Valproate: re-analysis of study on risks in children of men taking valproate

We are providing an update on a retrospective observational study on the risk to children born to men who took valproate in the 3 months before conception and on the need for the re-analysis of the data from this study before conclusions can be drawn. No action is needed from patients. It is vitally important that patients do not stop taking valproate unless they are advised by their specialist to do so. For female patients, healthcare professionals should continue to follow the existing strict precautions related to preventing the use of valproate in pregnancy (Valproate Pregnancy Prevention Programme).

From:
Medicines and Healthcare products Regulatory Agency
Published
30 August 2023
Therapeutic area:
Neurology, Obstetrics, gynaecology and fertility, Psychiatry

Post-publication note - January 2024

While the review of this data is ongoing, interim advice has been issued, see Drug Safety Update January 2024 . This will be updated upon conclusion of the review by the Commission on Human Medicines.

Advice for healthcare professionals:

  • we continue to rigorously review all emerging data on valproate-containing medicines including findings from a retrospective observational study suggesting an increased risk of neurodevelopmental disorders in children whose fathers took valproate in the 3 months before conception, compared to those whose fathers took lamotrigine or levetiracetam
  • however errors have been subsequently identified in the study that may impact on the results; a full re-analysis is required before conclusions can be drawn
  • as soon as the revised study analysis is available, it will be carefully re- assessed by the MHRA, and any further guidance will be communicated to patients and healthcare professionals as soon as possible
  • for female patients, continue to follow the existing strict precautions related to the known and significant harms of valproate in pregnancy (Valproate Pregnancy Prevention Programme, see below)
  • GPs and pharmacists should continue to provide repeat prescriptions for valproate; patients currently taking valproate must be advised not to stop taking it unless they are advised by a specialist to do so
  • report any suspected adverse drug reactions associated with valproate on a Yellow Card

Advice for healthcare professionals to provide to patients:

  • valproate is a medicine for epilepsy and bipolar disorder; brand names of valproate include Convulex, Depakote, Epilim, Epilim Chrono or Chronosphere, Episenta, Epival, and Syonell
  • do not stop taking valproate or alter your dose without checking with your specialist first; if you stop taking valproate without your specialist’s advice your condition may get worse
  • valproate is associated with a significant risk of birth defects and neurodevelopmental disorders in children born to women who take valproate during pregnancy – see our existing advice to women and girls
  • findings of a study submitted to the MHRA have suggested that there may be an increased risk of neurodevelopmental disorders in children of men who took valproate in the 3 months before conception in comparison to children born to men taking lamotrigine or levetiracetam
  • however, errors have been identified in the study that may impact on the results; these mean a full re-analysis is being done before conclusions can be drawn
  • as soon as the revised study analysis is available, it will be carefully re- assessed by the MHRA and any further guidance will be communicated to patients as soon as possible
  • it is vitally important that you do not stop taking valproate unless a specialist tells you to; talk to a healthcare professional if you are concerned about your medicine or your or your child’s health

Background

Valproate (as sodium valproate, valproate semisodium, or valproic acid) is authorised for use in epilepsy and bipolar disorder.

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders.

Valproate should not be prescribed to female children or women of childbearing potential unless other treatments are ineffective or not tolerated. Valproate is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled – see Conditions of the valproate Pregnancy Prevention Programme below.

Clinicians prescribing in epilepsy should continue to consult the findings of the epilepsy medicines in pregnancy review, particularly that lamotrigine (Lamictal) and levetiracetam (Keppra) were not associated with an increased risk of birth defects compared with the rate in the general population.

Valproate administration may also impair fertility in men. Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation, however in some cases the reversibility of male infertility was unknown. In addition, pre-clinical studies have reported adverse effects to the male reproductive system in juvenile and adult animals receiving valproate.

Re-analysis of study examining risk in children of men taking valproate

The MHRA has kept under close review the possibility of risks to children associated with paternal exposure to valproate (in other words, whether a child could be affected if a father was taking valproate). Two studies were conducted by researchers in 2013 that did not find evidence of an increased risk to children with paternal use of epilepsy medicines, but the studies had limitations. [footnote 1] [footnote 2] As part of the outcome of the 2018 European review of valproate, a new retrospective study was requested from the marketing authorisation holders to examine this risk. [footnote 3]

The study report submitted to the MHRA and to other regulatory authorities suggested an increased risk of neurodevelopmental disorders in children whose fathers took valproate during the 3-month period before they were conceived compared to children whose fathers had taken the antiseizure medicines lamotrigine or levetiracetam. However, we were subsequently informed of errors in the study that may impact on the results. A full re-analysis is required before conclusions can be drawn. As soon as the revised study analysis is available, it will be re-assessed by the MHRA.

No action is currently needed from patients. No one should stop taking valproate without advice from their specialist.

Reminder of the conditions of the valproate Pregnancy Prevention Programme

The prescriber must ensure that:

  • individual circumstances are evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks
  • the potential for pregnancy is assessed for all female patients
  • the patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero
  • the patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed
  • the patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception, without interruption during the entire duration of treatment with valproate
  • the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy.
  • the patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued
  • the patient understands the need to urgently consult her physician in case of pregnancy
  • the patient has received the patient guide
  • the patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Pharmacists should continue to ensure patients receive the patient card, a copy of the Patient Information Leaflet and packaging bearing pregnancy warnings.

Article citation: Drug Safety Update volume 17, issue 1: August 2023: 3.

  1. Veiby G and others. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia 2013: volume 54, pages 1462 to 1472. ↩

  2. Engeland A and others. Effects of preconceptional paternal drug exposure on birth outcomes’: cohort study of 340000 pregnancies using Norwegian population-based databases. British Journal of Clinical Pharmacology 2013: volume 75, pages 1134 to 1141. ↩

  3. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Study protocol EUPAS34201 (accessed August 2023). ↩

Published 30 August 2023
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