Introduction: Emerging evidence suggests an association between antidepressant exposure during pregnancy and an increased risk of fetal mortality (i.e., fetal death and stillbirth). Given that antidepressant use is most prevalent during the first trimester – a critical period for fetal organogenesis and placental vascular development – this meta-analysis aimed to quantify the risk of fetal mortality associated with first-trimester antidepressant exposure. Methods: A systematic literature search was conducted across PubMed, ClinicalTrials, and the Cochrane Central Register of Controlled Trials. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Nine population-based cohort studies were included, encompassing over 8 million pregnancies. First-trimester exposure to any antidepressant was associated with a significantly increased risk of stillbirth (Peto OR = 1.52 [1.28 – 1.82], p<.01, I2 = 52%)., with a moderate certainty of evidence. Sensitivity analyses supported the robustness of this finding. Subgroup analyses showed a significant associations for both selective serotonin reuptake inhibitors (SSRIs) (Peto OR = 1.41 [1.04 – 1.89], p<.05, I2 = 47%, six studies) and non-SSRIs (Peto OR = 4.93 [1.08 – 22.42], p<.05, I2 = 79%, three studies). Conclusions: This meta-analysis highlights potential risks for stillbirth associated with antidepressants use during the first trimester of pregnancy, particularly with non-SSRIs. While causality remains uncertain, these findings underscore the importance of personalized treatment counseling for women planning pregnancy and the need for further research on the safety profiles of specific antidepressants during pregnancy.
KEYWORDS: Antidepressive Agents; Fetal Death; Fetus; Meta-analysis; Pregnancy; Pregnancy Trimester, First.
Fabian Guénolé
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