EMA’s PRAC found inconsistent evidence linking paternal valproate exposure to neurodevelopmental disorders in children and will maintain existing precautionary measures pending further research.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that current evidence linking paternal valproate exposure before conception to neurodevelopmental disorders (NDDs) in children remains inconsistent, prompting the committee to maintain existing precautionary measures while updating product safety information.
Valproate is used to treat epilepsy and bipolar disorder and is also approved for migraine prevention in some European countries. After assessing newly available registry and observational data, PRAC determined that a causal relationship between paternal valproate use and NDDs in children could not be established. As a result, the precautionary measures introduced in April 2024 will remain in place while additional evidence continues to emerge.
Background of the Review
Concerns were first raised in January 2024 following a post-authorisation safety study (PASS) using registry data from Denmark, Norway, and Sweden. That analysis suggested a possible increased risk of NDDs among children fathered by men treated with valproate in the three months before conception compared with men receiving lamotrigine or levetiracetam.
Although PRAC acknowledged methodological limitations in the study, it concluded that a potential risk could not be excluded and introduced precautionary measures for male patients. The committee also requested a larger multinational study specifically intended to address the limitations of the earlier analysis. That EMA-mandated investigation is ongoing and is expected to conclude in 2028.
New Data Challenges Earlier Findings
The latest review was triggered in July 2025 following publication of a nationwide Danish registry study that did not identify an increased risk of neurodevelopmental disorders associated with paternal valproate exposure.
PRAC reviewed the Danish findings alongside several retrospective observational studies examining the same question. While one analysis suggested a possible association, most studies failed to demonstrate an increased risk of NDDs. The committee noted that differences in study design, patient selection, and adjustment for underlying medical conditions may explain the conflicting results.
Based on the available evidence, PRAC concluded that it remains unclear whether any potential risk is attributable to valproate itself or to other factors, including the father’s underlying medical condition. Consequently, a causal relationship with the medicine remains uncertain.
Precautionary Measures and Updated Guidance
Given the remaining uncertainties, PRAC recommended maintaining the precautionary measures introduced in 2024 until additional evidence becomes available.
The committee also recommended updating product information, including the Summary of Product Characteristics (SmPC) and patient information leaflets, to reflect the latest evidence. Healthcare professional guidance and educational materials for male patients will also be revised to ensure that clinicians and patients have access to the most current safety information.
Broader Safety Actions
Beyond the valproate review, PRAC also issued new safety recommendations affecting the chikungunya vaccine Ixchiq and the vasculitis treatment Tavneos (avacopan).
For Ixchiq, the committee recommended restricting use to individuals at high risk of chikungunya infection after reviewing reports of serious adverse events, including neurological complications, hospitalisations, and deaths. PRAC emphasized that the vaccine remains available but should be used only after careful assessment of its benefits and risks.
For Tavneos, PRAC strengthened liver monitoring requirements following reports of serious drug-induced liver injury and rare cases of vanishing bile duct syndrome. Updated guidance requires more frequent liver function testing and stricter treatment discontinuation criteria to help reduce the risk of severe hepatic complications.
Path Forward
Further details from the valproate assessment, including the full review report, will be published by EMA in the coming months. Regulators will continue monitoring emerging evidence while the dedicated multinational study progresses toward its expected completion in 2028.
Until then, existing precautionary measures for male patients treated with valproate will remain in place, reflecting the continuing uncertainty surrounding the potential risk of neurodevelopmental disorders in children fathered by men receiving the medicine before conception.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.
