A population-based study reported by a Danish group (J. Christiansen and colleagues, JAMA Netw Open 2019 January 4; 2(1):e186606) is a recently published example that prenatal exposure to valproate may be associated with a childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD).
The authors assess the statistical significance of an association between in utero exposure to valproate and subsequent diagnosis of attention-deficit/hyperactivity disorder (ADHD). Identifying from a Danish national registry 913,302 children who had been exposed to valproate or other (unspecified) antiepileptic drugs in utero and been born over a 15-year span, they compared 580 who had been exposed to valproate in utero with the rest of the children in their sample who had been exposed in utero to other antiepileptic drugs, with respect to the proportions with ADHD (from a register of those diagnosed with ADHD or a register of those with a proxy of having been so diagnosed (by virtue of having filled a prescription for unspecified “ADHD medication”).
Among 912,722 children who had been exposed in utero to an anti-epileptic drug other than valproate, 29,296 (3.2 percent) were found to have ADHD by diagnosis or diagnosis proxy; by comparison, 49 of 580 children (8.4 percent) who had been exposed to valproate in utero were identified as having been diagnosed with ADHD or having had a prescription for an unspecified “ADHD medication” on their behalf. They then calculated an adjusted hazard ratio of 1.48 in valproate-exposed children, indicating that they were 48 percent more likely to have ADHD than were children who had been exposed in utero to an anti-epileptic drug other than valproate. (Obiter: Stimulant “ADHD medication” also is prescribed for narcolepsy and for additive antidepressant effect in persons with treatment-resistant depressive disorders—diagnostic categories that, had they been excluded from analysis, may have affected the statistical significance of the authors’ finding.)