British medical authorities have issued further warnings for valproate use by men, after a retrospective observational study indicated a possible association between use around the time of conception and an increased risk of neurodevelopmental disorders in their children.
The experts advise doctors to alert male patients, who may father children, to this possible increased risk and to recommend they rather use effective contraception during valproate treatment and for at least three months after stopping the drug.
The findings, combining analyses of electronic medical records in Norway, Denmark and Sweden, indicate a possible increased risk of neurodevelopmental disorders in children born to men treated with valproate in the three months before conception, compared with those born to men treated with lamotrigine or levetiracetam.
The researchers said the cumulative risk of neurodevelopmental disorders ranged from 4.0% to 5.6% in the valproate treated group versus 2.3% to 3.2% in the composite lamotrigine/levetiracetam monotherapy treated group (pooled adjusted hazard ratio 1.50, 95% CI 1.09 to 2.07).
This potential risk is much lower than the up to 30%-40% risk of neurodevelopmental disorders in children born to mothers taking valproate during pregnancy, estimated from several studies.
The study did not include an untreated group and background risk in this patient population is therefore unknown.
Advice for healthcare professionals:
• inform male patients who may father children of the possible risk at initiation of valproate or at their next regular treatment review – this counselling should be given irrespective of the indication for valproate and also after intravenous use of valproate
• as a precaution, recommend that male patients use effective contraception throughout the valproate treatment period and for three months after stopping valproate, to allow for one completed sperm cycle not exposed to valproate
• at the next regular treatment review, discuss with men on oral valproate treatment whether they are planning a family in the next year and if they are, refer to a specialist to discuss alternative treatment options
• if a female patient reports they are pregnant or planning a pregnancy with a man on valproate (including those undergoing IVF), refer for prenatal counselling
• advise men not to donate sperm during valproate treatment and for three months after stopping valproate
Valproate (as sodium valproate, valproic acid or valproate semisodium) is authorised for the treatment of epilepsy and bipolar disorder. It is also used outside the licence (off label) to treat other conditions.
During the 2018 European review into the risks of valproate in pregnancy, a number of concerns were considered about risks in all patient groups, including the potential risks to children born to fathers who take the medication.
A retrospective observational study was requested by the European regulatory authority to examine any association between exposure to valproate in men and the risk of congenital abnormalities and developmental disorders, including autism, in their offspring.
The Medicines and Healthcare products Regulatory Agency (MHRA) review of these findings was considered by the Commission on Human Medicines (CHM).
Changes will be made to the product information available online. The Patient Information Leaflet in the box and hard-copies of the updated safety and educational materials will be available in the coming months.
Given the typical-use failure rate of condoms, it is advised that women whose sexual partners are using valproate should use effective contraception during use of valproate and for three months after the male partner stops valproate. It should be noted that if there is no pregnancy risk or if the woman is already using highly effective contraception, then condom use is not required to prevent pregnancy.
The study was not large enough to determine the absolute risk of each of the specific neurodevelopmental disorder subtypes included in the study (autism spectrum disorder, intellectual disability, communication disorder, attention deficit hyperactivity disorder, movement disorders).
Study limitations included potential confounding by indication.
See more from MedicalBrief archives:
Valproate treatment rules tightened over children’s disorder risk
Sanofi ordered to compensate for epilepsy drug’s autism side-effect in pregnancy
UK medicines’ regulator investigates unsafe epilepsy drug being given to pregnant women