Study on the Impact of Valproate Exposure in Men Wanting to Have Children: Risk of Neurodevelopmental Disorders and PRAC Recommendations

Report on the impact side from PDF to report suspected adverse effects.

The use of valproate is prohibited 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 taken as part of a pregnancy prevention program. [zie Folia juni 2018 en het symbool  t.h.v. de specialiteiten]. Following the 2018 EMA risk mitigation measures on the use of valproate in women, manufacturers of valproate-based medicines were asked to investigate the risks of valproate exposure in men who wanted to have children. The results of that study suggest that there may be an increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate 3 months before they were born.1. The study was not large enough and had several limitations, which means that a causal relationship cannot be determined between the use of valproate in pregnant men and the development of neurological disorders in their children.
Following these study data, the European Medicines Committee PRAC evaluated the risks of valproate exposure in men of childbearing potential and formulated risk mitigation measures.

A little about the study

This is a retrospective study based on 3 Scandinavian registries. This research has not yet been published.
The aim of the study was to investigate 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 findings of PRAC

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

Risk reduction measures for pregnant men

For exposure to valproate in pregnant men, the following risk reduction measures are now in place1:

• Special instructions are recommended when starting treatment with valproate in men.

• Inform patients about the potential 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 after stopping it.

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

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

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

• Male patients will be given educational material about the teratogenic risk [nog niet beschikbaar op 05/03/2024].

Some thoughts

• Valproate has indications in the SPC for the treatment of certain types 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 says that, based on the data currently available and pending additional information about this study, it is not reasonable to change or stop valproate treatment in a man who wants to have children.2.

• Lareb places a critical note on the interpretation of the retrospective study on which the PRAC advice is based. In this study there was uncertainty about what type of epilepsy the men had (with the risk of passing through with a symptom) and the study was generally not large enough to determine which developmental problems the risk was higher. Lareb also emphasizes the fact that the potential risk of the father using valproate in this study (5%) is much lower than the risk shown for non- developmental prescriptions (30-40%) in children whose mothers took valproate during pregnancy3.

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

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

Special names:

Valproate: Depakine®, Valproate (see Repertoire)

Sources

1 EMA. https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures. DHPC was sent to the health care providers: via https://geneeemiddelsdatabank.be/human-use > search term: valproate > download the DHPC for each specialty via “DHPC”
2 CRAT https://www.lecrat.fr/1778/ to arrive on 03/05/2023
3 lareb. Use of valproic acid by men who wish to have children. Available on 03/05/2024. Lareb website
4 Tomson T, Muraca G, Razaz N. Paternal exposure to antiepileptic drugs and offspring outcomes: a national population-based cohort study in Sweden. J Neurol Neurosurg Psychiatry. 2020; 91(9):907-13. PMID:32651245
5 Paternal exposure to valproic acid before birth: neuropsychological developmental disorders in offspring? Rev. Ordinance 2024; 44 (485): 190-192