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ARTICLE
Hyperbilirubinemia, Phototherapy, and Childhood AsthmaMichael 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 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.
abstract
aDivision of Research, Kaiser Permanente, Oakland, California;
and Departments of bPediatrics and cEpidemiology and Biostatistics,
University of California, San Francisco, San Francisco,
California
Dr Kuzniewicz assisted with obtaining funding, supervised data
management and the creation of Kaiser Permanente Northern
California data sets, analyzed data, and drafted the initial
manuscript and revisions; Dr Newman conceptualized, designed, and
led efforts to obtain funding for the study and reviewed the
manuscript; Mr Niki helped design data analyses, assisted with the
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
statistical and design consultation, assisted with obtaining
funding, and reviewed and revised the manuscript; and all authors
approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
DOI: https:// doi. org/ 10. 1542/ peds. 2018- 0662
Accepted for publication Jul 11, 2018
Address correspondence to Michael W. Kuzniewicz, MD, MPH,
Division of Research, Kaiser Permanente, Office 022R09, 2000
Broadway, Oakland, CA 94612. E-mail:
[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2018 by the American Academy of Pediatrics
PEDIATRICS Volume 142, number 4, October 2018:e20180662
WHAT’S KNOWN ON THIS SUBJECT: Observational studies have
revealed an association between hyperbilirubinemia and/or
phototherapy and childhood asthma. In many studies, researchers
have only used codes for hyperbilirubinemia or jaundice and have
lacked the ability to distinguish between the effects of
hyperbilirubinemia and its treatment.
WHAT THIS STUDY ADDS: By using actual bilirubin levels, modest
levels of hyperbilirubinemia were associated with a slightly
increased risk of asthma in a large modern cohort, but an
association was not seen at higher levels. Phototherapy did not
alter the risk of asthma.
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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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
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
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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
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%
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CI: 0.92–1.11; Table 3). Maximum TSB levels between 9 and 17.9
mg/dL were associated with an elevated HR for asthma; however,
there was no association between a TSB level of ≥18 mg/dL and
asthma. In our cohort, 88% of those who met criteria for an asthma
diagnosis, met criteria before 5 years of age. Limiting the
analysis to individuals with at least 5 years of follow-up
yielded similar associations with TSB levels. In additional
analyses, we separated home phototherapy and inpatient
phototherapy. Neither was associated with asthma (HR: 0.98 [95% CI:
0.86–1.16] for inpatient phototherapy; HR: 1.01 [95% CI:
0.85–1.19]
for home phototherapy). Lastly, restricting the model to infants
with a positive Coombs test revealed higher TSB levels to be
protective.
In the subset of infants with a TSB level within 3 mg/dL of the
AAP phototherapy threshold before any treatment with phototherapy
(n = 28 290), phototherapy was not associated with childhood asthma
(HR: 1.07; 95% CI: 0.96–1.20; controlling for the propensity to
receive phototherapy).
DISCUSSION
In a large modern cohort, with TSB levels for all subjects, we
found that infants with moderately elevated maximum TSB levels
(9–17.9 mg/dL) were more likely to develop asthma later in
childhood. This association did not persist for infants with
maximum TSB levels of ≥18 mg/dL. We found no association between
phototherapy and asthma when adjusting for the maximum TSB level or
in analyses when adjusting for a propensity to receive
phototherapy.
Although we have confirmed an association between moderately
elevated bilirubin levels at birth and the development of asthma
later in childhood, the question is if the association is causal.
There is undoubtedly consistency because this association has now
been seen in diverse populations in Sweden, 10, 11 Taiwan, 12
China, 9 and now in a historic13 and modern cohort in the United
States. The strength of the association in the aforementioned
studies ranged from aORs of 1.37 to 1.64. The strength of the
association in our study was attenuated, which may be secondary to
our controlling for other important predicators, such as a history
of maternal asthma and the more specific definition of asthma that
we used.
Is there any biological plausibility for why hyperbilirubinemia
or phototherapy may result in asthma?
KUZNIEWICZ et al4
TABLE 1 Characteristics of the Cohort by Asthma Status
Variable Nonasthma, n (%) Asthma, n (%)
Total 104 358 (100) 4854 (100)Male sex 52 632 (50.4) 3031
(62.4)Race Asian American 22 319 (21.4) 1008 (20.8) African
American 6469 (6.2) 552 (11.4) Hispanic 21 197 (20.3) 1117 (23.0)
Non-Hispanic white 44 202 (42.4) 1747 (36.0) Other 10 171 (9.7) 430
(8.9)Maternal age, y 1 formula feed 34 249 (32.8) 1999 (41.2) No
data 379 (0.4) 30 (0.6)Birth hospitalization phototherapy 6692
(6.4) 423 (8.7)Readmission phototherapy 2859 (2.7) 174 (3.6)Home
phototherapy 3673 (3.5) 166 (3.4)Any phototherapy 11 831 (11.3) 702
(14.5)Maximum TSB level, mg/dL
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In vivo, bilirubin plays an important role as an antioxidant;
however, at higher levels (>20 mg/dL) bilirubin fails to provide
protection.27 – 30 Perhaps a resultant oxidant–antioxidant
imbalance may result in airway inflammation, with the development
of asthma later in life.3 Our results do not support this mechanism
because it would predict the risk to be greatest in children with
the highest maximum TSB level. This rationale also requires that a
brief exposure early in life would result in enough injury that
would predispose an individual to asthma many years later, which
seems unlikely.
