Study finds potential link between infant acid-suppressants and celiac disease

Tel Aviv University-led research has found that infants prescribed acid-suppressive medications during their first six months of life had an increased risk of developing celiac disease autoimmunity under certain study conditions.

Associations were present in a cohort study of more than 79,000 children, yet did not appear in a separate test-negative case-control analysis. Findings fail to answer questions about whether an observable relationship exists.

Infant use of acid-suppressive therapy, including proton-pump inhibitors and histamine-2 receptor antagonists, such as omeprazole (Prilosec) and ranitidine (Zantac), has been increasing worldwide in recent years. Observational studies found an association between early-life use of these medications and long-term adverse effects, including fractures and celiac disease.

Celiac disease is an immune‑mediated enteropathy in which an aberrant immune response to gluten damages the small‑intestinal lining, leading to increased mucosal permeability and chronic immune activation. Prevalence and incidence have increased in most countries during recent decades, for both seropositive celiac disease autoimmunity and biopsy-confirmed celiac disease.

Known mechanisms suggest that acid-suppressive therapy could contribute to celiac disease by disrupting protein digestion and altering gut microbiota.

In the study, “Early-Life Exposure to Acid-Suppressive Therapy and the Development of Celiac Disease Autoimmunity,” published in JAMA Network Open, researchers conducted retrospective analyses using population-level data to assess the association between early-life use of acid-suppressive therapy and the risk of celiac disease autoimmunity.

Researchers used two retrospective observational designs: a matched cohort study and a test-negative case-control design. Both analyses relied on population-level data from Maccabi Healthcare Services, which covers more than a quarter of the Israeli population. Data were drawn from children born between 2005 and 2020 who remained enrolled in the system through the first six months of life.

A total of 79,820 children were included in the matched cohort study. Of these, 19,955 had used acid-suppressive therapy, either omeprazole (Prilosec) or ranitidine (Zantac), within the first six months after birth. Each exposed child was matched with up to three non-exposed children. Follow-up continued until the age of 10, the child’s exit from the health system, or diagnosis of celiac disease autoimmunity.

In the cohort study, 1.6% of children who used acid-suppressive therapy developed celiac disease autoimmunity, compared to 1.0% of those who did not. Acid-suppressive therapy users had an adjusted hazard ratio of 1.52 for developing the condition. A stronger association was observed in children who used acid-suppressive therapy for more than one month. The adjusted hazard ratio for prolonged use was 1.65.

Researchers also analyzed data from a test-negative case-control group of 24,684 children who had been tested for celiac disease autoimmunity. Among those who tested positive, 5.0% had used acid-suppressive therapy. Among those who tested negative, 4.6% had used the medication. The adjusted odds ratio for this group was 1.07, which was not statistically significant.

In the cohort study, acid-suppressive therapy was significantly associated with celiac disease autoimmunity. In contrast, no significant association was observed in the test-negative case-control analysis.

While the authors note that the cohort design may have reflected residual confounding associated with the likelihood of being tested, they were not able to confirm this. The findings highlight the complexity of drawing conclusions from observational data alone.

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