Valproate use in migraine prevention in women of childbearing age – Why are we still discussing it?

The European Headache Federation (EHF) and European Medicines Agency (EMA) have published their latest clinical recommendation on valproate use for migraine prophylaxis in women of childbearing age in The Journal of Headache and Pain. We have invited Dr Anna Andreou, director of headache research at the Headache Centre, King’s College London and The Journal of Headache and Pain’s advisory board member to explain the challenges in preventive treatment of migraine, and why valproate should be used with caution in women of childbearing age.

What preventive treatment options are there for migraine?

Migraine is not curable, but preventive treatments are usually used to decrease the intensity and frequency of headache attacks in patients with frequent or chronic migraine. Usually, oral preventives such as topiramate, an anti-convulsive medication, and b-blockers are considered as first line treatments. Injectable treatments such as botulinum toxin (botox) and even greater occipital nerve block show good efficacy if first line treatments fail. Valproate and its derivatives, such as divalproex sodium, is an antiepileptic treatment also approved by the FDA and indicated in some European countries for the preventive treatment of migraine. We are now entering a new exciting era for the treatment of migraine with new migraine preventive treatments becoming available for our patients. The monoclonal antibodies against the calcitonin gene-related peptide, a small protein believed to be involved in migraine, offer new hopes to both patients and their clinicians. Non-pharmacological approaches may be preferred by some patients. Non-invasive neuromodulation techniques, for example, such as single pulse transcranial magnetic stimulation and vagus nerve stimulation have gained considerable ground in the treatment pathway of patients, particularly for those who fail or do not tolerate oral preventives and injectable treatments.

What are the current challenges in the preventive treatment of migraine?

Selecting the right treatment for each patient can be a daunting task as one has to consider efficacy, side effects, treatment compliance and often cost and reimbursement.

Selecting the right treatment for each patient can be a daunting task as one has to consider efficacy, side effects, treatment compliance and often cost and reimbursement. Treatment compliance, potentially due to side effects, is often a limitation for oral preventives. Different countries may have guidelines for the treatment pathway a patient needs to follow. When it comes to treating women during pregnancy and breastfeeding non-pharmacological treatments should be preferred.

What are the latest breakthroughs in the prophylaxis of migraine with valproate?

Valproate has been approved for the prophylactic treatment of migraine after clinical trials found it effective in reducing migraine frequency, severity and duration of attacks in almost 40% of the patients. A double-blind crossover trial comparing the effectiveness of topiramate to valproate demonstrated that both medications were efficacious in decreasing headache frequency, intensity, and duration. Newer clinical studies that mainly aimed to compare the effect of alternative treatments to valproate show that valproate can still be an effective preventive treatment in reducing migraine frequency. Valproate has never been a first line treatment but our clinical experience and published case series suggest a role for valproate in the treatment pathway of vestibular migraine, rare forms of migraine with aura, such as hemiplegic migraine and migraine with complex sensory motor aura, and in post-traumatic headache, particularly with migraine features. Valproate has been also used in cases of status migrainosus and, randomised control studies suggest a role for valproate in the treatment of medication overuse headache in migraine patients. However, one has to consider the side effect profile, which includes, nausea, tremor, hair fall, menstrual irregularity, polycystic ovary, and weight gain. In women at the childbearing age, and during pregnancy, the use of valproate has even greater considerations.

What is the mechanism of action of valproate in migraine?

Much is yet unknown on the mechanism of action of valproate in migraine. Part of my research has shown an action of valproate in reducing trigeminothalamic excitability of third order thalamic neurons through interactions with the GABAergic system. Although there are still many aspects of the mechanisms of action of valproate that remain unknown, its effects on trigeminal nociceptive transmission within the thalamus have been since confirmed by others as well. It has been further shown to suppress cortical spreading depression, the experimental model of migraine aura. Other mechanisms have been suggested for its mode of action in other disorders, such as interference with the ERK signalling pathway and with inositol and arachidonate metabolism. Valproate treatment is also known to enhance a DNA binding protein and consequently causes alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, cytoskeletal modifications and signal transduction. Although these biological effects may be related to its anticonvulsant mechanism of action, they may also be responsible for the significant birth defects valproate is causing.

