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. 2023 Mar 1;177(3):267-277.
doi: 10.1001/jamapediatrics.2022.5193.

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

Yunha Noh  1   2 , Han Eol Jeong  1   2 , Ahhyung Choi  1 , Eun-Young Choi  1 , Björn Pasternak  3   4 , Hedvig Nordeng  5   6 , Mette Bliddal  7   8 , Kenneth K C Man  9   10   11 , Ian C K Wong  9   10   11   12 , Dong Keon Yon  13   14 , Ju-Young Shin  1   2   15
Affiliations

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

Yunha Noh et al. JAMA Pediatr. .

Abstract

Importance: Existing 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.

Objective: To evaluate the association of prenatal or infant exposure to ASMs with risk of allergic diseases in children.

Design, setting, and participants: This 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.

Exposures: Prenatal and infant exposure to ASMs (histamine 2 receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]).

Main outcomes and measures: Composite 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.

Results: The 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 relevance: The 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Man reported receiving grants from the C W Maplethorpe Fellowship, European Union Horizon 2020, National Institute for Health and Care Research (NIHR), and the Innovation and Technology Commission of the Government of the Hong Kong Special Administration Region, and the Hong Kong Research Grants Council (RGC) and receiving personal fees from IQVIA Ltd outside the submitted work. Dr Wong reported receiving grants from the Hong Kong RGC, NIHR, Innovative Medicines Initiative, Shire, Janssen-Cilag, Eli Lilly & Company, Pfizer, Bayer, Bristol Myers Squibb, Takeda, Amgen, AstraZeneca, and the European Union Seventh Framework Programme and receiving personal fees from IQVIA Ltd and Jacobson Pharma Corp outside the submitted work. Dr Shin reported receiving grants from the National Research Foundation of Korea, the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the government-wide R&D fund for infectious disease research, Daiichi Sankyo, GSK, and Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart of Study Cohort Identification
ASM indicates acid-suppressive medication; NHIS, National Health Insurance Service; PS, propensity score.
Figure 2.
Figure 2.. Risk of Allergic Diseases in Children Following Exposure to Acid-Suppressive Medications (ASMs) During Pregnancy in Propensity-Score (PS)–Matched Analyses
Squares indicate hazard ratios (HRs), with horizontal lines indicating 95% CIs. H2RA indicates histamine 2 receptor antagonist; PPI, proton pump inhibitor; PY, person-years. aExposed: 808 067; unexposed: 808 067 (1:1 matching). bExposed: 36 529; unexposed: 146 116 (1:4 matching). cExposed: 763 755; unexposed: 763 755 (1:1 matching).
Figure 3.
Figure 3.. Risk of Allergic Diseases in Children Following Exposure to Acid-Suppressive Medications (ASMs) During Infancy in Propensity-Score (PS)–Matched Analyses
Squares indicate hazard ratios (HRs), with horizontal lines indicating 95% CIs. H2RA indicates histamine 2 receptor antagonist; PPI, proton pump inhibitor; PY, person-years. aExposed: 84 263; unexposed: 84 263 (1:1 matching). bExposed: 7496; unexposed: 29 984 (1:4 matching). cExposed: 74 188; unexposed: 74 188 (1:1 matching).
Figure 4.
Figure 4.. Risk of Allergic Diseases in Children Following Prenatal and Infant Exposure to Acid-Suppressive Medications (ASMs) in Sibling-Matched Analyses
Squares indicate hazard ratios (HRs), with horizontal lines indicating 95% CIs. PS indicates propensity score; PY, person-years.
See this image and copyright information in PMC

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