Valproate use in men: as a precaution, men and their partners should use effective contraception

A retrospective observational study has indicated a possible association between valproate use by men around the time of conception and an increased risk of neurodevelopmental disorders in their children. Inform male patients who may father children of this possible increased risk and the recommendation to use effective contraception during valproate treatment and for at least 3 months after stopping valproate.

From:
Medicines and Healthcare products Regulatory Agency
Published
5 September 2024
Therapeutic area:
Neurology, Psychiatry

See a previous Drug Safety Update for the introduction of the prescribing requirements in patients under 55 years of age (female and male) – the new advice provided here is in addition to these measures.

No one should stop taking valproate without talking to their healthcare professional.

Information for healthcare professionals:

  • findings from a retrospective observational study, 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 3 months prior to conception, compared to those born to men treated with lamotrigine or levetiracetam
  • in the study, 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
  • an increased risk of neurodevelopmental disorders in children of fathers treated with valproate in the 3 months prior to conception is possible however the causal role of valproate is not confirmed. As such this advice is precautionary

Advice for healthcare professionals:

  • inform male patients (of any age) 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 (condoms, plus contraception used by the female sexual partner) throughout the valproate treatment period and for 3 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 3 months after stopping valproate
  • report any suspected adverse drug reactions associated with valproate on a Yellow Card

Information for healthcare professionals to provide to patients:

Advice for healthcare professionals to provide to patients:

  • it is recommended that you and your female sexual partner should both use effective birth control (condoms and another form of female contraception) as a precaution while you are taking valproate and for at least 3 months after stopping valproate
  • allow at least 3 months to pass after stopping valproate before trying to father a child
  • you should not donate sperm whilst taking valproate and for 3 months after stopping
  • do not stop taking valproate unless you are advised to do so by a healthcare professional
  • report any suspected adverse drug reactions associated with valproate on a Yellow Card

Review of data regarding potential risk to children with paternal use of 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 of 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 valproate. 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 MHRA review of the findings of the study was considered by the Commission on Human Medicines (CHM). We have published a Public Assessment Report of the review.

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. The current patient card will be amended to include advice for male patients in addition to the measures relating to the Pregnancy Prevention Programme for women. The manufacturers of valproate will also send a letter to relevant healthcare professionals in October 2024.

This advice is in addition to the existing requirements for oral formulations of valproate for two specialists to independently consider and document that there is no other effective or tolerated treatment or the risks are not applicable at initiation of treatment in male patients under 55 years. It is however noted that reproductive potential in male patients continues beyond 55 years and men older than 55 years on valproate should be counselled on the risk as appropriate.

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 3 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 potential risk to the offspring of men taking valproate around conception apply to both those taking valproate orally and intravenously (IV), however discussions with men on treatment options apply only to those taking valproate orally. For those who receive IV valproate in an acute care setting, advise the use of contraception for 3 months after treatment.

Information about the study findings

The study looked at medical records from national registries in Norway, Denmark and Sweden. There was no observed association between paternal valproate exposure and neurodevelopmental adverse outcomes in the individual country specific study results, but when the results from the three countries were pooled using meta-analysis a statistically significant association was observed.

Overall, an increased risk of neurodevelopmental disorders in children of fathers treated with valproate in the 3 months prior to conception is possible however the causal role of valproate is not confirmed. In addition, the study did not evaluate the risk of neurodevelopmental disorders to children born to men stopping valproate for more than 3 months prior to conception (allowing new spermatogenesis without valproate exposure).

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.

The study used secondary data, therefore data on some known risk factors and causal factors for neurodevelopmental disorders were not available. There was also a difference in follow-up time between comparator groups which may impact the findings. The mean follow-up time of children in the valproate group ranged between 5.0 and 9.2 years compared to 4.8 and 6.6 years for children in the lamotrigine/levetiracetam group. Further studies and data are needed to better understand this risk.

Proposed mechanism of action of paternal transmission

The 2018 European review considered the potential mechanisms for paternal transmission of adverse effects of valproate. These included the valproate level of the seminal fluid of patients treated with valproate, evidence for genetic changes in the sperm DNA and evidence for epigenetic changes. It is noted that concentrations of valproate in the semen are 25,000 times less than concentrations that would be present in maternal plasma after a standard dose of valproate and so this mechanism of transfer is considered unlikely. Further studies are being performed to evaluate the possible impact of valproate on the genome and epigenome of germ cells.

There have been reports of infertility in men taking valproate but the mechanism of this is unclear. Preclinical data shows testicular toxicity in both juvenile and adult animals. Some preclinical data has also shown behavioural abnormalities transferred via the maternal and paternal lines through to the third generation. A CHM epigenetics Expert Working Group is currently considering evolving data on the potential for valproate to be associated with epigenetic effects, including the histone deacetylase (HDAC) inhibitory properties of valproate.

Report suspected reactions on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme. Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Article citation: Drug Safety Update volume 18, issue 2: September 2024: 1. This article was issued on 5 September, ahead of the rest of the September 2024 issue.

Updates to this page

Published 5 September 2024
Contents