Scientists in Denmark have identified a link between maternal use of the antiepilepsy drug (AED) valproate during pregnancy, and attention deficit hyperactivity disorder (ADHD) in their offspring. The population-based observational study, led by Jakob Christensen, MD, clinical associate professor, and a team at Aarhus University Hospital, included more than 913,000 children.

After taking into account a range of potential confounding factors, the results indicated that children who had been exposed in utero to valproate—but not to any other epilepsy drug—were at a small, but statistically significant increased risk of developing ADHD. “These findings have important implications for the counseling of women of childbearing potential using valproate,” the authors stated in their published paper in JAMA Network Open. “The study, therefore, adds to the increasing number of studies suggesting that valproate in pregnancy is associated with a number of adverse neurodevelopmental outcomes, including poor cognitive function and autism, in addition to an increased risk of congenital malformations.” Their published paper is titled, “Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring.”

The heritability of ADHD is estimated to be about 75%, and a number of genetic markers for the condition have now been identified, the authors write. However, environmental factors may also be associated with an increased risk for the condition. While prior studies have suggested that the use of antiepileptic drugs during pregnancy is associated with an increased risk for congenital malformations and delayed cognitive development in offspring, only a handful of small studies and one meta-analysis has investigated any possible link between fetal exposure to valproate in utero and subsequent ADHD. “Prenatal valproate exposure may be associated with ADHD, although previous studies showed no clear evidence of this,” the team continued. “If so, this would be a modifiable environmental exposure and of major importance for women of childbearing potential using valproate.”

To investigate any link between maternal use of valproate during pregnancy and ADHD in offspring, the team carried out a population-based cohort study that encompassed all singleton children born in Denmark between the start of 1997 and the end of 2011. The children were followed from birth until the day of ADHD diagnosis and/or use of ADHD medication, up until the end of 2015. Data from the Danish National Prescription Registry were analysed to define maternal prescriptions for antiepileptic medications, which were filled from about a month before the estimated conception date, to their children’s birth dates.

The final study cohort included 913,302 children, with a mean age of 10.1 years at end of the study. Of this overall cohort, 580 children had been exposed to valproate during pregnancy (whether taken by their mothers as monotherapy or as part of polytherapy). “Of the 912,722 children who were unexposed to valproate, 29,396 (3.2%) had ADHD,” the authors reported. “Of the 580 children who had been exposed to valproate, 49 (8.4%) had ADHD.”

The team’s analyses indicated that overall, children who had been prenatally exposed to valproate were at a 48% increased risk of ADHD compared with the unexposed children. The absolute 15-year risk of ADHD was 4.6% in unexposed children, and 11.0% in those children who had been exposed to valproate during pregnancy. “In the offspring of women who used valproate in monotherapy during pregnancy (n = 431), the risk of ADHD was increased by 52% compared with the risk in the offspring of women who did not use AEDs during pregnancy,” the researchers stated. In contrast, the risk of ADHD with exposure to monotherapy using other antiepileptic drugs, including carbamazepine, clonazepam, oxcarbazepine, and lamotrigine, wasn’t raised. “Compared with the offspring unexposed to AEDs in pregnancy, the risk of ADHD associated with exposure to monotherapy with other AEDs was not statistically different,” they stated. In fact, when compared with prenatal exposure to lamotrigine as the reference, the risk of ADHD linked with prenatal valproate exposure was more than two-fold higher.

The team also used the Danish National Prescription Registry data to link the timing of valproate use (assessed as when before or during pregnancy the prescriptions were filled) with risk of ADHD in their children. The analyses found that compared with valproate-unexposed offspring, the risk of ADHD was 52% higher for those exposed to the drug during the first trimester, and 22% higher for those exposed to valproate in utero only after the first trimester. “The valproate-exposed children who were born to mothers who used valproate 90 days before conception to birth had a 48% increased risk of ADHD,” the researchers also reported. “The risk of ADHD was also increased in valproate-exposed offspring compared with the offspring of women who used valproate prior to but not during their pregnancy and compared with children who were prenatally exposed to lamotrigine.” And after excluding mothers with ADHD, children who were exposed to valproate prenatally had an adjusted risk of ADHD of 1.56 compared with those whose mothers did not take valproate.

“This study identifies an association between prenatal exposure to valproate during pregnancy and the risk of ADHD in the offspring,” the authors concluded. “The association between prenatal exposure to valproate and an increased risk of ADHD was quite robust and persisted after adjusting for maternal psychiatric disorders, maternal epilepsy, maternal diabetes, maternal age, sex, year of birth, and parity, and the association remained after excluding women who smoked during pregnancy.”

The team acknowledged that their study has a number of important limitations, including the existing contraindication of using valproate during pregnancy. “ … we cannot rule out that the observed risk increase for ADHD is at least in part explained by the mother’s health condition that triggered the prescription of valproate during pregnancy,” they wrote, although more than 50% of valproate-exposed children were born before it was widely recognized that the drug was linked with adverse birth outcomes, including neurodevelopmental effects. Other limitations included the use of registry data, which could not confirm whether or how much of the prescribed valproate the women took, and the potential that other, non-AED medications taken by the mothers may have impacted on ADHD risk, and low power of some of the subgroup analyses. Nevertheless, the authors concluded, “As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy. Replication of our findings in large-scale observational studies of adverse drug effects is warranted as such effects have not been evaluated adequately in controlled trials (i.e., during pregnancy).”