A 34-YEAR-OLD woman, who was 20 weeks pregnant on her fourth pregnancy, booked for antenatal care in her local maternity hospital. She had a history of epilepsy which she had developed during adolescence. She had attended a neurology service in the past for specialist opinion prior to planning her pregnancies. She had been seizure free on sodium valproate for many years and was getting repeat prescriptions for sodium valproate from her GP. 

She presented to me in the epilepsy clinic in the local maternity hospital and during the consultation she explained to me that her three children all had a variety of developmental delays and she was confused why this kept happening to her and wanted an explanation. She expressed her wish to have a happy, healthy, normal baby. I explained that sodium valproate was known to increase risk of developmental delay. She said this was the first time she had heard about the risks of valproate. 

We switched her to another medication, a safer one for women with epilepsy planning a family, gradually weaning the valproate. This of course was not without its risks. Maternal mortality from epilepsy is heightened 10-fold in pregnancy.¹ We also had to restrict her driving, she immediately lost her independence and this was very distressing for her. 

Could this scenario have been avoided?  

On November 21, 2014, the European Medicines Agency ruled that “Doctors in the EU are now advised not to prescribe VPA for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. Those for whom valproate is the only option for epilepsy or bipolar disorder should be advised on the use of effective contraception and treatment should be started and supervised by a doctor experienced in treating these conditions. Women and girls who have been prescribed valproate should not stop taking their medicines without consulting their doctor as doing so could result in harm to themselves or to an unborn child.”²

Is this medication still being prescribed in primary care for women with epilepsy of childbearing potential? Are women with epilepsy planning a pregnancy actively encouraged to seek expert opinion before becoming pregnant? 

Epilepsy, characterised by recurrent unprovoked seizures,³ affects approximately 1:115 or 40,000 individuals over five years of age in Ireland. Prof Delanty at Beaumont Hospital would estimate that approximately 10,000 of these are women of childbearing potential.⁴

Sodium valproate (Epilim) is a broad spectrum anti-seizure medication used to treat epilepsy but can also be prescribed for migraine and psychiatric disorders. It was first licensed for use in epilepsy in 1969 and is still found by many to treat the condition of epilepsy quite successfully. In a recent review carried out in Ireland in 2013 it is estimated that valproate is still being prescribed to 3.14 per 1,000 women with epilepsy aged between 16-44 years, while valproate alone accounted for 20% of all anti-epileptic drugs (AEDs) prescribed in 2013.⁵

So why the harm?

Recognising the special health issues related to anti-epileptic medication treatment during pregnancy, several registries have been established worldwide to gather information about the effects of specific anti-epileptic medication on foetal and embryo development. Research first published in 1997 demonstrated that valproate is associated with an increased risk of major congenital malformation in babies born to mothers with epilepsy.^6,7,8,9,10 To date all of the registers large and small have consistently agreed with this information. The rate of the major congenital malformation would appear to be dose related, with some studies suggesting a major congenital malformation rate varying between as much as 9.7% where exposed to > 1,500mg daily of valproate.¹¹

In addition to this, there are reports of cognitive difficulties experienced by children born to mothers that took valproate during their pregnancy. Children exposed to sodium valproate in pregnancy had lower development and IQs compared to children born to women without epilepsy and children born to women with untreated epilepsy. Compared to children exposed pre-natally to carbamazepine, lamotrigine and phenytoin the children exposed to sodium valproate had significantly lower IQs by as much as 11 points.^12,13 Furthermore, studies have demonstrated a dose effect correlation for valproate, with poorer cognitive outcomes in children associated with higher doses (800-1,000mg daily or higher).¹⁴

Prospective studies and a population based registry also indicate a higher than expected rate of abnormal behavioural development with autism and autistic spectrum disorder. One study demonstrated a six or 10 times increased prevalence of neurodevelopmental disorders reported for children with a history of prenatal VPA exposure respectively for monotherapy and polytherapy exposure. The most common neurodevelopmental disorder at six years of age for valproate exposed children in this study was autistic spectrum disorder (ASD).¹⁵

However, we must remember that for some women with epilepsy valproate is the most effective drug at controlling seizures and to them seizure control is of utmost importance. Many women have unsuccessfully tried to wean valproate while planning a pregnancy and feel they have no choice but to remain on this medication.

So what should we do as the clinicians? Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. Each treatment option should be tailored to the individual woman. Ideally once pregnancy is a consideration specialist opinion should be sought. This is probably best achieved via an urgent referral letter to the local consultant neurologist or epilepsy nurse specialist, as very often these cases can be prioritised depending on the information given and suggestions about treatment options agreed and multidisciplinary input provided.

Women with epilepsy should always be encouraged to continue their medication during pregnancy as uncontrolled seizures also carry a maternal risk. Consistent information regarding the risks and benefits of individual treatments and doses should be presented at each consultation to women during their potential childbearing years by all clinicians to allow for informed decisions about treatment. 

Preconceptual counselling is the essential key for women with epilepsy and contraception education a must. If at all a plan should be put in place tailored to the woman and communicated effectively to those caring for her.

The updated UK National Institute for Health and Care Excellence (NICE) guidelines for epilepsy highlight this for preconceptual counselling,¹⁵ with a view to balancing the potential risk to the unborn child against the mother’s personal circumstances. They also suggest that every woman with a history of epilepsy, active or not, planning a pregnancy should be referred to a neurology service for a review prior to embarking on a pregnancy. 

Women with epilepsy of childbearing age should ideally be on a single tolerated anti-epileptic drug at the lowest effective dose to control seizures. Valproate for any woman of childbearing potential should generally be avoided where possible. The importance of seizure control should not be underestimated and the woman’s input carefully considered. Women should at the very least be prescribed high dose folic acid 5mg preconceptually or as soon as any anti-epileptic drug is commenced. A ‘trough level’ anti-seizure drug blood test is reserved for prior to planning a pregnancy.

For the children who are exposed to medications and who show early signs of altered physical development they should have their cognitive development closely monitored, allowing for early intervention should it be necessary. For now I will continue to closely review this woman and I hope her wish of having a happy, healthy baby is granted. 

Note: For more information see the draft document from the National Epilepsy Programme Effective management of women with epilepsy in the non-acute setting. The document can be viewed on women’s health page (news section) of the ICGP website. see www.icgp.ie/womenshealth

References available on request