Prenatal Exposure to Acid-Suppressive Medications and Risk of Neuropsychiatric Disorders in Children

Overview

This retrospective cohort study examined associations between prenatal exposure to acid-suppressive medications and neuropsychiatric disorders in offspring using data from the South Korean National Health Insurance Service database. The investigation analyzed 2,777,119 mother-child pairs with births occurring between January 2010 and December 2017, with offspring followed through December 2023. The study focused on exposure to histamine 2 receptor antagonists and proton pump inhibitors during pregnancy and subsequent diagnoses of attention-deficit/hyperactivity disorder, autism spectrum disorders, intellectual disability, severe neuropsychiatric disorder, and obsessive-compulsive disorder in children. Two analytical approaches were employed: a propensity score-based overlap-weighted cohort and a sibling-matched cohort design to control for familial confounding factors.

Methods and approach

The study utilized administrative health insurance data to identify mother-child pairs and ascertain prenatal medication exposure and offspring neuropsychiatric outcomes. Exposure was defined as at least one prescription for a proton pump inhibitor or histamine 2 receptor antagonist during pregnancy. Neuropsychiatric disorders were identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes. Two distinct analytical strategies were implemented to address potential confounding: an overlap-weighted cohort analysis using propensity score methods to balance exposed and unexposed groups, and a sibling-control analysis comparing outcomes between siblings with differential prenatal exposure to acid-suppressive medications. The sibling-control design accounted for shared familial factors including genetics, maternal characteristics, and environmental influences that remain constant within families. Mean follow-up duration was 10.3 years, with 507,845 mother-child pairs classified as exposed to prenatal acid-suppressive medication.

Results

In the overlap-weighted cohort comprising 403,658 exposed and 403,659 unexposed mother-child pairs, prenatal exposure to acid-suppressive medication was associated with statistically significant but modest increases in risk across all examined neuropsychiatric outcomes. Adjusted hazard ratios ranged from 1.07 for autism spectrum disorders to 1.16 for severe neuropsychiatric disorder, with attention-deficit/hyperactivity disorder showing a hazard ratio of 1.14. However, the sibling-control analysis including 157,069 exposed and 164,669 unexposed offspring revealed no statistically significant associations between prenatal acid-suppressive medication exposure and any neuropsychiatric outcome. Adjusted hazard ratios in the sibling analysis ranged from 0.95 to 1.02, with confidence intervals crossing the null value for all outcomes examined. The discrepancy between the overlap-weighted and sibling-control findings indicates that observed associations in conventional cohort analyses likely reflect confounding by factors shared within families rather than direct medication effects.

Implications

The absence of associations in sibling-control analyses suggests that prenatal exposure to acid-suppressive medications does not increase risk of neuropsychiatric disorders in offspring when accounting for shared familial confounding factors. The modest associations observed in overlap-weighted models appear attributable to unmeasured familial characteristics including genetic predisposition, maternal health status, and environmental factors that influence both medication use during pregnancy and offspring neuropsychiatric outcomes. These findings provide reassurance regarding the neuropsychiatric safety profile of acid-suppressive medications during pregnancy, addressing clinical concerns about their use in managing gastroesophageal conditions in pregnant individuals. The results demonstrate the importance of employing analytical methods that control for familial confounding in pharmacoepidemiologic studies of prenatal exposures, as conventional cohort analyses may produce spurious associations. The study contributes to evidence-based prenatal prescribing practices by indicating that acid-suppressive medication use during pregnancy should not be avoided solely due to concerns about offspring neuropsychiatric outcomes.

Disclosure

• Research title: Prenatal Exposure to Acid-Suppressive Medications and Risk of Neuropsychiatric Disorders in Children
• Authors: Seohyun Hong, Sooji Lee, Hyunjee Kim, Hyesu Jo, Kyeongmin Lee, Yeona Jo, Tae Hyeon Kim, Jaeyu Park, Jinseok Lee, Ho Geol Woo, Hayeon Lee, Dong Keon Yon
• Publication date: 2026-01-07
• DOI: https://doi.org/10.1001/jama.2025.23956
• OpenAlex record: View
• Image credit: Photo by CDC on Unsplash (Source • License)
• Disclosure: This post was generated by artificial intelligence. The original authors did not write or review this post.