Antidepressant Use During Pregnancy: An Evidence-based Review of Risk–Benefit Balance and Drug-specific Considerations

Abstract

Antenatal depression affects approximately 12% of pregnancies, and antidepressant exposure during pregnancy-predominantly selective serotonin reuptake inhibitors (SSRIs)-is estimated at approximately 3% of pregnancies in multinational estimates.Clinical decision-making requires balancing the risks of untreated maternal depression against those associated with in utero antidepressant exposure, rather than considering pharmacotherapy as the sole source of risk.This review synthesizes evidence from large population-based cohort studies, meta-analyses, and advanced observational designs, integrating biological mechanisms, exposure epidemiology, and clinical outcomes, with emphasis on confounding by indication.The evidence suggests that initial associations between SSRI exposure and adverse outcomes-including cardiac malformations, preterm birth, and neurodevelopmental disorders-are substantially attenuated after adjustment for maternal psychiatric illness using disease comparator, sibling-controlled, and negative control designs.The most consistently observed short-term outcome is poor neonatal adaptation syndrome, affecting approximately 25-30% of neonates exposed in late pregnancy, typically transient and self-limiting.Discontinuation of antidepressant therapy during pregnancy is associated with relapse rates up to 68% among women with recurrent major depression.This review classified individual antidepressants into three evidence tiers based on the availability of large, confounding-controlled cohort data, providing drug-specific clinical considerations.Sertraline has the most extensively characterized and reassuring evidence base among individual agents.Paroxetine retains a modest cardiac signal, though the absolute risk increment remains small.The strength of available evidence varies considerably among other antidepressants, as detailed in this review.These findings propose personalized, severity-based treatment decisions and also reinforce that untreated maternal depression should be considered alongside medication exposure when evaluating perinatal risk.