Sodium valproate: balancing benefits and risks especially in people of childbearing potential

SUMMARY

Sodium valproate (valproate) is an approved treatment for epilepsy and bipolar disorder in Australia.

It is associated with a range of adverse effects that require monitoring and may limit its use.

Due to its teratogenicity, valproate should not be prescribed to women of childbearing potential. Lamotrigine or levetiracetam are preferred alternatives in epilepsy. If no alternative is suitable and valproate is prescribed, contraception should be co-prescribed.

Concerns have been raised about the potential risk of neurodevelopmental disorders in children born to men taking valproate; although these findings have not been confirmed in robust studies, male patients should be informed of the potential risk.

 

Introduction

Sodium valproate (valproate) is an antiepileptic drug that also has efficacy for other conditions such as bipolar disorder. Over the past 15 years, prescribing patterns for valproate in Australia have shifted. For much of this period, valproate was the most prescribed antiepileptic drug; however, its use has declined due to an improved understanding of its teratogenic effects and the availability of safer alternative antiepileptic drugs in pregnancy.^1,2

As there have been recent concerns about the safety of valproate use in males of childbearing potential, this article aims to reinforce the place of valproate in clinical practice given its high teratogenic risk and to discuss the benefit–risk considerations for prescribing, especially in the context of pregnancy and people of childbearing potential.

 

Clinical indications

Valproate was first registered in Australia as a treatment for epilepsy. It is first line for managing genetic generalised epilepsies, which include absence, myoclonic and tonic-clonic seizures.³

Valproate is also approved in Australia as a treatment for mania in people with bipolar disorder. It is recommended as adjunct therapy to an antipsychotic for acute mania and is an option for maintenance therapy if lithium cannot be used.^4,5

Valproate is also used off label for the prevention of migraine,^3,6 with efficacy comparable with topiramate or candesartan.⁷ Other off-label uses include neuropathic pain, status epilepticus and status migrainosus; however, the efficacy of valproate for these conditions has not been established.^8-10

Valproate has also been used off label to manage behavioural and psychological symptoms of dementia. However, studies have shown that these symptoms are not improved by valproate and its use is associated with increased serious adverse effects;^11,12 therefore, it is not recommended for this indication.

 

Adverse effects

Common adverse effects of valproate (at least 1%) include increased appetite (which can lead to weight gain), tremor, drowsiness and hair loss.^13,14 These may require valproate dose reduction or withdrawal to resolve. Valproate can also cause paraesthesia that is usually mild and transient.

Polycystic ovary syndrome (PCOS) occurs at a higher rate in women taking valproate for epilepsy than in women receiving other antiepileptic drugs (almost a twofold increased risk), although the magnitude of this association varies between studies because of differences in PCOS definitions and diagnostic criteria.^15,16 If PCOS is suspected in an individual taking valproate, consider an alternative antiepileptic drug and refer the patient to an endocrinologist or gynaecologist.

Mild, usually asymptomatic thrombocytopenia is the most common haematological effect of valproate (12 to 18% of patients) and generally resolves on dose reduction.¹⁷ Leucopenia can occur (0.4 to 5% of patients) and pancytopenia is rare.¹⁸

Valproate-induced hepatotoxicity is rare (1 in 20,000) but can be fatal.¹³ Hepatotoxicity risk is highest in the first 6 months of valproate therapy (95% of cases).¹⁹ Valproate should be avoided in patients with hepatic impairment.²⁰ Significant risk factors for valproate-associated hepatotoxicity include age 3 years and below, congenital metabolic disorders (carnitine deficiency, urea cycle disorders, POLG mutations), degenerative disorders, organic brain disease, brain damage or mental retardation, and concurrent use of multiple antiepileptic drugs.^13,19,20 Asymptomatic elevation of liver enzymes (alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase) occurs in approximately 10% of people taking valproate.^21,22 If this occurs, consider reducing the valproate dose and repeat liver function tests after 1 month. Unlike some other antiepileptic drugs (e.g. carbamazepine, phenytoin), valproate does not cause elevations of gamma-glutamyl transferase.²¹

Stevens-Johnson syndrome (SJS) is a rare but potentially fatal skin reaction associated with some antiepileptic drugs (e.g. carbamazepine, phenytoin, lamotrigine). It typically presents as a rash that spreads quickly over a few days, often with fever and sore throat. The occurrence of SJS with valproate has been reported but may have been confounded by concomitant administration of lamotrigine.²³ SJS is more likely to occur in the first 8 weeks of antiepileptic therapy; patients should be advised to stop taking valproate if a rash appears and to inform the prescriber.

