Potential risk of neurodevelopmental disorders in children born to men taking sodium valproate

Summary

A retrospective observational study in Europe has suggested there may be an increased risk of neurodevelopmental disorders in children born to men* who had been taking sodium valproate in the 3 months before conception compared to children born to men treated with lamotrigine or levetiracetam.¹

Neurodevelopmental disorders studied included autism spectrum disorder, intellectual disability, communication disorder and attention deficit/hyperactivity disorder, and movement disorders.

Due to methodological limitations, the findings of this study should be interpreted with caution.

As a precaution, Sanofi-Aventis, the sponsor of Epilim, which is the original brand of sodium valproate, have added new warnings about paternal exposure to the Product Information - external site (PI) and Consumer Medicine Information - external site (CMI). Sponsors of generic sodium valproate products will be required to align their safety information with Epilim.

What health professionals should do

The new warnings instruct health professionals to inform their male patients about the potential risks of sodium valproate and discuss the need for effective contraception, for both the patient and their female partner.

Male patients taking sodium valproate should be specifically advised:

• to consult their doctor to discuss alternative treatment options if they are planning to father a child, and before discontinuing contraception
• to contact their doctor for counselling if pregnancy occurs and they have taken sodium valproate in the 3 months prior to conception
• not to donate sperm during, and for 3 months after stopping, sodium valproate treatment.

Men taking sodium valproate should be reviewed regularly (at least annually) by a specialist experienced in the management of epilepsy or bipolar disorder to consider whether valproate-containing medicine remains the most suitable option, particularly when the patient is planning to conceive a child.

Existing recommendations in the PI about maternal exposure to sodium valproate remain unchanged as we continue routine safety monitoring and surveillance of this medicine. Patients with childbearing potential and taking sodium valproate are encouraged to discuss any concerns with a health professional.

Background

Sodium valproate belongs to a group of medicines called anticonvulsants. It is used to treat epilepsy and mania.

Epilim, the originator brand, is subsidised under the Pharmaceutical Benefits Scheme along with 5 generic products.

We reviewed the evidence provided by the sponsor and approved the sponsor’s application to add warnings to the PI in April 2024. After reviewing further evidence, including careful consideration of the limitations of the European study, we made the decision to retain the new warnings in the PI out of an abundance of caution, and to align with other regulators.

Cases reported to the TGA

No Australian adverse events relating to paternal exposure to sodium valproate have been reported to the TGA.

Additions to the PI

The following warnings are included in the Australian PIs - external site for all products containing sodium valproate.

Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Use in males of reproductive potential

A retrospective observational study indicates an increased risk of neurodevelopmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception, compared to those treated with lamotrigine or levetiracetam (see Section 4.6 Fertility, Pregnancy and Lactation).

Despite study limitations, by way of precaution, the prescriber should inform the male patients of this potential risk. The prescriber should discuss with the patient the need for effective contraception, including for the female partner, while using valproate and for 3 months after stopping the treatment. The risk to children born to men stopping valproate at least 3 months prior to conception (i.e., allowing a new spermatogenesis without valproate exposure) is not known.

The male patient should be advised:

• not to donate sperm during treatment and for 3 months after stopping the treatment
• of the need to consult his doctor to discuss alternative treatment options, as soon as he is planning to father a child, and before discontinuing contraception
• that he and his female partner should contact their doctor for counselling in case of pregnancy if he used valproate within 3 months prior to conception.

The male patient should also be informed about the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy or bipolar disorder.

The specialist should at least annually review whether valproate is the most suitable treatment for the patient. During this review, the specialist should ensure the male patient has acknowledged the risk and understood the precautions needed with valproate use.

Educational materials

To reinforce the warnings and provide guidance regarding use of valproate in men of reproductive potential, educational materials are available electronically through a QR code on the carton (www.sanofi.com.au/valproate - external site). A patient guide should be provided or made available to all men of reproductive potential using valproate.

Section 4.6 FERTILITY, PREGNANCY AND LACTATION

Risk to children of fathers treated with valproate

A retrospective observational study on electronic medical records in 3 European Nordic countries indicates an increased risk of neurodevelopmental disorders (NDDs) in children (from 0 to 11 years old) born to men treated with valproate in the 3 months prior to conception compared to those treated with lamotrigine or levetiracetam.

The adjusted cumulative risk of NDDs ranged between 4.0% to 5.6% in the valproate group versus between 2.3% to 3.2% in the composite lamotrigine/levetiracetam monotherapy group exposure. The pooled adjusted hazard ratio (HR) for NDDs overall obtained from the meta-analysis of the datasets was 1.50 (95% CI: 1.09-2.07).

Due to study limitations, it is not possible to determine which of the studied NDD subtypes (autism spectrum disorder, intellectual disability, communication disorder, attention deficit/hyperactivity disorder, movement disorders) contributes to the overall increased risk of NDDs. Alternative therapeutic options and the need for effective contraception while using valproate and for 3 months after stopping the treatment should be discussed with male patients of reproductive potential, at least annually (see section 4.4 Special Warnings and Precautions for Use).

Maternal exposure to sodium valproate during pregnancy

Sodium valproate is a known teratogen with a long-documented history of congenital malformations (including spina bifida) and neurodevelopmental disorders following maternal sodium valproate exposure. There are already recommendations in the Australian PI - external site to avoid this medicine in pregnancy and advice about its use in people with childbearing potential.

Prescribing restrictions for sodium valproate for all patients under 55 years have been recently introduced in the UK. In response to this change, we conducted a review and requested expert advice from the Advisory Committee on Medicines (ACM) on whether Australia should follow the UK in imposing similar restrictions. 

The ACM advised there has been no real change in the risk profile to children following maternal exposure since they last reviewed this issue in 2018, and that there was insufficient evidence to amend the indication or implement restrictions for sodium valproate to exclude particular patient groups.

We will continue to monitor this signal as part of our routine safety monitoring of medicines.

*Please note that we follow a policy to use inclusive language according to the Australian Government Style Manual - external site, including language that respects gender and sexual diversity. This update contains references to the sex characteristics of people, and the relationships that may be involved in human reproduction, in a medical context. These concepts are difficult to express with the accuracy needed using the inclusive language currently available to us. This update also contains excerpts of material produced by the sponsor, which we cannot control.

Reference

1. 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 – Stand Alone Abstract: https://catalogues.ema.europa.eu/system/files/2024-02/Valproate_PASS_Abstract_V2.0_0.pdf - external site