CME Author: Vicki Brower
Study Authors: Jakob Christensen, Lars H. Pedersen, et al.
Target Audience and Goal Statement:
Neurologists, obstetricians/gynecologists, primary care physicians, internists, and family doctors
The goal was to determine whether prenatal exposure to valproate and other antiepileptic drugs is associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in the offspring.
What is the risk of ADHD in children prenatally exposed to valproate and other antiepileptic drugs?
Study Synopsis and Perspective:
Children of women who used the anti-convulsant drug valproate during pregnancy had a 48% increased risk of ADHD, according to a large population-based cohort study by Danish researchers. A total of 8.4% of children exposed to valproate prenatally were diagnosed with ADHD, compared with 3.2% of children who were not exposed, reported Jakob Christensen, MD, PhD, of Aarhus University Hospital, and colleagues, writing online in JAMA Network Open.
Valproate is currently prescribed for epilepsy, bipolar disorder, and less frequently, for migraines.
The research, which covers the period of 1997 through 2011, adds to a growing body of literature linking valproate taken during pregnancy with numerous adverse neurodevelopmental outcomes. In the U.S. and Europe, valproate labeling warns that children exposed to the drug during gestation may have cognitive deficits and physical birth defects, including poor cognitive function, autism, and an increased risk of congenital malformations. Both the U.S. Department of Health and Human Services and the European Medicines Agency have issued warnings about use of valproate during pregnancy.
Compared with the risk in children who were not exposed to valproate, the risk of ADHD was 52% higher for those exposed to the drug in the first trimester of pregnancy, and 22% higher for those exposed to valproate after the first trimester. “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,” Christensen and co-authors wrote.
The association between prenatal valproate exposure and increased 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 researchers reported.
“The study raises concern that treatment with valproate in pregnancy may be associated with increased risk of ADHD in the offspring — this is a new finding,” Christensen told MedPage Today. “However, because the results are based on observations, other factors may explain the association. The risk of ADHD in offspring of women with epilepsy using anti-epileptic drugs should therefore be further studied.”
The study included 913,302 children born in Denmark from 1997 through 2011. The researchers used national registries to identify children who were diagnosed with ADHD or who redeemed a prescription for ADHD medication, following them from birth until the day of ADHD diagnosis or the end of 2015. Children were an average of 10.1 years at the end of the study, and 51.3% were male.
The researchers identified 580 children who had been exposed to valproate during pregnancy; of them, 49 (8.4%) had ADHD. Of the 912,722 children who were not exposed to valproate, 29,396 (3.2%) had ADHD. The mean age at ADHD diagnosis was 8.8.
When the analysis was restricted to children of women with epilepsy, the increased risk for valproate-exposed children (n=516) dropped to 39%. When restricted to children of women without epilepsy, the increased risk was higher, but not statistically significant due to small sample size.
The study authors stressed that while valproate exposure “clearly poses a greater risk for both anatomical and behavioral teratogenesis than several other anti-seizure medications, there remains a great need for further research as the teratogenic risks of many anti-seizure medications remain uncertain. The researchers said that given the potential lifelong consequences of fetal medication exposures, new approaches should be used to determine these risks more expediently.
The team suggested a national reporting system for congenital malformations, routine preclinical testing of all anti-seizure medications for neurodevelopmental effects, monitoring of anti-seizure medication prescription practices for women of childbearing age, and improved funding of basic and clinical research to fully determine the risks and underlying mechanisms of harm from anti-seizure medications.
Christensen and colleagues noted several limitations to the study: For example, ADHD risk may also be tied to the mother’s health — i.e., since pregnancy is a contraindication for valproate, women who take it during pregnancy may actually have a different presentation and severity compared with other women. In addition, seizures during pregnancy, which could not be identified in the study, may have affected the outcomes. Also, clinical practices may be more restrictive in diagnosing ADHD in Denmark than in countries like the U.S., with the result that only more severe cases are included in Danish registries.
Source References: JAMA Network Open, Jan. 4, 2019, 2(1):e186606; and JAMA Network Open, Jan. 4, 2019, 2(1):e186603
Study Highlights: Explanation of Findings
Overall, children who were prenatally exposed to valproate had a 48% increased risk of ADHD (adjusted HR 1.48, 95% CI 1.09-2.00) compared with unexposed children. The absolute 15-year risk of ADHD was 4.6% (95% CI 4.5%-4.6%) in children not exposed to valproate and 11.0% (95% CI 8.2%-14.2%) in exposed children.
The authors noted that the risk of ADHD related to valproate exposure was mainly in the first trimester, although there were still cases of exposure later in pregnancy. Higher doses seemed to be associated with higher risks, although the difference was “not significant,” the researchers said, adding that other studies, however, have indicated that harmful effects of valproate during pregnancy may be linked to dose. In addition, the risk of ADHD remained significant after adjusting for congenital malformations and excluding children with valproate-induced congenital malformations.
The findings contrast with the results from a recent meta-analysis of four studies including 750 individuals that showed no statistically significant increased risk of ADHD from in utero valproate exposure. The discrepancy might be due to methodology: the meta-analysis used different analytical approaches, and examined studies with smaller sample sizes, higher attrition rates, shorter follow-ups, and cohort differences, noted Kimford Meador, MD, of Stanford University School of Medicine in California, writing in an accompanying editorial.
“Nevertheless, the findings by Christensen et al. are consistent with multiple studies demonstrating adverse neurodevelopmental effects associated with fetal valproate exposure,” Meador wrote. In addition, he said, the large population-based cohort design of the current study may have advantages over meta-analyses, and it did control for multiple potentially confounding factors such as maternal diagnosis of psychiatric disease, epilepsy, and diabetes, and other important factors.
Meador observed that along with new evidence of a link with ADHD, prenatal risks of valproate exposure include a 9-10% risk of major congenital malformations, which is the highest risk among anti-seizure medications, dose-dependent reduction of IQ (by 7-10 points, compared with several commonly used seizure medications), and other cognitive domains (such as language, nonverbal abilities, memory, and executive functions), and increased behavioral problems, including a 4.42% absolute risk of autism spectrum disorder.
Another weakness of the study, Meador said, is that other fetal medication exposures — prescription, recreational, and abused drugs, including alcohol — were not controlled for.
Counseling about valproate’s risk of causing ADHD, major congenital malformations, and other neurodevelopmental problems 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,” he emphasized. “There are a limited number of women for whom valproate may be the best choice, but this drug should not be prescribed without appropriate informed consent.”
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco