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
has been increasing worldwide,
and asthma is one of the most
common childhood diseases, yet
much remains to be elucidated
concerning its etiology.‍1 There is
clearly a genetic predisposition,
and the interaction between the
environmental pollutants and/or
allergens, inflammatory mediators,
and cellular response play a crucial
role in its pathogenesis.‍2–‍‍ 6‍ Reactive
oxygen species that are generated
by both cellular metabolism and
environmental pollutants result in
oxidant injury and contribute to the
severity and symptom exacerbation
of asthma.‍3,​7,​
‍ 8‍
Observational studies have
revealed an association between
hyperbilirubinemia and/or
phototherapy and childhood
asthma.‍9–‍‍‍ 14
‍ Using the Swedish birth
registry, Aspberg et al‍10 first reported
an association between a diagnosis
of icterus or history of phototherapy
and hospitalizations for asthma after
2 years of age (adjusted odds ratio
[aOR]: 1.27; 95% confidence interval
[CI]: 1.08–1.50). The group confirmed
their findings using an outcome
of asthma, which was defined by
receiving medications for asthma.‍11
Similarly, a Chinese‍9 (aOR: 1.64;
95% CI: 1.36–1.98) and Taiwanese
study12 (adjusted hazard ratio [HR]:
1.21; 95% CI: 1.15–1.27) revealed an
association between a diagnosis of
neonatal jaundice and an inpatient or
outpatient diagnosis of asthma later
in childhood.
None of the authors of these studies
analyzed actual bilirubin levels; all
relied only on a diagnosis of jaundice.
Because phototherapy is a primary
treatment of neonatal jaundice, it
is hard to distinguish the effects of
phototherapy from those of jaundice.
The only study in which actual
bilirubin levels were included was
an examination of data from the
US Collaborative Perinatal Project;
subjects were enrolled in 1959–1965,
before the use of phototherapy.‍13
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2 KUZNIEWICZ et al
Total serum bilirubin (TSB) levels
were obtained on all infants at 36
to 60 hours after birth and repeated
24 hours later if the TSB level was
>10 mg/dL. Compared with infants
with a maximum TSB level of
≤3 mg/dL, infants with a maximum
TSB level as low as 6.1 to 9 mg/dL
were more likely to be diagnosed
with asthma before age 7 years.
Infants with a maximum TSB level of
≥15 mg/dL had the highest increased
risk of asthma (aOR: 1.61; 95%
CI: 1.04–2.08).
Our objective was to quantify
the associations of both
hyperbilirubinemia and
phototherapy with childhood asthma,
controlling for confounding using a
large, modern, and population-based
cohort and actual TSB levels.
METHODS
Study Design
We performed a retrospective cohort
study as an extension of the Late
Impact of Getting Hyperbilirubinemia
or Phototherapy study.‍15–‍‍‍ 20
‍ The
Institutional Review Boards at Kaiser
Permanente Northern California
(KPNC) and the University of
California, San Francisco, approved
the study.
Population
The cohort included infants born
at ≥35 weeks’ gestation at KPNC
hospitals between January 1, 2010,
and December 31, 2014. Only the
11 facilities that were employing
universal bilirubin screening
with TSB levels before discharge
were included. To ensure full
ascertainment of bilirubin levels,
infants had to remain in the KPNC
system during their entire birth
hospitalization (n = 126 376). To
assess asthma outcomes, we excluded
children who did not remain in the
health plan for at least 25 months
after birth (n = 17 496). We excluded
332 children with no TSB levels.
The final study cohort consisted of
109 212 children.
Predictors
Bilirubin Measurement
From existing KPNC laboratory
databases, we obtained all TSB
levels from an infant’s first month
after birth using previously
described methods.‍21 We excluded
any TSB measurements for which
a corresponding conjugated or
direct bilirubin measurement
constituted ≥50% of the TSB level.
