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

Importance: Although acid-suppressive medications are commonly prescribed during pregnancy, comprehensive studies on their association with neuropsychiatric disorders in children are limited. Objective: To investigate potential associations between prenatal exposure to acid-suppressive medication (histamine 2 [H2] receptor antagonists and proton pump inhibitors [PPIs]) and neuropsychiatric disorders in children. Design, Setting, and Participants: Retrospective cohort study of mother-child pairs in the South Korean National Health Insurance Service database with births from January 2010 through December 2017, with follow-up of offspring through December 2023. Analyses were conducted using a propensity score-based overlap-weighted cohort and a sibling-matched cohort. Exposure: Prenatal exposure to at least 1 prescription for a PPI or H2 receptor antagonist. Main Outcomes and Measures: Offspring neuropsychiatric disorders identified via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), intellectual disability, severe neuropsychiatric disorder, and obsessive-compulsive disorder. Results: Of 3 012 992 mother-child pairs initially identified, 2 777 119 were included, with 507 845 pairs exposed to prenatal acid-suppressive medication and were followed up a mean of 10.3 (SD, 2.3) years. In the overlap-weighted cohort (403 658 mother-child pairs exposed and 403 659 pairs unexposed to an acid-suppressive medication), respective risks among offspring exposed vs not exposed were 4.85% vs 4.25% for ADHD, 1.45% vs 1.33% for ASD, 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. In the overlap-weighted cohort, the adjusted hazard ratio (HR) following prenatal acid-suppressive medication exposure was 1.14 (95% CI, 1.12-1.17) for ADHD, 1.07 (95% CI, 1.03-1.11) for ASD, 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 that included 157 069 exposed and 164 669 unexposed offspring revealed no significant associations between prenatal exposure and offspring outcomes. The adjusted HR for ADHD was 0.98 (95% CI, 0.95-1.02); for ASD, 0.98 (95% CI, 0.92-1.04); intellectual disability, 1.02 (95% CI, 0.95-1.09); severe neuropsychiatric disorder, 1.00 (95% CI, 0.93-1.08); or obsessive-compulsive disorders, 0.95 (95% CI, 0.82-1.10). Conclusions and Relevance: Exposure to acid-suppressive medication during pregnancy was not associated with children's risk of ADHD, severe neuropsychiatric disorder, obsessive-compulsive disorder, intellectual disability, or ASD in sibling-control analyses. Small associations were observed in overlap-weighted models; these may reflect confounding by shared familial factors.