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Concerns with using sodium valproate to treat epilepsy in pregnant women

Using sodium valproate during pregnancy can put babies at risk of developmental problems. Kalliopi Dodou and Paul Whiteley explore some of the recent evidence


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An elevated risk of neurodevelopmental disorders in babies exposed prenatally to valproate has been reported

Using sodium valproate during pregnancy can put babies at risk of developmental problems. Kalliopi Dodou and Paul Whiteley explore some of the recent evidence.

Epilepsy can kill. This statement is not intended to shock, but represents the reality that the risk of premature death in those diagnosed with epilepsy is increased by uncontrolled seizures.1

Managing epilepsy and seizure frequency, particularly with antiepileptic medicines, represents an important strategy for maintaining quality of life and reducing the risk of early death.

Premature death also continues to be a risk for those with epilepsy even after long periods of symptom remission.2 Psychiatric comorbidities, such as depression, can also increase the incidence of early death observed in epilepsy.3

The type of drug used to manage epilepsy is, to some extent, governed by the type of epilepsy being treated, alongside other factors such as age and concomitant medication. Pregnancy or an intention to become pregnant must also be considered. Importantly there is no one-size-fits-all management or intervention strategy for epilepsy. Therefore the more treatment options that are available to a patient the better.
Sodium valproate is one of the more common treatments for epilepsy. The teratogenic effects of valproate have been known for some time — as evidenced by the description of fetal valproate syndrome (FVS).4

Characteristics of the syndrome include the variable presence of neural tube defects, a variety of congenital malformations (potentially affecting the heart and lungs) and the possible development of learning difficulties and autism-spectrum conditions.

FVS is relatively rare and, for some patients, sodium valproate will be the only treatment that provides satisfactory seizure control. As a result, use of the drug during pregnancy has never been completely avoidable.

Epilepsy: the basics

Epilepsy is a spectrum of clinical presentations primarily characterised by a disturbance of electrical activity in the brain. Convulsive seizures represent perhaps the most commonly viewed symptom of epilepsy — characterised by initial muscle contraction (tonic phase), then rapid contraction and relaxation (clonic phase) and loss of consciousness. Other, more subtle, types of seizure can also occur, eg, an absence (petit mal) seizure where a person experiences a transient loss of consciousness.

Epilepsy can develop in many ways. The cause may be:

- Acquired — eg, following a head injury

- A consequence of having another condition — eg, cerebral palsy, meningitis

- Due to a birth defect or a problem at birth

Estimates of the number of people living with epilepsy range in accuracy. In the UK, it is estimated that around 500,000 people have the condition.

New regulatory concerns

In November 2013, the Medicines and Healthcare products Regulatory Agency issued a safety update5 on the use of sodium valproate during pregnancy. This update was made in light of several investigations (outlined below) suggesting an increased risk of adverse neurodevelopmental outcomes in the offspring of women who used the drug during pregnancy.

The update followed a similar move from the US Food and Drug Administration suggesting that pregnant women reconsider using valproate for preventing or relieving migraine.6

Bromley and colleagues7 reported an elevated risk of neurodevelopmental disorders in babies exposed prenatally to valproate when compared with non-exposed children. An autism-spectrum condition was the most frequently cited neurodevelopmental diagnosis.

A similar finding was also reported by Christensen and colleagues.8 Following their population-based study, they concluded that prenatal exposure to valproate resulted in an absolute risk of 4.4 per cent for an autism-spectrum condition and 2.5 per cent for classic autism.

Having analysed a large population database, Veiby and colleagues9 observed greater reports of autistic traits and issues with motor function among children exposed to valproate compared with non-exposed children. Importantly, they note that “children born to women with epilepsy who did not use antiepileptic drugs had no increased risks” in terms of neurodevelopmental issues. Therefore, to some degree, this rules out epilepsy itself as the cause of such issues.

Non-drug treatments  

Several other non-pharmacological treatment options have emerged. These range from the use of dietary changes (eg, high-fat, low-carbohydrate diet)10 through to invasive surgery to remove affected parts of the brain.11 Vagus nerve stimulation also represents a promising intervention strategy for some patients.12


When treating epilepsy in pregnant women, other antiepileptic medicines may offer a more favourable safety profile than sodium valproate for their offspring. However, the issue of how to control epilepsy during pregnancy is complicated by the fact that the condition is potentially life-threatening to mother and unborn child if not managed properly.

Ultimately, clinical decisions need to balance patient and fetal needs and discussions need to take place about the potential risks and benefits of the various treatments.

Kalliopi Dodou, MRPharmS, is senior lecturer in pharmaceutics at the University of Sunderland and Paul Whiteley is director at ESPA Research. 

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11137938

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