These infants represent a small
and different population of infants
and are also excluded from the
American Academy of Pediatrics
(AAP) guideline.‍22 TSB levels were
obtained before discharge or if
clinically indicated. Subsequent TSB
testing was done at the discretion of
the treating physicians. A bilirubin
measurement was performed by
using the Vitros BuBc Neonatal
Bilirubin assay (Ortho Clinical
Diagnostics, Raritan, NJ).‍23,​24
‍ In May
2012, Ortho Clinical Diagnostics
adjusted the calibrator values for
Vitros BuBc Slides,​25 so we included
an indicator variable for whether
the TSB level was obtained before or
after recalibration in analyses.
Phototherapy
We classified infants as having
received inpatient phototherapy
if they had either a phototherapy
nursing flow sheet or both a
procedure code and an order for
phototherapy. Home phototherapy
was determined from the KPNC
durable medical equipment database.
Additional Covariables
From the KPNC electronic data
sources, we abstracted covariates,
including maternal age, maternal
race and/or ethnicity, infant sex,
gestational age, birth weight,
5-minute Apgar score, year, and
hospital of birth, and the results
of a direct antiglobulin test and
glucose-6-phosphate dehydrogenase
activity, if performed. A maternal
history of asthma was defined as
2 asthma diagnoses (International
Classification of Diseases, Ninth
Revision diagnosis code 493.×) in
the mother from any outpatient or
inpatient encounter, separated by at
least 30 days, occurring within 10
years before the birth of the infant
(obtained from the KPNC Virtual Data
Warehouse).‍26 We classified feeding
during the birth hospitalization
as exclusively breastfed, received
1 formula feeding, or received >1
formula feeding.
Outcomes
An occurrence of asthma was
defined as a child having both (1) at
least 2 asthma diagnoses from any
outpatient or inpatient encounter,
separated by at least 30 days,
occurring after 2 years of age and
(2) at least 2 asthma medication
prescriptions in a 12-month period,
separated by at least 30 days,
prescribed after 2 years of age.
Medications that were considered
asthma medications were short-
or long-acting β-agonists, inhaled
corticosteroids, a combination
inhaled corticosteroid and long-
acting β-agonist, or a montelukast.
Follow-up Time
Length of follow-up varied in
this study because some subjects
left the KPNC health care system
and follow-up began at birth
(2010–2014) but ended in 2017
for all subjects. For purposes of
quantifying incidence rates and
using proportional hazards models,
follow-up for each member of the
cohort began at either age 2 years
and ended at death, at the date
when the individual met all criteria
for asthma (2 asthma diagnoses
and 2 medication prescriptions),
or at the last follow-up date, which
was defined as the last day of the
last calendar month of coverage
by the KPNC health plan or the last
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PEDIATRICS Volume 142, number 4, October 2018
encounter date through April 30,
2017, whichever came later.
Statistical Analysis
We calculated crude incidence
rates by dividing asthma cases
by person years of follow-up, and
we calculated CIs for comparing
incidence rate ratios (IRRs) using
exact binomial calculations.
We used Cox proportional
hazards models to evaluate the
independent associations between
hyperbilirubinemia and asthma
and phototherapy and asthma,
adjusting for potential confounders.
We investigated which variables
were independently associated
with asthma in models that
included maximum TSB levels and
phototherapy. Covariables with a
significance value of P < .05 were
included in the final model.
In addition to traditional models,
we used a phototherapy propensity
score among infants who had a
TSB level within 3 mg/dL of the
AAP phototherapy threshold,
as previously described.‍16 We
categorized propensity scores
for phototherapy by decile. In
propensity-adjusted analyses we
controlled for measured confounding
variables by creating a model for the
probability of exposure (in this case,
phototherapy) and then controlled
for that probability. This allowed us
to adjust for TSB levels before but not
after phototherapy, thus allowing us
to investigate whether phototherapy
might reduce the risk of asthma
by preventing hyperbilirubinemia.
