Offspring Outcomes in Studies of Antidepressant-Treated Pregnancies Depend on the Choice of Control Group

Abstract

Antenatal depression complicates 14%-23% of pregnancies; if the depression is left untreated, there is an increased risk of a wide range of adverse maternal and offspring outcomes. However, antidepressant use, and, more specifically, selective serotonin reuptake inhibitor (SSRI) use, has also been associated with adverse pregnancy outcomes. Regrettably, SSRIs have received bad press in this context even though the evidence linking them with the adverse outcomes has not disentangled depression effects from drug effects. The most important reason why depression and drug effects cannot be separated is that the evidence is derived mostly from retrospective observational studies and not from randomized controlled trials, which are necessary but which cannot be performed during pregnancy for ethical and practical reasons. In these observational studies, the control groups are formed from healthy women, depressed women, and/or propensity score-matched women who did not receive antidepressant drugs during pregnancy. A limitation of such control groups is that they cannot control for confounding arising from poorly measured, unmeasured, or unknown variables that influence the pregnancy outcomes being assessed. This article discusses problems involved in such research and illustrates how, when confounding is diminished by using sibling controls discordant for antidepressant exposure during pregnancy, the risks of adverse outcomes associated with antidepressant exposure diminish. However, a discordant sibling control group is associated with its own limitations, and these are also discussed.