Prenatal Antidepressant Exposure and the Risk of Attention-Deficit/Hyperactivity Disorder in Childhood: Accounting for Misclassification of Exposure

Background:Many studies of prenatal antidepressant exposure and the risk of attention-deficit/hyperactivity disorder (ADHD) have done little to reduce bias from exposure misclassification. We assessed the prenatal antidepressant-ADHD effect by incorporating information on repeatedly redeemed prescriptions and redemptions of drug classes commonly used in pregnancy in the analyses to reduce bias from exposure misclassification. Methods:Using population-based registries, we conducted a nationwide cohort study of all children born in Denmark from 1997 to 2017. In a former-user analysis, we compared children prenatally exposed, defined by a redeemed prescription by the mother during pregnancy, to a comparison cohort consisting of prenatally unexposed children whose mothers had redeemed a prescription before pregnancy. We incorporated information on repeatedly redeemed prescriptions and redemptions of drug classes commonly used in pregnancy in the analyses to reduce bias from exposure misclassification. We used incidence rate ratios (IRRs) and incidence rate differences (IRDs) as effect measures. Results:The cohort included 1,253,362 children, among whom 24,937 were prenatally exposed to antidepressants. The comparison cohort consisted of 25,698 children. During follow-up, 1,183 exposed children and 1,291 children in the comparison cohort developed ADHD yielding an IRR of 1.05 (95% confidence interval [CI] = 0.96, 1.15) and an IRD of 0.28 (95% CI = -0.20, 0.80) pr. 1,000 person-years. IRRs from analyses attempting to reduce exposure misclassification varied from 1.03 to 1.07. Conclusions:Our results were not consistent with the hypothesized effect of prenatal antidepressant exposure on the risk of ADHD. Attempts to reduce exposure misclassification did not alter this finding.