We performed all analyses using
Stata version 15 (Stata Corp, College
Station, TX).
RESULTS
Characteristics of the study cohort
by asthma status are shown in
‍Table 1. As expected, African
American children, children of
mothers with a history of asthma,
and infants of lower gestational
age were overrepresented in the
asthma group. Infants who were
exclusively breastfed during
the birth hospitalization were
underrepresented in the asthma
group. Infants who received
phototherapy were overrepresented
in the asthma group.
Of the 109 212 children in the cohort,
16.7% (18 205) had a maximum
TSB level of ≥15 mg/dL, and 4.7%
(4865) had a maximum TSB level
of ≥18 mg/dL. Phototherapy was
administered to 11.5% (12 533)
of the children. The majority of
children who were treated received
inpatient phototherapy (8.9%),
whereas a minority (2.5%) received
only home phototherapy. Children
were managed for a total of 263 967
person years after age 2 years. The
mean age at the last follow-up was
4.4 (SD: 1.5) years. In the study, 4854
(4.4%) children met the criteria for
asthma (incidence rate: 18.4 per
1000 person years). The mean age
to achieving criteria for an asthma
diagnosis was 3.6 (SD: 1.1) years old.
Asthma cases, the cumulative
incidence of asthma, the incidence
rate, and IRRs by maximum TSB
level category are shown in ‍Table 2.
Although incidence rates for asthma
increased significantly for maximum
TSB levels between 9 and 17.9 mg/dL
compared with maximum TSB levels
between 3 and 5.9 mg/dL, there was
not a significant increase in incidence
rates for asthma in children with
maximum TSB levels of ≥18 mg/dL.
‍Figure 1 includes the asthma
incidence rate by maximum TSB
level. No clear relationship is present.
For the Cox proportional hazards
models, sex, maternal history of
asthma, cesarean delivery, birth
hospitalization length of stay >7 days,
recalibration, race, maternal age,
gestational age, birth facility, birth
year, and feeding type during the
birth hospitalization were included
in the final model. In the final model,
phototherapy was not associated
with asthma (HR: 1.01; 95%
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
use of asthma medications. We were
able to control for a large number
of possible confounding variables,
including infant feeding type (breast
milk versus formula) during the birth
hospitalization, maternal history of
asthma, and gestational age. Using a
modern cohort, we were limited by
differential follow-up, although this
was accounted for in our analyses by
using Cox models.
There is a possible underdiagnosis
of asthma in those infants who were
born in the later birth years because
of a more limited follow-up. However,
when we limited the analysis to those
with at least 5 years of follow-up, the
same associations persisted.
Lastly, all bilirubin measurements
were obtained as clinically indicated.
Especially for infants with lower
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.
REFERENCES
1. Eder W, Ege MJ, von Mutius E. The
asthma epidemic. N Engl J Med.
2006;355(21):2226–2235
2. Subbarao P, Mandhane PJ, Sears
MR. Asthma: epidemiology,
etiology and risk factors. CMAJ.
2009;181(9):E181–E190
3. Nadeem A, Masood A, Siddiqui N.
Oxidant–antioxidant imbalance
in asthma: scientific evidence,
epidemiological data and
possible therapeutic options.
Ther Adv Respir Dis. 2008;2(4):
215–235
4. Wills-Karp M, Luyimbazi J, Xu X,
et al. Interleukin-13: central
mediator of allergic asthma.
Science. 1998;282(5397):
2258–2261
5. Holt PG, Macaubas C, Stumbles PA,
Sly PD. The role of allergy in the
development of asthma. Nature.
1999;402(suppl 6760):B12–B17
Downloaded from www.aappublications.org/news by guest on June 11, 2019
PEDIATRICS Volume 142, number 4, October 2018
maximum TSB levels, an infant’s
true maximum TSB level may have
been higher but unmeasured because
repeat testing may not have been
clinically indicated if there was a low
likelihood of reaching phototherapy
treatment levels. However, this
misclassification would have made it
more difficult to detect an association
in the study.
