The Medicines and Healthcare products Regulatory Agency (MHRA) has changed the licensing rules controlling the prescription of valproate drugs for women and girls of childbearing age with epilepsy. The new contraindication of drugs such as Epilim in pregnancy, follows evidence that up to 10% of babies born to mothers prescribed the drug have serious birth defects, with as many as 40% suffering developmental problems.

Birth defects associated with valproate in pregnancy

Birth defects suffered by babies of valproate-medicated mothers during pregnancy include congenital malformation of the spine (spina bifida), face and skull (such as cleft palate), limbs and organs including the heart, kidneys and sexual organs.

The long-term effects of the developmental problems suffered by valproate babies are not yet fully understood but include delayed walking and talking, reduced intelligence, impaired speech and language and memory problems.

Children exposed to valproate in the womb also have an increased risk of autism and attention deficit hyperactivity disorder (ADHD).

Valproate – little change despite warnings

“Valproate is a common treatment for epilepsy and bipolar disorder and is prescribed to thousands of women. The drug was introduced in 1974 and its product information for doctors has always included a warning that it carried a potential risk of birth defects.”

Over time, as more information has been gathered in Europe about the drug’s association with congenital malformations and developmental impairments, the MHRA’s warnings to doctors and pharmacists about the risks to the medicated woman’s unborn child have been strengthened. However, the MHRA’s latest alert confirms that despite the strengthened warnings that they issued to prescribers in 2015 and 2016 against prescribing valproate medicines in girls and women of childbearing age unless other treatments are ineffective and they are using effective contraception, one in five women taking valproate remain unaware of its risks in pregnancy. Without such information, women are unable to make informed decisions about their treatment. They risk becoming pregnant with high risk of serious injury to their child. MHRA’s previous communications appear to have had little impact on prescribing practice.

New regulation of valproate prescription from April 2018

In March 2018, after further research revealed the extent to which previous warnings had not been heeded, the European Medicines Agency, CMDh (Coordination Group for Mutual Recognition and Decentralised Procedures – Human), recommended tougher regulation of the prescription of valproate medicines. The new regulations will come into force at the end of April 2018 and will be backed up by amended guidance from The National Institute for Health and Care Excellence (NICE).

Valproate medicines are now contraindicated in women and girls of childbearing potential unless the conditions of a specified Pregnancy Prevention Programme are met, and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist [Sue – not sure if you want to make a comment on the interesting potential burden of proof issues here or not] . The Pregnancy Prevention Programme also applies to female patients who are not sexually active unless there are compelling reasons to indicate that there is no risk of pregnancy.

Compliance with the Pregnancy Prevention Programme means that all female patients taking valproate medicines:

  • have been told and understand the risks of pregnancy and have signed a risk acknowledgement form.
  • are on highly effective, user-independent contraception - such as long acting reversible contraceptive, a copper intrauterine device (coil), progesterone implant or levonorgestrel intrauterine system – or using two complementary forms of contraception including a barrier method and undergo regular pregnancy testing
  • see their specialist for review and re-evaluation at least once every year.

GPs must now identify and recall all valproate-medicated women and girls of childbearing potential to give them the patient guide, check that they have been reviewed by a specialist within the last year and are on highly effective contraception.

Specialists are required to review and re-evaluate their patients at least annually, provide clear explanations and complete and sign the risk acknowledgement form which must be copied to the patient or their carer and sent to the patient’s GP.

Pharmacists must ensure that where valproate medicines are dispensed to women and girls of childbearing potential the (ideally whole) packs must bear a pre-printed warning label or the pharmacist must place a warning sticker on the pack. Pharmacists are also required to discuss the risks in pregnancy with female patients each time they dispense their valproate medicines, and to check that they have the Patient Guide and have discussed their treatment and contraception with their GP or specialist.

I’m on valproate. What do I do now?

All women and girls who are prescribed valproate should now contact their GP and arrange to have their treatment reviewed. Meanwhile, MHRA emphasise that it is important women don’t stop taking valproate without first discussing it with their doctor.