The risks to unborn children of mothers prescribed valproate-containing drugs for the control of epilepsy, bipolar disorder and sometimes for migraine, have been well known for more than a decade, but still they are prescribed to women of childbearing age.
Writing in the BMJ, consultant psychiatrist Argelika Wieck said: ‘There is consistent evidence that valproate exposure is a major risk to the intrauterine development of children. About 11% of exposed children are born with congenital malformations, a roughly three times higher risk than in the general population. Anomalies can be severe and affect several organ systems.
‘Compared with children of mothers without epilepsy or who have untreated epilepsy, exposed children have been reported to be intellectually less able, seven times more likely to have developmental delay, and three and five times more likely to have autism spectrum disorder or autism, respectively. Taking into account other developmental problems, it has been estimated that 30-40% of exposed preschool children may be affected.
‘The spectrum of harm suggests that the developing child is vulnerable to valproate throughout pregnancy. A safe dose has not been identified, and concomitant folic acid provides, at best, only partial protection from adverse effects.
‘Despite these well known safety concerns, limited data suggest that valproate prescribing has not shown a consistent large decline across Europe or across indications. Recent audits in the UK and other European countries also indicate that substantial proportions of girls and women of childbearing age taking valproate have not been informed of the risks by health professionals, or are not aware of them.’
Now the EU has acted to impose stricter controls to avoid fetal exposure to valproate. The European Medicines Agency has banned the use of valproate medicines for migraine or bipolar disorder during pregnancy, and for epilepsy during pregnancy unless no other effective treatment is available.
It has also introduced curbs on the use of valproate in women and girls able to become pregnant, unless the patient agrees to a strict pregnancy prevention programme, designed to ensure that patients are made fully aware of the risks and the need to avoid becoming pregnant.
Manufacturers have been ordered to include visual warnings of pregnancy risks on packs and patient information inserts. Women and girls who have been prescribed valproate have been advised not to stop taking their medicine without consulting their doctor as doing so could result in harm to themselves or to an unborn child
The EMA said: ‘As before, valproate treatment should never be started unless alternative treatments are not suitable, including in young girls below the age of puberty.
‘In pregnancy, valproate is contraindicated and an alternative treatment should be decided on, with appropriate specialist consultation. However, there may be a small number of women with epilepsy for whom there is no suitable alternative treatment to valproate and who should be appropriately supported and counselled.
In the UK, the MHRA is updating the ‘valproate toolkit’, to emphasise the need to avoid the use of valproate in girls and women of childbearing potential, warn women of the very high risks to the unborn child of valproate in pregnancy, and emphasise the need for effective contraception planning and specialist oversight of changes to medication when planning a pregnancy, as abrupt changes to medication can be harmful.
The MHRA has instructed all NHS organisations to undertake systematic identification of girls and women who are taking valproate and to use MHRA resources to support them.
PREGNANCY PREVENTION PROGRAMME
- An assessment of each patient’s potential for becoming pregnant
- Pregnancy tests before starting and during treatment as needed
- Counselling about the risks of valproate treatment and the need for effective contraception throughout treatment,
- A review of ongoing treatment by a specialist at least annually
- Introduction of a new risk acknowledgement form that patients and prescribers will go through at each such annual review to confirm that appropriate advice has been given and understood.
The most common active ingredient in valproate-containing drugs is sodium valproate, marketed as Epilim, Depakote and other generic brands (check the BNF: https://bnf.nice.org.uk/drug/sodium-valproate.html).
Wieck A, Jones S. Dangers of valproate in pregnancy BMJ 2018;361:k1609
EMA New measures to avoid valproate exposure in pregnancy http://www.ema.europa.eu/docs/en_GB/document_library/
MHRA. Valproate use by women and girls (including the valproate toolkit). https://www.gov.uk/guidance/valproate-use-by-women-and-girls#toolkit