Hyperbilirubinemia, Phototherapy,

and Childhood Asthma

Michael W. Kuzniewicz, MD, MPH,​a,​b Hamid Niki, MS,​a Eileen M. Walsh, RN, MPH,​a
Charles E. McCulloch, PhD,​c Thomas B. Newman, MD, MPHb,​c

OBJECTIVES: Our aim was to quantify the associations of both hyperbilirubinemia and abstract
phototherapy with childhood asthma using a population-based cohort with total serum
bilirubin (TSB) levels.
METHODS: Retrospective cohort study of infants born at ≥35 weeks’ gestation in the Kaiser
Permanente Northern California health system (n = 109 212) from 2010 to 2014. Cox models
were used to estimate hazard ratios (HRs) for a diagnosis of asthma.
RESULTS: In the study, 16.7% of infants had a maximum TSB level of ≥15 mg/dL, 4.5%
of infants had a maximum TSB level of ≥18 mg/dL, and 11.5% of infants received
phototherapy. Compared with children with a maximum TSB level of 3 to 5.9 mg/L, children
with a TSB level of 9 to 11.9 mg/dL, 12 to 14.9 mg/dL, and 15 to 17.9 mg/dL were at an
increased risk for asthma (HR: 1.22 [95% confidence interval (CI): 1.11–1.3], HR: 1.18 [95%
CI: 1.08–1.29], and HR: 1.30 [95% CI: 1.18–1.43], respectively). Children with a TSB level
of ≥18 mg/dL were not at an increased risk for asthma (HR: 1.04; 95% CI: 0.90–1.20). In
propensity-adjusted analyses, phototherapy was not associated with asthma (HR: 1.07;
95% CI: 0.96–1.20).
CONCLUSIONS: Modest levels of hyperbilirubinemia were associated with an increased risk of
asthma, but an association was not seen at higher levels. No dose-response relationship
was seen. Using phototherapy to prevent infants from reaching these modest TSB levels is
unlikely to be protective against asthma.

WHAT’S KNOWN ON THIS SUBJECT: Observational

aDivision
studies have revealed an association between
of Research, Kaiser Permanente, Oakland, California; and Departments of bPediatrics and
cEpidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
hyperbilirubinemia and/or phototherapy and
childhood asthma. In many studies, researchers
Dr Kuzniewicz assisted with obtaining funding, supervised data management and the creation have only used codes for hyperbilirubinemia or
of Kaiser Permanente Northern California data sets, analyzed data, and drafted the initial jaundice and have lacked the ability to distinguish
manuscript and revisions; Dr Newman conceptualized, designed, and led efforts to obtain funding between the effects of hyperbilirubinemia and its
for the study and reviewed the manuscript; Mr Niki helped design data analyses, assisted with the
treatment.
interpretation of results, and reviewed and revised multiple drafts of the manuscript; Ms Walsh
assisted with data analyses and reviewed and revised the manuscript; Dr McCulloch provided WHAT THIS STUDY ADDS: By using actual bilirubin
statistical and design consultation, assisted with obtaining funding, and reviewed and revised levels, modest levels of hyperbilirubinemia were
the manuscript; and all authors approved the final manuscript as submitted and agree to be associated with a slightly increased risk of asthma
accountable for all aspects of the work. in a large modern cohort, but an association was not
DOI: https://​doi.​org/​10.​1542/​peds.​2018-​0662 seen at higher levels. Phototherapy did not alter the
Accepted for publication Jul 11, 2018 risk of asthma.
Address correspondence to Michael W. Kuzniewicz, MD, MPH, Division of Research, Kaiser
Permanente, Office 022R09, 2000 Broadway, Oakland, CA 94612. E-mail: michael.w.kuzniewicz@
kp.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2018 by the American Academy of Pediatrics
To cite: Kuzniewicz MW, Niki H, Walsh EM, et al. Hyperbil­
irubinemia, Phototherapy, and Childhood Asthma. Pediatrics.
2018;142(4):e20180662

