Pregnancy and Offspring Outcomes After Prenatal Stimulant or Atomoxetine Exposure: A Systematic Review and Meta-analysis.

Abstract

Objective: To evaluate associations of prenatal exposure to stimulants and atomoxetine for attention-deficit/hyperactivity disorder with pregnancy, congenital, perinatal, and neurodevelopmental outcomes.

Data sources: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to March 2026. Protocol was registered in the International Prospective Register of Systematic Reviews (CRD42024506319).

Study eligibility criteria: Randomized trials and observational studies comparing pregnancies or offspring exposed to stimulant medications, methylphenidate- or amphetamine-based agents, or atomoxetine with unexposed comparators and reported outcomes were eligible.

Study appraisal and synthesis methods: Reporting guidance for systematic reviews and observational meta-analyses was followed. Two reviewers screened studies, extracted data, and assessed quality with the Newcastle-Ottawa Scale. Random-effects meta-analyses pooled unadjusted and adjusted estimates separately. For neurodevelopmental outcomes, comparators restricted to attention-deficit/hyperactivity disorder populations were prioritized when available.

Results: Twenty-five studies were included; 23 contributed to quantitative analyses. Exposure windows included periconceptional, first-trimester, early-, late-, or continued-pregnancy exposure. Exposure was associated with major congenital malformations in unadjusted analyses (risk ratio, 1.25; 95% confidence interval, 1.14-1.37), but not after adjustment (adjusted risk ratio, 1.04; 95% confidence interval, 0.97-1.12). No adjusted association was observed with cardiovascular malformations (adjusted risk ratio, 1.20; 95% confidence interval, 0.88-1.63), although methylphenidate showed a modest increase (adjusted risk ratio, 1.33; 95% confidence interval, 1.01-1.74). In adjusted analyses, exposure was not associated with miscarriage, preterm birth, low birth weight, small for gestational age, neonatal intensive care unit admission, neurodevelopmental disorders, autism spectrum disorder, or offspring attention-deficit/hyperactivity disorder. Low 5-minute Apgar score remained associated with exposure after adjustment (adjusted risk ratio, 1.21; 95% confidence interval, 1.03-1.42). Lower adjusted autism spectrum disorder risk with stimulants was not replicated in methylphenidate-specific analyses.

Conclusions: Prenatal exposure to stimulants or atomoxetine for attention-deficit/hyperactivity disorder was not associated with increased adjusted risk of major congenital malformations or most adverse pregnancy, perinatal, and neurodevelopmental outcomes. Attenuation of crude associations after adjustment suggests confounding by indication, residual confounding, and maternal characteristics. The observed associations between methylphenidate and cardiovascular malformations and between exposure and low 5-minute Apgar score warrant continued investigation but should not be interpreted as evidence of causal harm.