According to a large Korean cohort study, there was no association between the use of acid-suppressive medications during pregnancy and neuropsychiatric disorders in offspring, including ADHD and autism spectrum disorders, after controlling for familial factors. Although initial analyses suggested modest risk increases, the absolute risk remained low. Importantly, sibling-control analyses eliminated this association, indicating that earlier observed risks were likely due to residual confounding rather than a true causal effect. The study was published in JAMA by Seohyun H. and colleagues.
Proton pump inhibitors and histamine-2 receptor agonists are often used during pregnancy to treat gastroesophageal reflux disease. Their long-term neurodevelopmental effects in children have been brought forth by some concerns. This was a retrospective study done using the National Health Insurance Service database from South Korea. Those who were part of this study were mother-child dyads with live birth outcomes from January 2010 to December 2017. Follow-ups of the offspring were completed by December 2023. Both overlap-weighted analyses by Proportion Score and Cohort analyses by sibling matchings were done to eliminate Confounders.
Of the initial 3,012,992 cases of identified mother-child pairs, a total of 2,777,119 were included in the analysis. In these cases, there were 507,845 children exposed to proton pump inhibitor and/or histamine-2 receptor antagonist prescription exposure in utero. The average time of exposure of offspring was a total of 10.3 years (standard deviation of 2.3) post-exposure. Exposure was considered to be the receipt of a prescription of an acid suppressor medication during pregnancy.
Key findings
In the overlap-weighted cohort, 403,658 exposed offspring were matched with 403,659 unexposed offspring.
The risks in exposed vs unexposed children were 4.85% vs 4.25% for attention-deficit/hyperactivity disorder, 1.45% vs 1.33% for autism spectrum disorder, 1.25% vs 1.09% for intellectual disability, 0.94% vs 0.81% for severe neuropsychiatric disorder, and 0.30% vs 0.27% for obsessive-compulsive disorder.
Adjusted hazard ratios were 1.14 (95% CI, 1.12–1.17) for attention-deficit/hyperactivity disorder, 1.07 (95% CI, 1.03–1.11) for autism spectrum disorder, 1.13 (95% CI, 1.09–1.18) for intellectual disability, 1.16 (95% CI, 1.10–1.21) for severe neuropsychiatric disorder, and 1.12 (95% CI, 1.03–1.21) for obsessive-compulsive disorder.
Sibling-control analyses comprised 157,069 exposed and 164,669 unexposed offspring within the same families.
No statistically significant associations of prenatal acid-suppressive medication exposure with neuropsychiatric outcomes were observed in this analysis.
The adjusted hazard ratios were 0.98 (95% CI, 0.95–1.02) for attention-deficit/hyperactivity disorder, 0.98 (95% CI, 0.92–1.04) for autism spectrum disorder, 1.02 (95% CI, 0.95–1.09) for intellectual disability, 1.00 (95% CI, 0.93–1.08) for severe neuropsychiatric disorder, and 0.95 (95% CI, 0.82–1.10) for obsessive-compulsive disorder.
There were no associations found between neonatal exposure and the risk of neuropsychiatric disorders in children when assessed by sibling control analysis. Small associations found in population-based models most probably indicate shared factors and do confirm the relative neurodevelopmental safety of these drugs in cases of pregnancy.
Reference:
Hong S, Lee S, Kim H, et al. Prenatal Exposure to Acid-Suppressive Medications and Risk of Neuropsychiatric Disorders in Children. JAMA. Published online January 07, 2026. doi:10.1001/jama.2025.23956
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