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PEDIATRICS Volume 142, number 4, October 2018:e20180662 ARTICLE
The prevalence of childhood asthma Total serum bilirubin (TSB) levels The final study cohort consisted of
has been increasing worldwide, were obtained on all infants at 36 109 212 children.
and asthma is one of the most to 60 hours after birth and repeated
common childhood diseases, yet 24 hours later if the TSB level was Predictors
much remains to be elucidated >10 mg/dL. Compared with infants Bilirubin Measurement
concerning its etiology.‍1 There is with a maximum TSB level of
clearly a genetic predisposition, ≤3 mg/dL, infants with a maximum From existing KPNC laboratory
and the interaction between the TSB level as low as 6.1 to 9 mg/dL databases, we obtained all TSB
environmental pollutants and/or were more likely to be diagnosed levels from an infant’s first month
allergens, inflammatory mediators, with asthma before age 7 years. after birth using previously
and cellular response play a crucial Infants with a maximum TSB level of described methods.‍21 We excluded
role in its pathogenesis.‍2–‍‍ 6‍ Reactive ≥15 mg/dL had the highest increased any TSB measurements for which
oxygen species that are generated risk of asthma (aOR: 1.61; 95% a corresponding conjugated or
by both cellular metabolism and CI: 1.04–2.08). direct bilirubin measurement
environmental pollutants result in constituted ≥50% of the TSB level.
Our objective was to quantify These infants represent a small
oxidant injury and contribute to the
the associations of both and different population of infants
severity and symptom exacerbation
hyperbilirubinemia and and are also excluded from the
of asthma.‍3,​7,​
‍ 8‍
phototherapy with childhood asthma, American Academy of Pediatrics
Observational studies have controlling for confounding using a (AAP) guideline.‍22 TSB levels were
revealed an association between large, modern, and population-based obtained before discharge or if
hyperbilirubinemia and/or cohort and actual TSB levels. clinically indicated. Subsequent TSB
phototherapy and childhood testing was done at the discretion of
asthma.‍9–‍‍‍ 14
‍ Using the Swedish birth the treating physicians. A bilirubin
registry, Aspberg et al‍10 first reported METHODS measurement was performed by
an association between a diagnosis using the Vitros BuBc Neonatal
of icterus or history of phototherapy Study Design
Bilirubin assay (Ortho Clinical
and hospitalizations for asthma after We performed a retrospective cohort Diagnostics, Raritan, NJ).‍23,​24
‍ In May
2 years of age (adjusted odds ratio study as an extension of the Late 2012, Ortho Clinical Diagnostics
[aOR]: 1.27; 95% confidence interval Impact of Getting Hyperbilirubinemia adjusted the calibrator values for
[CI]: 1.08–1.50). The group confirmed or Phototherapy study.‍15–‍‍‍ 20
‍ The Vitros BuBc Slides,​25 so we included
their findings using an outcome Institutional Review Boards at Kaiser an indicator variable for whether
of asthma, which was defined by Permanente Northern California the TSB level was obtained before or
receiving medications for asthma.‍11 (KPNC) and the University of after recalibration in analyses.
Similarly, a Chinese‍9 (aOR: 1.64; California, San Francisco, approved
95% CI: 1.36–1.98) and Taiwanese the study. Phototherapy
study12 (adjusted hazard ratio [HR]:
We classified infants as having
1.21; 95% CI: 1.15–1.27) revealed an Population received inpatient phototherapy
association between a diagnosis of
The cohort included infants born if they had either a phototherapy
neonatal jaundice and an inpatient or
at ≥35 weeks’ gestation at KPNC nursing flow sheet or both a
outpatient diagnosis of asthma later
hospitals between January 1, 2010, procedure code and an order for
in childhood.
and December 31, 2014. Only the phototherapy. Home phototherapy
None of the authors of these studies 11 facilities that were employing was determined from the KPNC
analyzed actual bilirubin levels; all universal bilirubin screening durable medical equipment database.
relied only on a diagnosis of jaundice. with TSB levels before discharge
Additional Covariables
Because phototherapy is a primary were included. To ensure full
treatment of neonatal jaundice, it ascertainment of bilirubin levels, From the KPNC electronic data
is hard to distinguish the effects of infants had to remain in the KPNC sources, we abstracted covariates,
phototherapy from those of jaundice. system during their entire birth including maternal age, maternal
The only study in which actual hospitalization (n = 126 376). To race and/or ethnicity, infant sex,
bilirubin levels were included was assess asthma outcomes, we excluded gestational age, birth weight,
an examination of data from the children who did not remain in the 5-minute Apgar score, year, and
US Collaborative Perinatal Project; health plan for at least 25 months hospital of birth, and the results
subjects were enrolled in 1959–1965, after birth (n = 17 496). We excluded of a direct antiglobulin test and
before the use of phototherapy.‍13 332 children with no TSB levels. glucose-6-phosphate dehydrogenase

