DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Valproate (as sodium valproate or valproic acid) is approved in Malaysia to treat epilepsy and mania associated with bipolar disorder.¹ The most likely mechanism of action involves potentiation of gamma amino-butyric acid (GABA) inhibitory effects through modulation of GABA synthesis or metabolism. There are currently ten (10) valproate-containing products registered with the Drug Control Authority (DCA).²

 

Overview of Safety Concerns

Neurodevelopmental disorders (NDDs) are conditions with development that emerge in early childhood, such as autism spectrum disorders (ASD), intellectual disabilities, communication disorders, attention-deficit/hyperactivity disorders (ADHD), specific learning disorders, and neurodevelopmental motor disorders.^3-5

Previous data have shown an 11% risk of birth defects and up to a 30-40% risk of permanent NDDs associated with valproate use during pregnancy.^4,6 In Malaysia,  the use of valproate for the treatment of epilepsy has been contraindicated in women of childbearing potential since January 2020, unless the conditions of the Pregnancy Prevention Programme are fulfilled. For further details, refer to the Directive [BPFK/PPP/07/25 (21) Jld. 3] and the NPRA Safety Alert (Jan 2020) concerning the risks of NDD and congenital malformation.

In light of these risks, concerns have been raised regarding patient groups beyond women of childbearing potential.^5-6 These included potential risks to children fathered by men taking valproate (paternal risks), the possibility of valproate-related side effects being transmitted across multiple generations (intergenerational or transgenerational effects), as well as the risk of male infertility.

 

Source of Safety Issues

In 2024, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) regarding new recommendations to mitigate the potential risk of NDDs in children born to men treated with valproate.^4-9

These recommendations are primarily based on reviews of a Scandinavian Post Authorisation Safety Study (PASS) conducted by companies upon the EMA’s request following a prior review of valproate use during pregnancy.^4-10 The EMA also considered additional data sources, including non-clinical studies and scientific literature, and consulted patients and clinical experts.⁴ While acknowledging limitations of the study, both the EMA and UK MHRA concluded that the findings should be reflected in the product information and that precautionary measures were warranted to keep patients and healthcare professionals informed.^4,5,7,9

In addition to the potential risk of NDD, the UK MHRA also extended the review to other known reproductive risks of valproate, including impaired male fertility.^5,6 The UK MHRA considered pre-clinical data on possible transgenerational risks with prenatal exposure, as well as data from studies in juvenile and adult animals suggesting adverse effects on the testes. Although human data remain limited and further studies are planned, the UK MHRA noted many patients receiving valproate may have alternative treatment options with fewer potential reproductive harms.

 

Background of the Safety Issues

1.  Potential risk of neurodevelopmental disorders (NDDs) due to paternal exposure prior to conception

The retrospective observational study, which was based on data from multiple national registry databases in three Nordic countries (Norway, Sweden, and Denmark), suggests a potential increased risk of NDDs in children (from 0 to 11 years old) born to men taking valproate in the 3 months before conception, compared to those treated with lamotrigine or levetiracetam.^4-9  

Specifically, the data indicate that approximately 5 out of 100 children born to fathers treated with valproate had NDD, compared with around 3 out of 100 children born to fathers treated with lamotrigine or levetiracetam.^4-9 The pooled analysis yielded an adjusted hazard ratio (HR) of 1.50 (95% CI: 1.09–2.07) for NDDs in children of fathers treated with valproate in the 3 months prior to conception, compared to lamotrigine or levetiracetam.^4,5 Although the results from individual countries did not reach statistical significance, the combined data showed a borderline statistically significant increase in risk.^5,9

This potential risk is lower than the well-established 30–40% risk of NDDs in children exposed to valproate in utero via maternal treatment during pregnancy.⁴ No difference in the risk of congenital malformation was seen between the two groups with paternal exposure.^5,9 It is important to note that the study did not assess the risk in children conceived more than 3 months after discontinuation of paternal valproate use.^4,9

However, considering several study limitations such as differences between the groups in the conditions for which the medicines were used and variations in follow-up times, it remains unclear if the increased risks suggested by the study were caused by paternal valproate use.^4,9 In addition, the study was not large enough to determine the specific types of NDDs that may develop.

 

2.  Potential risk of transgenerational epigenetic inheritance following paternal exposure to valproate

In mice, paternal valproate exposure has been linked to behavioural changes across first to third generations, including autism‐like traits.¹¹ The proposed mechanism involves valproate’s inhibition of histone deacetylases (which are key regulators of chromatin structure), leading to altered histone acetylation, changes in DNA methylation during spermatogenesis, disrupted gene expression, and modifications in sperm RNA content.^12,13 These epigenetic modifications may be transmitted across generations, potentially impacting offspring behaviour and development.