CONCLUSIONS
An association between modest levels
of hyperbilirubinemia and asthma
exists. The association is unlikely to
be causal because no dose-response
relationship was seen, with the
highest levels of hyperbilirubinemia
not being associated with asthma.
A confounder, such as a genetic
polymorphism, is more likely
associated with both asthma and
6. Marguet C, Jouen-Boedes F, Dean
TP, Warner JO. Bronchoalveolar cell
profiles in children with asthma,
infantile wheeze, chronic cough, or
cystic fibrosis. Am J Respir Crit Care
Med. 1999;159(5, pt 1):1533–1540
7. Henricks PA, Nijkamp FP. Reactive
oxygen species as mediators in
asthma. Pulm Pharmacol Ther.
2001;14(6):409–420
8. Sugiura H, Ichinose M. Oxidative
and nitrative stress in bronchial
asthma. Antioxid Redox Signal.
2008;10(4):785–797
9. Wei CC, Lin CL, Shen TC, Kao CH.
Neonatal jaundice and risks of
childhood allergic diseases: a
population-based cohort study.
Pediatr Res. 2015;78(2):223–230
10. Aspberg S, Dahlquist G, Kahan T,
Källén B. Is neonatal phototherapy
associated with an increased risk
for hospitalized childhood bronchial
modestly decreased bilirubin
conjugation. Phototherapy did
not alter the risk of asthma. Using
phototherapy to prevent infants from
reaching these modest TSB levels
is unlikely to be useful and would
require phototherapy use in ∼50% of
the birth population.
ABBREVIATIONS
AAP: American Academy of
Pediatrics
aOR: adjusted odds ratio
CI: confidence interval
HR: hazard ratio
IRR: incidence rate ratio
KPNC: Kaiser Permanente
Northern California
Th: T helper
Th2: T helper 2
TSB: total serum bilirubin
asthma? Pediatr Allergy Immunol.
2007;18(4):313–319
11. Aspberg S, Dahlquist G, Kahan T, Källén
B. Confirmed association between
neonatal phototherapy or neonatal
icterus and risk of childhood asthma.
Pediatr Allergy Immunol. 2010;
21(4, pt 2):e733–e739
12. Ku MS, Sun HL, Sheu JN, Lee HS,
Yang SF, Lue KH. Neonatal jaundice is
a risk factor for childhood asthma:
a retrospective cohort study. Pediatr
Allergy Immunol. 2012;23(7):623–628
13. Huang L, Bao Y, Xu Z, et al. Neonatal
bilirubin levels and childhood asthma
in the US Collaborative Perinatal
Project, 1959-1965. Am J Epidemiol.
2013;178(12):1691–1697
14. Das RR, Naik SS. Neonatal
hyperbilirubinemia and childhood
allergic diseases: a systematic
review. Pediatr Allergy Immunol.
2015;26(1):2–11
7
 15. Kuzniewicz MW, Wickremasinghe
AC, Wu YW, et al. Incidence, etiology,
and outcomes of hazardous
hyperbilirubinemia in newborns.
Pediatrics. 2014;134(3):504–509
16. Newman TB, Wickremasinghe AC,
Walsh EM, Grimes BA, McCulloch CE,
Kuzniewicz MW. Retrospective cohort
study of phototherapy and childhood
cancer in Northern California.
Pediatrics. 2016;137(6):e20151354
17. Newman TB, Wickremasinghe AC,
Walsh EM, Grimes BA, McCulloch CE,
Kuzniewicz MW. Phototherapy and
risk of type 1 diabetes. Pediatrics.
2016;138(5):e20160687
18. Wickremasinghe AC, Risley RJ,
Kuzniewicz MW, et al. Risk of
sensorineural hearing loss and bilirubin
exchange transfusion thresholds.