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2 KUZNIEWICZ et al
activity, if performed. A maternal encounter date through April 30, age were overrepresented in the
history of asthma was defined as 2017, whichever came later. asthma group. Infants who were
2 asthma diagnoses (International exclusively breastfed during
Classification of Diseases, Ninth Statistical Analysis the birth hospitalization were
Revision diagnosis code 493.×) in We calculated crude incidence underrepresented in the asthma
the mother from any outpatient or rates by dividing asthma cases group. Infants who received
inpatient encounter, separated by at by person years of follow-up, and phototherapy were overrepresented
least 30 days, occurring within 10 we calculated CIs for comparing in the asthma group.
years before the birth of the infant incidence rate ratios (IRRs) using Of the 109 212 children in the cohort,
(obtained from the KPNC Virtual Data exact binomial calculations. 16.7% (18 205) had a maximum
Warehouse).‍26 We classified feeding We used Cox proportional TSB level of ≥15 mg/dL, and 4.7%
during the birth hospitalization hazards models to evaluate the (4865) had a maximum TSB level
as exclusively breastfed, received independent associations between of ≥18 mg/dL. Phototherapy was
1 formula feeding, or received >1 hyperbilirubinemia and asthma administered to 11.5% (12 533)
formula feeding. and phototherapy and asthma, of the children. The majority of
adjusting for potential confounders. children who were treated received
Outcomes We investigated which variables inpatient phototherapy (8.9%),
were independently associated whereas a minority (2.5%) received
An occurrence of asthma was with asthma in models that only home phototherapy. Children
defined as a child having both (1) at included maximum TSB levels and were managed for a total of 263 967
least 2 asthma diagnoses from any phototherapy. Covariables with a person years after age 2 years. The
outpatient or inpatient encounter, significance value of P < .05 were mean age at the last follow-up was
separated by at least 30 days, included in the final model. 4.4 (SD: 1.5) years. In the study, 4854
occurring after 2 years of age and (4.4%) children met the criteria for
(2) at least 2 asthma medication In addition to traditional models,
asthma (incidence rate: 18.4 per
prescriptions in a 12-month period, we used a phototherapy propensity
1000 person years). The mean age
separated by at least 30 days, score among infants who had a
to achieving criteria for an asthma
prescribed after 2 years of age. TSB level within 3 mg/dL of the
diagnosis was 3.6 (SD: 1.1) years old.
Medications that were considered AAP phototherapy threshold,
asthma medications were short- as previously described.‍16 We Asthma cases, the cumulative
or long-acting β-agonists, inhaled categorized propensity scores incidence of asthma, the incidence
corticosteroids, a combination for phototherapy by decile. In rate, and IRRs by maximum TSB
inhaled corticosteroid and long- propensity-adjusted analyses we level category are shown in ‍Table 2.
acting β-agonist, or a montelukast. controlled for measured confounding Although incidence rates for asthma
variables by creating a model for the increased significantly for maximum
probability of exposure (in this case, TSB levels between 9 and 17.9 mg/dL
Follow-up Time
phototherapy) and then controlled compared with maximum TSB levels
Length of follow-up varied in for that probability. This allowed us between 3 and 5.9 mg/dL, there was
this study because some subjects to adjust for TSB levels before but not not a significant increase in incidence
left the KPNC health care system after phototherapy, thus allowing us rates for asthma in children with
and follow-up began at birth to investigate whether phototherapy maximum TSB levels of ≥18 mg/dL.
(2010–2014) but ended in 2017 might reduce the risk of asthma ‍Figure 1 includes the asthma
for all subjects. For purposes of by preventing hyperbilirubinemia. incidence rate by maximum TSB
quantifying incidence rates and We performed all analyses using level. No clear relationship is present.
using proportional hazards models, Stata version 15 (Stata Corp, College For the Cox proportional hazards
follow-up for each member of the Station, TX). models, sex, maternal history of
cohort began at either age 2 years asthma, cesarean delivery, birth
and ended at death, at the date hospitalization length of stay >7 days,
RESULTS
when the individual met all criteria recalibration, race, maternal age,
for asthma (2 asthma diagnoses Characteristics of the study cohort gestational age, birth facility, birth
and 2 medication prescriptions), by asthma status are shown in year, and feeding type during the
or at the last follow-up date, which ‍Table 1. As expected, African birth hospitalization were included
was defined as the last day of the American children, children of in the final model. In the final model,
last calendar month of coverage mothers with a history of asthma, phototherapy was not associated
by the KPNC health plan or the last and infants of lower gestational with asthma (HR: 1.01; 95%

