To the editor:
Acid suppressant medications (ASMs), such as proton pump inhibitors
(PPIs) or histamine-2 receptor antagonists (H2RAs), are commonly used
during pregnancy to treat symptoms of reflux or gastroesophageal reflux
disease (GERD). Prenatal exposure to ASMs is associated with increased
risk of atopic disease in childhood including recurrent wheeze and
asthma.1-3 The mechanism by which exposure to these
medications increase risk is unknown. Increased risk of allergen
sensitization has been proposed as a possible
mechanism.4, 5
The objective of this study was to estimate the association between
prenatal exposure to ASMs and risk of allergen sensitization in early
childhood.
We used data from the 35th Multicenter Airway Research
Collaboration (MARC-35), an ongoing multicenter prospective cohort study
comprised of children with a history of severe bronchiolitis during
infancy (n =921). Study design and participants have been previously
described.6 Briefly, infants (age <1 year)
were enrolled during hospitalization for bronchiolitis at 17 US
hospitals during the 2011-2014 winter seasons.
Prenatal exposure to ASMs was defined as maternal use of either PPI or
H2RA during pregnancy, which was obtained from parent/guardian report by
questionnaire at enrollment. Parents/guardians were asked, “When
pregnant with your child, did you/the biological mother take H2 blockers
or proton pump inhibitors for gastroesophageal reflux (heartburn, GERD)
or ulcers?” Examples were provided. Respondents were instructed not to
include antacids.
Data on maternal and infant characteristics were collected by
parent/guardian interview at enrollment visit during infancy. We linked
infants’ home address ZIP codes to median household income estimates
using Esri Business Analyst Desktop (Esri, Redlands, CA). Eczema during
the first year of life was determined by physician review of 2 data
sources: complete medical record review for clinician-diagnosed eczema
and parent report of eczema in the first year of life.
The outcome of allergen sensitization was defined by serum specific
immunoglobulin E (sIgE). Serum samples from early childhood (median age
42 months, n = 611) were analyzed for sIgE by ImmunoCAP at the Phadia
Immunology Reference Laboratory (Portage, MI). Samples were tested for
food (cow’s milk, egg white, peanut, cashew nut and walnut) and
environmental allergens (grasses, trees, weeds, molds, cat, dog,
cockroach, mouse, and dust mites). sIgE ≥0.35 kU/L was considered
sensitized. We used sIgE results from early childhood to create several
variables: food allergen sensitization (yes or no), aeroallergen
sensitization (yes or no), any allergen sensitization (i.e., food or
aeroallergen; yes or no). We limited analyses to those with complete
exposure and outcome data (n=594 for analyses of any allergen
sensitization and aeroallergen sensitization, n=598 for analyses of food
allergen sensitization).
We estimated the association between ASM exposure and allergen
sensitization outcomes using logistic regression models. We performed
unadjusted, partially adjusted (age at enrollment, sex, insurance,
maternal history of asthma and season of exam) and fully adjusted models
(partially-adjusted model plus median household income estimated by ZIP
code, maternal history of food allergy, and geographic region of
residence at time of exam). All models accounted for potential
clustering by site using robust standard errors. To assess for potential
effect modification, we performed stratified analysis by sex,
race/ethnicity and eczema during first year of life. All analyses were
performed using Stata 15.1 (Stata Corp, College Station, TX). All
P-values were two-tailed, with P<0.05 considered statistically
significant.
In this cohort, 95/598 (16%) children were exposed to ASMs prenatally
(Table 1 ). Any sensitization (food or aeroallergen) developed
in 247/594 (42%) children. The prevalence of sensitization was similar
among unexposed (207/499, 41%) and exposed (40/95, 42%) (Table
2 ). Those exposed to ASM prenatally did not have increased odds of
allergen sensitization (unadjusted odds ratio [OR] 1.03, 95%CI
0.65-1.63). The association remained null after adjustment for potential
confounders (fully adjusted OR 1.07, 95%CI 0.60-1.91). The prevalence
of food allergen sensitization was 171/598 (29%) overall, 140/503
(28%) among the unexposed and 31/95 (33%) among the exposed
(unadjusted OR 1.26, 95%CI 0.71-2.22). Those exposed were not at
increased odds of developing food sensitization after adjustment for
potential confounders (fully adjusted OR 1.38, 95%CI 0.69-2.76). The
prevalence of aeroallergen sensitization was 162/594 (27%) overall,
137/499 (27%) among the unexposed and 25/95 (26%) among the exposed.
Those exposed to ASM did not have increased odds of aeroallergen
sensitization (unadjusted OR 0.94, 95%CI 0.57-1.56; fully adjusted OR
0.94, 95%CI 0.53-1.67). In analysis stratified by sex, race/ethnicity
and eczema during first year of life we did not find evidence of effect
modification (Supplemental Table 1 ). However, there was a trend
toward increased odds among non-Hispanic Whites (NHW) for food allergen
sensitization which was not observed among non-Hispanic Blacks and
Hispanics.
In this study of children with history of severe bronchiolitis, we found
that prenatal ASM exposure was not associated with odds of developing
allergen sensitization by early childhood. Previous work in this cohort
found that prenatal ASM exposure was associated with increased risk of
recurrent wheezing.1 Taken together, these findings
suggest that allergen sensitization may not be the sole mechanism by
which prenatal ASM exposure increases risk of childhood respiratory and
allergic disease.
Exposure to ASM has been associated with specific food allergen
sensitization (e.g., hazelnut) in adults and animal
models7, 8; however, the mechanism by which prenatal
ASM exposure increases risk is not known. It is clear that the human gut
microbiome plays a central role in development of allergic
disease.9 ASMs alter the gut microbiome, thus this
remains a plausible mechanism.10
The generalizability of this study is limited as all children
experienced an episode of severe bronchiolitis during infancy. While
bronchiolitis is common, the patterns of allergen sensitization may
differ from the general population. Future work will need to confirm
these findings in healthy children.
While we did not detect significant effect modification by
race/ethnicity, our data suggest a trend toward increased risk for food
allergen sensitization among exposed NHW. This finding may be related to
demographics of our study sample where 61% of exposed children are NHW.
In conclusion, in a cohort of children with a history of severe
bronchiolitis those exposed to ASM prenatally are not at increased risk
of developing food or environmental allergen sensitization by early
childhood. The mechanism by which ASM exposure increases risk of
childhood asthma remains unclear, but alterations in the gut microbiome
merit consideration.
Sincerely,
Lacey B. Robinson, MD, MPH
Division of Rheumatology, Allergy and Immunology, Department of
Medicine, Massachusetts General Hospital, Harvard Medical School,
Boston, MA
ORCID ID: 0000-0002-0008-2902
Anna Chen Arroyo, MD, MPH
Division of Pulmonary, Allergy & Critical Care Medicine, Department of
Medicine, Stanford University School of Medicine, Stanford, CA
ORCID ID: 0000-0002-7785-4632
Ruth J. Geller, MHS
Department of Emergency Medicine, Massachusetts General Hospital,
Boston, MA
ORCID ID: 0000-0001-8828-0761
Ashley F. Sullivan, MS, MPH
Department of Emergency Medicine, Massachusetts General Hospital,
Harvard Medical School, Boston, MA
ORCID ID: 0000-0001-6783-1720
Carlos A. Camargo, Jr., MD, DrPH
Division of Rheumatology, Allergy and Immunology, Department of
Medicine, and Department of Emergency Medicine, Massachusetts General
Hospital, Harvard Medical School, Boston, MA
ORCID ID: 0000-0002-5071-7654
Table 1 . Maternal and child characteristics by prenatal
exposure to acid suppressant medications