Pediatrics. 2015;136(3):505–512
19. Wu YW, Kuzniewicz MW, Croen L,
Walsh EM, McCulloch CE, Newman
TB. Risk of autism associated with
hyperbilirubinemia and phototherapy.
Pediatrics. 2016;138(4):e20161813
20. 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):239–246
21. Kuzniewicz MW, Escobar GJ,
Newman TB. Impact of universal
bilirubin screening on severe
hyperbilirubinemia and phototherapy
use. Pediatrics. 2009;124(4):1031–1039
22. American Academy of Pediatrics
Subcommittee on Hyperbilirubinemia.
Management of hyperbilirubinemia
in the newborn infant 35 or more
weeks of gestation [published
correction appears in Pediatrics.
2004;114(4):1138]. Pediatrics.
2004;114(1):297–316
23. Kazmierczak SC, Robertson AF, Catrou
PG, Briley KP, Kreamer BL, Gourley GR.
Direct spectrophotometric method for
measurement of bilirubin in newborns:
comparison with HPLC and an
automated diazo method. Clin Chem.
2002;48(7):1096–1097
24. Wu TW, Dappen GM, Powers DM, Lo
DH, Rand RN, Spayd RW. The Kodak
Ektachem clinical chemistry slide for
measurement of bilirubin in newborns:
Downloaded from www.aappublications.org/news by guest on June 11, 2019
8 KUZNIEWICZ et al
principles and performance. Clin
Chem. 1982;28(12):2366–2372
25. Kuzniewicz MW, Greene DN, Walsh EM,
McCulloch CE, Newman TB. Association
between laboratory calibration of
a serum bilirubin assay, neonatal
bilirubin levels, and phototherapy use.
JAMA Pediatr. 2016;170(6):557–561
26. Chimmula S, Dhuru R, Folck B, et al.
PS2-44: VDW data sources: Kaiser
Permanente Northern California. Clin
Med Res. 2012;10(3):193
27. Shekeeb Shahab M, Kumar P, Sharma
N, Narang A, Prasad R. Evaluation
of oxidant and antioxidant status in
term neonates: a plausible protective
role of bilirubin. Mol Cell Biochem.
2008;317(1–2):51–59
28. Dani C, Masini E, Bertini G, et al. Role
of heme oxygenase and bilirubin in
oxidative stress in preterm infants.
Pediatr Res. 2004;56(6):873–877
29. Sedlak TW, Snyder SH. Bilirubin
benefits: cellular protection by a
biliverdin reductase antioxidant cycle.
Pediatrics. 2004;113(6):1776–1782
30. Stocker R, Yamamoto Y, McDonagh
AF, Glazer AN, Ames BN. Bilirubin
is an antioxidant of possible
physiological importance. Science.
1987;235(4792):1043–1046
31. Nejedlá Z. The development of
immunological factors in infants
with hyperbilirubinemia. Pediatrics.
1970;45(1):102–104
32. Ollinger R, Wang H, Yamashita K, et al.
Therapeutic applications of bilirubin and
biliverdin in transplantation. Antioxid
Redox Signal. 2007;9(12):2175–2185
33. Rocuts F, Zhang X, Yan J, et al. Bilirubin
promotes de novo generation of T
regulatory cells. Cell Transplant.
2010;19(4):443–451
34. Haga Y, Tempero MA, Kay D, Zetterman
RK. Intracellular accumulation of
unconjugated bilirubin inhibits
phytohemagglutin-induced
proliferation and interleukin-2
production of human lymphocytes.
Dig Dis Sci. 1996;41(7):1468–1474
35. Romagnani S. The Th1/Th2 paradigm
and allergic disorders. Allergy.
1998;53(suppl 46):12–15
36. Romagnani S. The role of lymphocytes
in allergic disease. J Allergy Clin
Immunol. 2000;105(3):399–408
37. Liao W, Lin JX, Leonard WJ. Interleukin-2
at the crossroads of effector responses,
tolerance, and immunotherapy.