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PEDIATRICS Volume 142, number 4, October 2018 3
TABLE 1 Characteristics of the Cohort by Asthma Status for home phototherapy). Lastly,
Variable Nonasthma, n (%) Asthma, n (%) restricting the model to infants with a
Total 104 358 (100) 4854 (100)
positive Coombs test revealed higher
Male sex 52 632 (50.4) 3031 (62.4) TSB levels to be protective.
Race
  Asian American 22 319 (21.4) 1008 (20.8) In the subset of infants with a TSB
  African American 6469 (6.2) 552 (11.4) level within 3 mg/dL of the AAP
  Hispanic 21 197 (20.3) 1117 (23.0) phototherapy threshold before any
  Non-Hispanic white 44 202 (42.4) 1747 (36.0) treatment with phototherapy
  Other 10 171 (9.7) 430 (8.9)
(n = 28 290), phototherapy was not
Maternal age, y
  <20 2803 (2.7) 196 (4.0) associated with childhood asthma
  20–29 39 345 (37.3) 1802 (37.1) (HR: 1.07; 95% CI: 0.96–1.20;
  30–39 57 174 (54.8) 2626 (54.1) controlling for the propensity to
 ≥40 5036 (4.8) 230 (4.7) receive phototherapy).
Maternal history of asthma 8548 (8.2) 822 (16.9)
Parity
  0 30 159 (28.9) 1333 (27.5)
  1 38 639 (37.0) 1811 (37.3) DISCUSSION
 ≥1 35 201 (33.7) 1688 (34.8)
  Unknown 359 (0.3) 22 (0.5)
In a large modern cohort, with TSB
Cesarean delivery 7488 (7.2) 1387 (28.6) levels for all subjects, we found that
SGA (<10th percentile) 4983 (4.8) 261 (5.4) infants with moderately elevated
LGA (>90th percentile) 8447 (8.1) 429 (8.8) maximum TSB levels (9–17.9 mg/dL)
Gestational age, wk were more likely to develop asthma
  35 1961 (1.9) 135 (2.8)
  36 3633 (3.5) 255 (5.3)
later in childhood. This association
  37 8451 (8.1) 447 (9.2) did not persist for infants with
  38 18 082 (17.3) 866 (17.8) maximum TSB levels of ≥18 mg/dL.
  39 35 422 (33.9) 1585 (32.7) We found no association between
  40 25 364 (24.3) 1105 (22.8) phototherapy and asthma when
 ≥41 11 445 (11.0) 461 (9.5)
Positive DAT 3461 (3.3) 181 (3.7)
adjusting for the maximum TSB level
Birth hospitalization length of stay ≥7 d 1550 (1.5) 140 (2.9) or in analyses when adjusting for a
Birth hospitalization feeding propensity to receive phototherapy.
  Exclusive breast milk 64 795 (62.1) 2539 (52.3)
  1 formula feed 4935 (4.7) 286 (5.9) Although we have confirmed an
  >1 formula feed 34 249 (32.8) 1999 (41.2) association between moderately
  No data 379 (0.4) 30 (0.6) elevated bilirubin levels at birth
Birth hospitalization phototherapy 6692 (6.4) 423 (8.7)
and the development of asthma
Readmission phototherapy 2859 (2.7) 174 (3.6)
Home phototherapy 3673 (3.5) 166 (3.4) later in childhood, the question is
Any phototherapy 11 831 (11.3) 702 (14.5) if the association is causal. There is
Maximum TSB level, mg/dL undoubtedly consistency because
  <3 5020 (4.8) 205 (4.2) this association has now been seen in
  3–5.9 26 166 (25.0) 1004 (20.7)
diverse populations in Sweden,​‍10,​11
‍
  6–8.9 24 677 (23.5) 1059 (21.8)
  9–11.9 14 867 (14.2) 757 (15.6) Taiwan,​‍12 China,​‍9 and now in a
  12–14.9 16 403 (15.6) 849 (17.5) historic13 and modern cohort in the
  15–17.9 12 588 (12.0) 752 (15.5) United States. The strength of the
 ≥18 4637 (4.4) 228 (4.7) association in the aforementioned
DAT, direct antiglobulin test; LGA, large for gestational age; SGA, small for gestational age. studies ranged from aORs of 1.37 to
1.64. The strength of the association
CI: 0.92–1.11; ‍Table 3). Maximum analysis to individuals with at least in our study was attenuated, which
TSB levels between 9 and 17.9 mg/dL 5 years of follow-up yielded similar may be secondary to our controlling
were associated with an elevated HR associations with TSB levels. In for other important predicators,
for asthma; however, there was no additional analyses, we separated such as a history of maternal asthma
association between a TSB level home phototherapy and inpatient and the more specific definition of
of ≥18 mg/dL and asthma. In our phototherapy. Neither was associated asthma that we used.
cohort, 88% of those who met criteria with asthma (HR: 0.98 [95% CI: 0.86– Is there any biological plausibility
for an asthma diagnosis, met criteria 1.16] for inpatient phototherapy; for why hyperbilirubinemia or
before 5 years of age. Limiting the HR: 1.01 [95% CI: 0.85–1.19] phototherapy may result in asthma?

