Despite risks and safety warnings, valproic acid (valproate) remains the most widely prescribed antiseizure medication globally, with prescription rates increasing, an international trends analysis shows. 

The “good news” is that access to antiseizure medicines is expanding globally. “But the continued widespread use of valproate in some parts of the world is concerning, given its known risks during pregnancy,” study investigator Adrienne Chan, PhD, with Aston School of Pharmacy, Aston University, Birmingham, UK, said in a statement. 

The study was published online on October 9 in eClinicalMedicine. 

Teratogenic Risk 

Due to valproate’s teratogenic risks, the World Health Organization (WHO) and other regulatory agencies have advised against its use in women and girls of childbearing age. The WHO recommends lamotrigine or levetiracetam as first-line therapy for epilepsy in this patient population. 

Using global pharmaceutical sales data, Chan and colleagues examined trends in antiseizure medication use between 2012 and 2022 in 41 high-income, 20 upper-middle income, and 12 lower-middle income countries or regions — representing 77% of the world’s population. 

Overall, antiseizure medication consumption rose steadily over the 10-year period, with an average annual percentage change of 2.6%. The greatest change in consumption was in southeastern Asia (+5.2%), followed by western Asia (+4.7%) and southern Asia (+3.8%). 

There has been growth in use of newer agents, including levetiracetam (+21.7% per year) and lamotrigine (+7.5%), coupled with a decline in use of older drugs, such as phenobarbital (-2.9%), phenytoin (-11.2%) and carbamazepine (-1.1%).

In 2022, the consumption rate of high-income countries was more than four times that of lower-middle income countries.

Valproate remained the most widely used antiseizure medication globally in 2022, with stronger growth observed in lower income (+4.2%) and upper-middle income (+3.1) countries compared with high-income countries (+0.9%). 

From 2012 to 2022, overall consumption of valproate increased at a rate of about 2.0% per year.

“The affordability and broad-spectrum efficacy of valproate may help to explain its continued rise where newer antiseizure medications remain prohibitively expensive, especially in lower-income settings,” the investigators wrote. 

They noted that in North America and other higher-income countries, prior data suggested that valproate is increasingly avoided as a first- or second-line antiseizure therapy, reflecting changes in prescribing practice following safety warnings and prescribing restrictions introduced in Europe and the US.

‘Very Concerning’ Data 

Reached for comment, Kimford Meador, MD, professor, Department of Neurology and Neurological Sciences at Stanford University School of Medicine in Palo Alto, California, said the overall growth in use of antiseizure medication is “not surprising. Also, the decline in phenobarbital, phenytoin, and carbamazepine, and the growth in newer agents (levetiracetam/lamotrigine) is not surprising.”

“However, the increased use of valproate and that it remains the most used antiseizure medication is not only surprising but very concerning,” said Meador, who was not involved in the research. 

He cautioned that the study does not provide information on the number of individuals exposed or the duration of exposure as well as gender and pregnancies. 

“However, given that valproate is the most used antiseizure medication, there are certain to be exposures affecting pregnancies. Given the known risks to their offspring for women and potential risks for men, the costs are enormous for malformations, cognitive impairments, and behavioral disorders,” Meador warned.

The study had no commercial funding. A complete list of author disclosures is available with the original article. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc.