The Risks of Valproate Exposure in Men: Neurodevelopmental Disorders in Children

2024-05-02 16:22:57

Report a side effect of PDF to report suspected adverse effects.

The use of valproate is contraindicated in pregnant women due to an increased risk of congenital abnormalities (including neural tube defects) and neurodevelopmental disorders. In girls and women of childbearing age, valproic acid should only be used if strict precautions are followed as part of a pregnancy prevention program.[zieFoliajuni2018enhetsymbool[zieFoliajuni2018enhetsymbool t.h.v. de specialiteiten]. Following the EMA’s 2018 risk mitigation measures regarding the use of valproate in women, manufacturers of valproate-based medicines were asked to investigate the risks of valproate exposure in men who wish to have children. The results of that study suggest a possible increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate 3 months before conception.1. The study was not large enough and had several limitations, which means that a causal relationship cannot be confirmed between the use of valproate in fertile men and the development of neurological disorders in their children.
Following these study data, the European Pharmacovigilance Committee PRAC assessed the risks associated with valproate exposure in men of childbearing potential and devised risk mitigation measures.

Briefly about the study

This is a retrospective observational study based on 3 Scandinavian registers. This research has not yet been published.
The aim of the study was to examine neurodevelopmental disorders in children of fathers treated with valproate around conception, compared to the risk in children of fathers who received lamotrigine or levetiracetam (all in monotherapy).
The hazard ratio for neurodevelopmental disorders in children whose fathers were treated with valproate compared to children whose fathers were treated with lamotrigine or levetiracetam was 1.5 (95% CI: 1.09-2.07).
The risk of developing neurodevelopmental disorders was between 4.0% and 5.6% in the valproate group and between 2.3% and 3.2% in the lamotrigine/levetiracetam group.

Key conclusions of the PRAC

The PRAC1 concluded that there may be an increased risk of neurodevelopmental disorders (5% versus 3%) in children (between 0 and 11 years of age) born to fathers treated with valproate monotherapy 3 months before conception in compared to men treated with lamotrigine or levetiracetam. treated. However, the limitations of the study are also highlighted, such as the variation in the indications for valproate use and the limited size of the population studied.

Risk reduction measures for fertile men

To avoid exposure to valproate in fertile men, the following risk reduction measures are now in place1:

• Specialist guidance is recommended when you start treatment with valproate in men.

• Inform patients about the possible risk of neurodevelopmental disorders and the need for effective contraception, including for the female partner, for the duration of treatment and up to 3 months after discontinuation.

• Regular review of treatment to determine whether valproate is still the most appropriate treatment for the patient.

• Men who wish to have children should consult a specialist. Valproate treatment should be reassessed and other treatment options discussed.

• Inform patients that they should not donate sperm during treatment and for at least 3 months after stopping.

• Educational material on the teratogenic risk will be provided to male patients [nog niet beschikbaar op 05/03/2024].

Some comments

• The indications for valproate in PSC are the treatment of certain forms of epilepsy as well as the treatment of manic episodes in bipolar disorder when lithium is contraindicated or not tolerated. Valproate is also used off-label in the prophylactic treatment of migraine.

• Lecrat states that, based on the data currently available and pending additional information about this study, it is not justifiable to change or stop valproate treatment in men who wish to have children.2.

• Lareb makes a critical note of the interpretation of the retrospective observational study on which the PRAC advice is based. In this study there was uncertainty as to what type of epilepsy the men had (with confounding risk by indication) and generally the study was not large enough to determine which developmental disorders were at higher risk. Lareb also emphasizes the fact that the potential risk associated with the use of valproate by the father in this study (5%) is much lower than the demonstrated risk of developmental disorders (30-40%) in children who took a valproate mothers during pregnancy used3.

• Another study (Thomson et al.4) found that the incidence of autism and intellectual disability was slightly higher in children of fathers who used valproate than in children of fathers who did not use anti-epileptic drugs. The increased risk was not statistically significant in this study.

• La Revue Préscrire says that these results give reason to reconsider the use of valproic acid in men who want to have children. Especially when alternatives can be considered, such as lamotrigine, levetiracetam, propranolol, amitriptyline and lithium, in the treatment of epilepsy, migraine and mood disorders such as bipolar disorder respectively.5.

Specialty names:

Valproate: Depakine®, Valproate (see Directory)

Sources

1 EMA. https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures. Address DHPC to healthcare providers: via > search term: valproate > download the DHPC for each specialty via “DHPC”
2 CRAT accessed on 03/05/2023
3 Lareb. Use of valproic acid by men who wish to have children. Accessed on 03/05/2024. Lareb website
4 Tomson T, Muraca G, Razaz N. Paternal exposure to antiepileptic drugs and offspring outcomes: a nationwide population-based cohort study in Sweden. J Neurol Neurosurg Psychiatry. 2020; 91(9):907-13. PM: 32651245
5 Paternal exposure to valproic acid before conception: developmental neuropsychological disorders in children? Rev Ordinance 2024; 44 (485): 190-192