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4 KUZNIEWICZ et al
TABLE 2 Cumulative Incidence, Incidence Rate, and IRRs of Asthma by Maximum TSB Level Category However, our data did not reveal a
TSB, No. Asthma Cumulative Incidence Per 1000 IRR (95% CI) P biological gradient or dose response
mg/dL Infants Cases Incidence of Asthma, Person Years of maximum bilirubin level and the
% risk of asthma. In fact, as maximum
<3 5225 205 3.9 16.69 1.01 (0.87–1.18) .9 TSB levels increased, we saw a fall
3–5.9 27 170 1004 3.7 16.46 Reference — in the incidence of asthma after a
6–8.9 25 736 1059 4.1 17.42 1.06 (0.97–1.15) .2 maximum TSB level of 16 mg/dL.
9–11.9 15 624 757 4.8 20.02 1.22 (1.11–1.34) <.001
12–14.9 17 252 849 4.9 19.45 1.18 (1.08–1.29) <.001
In comparison, the Collaborative
15–17.9 13 340 752 5.6 21.41 1.30 (1.18–1.43) <.001 Perinatal Project revealed a trend
≥18 4865 228 4.7 17.15 1.04 (0.90–1.20) .9 of an increasing risk of asthma with
—, not applicable. higher TSB levels at 48 hours and
maximum TSB levels,​‍13 with the
highest risk in children with a TSB
level of >15 mg/dL. However, we
were able to look at more gradations
>15 mg/dL rather than group all the
individuals together. Although the
Collaborative Perinatal Project had
901 infants with a TSB level of >15
mg/dL, we had 13 340 infants with
a maximum TSB level of 15 to
17.9 mg/dL and another 4865 infants
with a maximum TSB level of 18 to
20.9 mg/dL.
If hyperbilirubinemia is implicated in
the development of asthma, could the
effect be ameliorated or prevented
by treatment? No differences in the
risk of asthma were seen between
infants who were and were not
treated with phototherapy. This
FIGURE 1 may not fully answer the question,
Maximum TSB levels and asthma incidence rates. TSB levels are categorized by 1 mg/dL intervals (eg, however, because the increased risk
3–3.9 mg/dL = 3 mg/dL level group).
was seen at maximum TSB levels as
low as 9 mg/dL. Many infants may
In vivo, bilirubin plays an system.‍31–‍ 33
‍ Unconjugated bilirubin have already reached TSB levels that
important role as an antioxidant; may shift the T helper (Th) cell are associated with an increased
however, at higher levels (>20 mg/dL) balance of T helper 1 to T helper 2 risk of asthma but are well below
bilirubin fails to provide protection.‍27–‍‍ 30
‍ (Th2) toward the Th2 phenotype AAP recommended thresholds for
Perhaps a resultant oxidant– through an inhibition of interleukin-2 phototherapy. Because there was no
antioxidant imbalance may result production.‍34 A Th2 predominance dose-response relationship between
in airway inflammation, with the had been associated with the maximum TSB levels and asthma
development of asthma later in development of allergy and risk, preventing higher levels through
life.3 Our results do not support this phototherapy may not have any
asthma.35,​36‍ Interleukin-2 is
mechanism because it would predict effect on asthma risk unless started
essential for the development and
the risk to be greatest in children with at much lower thresholds.
maintenance of T regulatory cells,
the highest maximum TSB level. This
which play an important role in The most likely alternative
rationale also requires that a brief
exposure early in life would result in regulating immunologic processes in explanation for this association
enough injury that would predispose peripheral tolerance to allergens.‍37,​38
‍ is a confounder, such as a genetic
an individual to asthma many years The exposure is brief, but perhaps predisposition to both moderate
later, which seems unlikely. an alteration in cytokine production hyperbilirubinemia and asthma. A
with hyperbilirubinemia could potential example is polymorphisms
Others have suggested that favor intolerance at a critical time in the glutathione S-transferase (GST)
bilirubin may influence the immune in immune system development. gene. Mutations have been linked to