While animal studies support this risk, evidence for the transgenerational risk in humans following valproate exposure is limited.¹¹ Further research is needed to determine whether similar transgenerational effects occur in humans.

 

3.  Risk of male infertility

A meta-analysis indicates that valproate treatment has been associated with impaired male reproductive function in both human and animal studies, potentially contributing to reduced fertility.¹⁴ Reported effects include reduced free testosterone and follicle-stimulating hormone (FSH) levels, lower sperm count and motility, abnormal sperm morphology, and decreased testicular volume.^14-17

A study involving 55 adults with epilepsy receiving valproate (mean duration 9.55 ± 0.85 years) suggested that long-term valproate treatment was associated with reduced sperm count and motility, increased abnormal sperm count, and reduced testicular volume.¹⁵ High-dose animal studies have also demonstrated marked testicular atrophy and histological changes, such as germ cell degeneration and spermatogenic arrest, occurring within days of exposure.^15-16 Additionally, several human studies suggest a potential dose-dependent relationship, with  higher doses of valproate linked to more severe impact on male reproductive function.^15,17 However, the threshold at which these effects become clinically significant in humans remains unclear.

Notably, one case report documented a substantial decline in sperm count and motility as the valproate dosage increased from 500 mg/day for 6 years to 1000 mg/day for 4 months and 1500 mg/day for 2 years.¹⁷ The patient, who had been married for almost 7 years and attended regular urology follow-ups for infertility, showed semen parameters returning to normal within 9 months after gradual discontinuation of valproate and switching to lamotrigine. Twenty months later, the couple conceived a healthy baby.

 

Local Adverse Drug Reaction Reports¹⁸

To date, a total of 711 adverse drug reaction reports with 1,203 adverse events following valproate or valproic acid use were received by the NPRA. No local cases of any form of NDD and transgenerational epigenetic inheritance linked to paternal exposure have been reported. Additionally, no reports of male infertility related to valproate use have been received.

 

Advice for Healthcare Professionals

• Be aware of:
• Emerging evidence suggesting a potential risk of NDD, including autism spectrum disorders (ASD), in children born to fathers treated with valproate during the 3 months prior to conception. While a causal relationship has not been confirmed, precaution is warranted.
• Pre-clinical data indicating epigenetic inheritance to the next generations following paternal exposure to valproate.
• Human and animal studies indicating a potential risk of testicular toxicity and male infertility associated with valproate use.
  
  
• Counselling points for male patients receiving valproate:
• Advise on the need for effective contraception (including for the female partner) and to avoid sperm donation during treatment and for at least 3 months after discontinuation.
• Educate those planning to father a child to consult their doctor about alternative treatment options.
• Remind on the importance of reporting any sexual dysfunction or fertility concerns while on valproate.
• Emphasise on adherence that patients should not stop valproate treatment abruptly without medical advice, as this could worsen their underlying condition.
  
  
• Conduct regular (at least annual) treatment reviews to assess whether valproate is the most suitable treatment for the patient, including to:
• Consider alternative antiepileptic medications with a more favourable reproductive safety profile, while weighing the overall well-being of the patient.
• Ensure informed discussion and shared decision-making with patients when valproate treatment is considered necessary in male patients of reproductive age.
  
  
• Be reminded that existing recommendations remain in place to avoid exposure to valproate medicines in women during pregnancy due to the risk of congenital malformation and NDD .
• Report all suspected adverse events associated with valproate-containing products to the NPRA.

 

Regulatory Actions

The NPRA completed a review of this safety issue, and a directive [NPRA.600-1/9/13(62) Jld.1] has been issued for all registration holders of products containing valproate and its derivatives to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

As an additional risk minimisation measure, the DCA has requested product registration holders to develop and provide specific educational materials on sodium valproate. These materials aim to increase awareness of the potential risk of NDDs. The required materials are as follows:

1. Patient’s card
2. Annual Risk Acknowledgement Form (for prescribers)
3. Guide for Healthcare Professionals
4. Guide for Male Patients