Others have suggested that bilirubin may influence the
immune
system.31 – 33 Unconjugated bilirubin may shift the T helper
(Th) cell balance of T helper 1 to T helper 2 (Th2) toward the Th2
phenotype through an inhibition of interleukin-2 production.34 A
Th2 predominance had been associated with the development of
allergy and asthma.35, 36 Interleukin-2 is essential for the
development and maintenance of T regulatory cells, which play an
important role in regulating immunologic processes in peripheral
tolerance to allergens.37, 38 The exposure is brief, but perhaps an
alteration in cytokine production with hyperbilirubinemia could
favor intolerance at a critical time in immune system
development.
However, our data did not reveal a biological gradient or dose
response of maximum bilirubin level and the risk of asthma. In
fact, as maximum TSB levels increased, we saw a fall in the
incidence of asthma after a maximum TSB level of 16 mg/dL. In
comparison, the Collaborative Perinatal Project revealed a trend of
an increasing risk of asthma with 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 may not fully
answer the question, however, because the increased risk was seen
at maximum TSB levels as low as 9 mg/dL. Many infants may have
already reached TSB levels that are associated with an increased
risk of asthma but are well below AAP recommended thresholds for
phototherapy. Because there was no dose-response relationship
between maximum TSB levels and asthma risk, preventing higher
levels through phototherapy may not have any effect on asthma risk
unless started at much lower thresholds.
The most likely alternative explanation for this association is
a confounder, such as a genetic predisposition to both moderate
hyperbilirubinemia and asthma. A potential example is polymorphisms
in the glutathione S-transferase (GST) gene. Mutations have been
linked to
PEDIATRICS Volume 142, number 4, October 2018 5
TABLE 2 Cumulative Incidence, Incidence Rate, and IRRs of Asthma
by Maximum TSB Level Category
TSB, mg/dL
No. Infants
Asthma Cases
Cumulative Incidence of Asthma,
%
Incidence Per 1000 Person Years
IRR (95% CI) P
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both neonatal hyperbilirubinemia39, 40 and asthma.41 – 47 GSTs
can function both as enzymes and as intracellular binding proteins
for nonsubstrate ligands, such as bilirubin and bilirubin
conjugates, decreasing reflux from the hepatocytes back into
plasma.48 Neonates with the GSTM1-null genotype have higher TSB
levels compared with those with the wild phenotype.39, 40 GST is
also involved in cytoprotection from byproducts of oxidative
stress.49 GST is widely expressed in human airways and may play a
role in modifying the risk of allergic response to environmental
pollutants.50– 52 Multiple meta-analyses of the
association between GST genes and asthma have had conflicting
results and have been hampered by study heterogeneity.42 –45 The
polymorphism is not rare, which adds to the plausibility; the
frequency of the GSTM1-null genotype is ∼50% in white individuals
and ∼20% in African Americans.53
A possible explanation to why an association was seen between
moderate hyperbilirubinemia and asthma and not a more severe
hyperbilirubinemia may relate to the etiology of
hyperbilirubinemia. Moderate hyperbilirubinemia may be associated
with polymorphisms in the GST gene, whereas a more severe
hyperbilirubinemia may be seen more commonly with etiologies,
such as ABO incompatibility, glucose-6-phosphate dehydrogenase
deficiency, or sepsis. As a result, a common gene polymorphism that
leads to moderate hyperbilirubinemia may be the etiology of
hyperbilirubinemia in a greater percentage of infants with moderate
hyperbilirubinemia, whereas in infants with severe
hyperbilirubinemia, other etiologies are more common. Another
possibility may be that there are 2 conflicting mechanisms.
Bilirubin is both causal and protective at different levels, and at
a level of >18 mg/dL, the protective mechanism overcomes the
causal one.
Further lessening the case for causality, in both this study and
past studies, TSB levels of
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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
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
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 ratioCI: confidence intervalHR: hazard
ratioIRR: incidence rate ratioKPNC: Kaiser Permanente
Northern CaliforniaTh: T helperTh2: T helper 2TSB: total
serum bilirubin
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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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