To the editor,
Acid suppressant medications (ASMs), such as proton pump inhibitors (PPIs) and 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 reports 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. The mother’s duration of ASM use during pregnancy was assessed with the question, “For how many months of her pregnancy did she take these medications?”, with response options ≤1, 2–3, 4–5, or ≥6 months, or unknown.
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. We conducted two sensitivity analyses related to the duration of ASM use. First, we defined exposure as ≥2 months prenatal ASM use and excluded infants with ≤1 month prenatal ASM exposure (n = 18) or unknown duration of ASM exposure (n = 1). Second, to assess for a dose response relationship, we modeled duration of exposure as an ordinal variable. All analyses were performed using Stata 15.1 (Stata Corp, College Station, TX). All p-values were two-tailed, with p < .05 considered statistically significant.
In this cohort, 95/598 (16%) children were exposed to ASMs prenatally (Table 1) with 76/95 (80%) reporting ASM use for ≥2 months. 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 (Table S1). However, there was a trend toward increased odds among non-Hispanic Whites (NHW) for food allergen sensitization, which was not observed among non-Hispanic ft Blacks and Hispanics. In the sensitivity analysis excluding those exposed for ≤1 month, the results remained null (unadjusted OR 1.03, 95% CI: 0.64–1.64, Table S2). Similarly, in the sensitivity analysis modeling duration of exposure as an ordinal variable the results remained null (unadjusted OR 0.99, 95% CI 0.85– 1.17, Table S3).
TABLE 1.
Maternal and child characteristics by prenatal exposure to acid suppressant medications
| Characteristic | Total (n = 598) n (%) |
No prenatal ASM exposure (n = 503) |
Prenatal ASM exposure (n = 95) n (%) |
|---|---|---|---|
| Age at enrollment (months), median (IQR) | 3 (2–6) | 3 (2–6) | 3 (2–6) |
| Sex | |||
| Male | 352 (59) | 296 (59) | 56 (59) |
| Female | 246 (41) | 207 (41) | 39 (41) |
| Race/ethnicity | |||
| White, non-Hispanic | 252 (42) | 194 (39) | 58 (61) |
| Black, non-Hispanic | 140 (23) | 123 (25) | 17 (18) |
| Hispanic | 187 (31) | 169 (34) | 18 (19) |
| Other | 19 (3) | 17 (3) | 2 (2) |
| Median household income by ZIP code | |||
| <$40,000 | 210 (35) | 188 (37) | 22 (23) |
| $40,000–$79,999 | 313 (52) | 254 (51) | 59 (62) |
| ≥$80,000 | 75 (13) | 61 (12) | 14 (15) |
| Insurance | |||
| Private | 243 (41) | 184 (37) | 59 (62) |
| Public or none | 353 (59) 317 | (63) 36 | (38) |
| Maternal history of atopic condition | |||
| Food allergy | |||
| No | 523 (88) | 447 (89) | 76 (80) |
| Yes | 72 (12) | 53 (11) | 19 (20) |
| Infancy | |||
| Atopic dermatitis during first year of life | |||
| No | 466 (78) | 393 (78) | 73 (77) |
| Yes | 132 (22) | 110 (22) | 22 (23) |
| Early childhood exam | |||
| Age at exam (months), median (IQR) | 45 (41–51) | 45 (41–51) | 45 (40–54) |
| Geographic regiona | |||
| Northeast | 151 (25) | 123 (25) | 28 (30) |
| Midwest | 59 (10) | 42 (8) | 17 (18) |
| South | 244 (41) | 205 (41) | 39 (41) |
| West | 144 (24) | 133 (26) | 11 (12) |
| Season of exama | |||
| Spring | 172 (29) | 147 (29) | 25 (26) |
| Summer | 131 (22) | 109 (22) | 22 (23) |
| Fall | 165 (28) | 143 (28) | 22 (23) |
| Winter | 130 (22) | 104 (21) | 26 (27) |
Geographic regions were defined according to categories used by the U.S. Census.
Seasons were defined as: spring, Mar. 20th–Jun. 19th; summer, Jun. 20th–Sept. 21st; fall, Sept. 22nd–Dec. 20th; winter, Dec. 21st–Mar. 19th.
TABLE 2.
Association between prenatal acid suppressant medication exposure and allergic sensitization in early childhood
| Outcome | Prenatal ASM exposure OR (95%CI) |
|---|---|
| Any Allergen Sensitization | |
| Unadjusted | 1.03 (0.65–1.63) |
| Partially adjustedb | 1.08 (0.63–1.86) |
| Fully adjusteda | 1.07 (0.60–1.91) |
| Food Allergen Sensitization | |
| Unadjusted | 1.26 (0.71–2.22) |
| Partially adjustedb | 1.42 (0.75–2.68) |
| Fully adjusteda | 1.38 (0.69–2.76) |
| Aeroallergen Sensitization | |
| Unadjusted | 0.94 (0.57–1.56) |
| Partially adjusted | 0.93 (0.53–1.63) |
| Fully adjusted | 0.94 (0.53–1.67) |
Partially adjusted model includes age at enrollment, sex, insurance, maternal history of asthma, and season of exam.
Fully adjusted model includes age at enrollment, sex, median household income by ZIP code, insurance, maternal history of food allergy, maternal history of asthma, age at early childhood exam, geographic region of residence at exam, and season of exam.
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 previously been associated with specific food allergen sensitization (e.g., hazelnut) in adults and animal models7,8; however, the mechanism by which prenatal ASM exposure may increase risk of allergic disease 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 potentially 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,
Supplementary Material
FUNDING INFORMATION
This study was supported by the grants U01 AI-087881 (Camargo), R01 AI-114552 (Camargo), and UG3 OD-023253 (Camargo) from the National Institutes of Health (Bethesda, MD). Dr Arroyo was supported by the National Institutes of Health award R25AI147369. Partially adjusted Fully adjusted The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Robinson is employed by both Massachusetts General Hospital and Sanofi.
Footnotes
CONFLICT OF INTEREST
The authors have no conflicts of interest.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1111/pai.13760.
SUPPORTING INFORMATION
Additional supporting information may be found in the online version of the article at the publisher’s website.
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