Valproate therapy of more than 10 years duration is associated with decreased bone mineral density and increased risk of osteoporosis.^20,24 Assessment of vitamin D status may be considered depending on individual risk factors for osteoporosis.^3,20

Acute valproate toxicity (i.e. overdose) is dose related and may manifest as drowsiness, tremor, confusion and ataxia.²⁵

 

Monitoring

Clinical monitoring of a patient receiving valproate should address tolerability, alertness, weight gain and tremor.

There is not universal agreement on routine laboratory monitoring to reduce risk of valproate-associated hepatotoxicity. Baseline testing (e.g. full blood count, biochemical profile) has been suggested.^19,20 Further blood tests are undertaken only if significant clinical symptoms arise (e.g. anorexia, vomiting, malaise, loss of seizure control, oedema, jaundice). Patients or families should report these symptoms promptly to a healthcare professional and valproate should be stopped.

Therapeutic drug monitoring has a limited role, as there is no direct correlation between valproate plasma concentration and clinical efficacy.^20,26

 

Teratogenicity and neurodevelopmental risks

Maternal valproate exposure

Maternal valproate therapy is associated with an increased risk of major congenital malformations. This risk is dose dependent, with a reported incidence of 3.3% at valproate daily doses below 1100 mg, increasing to 30.2% at daily doses of 1100 mg or more.²⁷ Congenital malformations associated with valproate include neural tube defects such as spina bifida and anencephaly, craniofacial, cardiac and limb defects, and hypospadias.²⁸ Valproate can affect fetal neurodevelopment, leading to increased risks of intellectual disability (odds ratio [OR] 2.4 to 4.5), attention deficit hyperactivity disorder (OR 1.4 to 1.8) and autism spectrum disorder (OR 1.7 to 4.4).²⁹ To date, no dose of valproate has been established as completely free of risk.

Because of its teratogenicity, the Australian Therapeutic Goods Administration (TGA)³⁰ and overseas drug regulatory agencies³¹ recommend against the use of valproate in women of childbearing potential unless other drugs are ineffective or not tolerated. If valproate is prescribed, it should be prescribed by a specialist experienced in managing epilepsy or bipolar disorder³² and co-prescribed with effective contraception. Estrogen-containing contraceptives may increase the clearance of valproate and reduce plasma valproate concentrations;³³ prescribers should monitor clinical response when an estrogen-containing contraceptive is started.³⁴ A non–estrogen-containing contraceptive such as an intrauterine device or a progesterone-only pill is an option, depending on patient preference.

For women of childbearing potential who require treatment for epilepsy, levetiracetam or lamotrigine are preferred. Both are listed on the Australian Pharmaceutical Benefits Scheme for the initial treatment of epilepsy for women of childbearing potential, are safe during pregnancy, have no known long-term safety issues and are well tolerated.

If a woman taking valproate for epilepsy becomes pregnant, changing to levetiracetam or lamotrigine may be considered. If there is no effective alternative, the dose of valproate should be kept to the lowest dose that prevents seizures. Folic acid has not been shown to reduce the risk of major congenital malformations associated with valproate;²⁹ however, if used, a dose of at least 0.4 mg daily prior to conception and during pregnancy is recommended.³⁵

For women who require treatment for bipolar disorder and are planning pregnancy, the use of valproate should be avoided, if possible.⁴ Lithium is the most effective option, but it too can cause congenital malformations. Lamotrigine is less effective but is safe in pregnancy and requires slow titration over around 6 weeks to reach an effective dose. During this period, the patient is at risk of harm, and advice should be sought from the treating psychiatrist.

