Key takeaways:
- Prenatal exposure to acid-suppressive medications was not associated with increased neuropsychiatric disorder risk after sibling-comparison analysis.
- Initial cohort analyses showed modestly higher risks for ADHD, ASD, OCD, and intellectual disability among exposed children.
- Differences in risk between proton pump inhibitors and H2 receptor antagonists were not statistically significant.
- First-trimester exposure showed higher risk estimates than later pregnancy exposure in adjusted models.
- Findings suggest observed associations in traditional analyses may be explained by shared familial or genetic factors rather than medication exposure.
Prenatal acid-suppressive medication exposure does not influence children’s attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), intellectual disability, severe neuropsychiatric disorder, or obsessive-compulsive disorder (OCD) risks, according to a recent study published in JAMA Network Open.1
Concerns have arisen about adverse child outcomes following prenatal acid-suppressive medication exposure, with 1 study linking proton pump inhibitors (PPIs) exposure to offspring epilepsy risk.2 Experts have also described early-life microbiome as a key part of neurodevelopmental health.1
“Considering that acid-suppressive medications may modify the composition and diversity of the gut microbiota, maternal use during pregnancy may influence neurodevelopmental processes in offspring,” wrote investigators.
Neuropsychiatric assessment
The study was conducted to evaluate the link between acid-suppressive medication use during pregnancy and offspring neuropsychiatric disorder risk. Data was obtained from a large-scale mother-child linked cohort in South Korea. Mothers and children were linked through a unique family insurance identification number.
Participant demographics, clinical diagnoses, medical procedures, prescription records, and health care utilization information were obtained from the National Health Insurance Service of South Korea. Participants included women aged 13 to 58 years delivering a liveborn neonate between January 1, 2010, and December 31, 2017.
Exclusion criteria included inadequate socioeconomic information and being prescribed an acid-suppressive medication within 30 days before pregnancy. Participants were assessed in both a propensity score-based overlap cohort and a sibling-comparison cohort.
Exposures, outcomes, and participant characteristics
Maternal acid-suppressive medication use during pregnancy, based on the receipt of at least 1 PPI or histamine 2 (H2) receptor antagonist prescription, was the main exposure, reported based on type of medication and timing of administration. Women with no prenatal acid-suppressive use during pregnancy were included as controls.
Severe psychiatric disorders, ADHD, AHD, OCD, and intellectual disability were reported as outcomes. Covariates included maternal sociodemographic characteristics, maternal clinical characteristics, delivery-related factors, and infant characteristics.
There were 2,777,119 children and 2,075,648 paired mothers assessed, with a mean follow-up period of 10.3 years. Exposure to acid-suppressive medication was reported among 507,845 pairs. Exposed mothers were aged a mean 31.7 years and unexposed mothers a mean 31.8 years.
Risk estimates by neuropsychiatric outcome
The final analysis consisted of 807,317 pairs, with exposure reported in 403,658. These exposed infants were significantly more likely to develop neuropsychiatric disorders vs their unexposed peers, with an adjusted hazard ratio (HR) of 1.13. An HR of 1.14 was reported for ADHD, making it the most common outcome.
Additional HRs among exposed infants included 1.16 for OCD, 1.12 for ASD, and 1.13 for intellectual disability. This indicated increased risks of all outcomes among this population.
Increased risks were also reported for subgroup analyses, including an adjusted HR of 1.12 neuropsychiatric disorders when exposed to H2 receptor antagonists only vs 1.20 for PPIs only. Differences in the risk increase based on medication type were not statistically significant.
First-trimester exposure was linked to a significantly greater risk of neuropsychiatric disorders, with an overall adjusted HR of 1.14. Additionally, HRs of 1.18, 1.14, 1.16, 1.06, and 1.13 were reported for severe neuropsychiatric disorders, OCD, ADHD, ASD, and intellectual disability.
Second-trimester and third-trimester risks were mostly non-significant, except for links to ASH and intellectual disability following third-trimester exposure.
Sibling-comparison analysis suggests familial confounding
Correlations between acid-suppressive medication exposure and neuropsychiatric outcomes were not found in the sibling-matched analysis, with a rate of 5.72 per 1000 person-years among exposed siblings vs 5.77 per 1000 person-years among unexposed siblings. HRs for individual disorders included 1 for severe neuropsychiatric disorder, 0.95 for OCD, 0.98 for ADHD and ASD, and 1.02 for intellectual disability.
“Associations observed in other models may reflect confounding by shared familial factors,” wrote investigators.
References
- Hong S, Lee S, Kim H, et al. Prenatal exposure to acid-suppressive medications and risk of neuropsychiatric disorders in children. JAMA. 2026. doi:10.1001/jama.2025.23956
- Gudnadottir U, Wickström R, Gunnerbeck A, Prast-Nielsen S, Brusselaers N. Prenatal and early childhood exposure to antibiotics or gastric acid inhibitors and increased risk of epilepsy: a nationwide population-based study. Clin Pharmacol Ther. 2025;118(1):206-217. doi:10.1002/cpt.3679
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