ADHD Associated with Prenatal Exposure to Valproate

Jakob Christensen, MD, PhD

Attention-deficit hyperactivity disorder (ADHD) can be added to the list of adverse developments, including congenital malformations, that are associated with prenatal exposure to the antiepileptic drug valproate, according to findings of a large population study released today.

Jakob Christensen, MD, PhD, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark, and colleagues described the association as "quite robust," and noted that it remained so after the children diagnosed with congenital malformations were excluded from the analysis.

"This suggests that the increased ADHD risk was not confined to children with valproate-induced congenital malformations," the investigators indicated.

Records for 913,302 singleton children born in Denmark between January 1997 and December 2011 (51.3% male) were tracked through a mean age of 10.1 years (range 7.2 to 12.8 years). Data on prenatal medication exposure and on subsequent medication for ADHD were obtained from the Danish National Prescription Registry; and the diagnosis of ADHD was obtained from the Danish Psychiatric Central Research Register or inferred from the prescribed ADHD medications.

A total of 580 children had been exposed to valproate in utero, and 49 (8.4%) subsequently developed ADHD. Among the 912,722 children who were not exposed to valproate, 29,396 (3.2%) were diagnosed with ADHD. The investigators calculated a 48% increased risk of ADHD with exposure to valproate (adjust hazard ratio [aHR] 1.48, 95% confidence interval [CI] 1.09-2.00). The absolute 15-year risk of ADHD with prenatal exposure to valproate was 11% (CI 8.2-14.2%) compared to 4.6% (CI 4.5-4.6) in children without that exposure.

Christensen put the relative risk in perspective while discussing the study with MD Magazine®. "Based on the results of this study, about 90% of children—after prenatal exposure to valproate—will not be diagnosed with ADHD before age 15, and therefore systematic assessment of children (with exposure) is likely not warranted," he said.

In invited commentary accompanying the study, Kimford Meador, MD, Stanford Neuroscience Health Center, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, points out that valproate not only presents the highest risk among antiepileptic drugs (AEDs) for major congenital malformations, but that prenatal exposure is also associated with increased risk for behavioral problems and autism spectrum disorders, reduced IQ, and dose-dependent reduction across multiple cognitive domains.

"The increased risks from fetal valproate exposure of major congenital malformations and neurodevelopmental problems including ADHD as well as other cognitive and behavioral problems should be communicated to women of childbearing potential who are prescribed valproate for epilepsy or other conditions," Meador recommended.

In comparing valproate to other AEDs relative to no AED exposure, Christensen and colleagues determined that the risk for ADHD with valproate (aHR 1.52, CI 1.05-2.19) was more than 2-fold greater than with the reference lamotrigine (aHR .84, CI .59-1.19). Oxcarbazepine was not found to pose risk (aHR 1.10, CI .72-1.67).

Clonazepam and carbamazepine did pose possible increased risk compared with no prenatal AED, however, with aHR of 1.43 (CI .95-2.16) and 1.23 (CI .84-1.82), respectively. The investigators note that that this finding has not previously been described.

Christensen and colleagues reference a recent meta-analysis of 5 published studies which had not found statistically significant increased risk of ADHD with valproate, but they attribute the different finding of the meta-analysis to those studies having different and smaller cohorts, higher attrition rates, and shorter periods of follow-up.

"A major strength of this study is its population-based nature and the completeness of follow-up without attrition," Christensen and colleagues indicated. "The analyses showed that most children who had been diagnosed with ADHD after prenatal valproate exposure were identified from both the hospital register and the prescription register, suggesting a high validity of both ways of identifying ADHD in children."

Christensen acknowledged other limitations of the study, however, noting that the study showed only association, not causation. "Because the results are based on observations, other factors may explain the association and the risk of ADHD in offspring of women with epilepsy using antiepileptic drugs. The study should thus be replicated—preferably in other populations to confirm or reject the association," he said.

While recognizing study limitations, Meador found the findings compelling, and argued that they should inform prescribing practice going forward.

"The counseling about valproate's risks to women of childbearing potential should occur not only well before pregnancy, but also at any time a prescription for valproate is written for a woman of childbearing potential since approximately half of pregnancies are unplanned," Meador urged.

The study, “Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs with Risk for Attention-Deficit/Hyperactivity Disorder in Offspring,” and commentary, “Fetal Valproate Exposure and Attention-Deficit/Hyperactivity Disorder,” were published in the Journal of the American Medical Association (JAMA).