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PEDIATRICS Volume 142, number 4, October 2018 5
TABLE 3 Cox Proportional Hazards Model hyperbilirubinemia may be seen
Variable Adjusted HRa (95% CI) P more commonly with etiologies, such
Maximum TSB level, mg/dL
as ABO incompatibility, glucose-6-
  <3 1.00 (0.86–1.16) 0.98 phosphate dehydrogenase deficiency,
  3–5.9 Reference — or sepsis. As a result, a common
  6–8.9 1.04 (0.96–1.14) .3 gene polymorphism that leads to
  9–11.9 1.14 (1.04–1.26) .007 moderate hyperbilirubinemia may
  12–14.9 1.12 (1.02–1.24) .02
  15–17.9 1.22 (1.10–1.36) <.001
be the etiology of hyperbilirubinemia
 ≥18 0.99 (0.84–1.16) .9 in a greater percentage of infants
Any phototherapy 1.01 (0.92–1.11) .8 with moderate hyperbilirubinemia,
Male sex 1.61 (1.52–1.71) <.001 whereas in infants with severe
Maternal history of asthma 2.34 (2.17–2.52) <.001 hyperbilirubinemia, other etiologies
Cesarean delivery 1.01 (0.94–1.08) .839
Birth hospitalization length of stay >7 d 1.51 (1.26–1.17) <.001
are more common. Another
Recalibration 1.03 (0.91–1.17) .622 possibility may be that there are 2
Race conflicting mechanisms. Bilirubin
  Asian American 1.13 (1.04–1.23) .003 is both causal and protective at
  African American 1.95 (1.76–2.16) <.001 different levels, and at a level of >18
  Hispanic 1.25 (1.16–1.36) <.001
  White Reference —
mg/dL, the protective mechanism
  Other 1.11 (0.99–1.24) .080 overcomes the causal one.
Maternal age, y Further lessening the case for
  <20 1.17 (1.01–1.36) .038
  20–29 Reference —
causality, in both this study and past
  30–39 1.04 (0.97–1.10) .253 studies, TSB levels of <10 mg/dL
 ≥40 0.93 (0.81–1.07) .291 were associated with asthma. The
Gestational age, wk low bilirubin levels make it more
  35 1.13 (0.93–1.37) .202 plausible that it is not the bilirubin
  36 1.28 (1.11–1.48) .001
  37 1.10 (0.98–1.23) .095
itself that is increasing the risk of
  38 1.05 (0.96–1.15) .276 asthma but rather a confounder.
  39 1.00 (0.93–1.08) .931 A finding in our results that deserves
  40 Reference —
 ≥41 0.94 (0.84–1.04) .240
further examination was that any
Birth hospitalization feeding formula feeding, even a single
  Exclusive breast milk Reference — formula feeding during the birth
  1 formula feed 1.25 (1.10–1.41) <.001 hospitalization, was associated with
  >1 formula feed 1.17 (1.10–1.25) <.001 an increased risk for developing
—, not applicable. childhood asthma. The extent to
a Adjusted for facility and birth year.
which formula feeding during the
birth hospitalization serves as simply
both neonatal hyperbilirubinemia‍39,​‍40 association between GST genes an indication of formula feeding in
and asthma.‍41–‍‍‍‍ 47
‍ GSTs can function and asthma have had conflicting the subsequent months is unknown.
both as enzymes and as intracellular results and have been hampered
by study heterogeneity.‍42–45
‍‍ The A major strength of our study is
binding proteins for nonsubstrate
polymorphism is not rare, which the large, modern, and diverse
ligands, such as bilirubin and
adds to the plausibility; the frequency cohort. Homogenous populations
bilirubin conjugates, decreasing
of the GSTM1-null genotype is ∼50% were used in many of the previous
reflux from the hepatocytes back into studies, whereas in our cohort,
plasma.48 Neonates with the GSTM1- in white individuals and ∼20% in
African Americans.‍53 there was representation of many
null genotype have higher TSB levels races and ethnicities, increasing
compared with those with the wild A possible explanation to why an its generalizability. For our main
phenotype.‍39,​40
‍ GST is also involved association was seen between predictors, we had actual bilirubin
in cytoprotection from byproducts moderate hyperbilirubinemia and levels rather than codes for jaundice,
of oxidative stress.‍49 GST is widely asthma and not a more severe and we used both orders and flow
expressed in human airways hyperbilirubinemia may relate to sheets for phototherapy rather than
and may play a role in modifying the etiology of hyperbilirubinemia. administrative codes. Additionally,
the risk of allergic response to Moderate hyperbilirubinemia may our outcome variable was specific;
environmental pollutants.‍50–52 ‍ be associated with polymorphisms in multiple encounters were used with
Multiple meta-analyses of the the GST gene, whereas a more severe diagnostic codes in conjunction with