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). EPILIM (sodium valproate) [Package Insert]. QUEST3+ Product Search. 2025 June [cited 2025 Jun 30]. Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Jun 30). Available from https://www.npra.gov.my
3. Morris-Rosendahl DJ, Crocq MA. Neurodevelopmental disorders—the history and future of a diagnostic concept. Dialogues Clin Neurosci. 2020;22(1):65-72. Available from; http://doi.org/10.31887/DCNS.2020.22.1/macrocq
4. European Medicines Agency (EMA). Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures. [Internet] 2024 January 12 [cited 2025 Jun 30]. Available from: https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures
5. Medicines and Healthcare products Regulatory Agency (MHRA).Paternal exposure to valproate and risk of neurodevelopmental disorders and congenital malformations in offspring.[Internet] 2024 Sep [cited 2025 Jun 30]. Available from: https://assets.publishing.service.gov.uk/media/675330d420bcf083762a6d47/Valproate-PAR-PASS-_accessible_-_PUBLISH.pdf
6. Medicines and Healthcare products Regulatory Agency (MHRA). Valproate (Belvo, Convulex, Depakote, Dyzantil, Epilim, Epilim Chrono or Chronosphere, Episenta, Epival, and Syonell▼): new safety and educational materials to support regulatory measures in men and women under 55 years of age [Internet] 2024 Jan 22 (cited 2025 Jun 30). Available from: https://www.gov.uk/drug-safety-update/valproate-belvo-convulex-depakote-dyzantil-epilim-epilim-chrono-or-chronosphere-episenta-epival-and-syonellv-new-safety-and-educational-materials-to-support-regulatory-measures-in-men-and-women-under-55-years-of-age
7. Medicines and Healthcare products Regulatory Agency (MHRA). MHRA advises men taking valproate and their partners to use effective contraception. [Internet] 2024 Sep 5 [cited 2025 Jun 30]. Available from: https://www.gov.uk/government/news/mhra-advises-men-taking-valproate-and-their-partners-to-use-effective-contraception
8. Medicines and Healthcare products Regulatory Agency (MHRA). MHRA update on new study on risk in children born to men taking valproate [Internet] 2024 January 15 [cited 2025 Jun 30]. Available from: https://www.gov.uk/government/news/mhra-update-on-new-study-on-risk-in-children-born-to-men-taking-valproate
9. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Sodium valproate [Internet]. 2024 Jan [cited 2025 Jun 30]. Available from: https://www.ema.europa.eu/en/documents/other/valproate-cmdh-scientific-conclusions-grounds-variation-amendments-product-information-timetable-implementation-emea-h-n-psr-j-0043_en.pdf
10. European Medicines Agency (EMA).A post-authorization safety study (PASS) to evaluate the paternal exposure to valproate and the risk of neurodevelopmental disorders including autism spectrum disorders as well as congenital abnormalities in offspring - a population-based retrospective study [Internet} 2020 Apr 30 [cited 2025 Jun 30]. Available from: https://catalogues.ema.europa.eu/node/3611/administrative-details
11. Choi CS, Gonzales EL, Kim KC, Yang SM, Kim J, Mabunga DF, et al. The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy. Sci Rep. 2016;6:36250. Available from: https://doi.org/10.1038/srep36250
12. Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science. 2015;350(6261):eab2006. Available from: https://doi.org/10.1126/science.aab2006.
13. Sakai K, Hara K, Tanemura K. Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation. PLoS One. 2023 Mar 9;18(3):e0282898. Available from: https://doi.org/10.1371/journal.pone.0282898
14. Zhao S, Wang X, Wang Y, Xu J, Zhu G, Zhao C, Teng W. Effects of valproate on reproductive endocrine function in male patients with epilepsy: A systematic review and meta-analysis. Epilepsy Behav. 2018;85:120-128. Available from: https://doi.org/10.1016/j.yebeh.2018.04.029
15. Hamed SA, Moussa EMM, Tohamy AM, Mohamed KO, Mohamad ME, Sherif TMK, Abdellah MM. Seminal fluid analysis and testicular volume in adults with epilepsy receiving valproate. J Clin Neurosci. 2015;22(3):508-12. Available from: https://doi.org/10.1016/j.jocn.2014.08.029
16. Røste LS, Taubøll E, Berner A, Berg KA, AleksandersEN M, Gjerstad L. Morphological changes in the testis after long-term valproate treatment in male Wistar rats. Seizure. 2001;10(8):559-65. Available from: https://doi.org/10.1053/seiz.2001.0545
17. Kose-Ozlece H, Ilık F, Cecen K, Huseyınoglu N, Serım A. Alterations in semen parameters in men with epilepsy treated with valproate. Iran J Neurol. [Internet]. 2015 Feb 27 [cited 2025 Apr 23]; 2015;14(3):164-7. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4662690/
18. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 June 20]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Norleen Mohamed Ali