Genes as Unmeasured and Unknown Confounds in Studies of Neurodevelopmental Outcomes After Antidepressant Prescription During Pregnancy.

In observational studies, significant associations have often been identified between antidepressant drug prescription during pregnancy, on the one hand, and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), on the other. Interpreting these associations is problematic because they are based on analyses that could not adjust for inadequately measured, unmeasured, and unknown confounds. Recent clinical data suggest that a genetic relationship exists between depression and neurodevelopmental disorders. A very recent study identified many genetic loci that were common to depression, ASD, and ADHD. These findings suggest the possibility that depression in a pregnant woman may predispose to neurodevelopmental disorders in offspring through shared genes and not through antidepressant use during pregnancy. Previous studies that significantly associated gestational exposure to antidepressants with adverse pregnancy outcomes could not adjust for genetic factors because they were unknown confounds at the time. Now that common risk loci have been identified, at least some of the unknown (genetic) confounds are no longer unknown; however, unless specifically examined in prospective studies, they will remain as unmeasured confounds that will continue to compromise the interpretation of study results. The possibility of confounding by inadequately measured, unmeasured, and unknown risk factors must therefore be considered before indicting antidepressant use during pregnancy in neurodevelopmental risks. In this context, the importance of genetic factors as unmeasured and unknown confounds must be acknowledged.