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Debate goes on over valproate in pregnancy

Should there be an outright ban or restricted use of valproate in women who could get pregnant?

Louise Prime

Friday, 20 April 2018

Despite international consensus that valproate is a serious teratogen there is still no agreement on the level of appropriate regulation of the drug in people who could become pregnant – with some calling for an outright ban in women and girls while others support restricted availability. An analysis* in the BMJ investigates both arguments, while an editorial** in the same issue calls urgently for a better regulatory system to collect pregnancy outcomes data for new and existing drugs that might harm offspring.

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended on 9 February that valproate should not be used in pregnancy unless the woman has a form of epilepsy that is unresponsive to other anti-epilepsy drugs; nor should it be prescribed to patients with childbearing potential unless they follow a comprehensive ‘pregnancy prevention programme’.

The analysis authors cite consistent evidence that valproate exposure poses a major risk to the intrauterine development of children – about one in nine exposed babies are born with congenital malformations, roughly three times the risk seen in unexposed babies. They point out that intrauterine valproate exposure carries a 10% chance of causing physical abnormalities and a 30-40% risk of developmental problems such as autism and developmental delay; and in the UK alone, around 20,000 children have been harmed since valproate was introduced in the 1970s.

They explain that arguments for a ban include that: valproate’s risks are so great in pregnancy that they override the matter of informed consent; no woman who was truly informed of the risks would consent to taking the drug; and that in most cases, less teratogenic alternatives are available.

On the other hand, arguments for restrictions on use are that: alternative drugs are sometimes less effective; that poorly controlled epilepsy in pregnancy itself has negative effects, as frequent seizures during important periods of intellectual and social development might adversely affect cognition and behaviour; and that many bodies including the World Health Organization and General Medical Council have stressed patients’ rights to informed choice based on full disclosure of relevant risks and benefits.

They comment that population-based monitoring of the effects of valproate regulations in women and their offspring is essential, but currently lacking.

In their editorial, two consultant perinatal psychiatrists explain that if PRAC’s recommendations are accepted:

  • All women of childbearing age who are being prescribed valproate will probably have to be identified, and their treatment reviewed within a specified time frame.
  • Primary and secondary care will have to collaborate closely.
  • If the patient is not pregnant, a specialist should review whether valproate is still needed or can be replaced by another drug.
  • All those who continue treatment with valproate must follow the pregnancy prevention programme.
  • Patients will be required to have specialist reviews and complete a risk acknowledgement form every year.
  • Valproate packaging will carry a visual warning of the pregnancy risks and patients will receive a warning card with each prescription.
  • Pharmacists will be required to discuss the risks every time they dispense valproate to women of childbearing age.

They conclude: “Although challenging to achieve, “we urgently need a regulatory system for the standardised and timely collection of pregnancy outcome data for new and existing drugs that may harm offspring,” they add. “Mandatory pregnancy registers, targeted data mining of other resources, and regular evaluation of all available evidence would be key elements to achieve this aim.”

* Angus-Leppan H, Liu RSN. Weighing the risks of valproate in women who could become pregnant. BMJ 2018; 361: k1596.

** Wieck A, Jones S. Dangers of valproate in pregnancy. BMJ 2018; 361: k1609.

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