Prenatal and Infant Exposure to Acid-Suppressive Medications and Risk of Allergic Diseases in Children

Abstract

ImportanceExisting observational data have indicated positive associations of acid-suppressive medication (ASM) use in prenatal and early life with allergic diseases in children; however, no study to date has accounted for confounding by indication or within-familial factors.ObjectiveTo evaluate the association of prenatal or infant exposure to ASMs with risk of allergic diseases in children.Design, Setting, and ParticipantsThis nationwide, cohort study included data from South Korea’s National Health Insurance Service mother-child–linked database from January 1, 2007, to December 31, 2020. Participants included mother-child pairs of neonates born from April 1, 2008, to December 31, 2019.ExposuresPrenatal and infant exposure to ASMs (histamine 2 receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]).Main Outcomes and MeasuresComposite and individual outcomes of allergic diseases (asthma, allergic rhinitis, atopic dermatitis, and food allergy) in children (followed up to 13 years of age) were assessed. The ASM-exposed individuals were compared with unexposed individuals in propensity score (PS)–matched and sibling-matched analyses to control for various potential confounders and within-familial factors. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazards regression models.ResultsThe study included 4 149 257 mother-child pairs. Prenatal exposure analyses included 808 067 PS-matched pairs (763 755 received H2RAs, 36 529 received PPIs) among women with a mean (SD) age of 31.8 (4.2) years. The PS-matched HR was 1.01 (95% CI, 1.01-1.02) for allergic diseases overall (asthma: HR, 1.02 [95% CI, 1.01-1.03]; allergic rhinitis: HR, 1.02 [95% CI, 1.01-1.02]; atopic dermatitis: HR, 1.02 [95% CI, 1.01-1.02]; food allergy: HR, 1.03 [95% CI, 0.98-1.07]); in sibling-matched analyses, the HRs were similar to those of PS-matched analyses but were not significant (allergic diseases: HR, 1.01; 95% CI, 0.997-1.01). Infant exposure analyses included 84 263 PS-matched pairs (74 188 received H2RAs, 7496 received PPIs). The PS-matched HR was 1.06 (95% CI, 1.05-1.07) for allergic diseases overall (asthma: HR, 1.16 [95% CI, 1.14-1.18]; allergic rhinitis: HR, 1.02 [95% CI, 1.01-1.03]; atopic dermatitis: HR, 1.05 [95% CI, 1.02-1.08]; food allergy: HR, 1.28 [95% CI, 1.10-1.49]); asthma risk (HR, 1.13; 95% CI, 1.09-1.17) remained significantly higher among children exposed to ASMs during infancy in sibling-matched analyses. The findings were similar for H2RAs and PPIs analyzed separately and were robust across all sensitivity analyses.Conclusions and RelevanceThe findings of this cohort study suggest that there is no association between prenatal exposure to ASMs and allergic diseases in offspring. However, infant exposure to ASMs was associated with a higher risk of developing asthma, although the magnitude was more modest than previously reported. Clinicians should carefully weigh the benefits of prescribing ASMs to children, accompanied by subsequent close monitoring for any clinically relevant safety signals.

Proton Pump Inhibitor Use and Risk of Serious Infections in Young Children

“…PPI use has been associated with bone fractures, acute kidney injury, allergy, asthma, and inflammatory bowel diseases in children. They are also suspected of leading to infections through pH modification or direct action on the immune system .…”

“…4 In the first year of life, prevalence of PPI use increased from 2.4% to 5.2% between 2005 and 2012 in New Zealand, 5 while prescription rates were 1.9% in Sweden, 2.3% in Norway, and 4.6% in Denmark in 2020, a 3-to 5-fold increase since 2000. 6,7 PPI use has been associated with bone fractures, 8 acute kidney injury, 9 allergy, 10 asthma, 11 and inflammatory bowel diseases 12 in children. They are also suspected of leading to infections 13 through pH modification or direct action on the immune system.…”

Probing Deeper Into the Association Between Acid-Suppressive Medication Use and Allergic Diseases—Reply

“…In Reply We thank Hsieh and Lin for their interest in our study 1 on the association between prenatal and infant exposure to acidsuppressive medications (ASM) and the risk of allergic diseases in children. We have responded to their comments as follows.…”

“…However, the sibling-matched cohorts in our study had similar baseline characteristics as those of the source population. For instance, the prevalence of gastroesophageal reflux disease in infants who were exposed to ASMs and those who were not was 12.8% and 2.5% (standardized mean difference = 0.40) in the full cohort, respectively, vs 13.7% and 3.1% (standardized mean difference = 0.346) in the sibling cohort (eTables 5 and 7 in the Supplement). We also adjusted such nonshared factors to mitigate potential confounding.…”

Probing Deeper Into the Association Between Acid-Suppressive Medication Use and Allergic Diseases

“…To the Editor We read with great intrigue the nationwide cohort study by Noh et al on prenatal and infant exposure to acid-suppressive medications (ASM) and the risk of allergic diseases in children using the National Health Insurance Service database of South Korea. The authors noted that infant exposure to ASMs was associated with a higher risk of developing asthma and found no association between prenatal exposure to ASMs and allergic diseases in offspring.…”