Maternal and paternal antidepressant use before and during pregnancy and offspring risk of neurodevelopmental disorders: a systematic review and meta-analysis

Background

The potential risk of neurodevelopmental disorders following prenatal antidepressant exposure is concerning. Meta-analyses conducted in the past decade have had small study numbers and insufficient assessment of confounding by treatment indication. We aimed to synthesise risk of neurodevelopmental disorders, including ADHD and autism spectrum disorder (ASD), with antidepressant exposure before or during pregnancy in mothers and fathers, accounting for antidepressant classes, agents, dose, and confounding.

Methods

In this systematic review and meta-analysis, we searched Embase, MEDLINE, PsycINFO, and Web of Science from database inception to May 14, 2025, for studies that included mothers or fathers with antidepressant use before or during the pregnancy period and that reported data on neurodevelopmental disorders. Relative risks (RRs) were pooled using random-effect meta-analyses. We assessed publication bias, subgroup analyses, and quality assessment (Newcastle-Ottawa scale). No people with relevant lived experience were involved in the research and writing process. Only two studies reported ethnicity data. This study is registered with PROSPERO (CRD420251052595). Findings We identified 37 studies involving 648 626 antidepressant-exposed and 24 967 806 unexposed pregnancies (weighted average mean age 28·8 years, range 28·5–32·3). Prenatal antidepressant use was associated with a modestly increased risk of neurodevelopmental disorders in offspring (RR 1·13, 95% CI 1·08–1·18; k=2; I2=64·9%; p=0·051), including ADHD (1·35, 1·24–1·47; k=14; I2=90·2%; p<0·0001) and ASD (1·69, 1·24–2·30; k=25; I2=98·1%; p<0·0001), but not intellectual disabilities, motor disorders, or speech and language disorders. No significant difference in ASD risk was found between high-dose and low-dose exposure, and paternal antidepressant use around conception was not linked to ASD. Both SSRI and non-SSRI antidepressants exhibited increased risk for ADHD (SSRI 1·35, 1·20–1·51; k=11; I2=87·3%; p<0·0001; non-SSRI 1·41, 1·33–1·50; k=3; I2=0%; p=0·35) and ASD (SSRI 1·52, 1·39–1·65; k=21; I2=55·6%; p<0·0001; non-SSRI 1·19, 1·03–1·45; k=4; I2=0%; p=0·38). Notably, similar associations were found for pre-conception exposure. Observed associations were attenuated or became non-significant in sensitivity analyses accounting for confounding factors, such as maternal mental disorders, familial or genetic influences, and misclassification. Paternal antidepressant use during pregnancy served as a negative control and was associated with increased ADHD risk (1·46, 1·38–1·56; k=2; I2=25·3%; p=0·24) and ASD risk (1·28, 1·16–1·40; k=6; I2=35·0%; p=0·20). When confounding by indication was minimised, only amitriptyline and nortriptyline were associated with increased risk of ADHD (amitriptyline 1·74, 1·00–3·03) or ASD (amitriptyline and nortriptyline 2·02, 1·32–3·10), whereas no significant associations were found for specific SSRIs or SNRIs. The certainty of evidence was low to very low. Interpretation This systematic review and meta-analysis indicated a small association between antidepressants and ADHD or ASD, which was attenuated or became non-significant after adjusting for confounding factors. Antidepressant treatment should be continued for pregnant women with moderate-to-severe depression. Optimising both maternal and paternal mental health is essential for the child's long-term neurodevelopment. Funding None.