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6 KUZNIEWICZ et al
pharmacy data that indicated the maximum TSB levels, an infant’s modestly decreased bilirubin
use of asthma medications. We were true maximum TSB level may have conjugation. Phototherapy did
able to control for a large number been higher but unmeasured because not alter the risk of asthma. Using
of possible confounding variables, repeat testing may not have been phototherapy to prevent infants from
including infant feeding type (breast clinically indicated if there was a low reaching these modest TSB levels
milk versus formula) during the birth likelihood of reaching phototherapy is unlikely to be useful and would
hospitalization, maternal history of treatment levels. However, this require phototherapy use in ∼50% of
asthma, and gestational age. Using a misclassification would have made it the birth population.
modern cohort, we were limited by more difficult to detect an association
differential follow-up, although this in the study.
was accounted for in our analyses by ABBREVIATIONS
using Cox models. CONCLUSIONS AAP: American Academy of
There is a possible underdiagnosis Pediatrics
An association between modest levels
of asthma in those infants who were aOR: adjusted odds ratio
of hyperbilirubinemia and asthma
born in the later birth years because CI: confidence interval
exists. The association is unlikely to
of a more limited follow-up. However, HR: hazard ratio
be causal because no dose-response
when we limited the analysis to those IRR: incidence rate ratio
relationship was seen, with the
with at least 5 years of follow-up, the KPNC: Kaiser Permanente
highest levels of hyperbilirubinemia
same associations persisted. Northern California
not being associated with asthma.
Th: T helper
Lastly, all bilirubin measurements A confounder, such as a genetic
Th2: T helper 2
were obtained as clinically indicated. polymorphism, is more likely
TSB: total serum bilirubin
Especially for infants with lower associated with both asthma and

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: 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.

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PEDIATRICS Volume 142, number 4, October 2018 9
 Hyperbilirubinemia, Phototherapy, and Childhood Asthma
Michael W. Kuzniewicz, Hamid Niki, Eileen M. Walsh, Charles E. McCulloch and
Thomas B. Newman
Pediatrics 2018;142;
DOI: 10.1542/peds.2018-0662 originally published online September 12, 2018;

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 Hyperbilirubinemia, Phototherapy, and Childhood Asthma
Michael W. Kuzniewicz, Hamid Niki, Eileen M. Walsh, Charles E. McCulloch and
Thomas B. Newman
Pediatrics 2018;142;
DOI: 10.1542/peds.2018-0662 originally published online September 12, 2018;

The online version of this article, along with updated information and services, is
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http://pediatrics.aappublications.org/content/142/4/e20180662

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