Why is it important to raise awareness about the use of valproate?

Migraine is a common neurological disorder affecting more women than men, especially during their reproductive age. In women of childbearing age, and during pregnancy, the use of valproate should be forbidden given its undoubtable association with neural tube defects, other congenital malformations and cognitive problems of the unborn child.

Migraine is a common neurological disorder affecting more women than men, especially during their reproductive age. In women of childbearing age, and during pregnancy, the use of valproate should be forbidden given its undoubtable association with neural tube defects, other congenital malformations and cognitive problems of the unborn child. Studies found a significant association between the prenatal use of valproate and lower intelligent scores, as well as, poor communication skills and memory problems in children whose mother was treated with valproate . Also, children from mothers who used valproate have five times higher risk of developing an autism spectrum disorder. Beyond the mental development adverse effects, valproate use is also link with delayed physical development in children exposed to valproate in utero.

Why was the consensus article developed?

The consensus paper is a collaboration between European Medicines Agency and European Headache Federation. It was developed following the latest 2018 review of the pharmacovigilance and risk assessment committee on reinforcement of the risk minimisation measures and update of the clinical recommendations for the use of valproate in in women of childbearing age. The first review published in 2014 recommended the restricted use of valproate in female children, women of childbearing potential and pregnant women, due to the risk of malformations and neurodevelopmental problems in children exposed to valproate in the uterus. Data on the effectiveness of the implemented restrictions published first in 2014, showed that while prescribing behaviour changed, there was still room for improvement. A French study for example, showed that exposure of women of childbearing age to valproate did not change, and only one third of the female bipolar patients exposed to valproate fulfil the criteria indicated in the 2014 recommendation. A survey from the epilepsy society in UK also showed that 70% of females taking valproate were not aware of the safety warnings about the dangers of taking it during pregnancy. Although data on the use of valproate in migraine are not available, one can assume that prescriber behavioural and communication of the risks with migraine patients could also be problematic.

What is the aim of the consensus article?

This consensus paper aimed to accumulate the PRAC updated guidelines that are relevant to the preventive treatment of migraine with valproate, and to list the required measures needed by both clinicians and patients for the implementation of the guidelines, in order to minimize exposure to valproate during pregnancy. The overall aim is to alleviate the neurodevelopmental risks of valproate, by minimising exposure.

What benefit should it bring to the headache specialists/neurologist/ patients, what benefit are you hoping for?

The consensus paper emphasizes the contraindicated use of valproate for the prophylaxis of migraine in pregnancy or in women of childbearing age who are not using effective methods of contraception. It includes educational support to treating clinicians with regards to adherence to the pregnancy prevention programme and annual checks and discussions between treating physician and patient to evaluate individual circumstances and ensure engagement with contraception and understanding of the risks by the patient. It also includes important educational material that the patients need to have access to with regards to the use of valproate at different stages of life.

Would you like to pick out a relevant examples to illustrate the benefit/importance?

I think it is very essential to understand that patient needs and circumstances change in the course of life. While valproate use may not present any risk at one stage of life, it may do so at another. From the beginning of the treatment a risk acknowledgment leaflet or form should be made available to the patient. Pregnancy should be excluded and highly effective contraception should be arranged. However, it is also important to ensure frequent consultation for female patients of childbearing potential as they may consider to have a child, or even have an unplanned pregnancy. More importantly, as more migraine preventive treatments become available, a more effective and appropriate treatment may be considered for patients who use valproate. The risks to the children of women who are using valproate outweigh any treatment benefits for this use. Hence, correct communication and frequent consultation of female patients currently using valproate, will ensure that patients are given the correct treatment for their condition, minimizing the adverse effects.


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