR = discontinue phototherapy. For
gestation. 0.68). These results suggest that a example, consider a 37-week
clinician aiming to reduce the risk gestational age infant who starts
Additional significant predictors of rebound hyperbilirubinemia phototherapy at 4 days of age.
of rebound hyperbilirubinemia further could consider Discontinuing phototherapy at a
FIGURE 2
Probability of rebound hyperbilirubinemia by score. Score = 15 (if gestational age <38 weeks) − 7 × (age in days at phototherapy initiation) − 4 × (AAP
phototherapy threshold − TSB at phototherapy termination) + 50.
TSB of 5 mg/dL below treatment for whom follow-up TSB testing This study has limitations. One of our
threshold gives a score of 17 is difficult or readmission for key predictor variables, the TSB at
and an estimated 2.8% probability hyperbilirubinemia presents time of phototherapy termination,
of rebound hyperbilirubinemia. a greater hardship, it may make was estimated by extrapolation
In comparison, the probability sense to continue phototherapy for the majority of our subjects,
of rebound would increase to 6.0% longer. On the other hand, a 10% which presumably worsened the
at a TSB of 3 mg/dL below and or 15% risk may be acceptable for discrimination of the prediction rule.
12.3% at a TSB of 1 mg/dL below a reliable family close to an infant However, we envision clinicians
treatment threshold. In infants care center. using the rule to decide whether to
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continue phototherapy each time a TABLE 4 Risk of Rebound Hyperbilirubinemia by Score
TSB result becomes available. Thus, Infants With Rebound Hyperbilirubinemia
they will know the TSB at the time of Derivation Group (N = 3518) Validation Group (N = 3530)
phototherapy termination and will
Prediction Score N % N %
not need to extrapolate. In the subset
of subjects in whom the TSB at time ≤9 6/1792 0.3 5/1723 0.3
10–19 20/707 2.8 13/708 1.8
of phototherapy termination was 20–29 27/568 4.8 38/617 6.1
known rather than extrapolated, the 30–39 56/303 18.5 55/316 17.4
AUROC for the clinical prediction rule 40–49 36/109 33.0 32/124 25.8
was 0.90. ≥50 19/39 48.7 17/42 40.5
Additionally, we based our variable externally validate our prediction about when to discontinue
for home phototherapy on equipment rule, a consideration for future phototherapy.
orders, and therefore we did not research.
know precisely whether and when ACKNOWLEDGMENT
home phototherapy was used. There The authors thank Dr Andrea C.
may have been infants whose TSB Wickremasinghe for her critical review
returned to treatment threshold CONCLUSIONS
of the manuscript and invaluable
within 72 hours who did not have Rebound hyperbilirubinemia revisions and suggestions.
a TSB measurement until later. can be predicted with
Given this limitation and the use excellent discrimination by an ABBREVIATIONS
of home phototherapy, the risk of infant’s gestational age, age at
AAP: American Academy of
rebound hyperbilirubinemia may be initiation of phototherapy, and
Pediatrics
underestimated in our study, which relative TSB at phototherapy
aOR: adjusted odds ratio
may not be generalizable to infants termination. With a prediction
AUROC: area under the receiver
for whom home phototherapy is not score of <20, phototherapy
operating characteristic
an option. We also only examined can be discontinued with <4%
curve
rebound hyperbilirubinemia after probability of rebound. Clinical
CI: confidence interval
infants’ first inpatient phototherapy, implementation of this prediction
DAT: direct antiglobulin test
and rebound risks may be different rule via a Web-based calculator or
OR: odds ratio
after subsequent phototherapy. integration into electronic medical
TSB: total serum bilirubin
Finally, we were not able to records could help guide decisions
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Partially supported by grant R01HS020618 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The funder played no role in the design and conduct of
the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-3832.
REFERENCES
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A Clinical Prediction Rule for Rebound Hyperbilirubinemia Following Inpatient
Phototherapy
Pearl W. Chang, Michael W. Kuzniewicz, Charles E. McCulloch and Thomas B.
Newman
Pediatrics originally published online February 14, 2017;
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016-2896
References This article cites 15 articles, 5 of which you can access for free at:
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.