In some circumstances, such as a pregnant individual with severe or unstable epilepsy or bipolar disorder, the benefits of continuing valproate treatment may outweigh the risks of harm to the fetus; for example, stopping valproate may lead to a relapse of bipolar disorder, which can increase risk of maternal self-harm or suicidality. Assessment of the benefits and risks of valproate use should be contextualised to the patient, considering the severity of their condition, the risk and impact of adverse effects on the mother and fetus, gestational timing and patient preferences.³⁶

Paternal valproate exposure

Male-mediated teratogenesis associated with valproate intake was suggested by a retrospective cohort study published in 2023,³⁷ which reported an increased risk of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder) in the offspring of men who took valproate in the 3 months before conception, compared with men who took lamotrigine or levetiracetam. However, these findings were regarded as unsubstantiated by the TGA³⁸ and the Epilepsy Society of Australia³⁹ because of methodological issues, and subsequent studies were not able to reproduce these findings.^40-42 The European Medicines Agency is undertaking a signal procedure to analyse the conflicting results of these studies.⁴³

Despite study limitations, as a precaution, sponsors of sodium valproate products have added new warnings to their product information and consumer medicine information documents. In 2025, the TGA issued a safety update advising prescribers to inform male patients of the potential risks and the need for effective contraception (for both partners) during valproate treatment and for 3 months after stopping it. Male patients should be advised to consult their doctor about alternative treatments if they plan to father a child, before stopping contraception, or if pregnancy occurs. They should also be advised not to donate sperm during valproate treatment and for 3 months after stopping treatment.³⁸

 

Conclusion

Valproate is a highly effective treatment for epilepsy and bipolar disorder. It is associated with a range of adverse effects that require monitoring and may limit its use. Due to its teratogenic risks, valproate should not be prescribed for women of childbearing potential unless other treatments are unsuitable and contraception is co-prescribed. Concerns have been raised about potential neurodevelopmental risks in the offspring of men taking valproate; although these have not been confirmed in robust studies, male patients should be informed of the potential risks.

This article was finalised on 21 April 2026.

Conflicts of interest: Dan McLaughlin is the chair of the Epilepsy Society of Australia's Drugs and Devices Committee. Dan was a co-author of the Epilepsy Society of Australia's position statements on 'Generic Drug Use in Epilepsy' and 'Valproate Use in Men and Offspring Risk'.

This article is peer reviewed.

 

