Acid-Suppressive Medications in Pregnancy Show Only Modest Link to Childhood Autoimmune Disease in 2.7 Million Children

One of the largest investigations ever conducted into the long-term effects of prenatal medication exposure has delivered a broadly reassuring verdict on a class of drugs taken by millions of pregnant women each year. In a nationwide birth cohort drawing on the health records of more than 2.7 million South Korean children, researchers found that prenatal exposure to acid-suppressive medications—proton pump inhibitors and histamine-2 receptor antagonists—was associated with only a modest increase in the risk of autoimmune diseases in offspring. Crucially, when the investigators compared siblings born to the same mothers, a design that controls for shared genetic and family-level factors, the association largely disappeared, suggesting that the apparent signal may reflect confounding rather than a true causal effect of the drugs themselves.

The study, conducted by a team led by Dong Keon Yon of Kyung Hee University College of Medicine and published in the World Journal of Pediatrics, capitalized on a uniquely powerful data resource: the National Health Insurance Service of Korea, which covers virtually the entire population. The researchers identified 3,012,992 mother-child pairs between January 1, 2009, and December 31, 2023, and after applying inclusion criteria, followed 2,777,119 children for a mean of 9.6 years. Of these, 507,845 had been exposed in utero to acid-suppressive medications, making this by far the largest dataset ever assembled to address the question of whether these common drugs leave a lasting imprint on the developing immune system.

Acid-suppressive medications are among the most frequently prescribed drugs in pregnancy. Proton pump inhibitors, or PPIs, block the hydrogen-potassium ATPase enzyme in gastric parietal cells, dramatically reducing stomach acid secretion, while histamine-2 receptor antagonists, or H2RAs, achieve a similar effect by blocking histamine signaling at the H2 receptor. Pregnant women take them for gastroesophageal reflux disease, dyspepsia, and related conditions, and their use has been considered relatively safe based on decades of pharmacovigilance. Yet the biological rationale for concern is real. Gastric acid serves as a chemical barrier shaping the gut microbiome, and animal and human studies have shown that acid suppression can alter microbial composition, promote oral-to-gut bacterial transmission, and influence immune programming. Because the fetal immune system undergoes critical developmental windows in utero—including thymic selection of the T cell repertoire—researchers have long wondered whether perturbing the maternal and fetal microbial environment could tilt immune development toward autoreactivity.

To answer that question rigorously, the team classified outcomes using International Classification of Diseases, 10th Revision codes, capturing systemic autoimmune diseases, autoimmune endocrine diseases, autoimmune thyroid diseases, autoimmune hepatitis, and other autoimmune conditions such as lupus erythematosus, psoriasis, and rheumatoid arthritis. To reduce the bias that plagues observational studies of medication use, the researchers employed propensity score-based overlap weighting, a technique that reweights exposed and unexposed children so that their measured baseline characteristics—maternal age, comorbidities, co-medications, and other confounders—become statistically balanced. After weighting, the analytic cohort comprised 404,550 exposed and 404,551 unexposed pairs, and Cox proportional hazards models were used to estimate adjusted hazard ratios with 95 percent confidence intervals.

The headline findings were statistically significant but numerically small. Prenatal exposure to acid-suppressive medications was associated with an 11 percent increase in the risk of systemic autoimmune diseases (adjusted hazard ratio 1.11, 95 percent confidence interval 1.01 to 1.21) and a 9 percent increase in other autoimmune diseases (adjusted hazard ratio 1.09, 95 percent confidence interval 1.05 to 1.12). Translated into absolute terms, however, the excess risk was vanishingly small: the numbers needed to harm were 37,716 per year for systemic autoimmune diseases and 6,102 per year for other autoimmune conditions. In other words, for every several thousand exposed pregnancies followed for a year, at most one additional case of autoimmune disease would be expected beyond what would occur anyway—a magnitude of risk that is difficult to detect at the individual patient level and of questionable clinical consequence.

