Prenatal acid-suppressive medication exposure shows no consistent link to pediatric inflammatory bowel disease

Prenatal exposure to proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) was not consistently associated with childhood-onset inflammatory bowel disease (IBD) once investigators accounted for shared genetic and environmental factors between siblings, according to a nationwide cohort study published in JAMA Network Open.¹ The findings offer reassurance for the substantial share of pregnant patients who use acid-suppressive medications for reflux symptoms, which affect more than one-third of pregnancies.¹

Study design and key findings on prenatal PPI and H2RA exposure

Using South Korea's National Health Insurance Service database, researchers led by Hayeon Lee, PhD, and Tae Hyeong Kim, MD, PhD, of Kyung Hee University identified 2,631,880 mother-child pairs born between 2010 and 2017, with follow-up through 2023.¹ After 1:3 propensity score matching, exposure to acid-suppressive medications during pregnancy was associated with a modestly elevated risk of any IBD (hazard ratio [HR], 1.08; 95% CI, 1.01-1.15) and Crohn disease specifically (HR, 1.10; 95% CI, 1.02-1.19), but not ulcerative colitis (HR, 1.04; 95% CI, 0.93-1.17).¹ Absolute risk differences were small and not statistically significant across all three outcomes, at fewer than 1 additional case per 1000 children.¹ Critically, when the investigators restricted analysis to 199,448 sibling pairs discordant for prenatal exposure—a design that inherently controls for shared familial confounding—no significant associations remained for IBD (HR, 1.06; 95% CI, 0.88-1.27), Crohn disease (HR, 1.03; 95% CI, 0.84-1.27), or ulcerative colitis (HR, 1.10; 95% CI, 0.78-1.55).

Disease burden and current management of reflux in pregnancy

Pediatric-onset IBD incidence has been rising globally, with the steepest increases occurring in younger children, and the disease carries a substantial burden through growth failure and failure to thrive.¹ Meanwhile, gastroesophageal reflux symptoms are common in pregnancy, and acid-suppressive agents remain a mainstay of treatment because they are generally considered safe.¹ Prior work from the same research group linked prenatal acid-suppressive medication exposure to other pediatric outcomes, including allergic disease, underscoring ongoing interest in how these agents shape early-life immune and microbial development.¹

Mechanism and prior evidence linking acid suppression to IBD risk

PPIs and H2RAs raise gastric pH, which can alter gut microbial composition and diversity—changes that some research suggests may exceed the disruptive effect of antibiotics on the microbiome.¹ Because microbial dysbiosis is a hallmark of IBD, this mechanism has plausibility, but existing clinical evidence has been mixed. A pooled analysis of three large adult cohorts previously linked regular PPI use to both Crohn disease and ulcerative colitis,² whereas a Mendelian randomization study found no evidence that genetically proxied PPI use raises IBD risk.³

Interpreting the sibling-comparison design

The divergence between the propensity-matched and sibling-comparison results is the study's central message. Sibling designs are increasingly used in perinatal pharmacoepidemiology because they implicitly adjust for genetic background, household environment, and other unmeasured familial factors that conventional matching cannot fully capture.⁴ That the elevated risks seen in the general matched cohort—particularly for PPI-only exposure and first-trimester exposure—did not persist within families suggests residual confounding, rather than a direct teratogenic or microbiome-mediated effect, may explain the initial signal.¹

Limitations and next steps for clinicians

The authors note several caveats: pediatric IBD may be underdiagnosed given its nonspecific early presentation, subgroup analyses were likely underpowered given low case counts, and claims-based diagnostic codes lacked physician adjudication.¹ Over-the-counter H2RA use was also not captured, though the authors note prolonged use in Korea is typically physician-prescribed.¹ The authors conclude that clinicians should weigh the minimal absolute risk against the therapeutic need for reflux treatment during pregnancy, supporting continued use when clinically indicated.

References

1. Oh J, Park J, Kim H, et al. Prenatal exposure to acid-suppressive medications and incident risk of inflammatory bowel disease in children. JAMA Netw Open. 2026;9(6):e2620030. doi:10.1001/jamanetworkopen.2026.20030

2. Xia B, Yang M, Nguyen LH, et al. Regular use of proton pump inhibitor and the risk of inflammatory bowel disease: pooled analysis of 3 prospective cohorts. Gastroenterology. 2021;161(6):1842-1852.e10. doi:10.1053/j.gastro.2021.08.005

3. An H, Zhong M, Gan H. Proton pump inhibitors and the risk of inflammatory bowel disease: a Mendelian randomisation study. Gut. 2024;73(12):e35. doi:10.1136/gutjnl-2024-331904

4. Ahlqvist VH, Lee BK, Chiu YH. Sibling comparisons to account for confounding in observational studies. JAMA. 2026;335(7):626-627. doi:10.1001/jama.2025.22234