The aim of this review was to critically appraise the existing literature with a particular focus on identifying methodological issues associated with studying outcomes following the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Existing studies evaluating outcomes following prenatal SSRI exposure suffer from a number of important methodological limitations that should be taken into account when interpreting their results. The contradictory results obtained from prospective and retrospective cohort studies and case-control studies could be accounted for by dissimilarity between study populations, selection bias, detection bias, confounding, or differences in underlying maternal illness, data sources used, exposure classification, follow-up and statistical power/analysis. Only a small number of studies actually account for underlying maternal illness and how this may lead to adverse pregnancy outcomes. Even when such information is available, studies that include data on maternal illness have small sample sizes, limiting the statistical power to identify statistically and clinically relevant associations. Pregnancy outcomes may be confounded by the higher incidence of smoking, alcohol consumption and substance abuse frequently encountered amongst those suffering from depression, factors that are often insufficiently controlled for. While evidence of associations between prenatal SSRI exposure and adverse pregnancy outcomes are conflicting, there is an urgent need to evaluate how the particular SSRI used, the dose, timing and duration of use, genetics (maternal, paternal and/or fetal), concomitant medication use, maternal characteristics and underlying maternal illness all interact to alter pregnancy outcomes.