The most informative analysis came from the sibling comparison. By treating each mother as a separate stratum and comparing exposed children with their unexposed siblings, the researchers effectively controlled not only for measured confounders but also for the stable, unmeasured factors that siblings share: genetics, household environment, socioeconomic background, and maternal health tendencies. In this within-family analysis, the associations vanished entirely. The adjusted hazard ratio for systemic autoimmune diseases fell to 0.89 (95 percent confidence interval 0.77 to 1.03) and for other autoimmune diseases to 0.97 (95 percent confidence interval 0.92 to 1.02)—both statistically indistinguishable from no effect. Because familial confounding is the dominant alternative explanation in pharmacoepidemiology, the null sibling findings weigh heavily against a causal interpretation of the modest between-family associations.

Timing mattered in one respect. When the researchers examined exposure by trimester, first-trimester exposure was associated with a slightly elevated risk of any autoimmune disease (adjusted hazard ratio 1.09, 95 percent confidence interval 1.06 to 1.13). The first trimester coincides with the earliest phases of immune system organogenesis, including the initial establishment of hematopoietic and lymphoid lineages, and it is also the window in which maternal physiological changes make reflux symptoms particularly common—raising the possibility that the underlying indication for treatment, rather than the medication, contributes to the observed signal. The authors note that exposure during this period may warrant careful clinical consideration, even as they emphasize that the overall evidence points to limited clinical concern.

The study’s sensitivity analyses strengthened its robustness. The team examined risks separately by medication type, distinguishing PPIs from H2RAs, and by trimester of exposure, and they modeled risk as a function of time since exposure. They also conducted stratified analyses across numerous subgroups. This methodological architecture matters because prior research on acid suppression in pregnancy and early life has produced a patchwork of associations with allergic diseases, asthma, celiac disease autoimmunity, and even neuropsychiatric disorders, and much of that literature has struggled to separate drug effects from confounding by indication. The present study’s scale—nearly 2.8 million children followed for close to a decade—gives it statistical power that smaller cohorts cannot match, while the sibling design addresses the confounding problem that has undermined earlier work.

The biological plausibility of a link between acid suppression and autoimmunity rests on several converging lines of evidence. Randomized trials have shown that PPIs induce stronger oral-to-gut microbial transmission and greater gut microbiome alterations than H2RAs, and the gut microbiome is increasingly recognized as a modulator of systemic immune tolerance. H2 receptor blockade has been shown to selectively affect B and T cell function in healthy subjects, and cimetidine in particular possesses immunomodulatory properties. Meanwhile, large-scale single-cell atlases of the human thymus have illuminated how precisely T cell self-tolerance is calibrated during development, and epidemiological studies have linked gut microbiota composition to genetic risk for rheumatoid arthritis. Against this backdrop, a true drug effect on fetal immune programming was biologically conceivable—which is precisely why a study of this scale was needed to test it.

For clinicians and expectant mothers, the practical takeaway is one of measured reassurance. Untreated severe gastroesophageal reflux in pregnancy carries its own burdens, from pain and sleep disruption to impaired nutrition, and the new findings provide no compelling basis to withhold acid-suppressive therapy when it is indicated. The authors conclude that the low absolute excess risks and the null sibling-comparison findings indicate limited clinical concern, while flagging first-trimester exposure as the one scenario deserving of thoughtful prescribing decisions. As with all observational research, residual confounding cannot be excluded entirely, and the study population was confined to South Korea, which may limit generalizability to other genetic and dietary environments. But in the hierarchy of evidence on prenatal medication safety, a nationwide cohort of 2.7 million children with sibling-based negative controls represents about as close to a definitive answer as the field can currently achieve—and that answer is, on balance, a comforting one.

Subject of Research: Prenatal exposure to acid-suppressive medications and the risk of autoimmune diseases in offspring

Article Title: Association between prenatal exposure to acid-suppressive medications and subsequent risk of autoimmune diseases in offspring: a nationwide birth cohort study in South Korea

Article References: Lee, Y., Lee, K., Jo, Y., Hong, S., Lee, S., Jo, H., Woo, S., Hwang, Y., Kim, S., Hwang, H. S., Lee, J., Park, J., Lee, H., & Yon, D. K. (2026). Association between prenatal exposure to acid-suppressive medications and subsequent risk of autoimmune diseases in offspring: a nationwide birth cohort study in South Korea. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01077-8

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01077-8

Keywords: acid-suppressive medications, proton pump inhibitors, histamine-2 receptor antagonists, autoimmune diseases, prenatal exposure, birth cohort, pediatrics, South Korea, National Health Insurance Service, gut microbiome, pregnancy, first trimester