References

1. Pharmaceutical Benefits Scheme. Drug Utilisation Sub-Committee Utilisation analysis of PBS-listed antiepileptic drugs in a cohort of epilepsy patients. Department of Health, Disability and Ageing; 2023. [cited 2025 Nov 7]
2. Ilomaki J, Ooi CE, Foster E, Ademi Z, Bell JS, Kwan P. Review of clinical guidelines and cost estimates for the use of AEDs for the treatment of epilepsy. Department of Health, Disability and Ageing; 2025. [cited 2025 Nov 10]
3. Neurology. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2025. [cited 2025 Dec 10]
4. Psychotropic. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2021. [cited 2025 Dec 10]
5. Jochim J, Rifkin-Zybutz RP, Geddes J, Cipriani A. Valproate for acute mania. Cochrane Database Syst Rev 2019;10:CD004052.
6. Jenkins B. Migraine management. Aust Prescr 2020;43:148-51.
7. Charles A. Migraine. N Engl J Med 2017;377:553-61.
8. Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2011.
9. Sharshar T, Porcher R, Asfar P, Grimaldi L, Jabot J, Argaud L, et al. Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial. Crit Care 2023;27:8.
10. Wang F, Zhang H, Wang L, Cao Y, He Q. Intravenous sodium valproate for acute migraine in the emergency department: A meta-analysis. Acta Neurol Scand 2020;142:521-30.
11. Baillon SF, Narayana U, Luxenberg JS, Clifton AV. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2018;10:CD003945.
12. Hatch S, Seitz DP, Bruneau MA, Ewa V, Feldman S, Goldberg Y, et al. The Canadian Coalition for Seniors' Mental Health Canadian Clinical Practice Guidelines for Assessing and Managing Behavioural and Psychological Symptoms of Dementia (BPSD). Can Geriatr J 2025;28:91-102.
13. Shorvon S. Handbook of epilepsy treatment. 3rd ed. John Wiley & Sons; 2010.
14. Schmidt D. Adverse effects of valproate. Epilepsia 1984;25 Suppl 1:S44-9.
15. Hu X, Wang J, Dong W, Fang Q, Hu L, Liu C. A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy. Epilepsy Res 2011;97:73-82.
16. Crawford PM. Managing epilepsy in women of childbearing age. Drug Saf 2009;32:293-307.
17. Buoli M, Serati M, Botturi A, Altamura AC. The Risk of Thrombocytopenia During Valproic Acid Therapy: A Critical Summary of Available Clinical Data. Drugs R D 2018;18:1-5.
18. Meijboom RW, Grootens KP. Dispensability of Annual Laboratory Follow-Up After More than 2 Years of Valproic Acid Use: A Systematic Review. CNS Drugs 2017;31:939-57.
19. Genton P, Gelisse P. Valproic Acid Adverse effects. In: Levy R. Antiepileptic Drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; p. 842-84.
20. Australian Medicines Handbook Pty Ltd. Australian Medicines Handbook 2026 (online). Adelaide; 2026. [cited 2026 Apr 5]
21. Valproate. [Updated 2020 Jul 31]. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
22. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut 1984;25:673-81.
23. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern R. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 1999;353:2190-4.
24. Hamed SA, Moussa EM, Youssef AH, Abd ElHameed MA, NasrEldin E. Bone status in patients with epilepsy: relationship to markers of bone remodeling. Front Neurol 2014;5:142.
25. Rahman M, Awosika AO, Nguyen H. Valproic Acid. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
26. Schobben F, van der Kleijn E, Vree TB. Therapeutic monitoring of valproic acid. Ther Drug Monit 1980;2:61-71.
27. Vajda FJ, O'Brien T J, Hitchcock A, Graham J, Cook M, Lander C, et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy. J Clin Neurosci 2004;11:854-8.
28. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study. Neurology 2015;85:866-72.
29. Valentino K, Teopiz KM, Kwan ATH, Le GH, Wong S, Rosenblat JD, et al. Anatomical, behavioral, and cognitive teratogenicity associated with valproic acid: a systematic review. CNS Spectr 2024;29:604-10.
30. Therapeutic Goods Administration. ACM meeting statement, Meeting 9, 31 May - 1 June 2018. Department of Health, Disability and Ageing; 2018. [cited 2025 Dec 9]
31. European Medicines Agency. Valproate and related substances - Referral. European Medicines Agency; 2014. [cited 2026 Mar 30]
32. European Medicines Agency Safety Committee. Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures. European Medicines Agency; 2024. [cited 2025 Apr 17]
33. Reimers A, Brodtkorb E, Sabers A. Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. Seizure - European Journal of Epilepsy 2015;28:66-70.
34. Therapeutic Goods Administration. Australian Product Information – EPILIM (sodium valproate) crushable tablets, enteric-coated tablets, syrup, liquid. Department of Health, Disability and Ageing; 2025. [cited 2026 Mar 30
35. Pack AM, Oskoui M, Williams Roberson S, Donley DK, French J, Gerard EE, et al. Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM. Neurology 2024;102:e209279.
36. Kennedy D, Batagol R. Drug safety in pregnancy. Australian Prescriber 2025;48:5-9.
37. IQVIA. A post-authorisation safety study (PASS) to evaluate the paternal exposure to valproate and the risk of neurodevelopmental disorders including autism spectrum disorder as well as congenital abnormalities in offspring—a population-based retrospective study. IQVIA; 2025. [cited 2025 Nov 9]
38. Therapeutic Goods Administration. Potential risk of neurodevelopmental disorders in children born to men taking sodium valproate. Medicines Safety Update. Department of Health, Disability and Ageing; 2025. [cited 2025 Nov 5]
39. Epilepsy Society of Australia. ESA Positions and Guidelines. Valproate use in men and offspring risk: a statement for health professionals by the Epilepsy Society of Australia. December 2024. Epilepsy Society of Australia; 2024. [cited 2026 Mar 27]
40. Honybun E, Cockle E, Malpas CB, O'Brien TJ, Vajda FJ, Perucca P, et al. Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review. Neurology 2024;102:e209175.
41. Christensen J, Trabjerg BB, Dreier JW. Risk of Neurodevelopmental Disorders and Paternal Use of Valproate During Spermatogenesis. JAMA Netw Open 2025;8:e2512139.
42. Christensen J, Trabjerg BB, Dreier JW. Valproate Use During Spermatogenesis and Risk to Offspring. JAMA Netw Open 2024;7:e2414709.
43. European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 7 — 10 July European Medicines Agency; 2025. [cited 2026 Mar 27]