Immunity. 2013;38(1):13–25
38. Akdis M, Blaser K, Akdis CA. T
regulatory cells in allergy: novel
concepts in the pathogenesis,
prevention, and treatment of allergic
diseases. J Allergy Clin Immunol.
2005;116(5):961–968; quiz 969
39. Abdel Ghany EA, Hussain NF, Botros
SK. Glutathione S-transferase
gene polymorphisms in neonatal
hyperbilirubinemia. J Investig Med.
2012;60(1):18–22
40. Muslu N, Dogruer ZN, Eskandari G,
Atici A, Kul S, Atik U. Are glutathione
S-transferase gene polymorphisms
linked to neonatal jaundice? Eur J
Pediatr. 2008;167(1):57–61
41. Hoskins A, Wu P, Reiss S, Dworski R.
Glutathione S-transferase P1 Ile105Val
polymorphism modulates allergen-
induced airway inflammation in human
atopic asthmatics in vivo. Clin Exp
Allergy. 2013;43(5):527–534
42. Piacentini S, Polimanti R, Simonelli
I, et al. Glutathione S-transferase
polymorphisms, asthma susceptibility
and confounding variables: a
meta-analysis. Mol Biol Rep.
2013;40(4):3299–3313
43. Minelli C, Granell R, Newson R, et al.
Glutathione-S-transferase genes and
asthma phenotypes: a Human Genome
Epidemiology (HuGE) systematic
review and meta-analysis including
unpublished data.Int J Epidemiol.
2010;39(2):539–562
44. Saadat M, Ansari-Lari M. Genetic
polymorphism of glutathione
S-transferase T1, M1 and asthma, a
meta-analysis of the literature. Pak J
Biol Sci. 2007;10(23):4183–4189
45. Li F, Li S, Chang H, et al. Quantitative
assessment of the association between
the GSTM1-null genotype and the risk
of childhood asthma. Genet Test Mol
Biomarkers. 2013;17(9):656–661
46. Karam RA, Pasha HF, El-Shal AS,
Rahman HM, Gad DM. Impact of
glutathione-S-transferase gene
polymorphisms on enzyme activity,
lung function and bronchial asthma
susceptibility in Egyptian children.
Gene. 2012;497(2):314–319
 47. Islam T, Berhane K, McConnell R, et al.
Glutathione-S-transferase (GST) P1,
GSTM1, exercise, ozone and asthma
incidence in school children. Thorax.
2009;64(3):197–202
48. Sherlock S, Dooley J. Diseases of the
Liver and Biliary System. 11th ed.
Milan, Italy: Blackwell Science; 2002
49. Hayes JD, Flanagan JU, Jowsey IR.
Glutathione transferases. Annu Rev
Pharmacol Toxicol. 2005;45:51–88
Downloaded from www.aappublications.org/news by guest on June 11, 2019
PEDIATRICS Volume 142, number 4, October 2018
50. Gilliland FD, Li YF, Saxon A, Diaz-
Sanchez D. Effect of glutathione-S-
transferase M1 and P1 genotypes on
xenobiotic enhancement of allergic
responses: randomised, placebo-
controlled crossover study. Lancet.
2004;363(9403):119–125
51. Rahman I, Biswas SK, Kode A.
Oxidant and antioxidant balance
in the airways and airway
diseases. Eur J Pharmacol.
2006;533(1–3):222–239
52. Strange RC, Spiteri MA, Ramachandran
S, Fryer AA. Glutathione-S-transferase
family of enzymes. Mutat Res.
2001;482(1–2):21–26
53. Ginsberg G, Smolenski S, Hattis D,
Guyton KZ, Johns DO, Sonawane
B. Genetic polymorphism in
glutathione transferases (GST):
population distribution of GSTM1,
T1, and P1 conjugating activity. J
Toxicol Environ Health B Crit Rev.
2009;12(5–6):389–439
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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;

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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
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/142/4/e20180662

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