Concerns with using sodium valproate to treat epilepsy in pregnant women

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.

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.

Conclusions

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.

References

1. Sperling MR, Feldman H, Kinman J et al. Seizure control and mortality in epilepsy. Annals of Neurology 1999;46:45–50. PMID: 10401779
2. Neligan A, Bell GS, Johnson AL et al. The long-term risk of premature mortality in people with epilepsy. Brain2011;134:388–95. doi: 10.1093/brain/awq378
3. Fazel S, Wolf A, Långström N et al. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. The Lancet 2013;382:1646–54. http://dx.doi.org/10.1016/S0140-6736(13)60899-5
4. Kini U. Fetal valproate syndrome: a review. Paediatric and Perinatal Drug Therapy 2006;7:123–30.
5. Medicines and Healthcare products Regulatory Agency. Sodium valproate: special reminder on risk of neurodevelopmental delay in children following maternal use — not for use in pregnancy unless there is no effective alternative. Drug Safety Update 2013;7:A2.
6. US Food and Drug Administration. FDA Drug Safety Communication: Valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. June 2013. Available at: www.fda.gov (accessed 23 April 2014).
7. Bromley RL, Mawer GE, Briggs M et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to anti-epileptic drugs. Journal of Neurology and Neurosurgical Psychiatry. 2013;84:637–43.
8. Christensen J, Grønborg TK, Sørensen MJ et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013;309:1696–703.
9. Veiby G, Daltveit AK, Schjølberg S et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia 2013;54:1462–72. 
10. Levy RG, Cooper PN & Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews 2012;3:CD001903. 
11. Miller JW. Confirmed! Durable benefits of epilepsy surgery. Epilepsy Currents 2014;14:26–8.
12. Englot DJ, Chang EF & Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. Journal of Neurosurgery 2011;115:1248–55.