The anti-convulsant drug, sodium valproate, is used to treat epilepsy. It is also used as a mood stabiliser for people with bipolar disorder. Valproate is also known by various trade names, including Epilim and Epival.
Valproate is very effective at reducing fits or seizures in epileptics. For some people it is the only effective way to manage their disabling epileptic condition. However, use of valproate during pregnancy is known to carry a high risk of serious injury to the unborn baby. Prescription of valproate to women of childbearing potential has now been banned for all except those women for whom no other equivalent drug works, and even then, only on the condition that they are using contraception under a pregnancy prevention programme (PPP).
How does sodium valproate affect babies in pregnancy?
1. 10% risk of birth defects or physical disabilities
Babies who are exposed in pregnancy, via their mother, to valproate, are known to be at increased risk of serious birth defects (physical disabilities) and long-term developmental problems.
The risk of physical disabilities is approximately 10%. That means one in ten valproate babies are born with these disabilities. These include:
- minor malformations, such as small fingers and toes;
- major malformations:
- of the spine, such as spina bifida;
- of the face and skull, such as cleft palate;
- of the limbs;
- of the organs, such as the heart, kidneys and sexual organs.
2. 40% risk of developmental or learning difficulties
There is also a 40% risk of persistent learning and developmental issues. That’s four of every ten babies. These learning and developmental problems are sometimes known as fetal valproate syndrome, fetal anti-convulsant syndrome (FACS), or fetal valproate spectrum disorder.
What is fetal anti-convulsant syndrome (FACS)?
Fetal anti-convulsant syndrome describes the developmental or learning difficulties suffered by babies who were exposed to valproate during pregnancy. Unlike physical birth defects which are often apparent at birth, developmental issues may not be noticeable until the child grows older and struggles to meet developmental milestones. Learning and developmental problems caused by fetal anti-convulsant syndrome include:
- delayed walking and talking;
- impaired speech and language;
- problems with memory;
- lower intelligence than other children of the same age;
- valproate-affected babies are also more likely to be on the autistic spectrum.
How long has it been known that sodium valproate is not safe to take in pregnancy?
When valproate was first marketed in the 1970s, animal studies had already shown that it carried serious risks of birth defects in the unborn baby if used by the mother in pregnancy.
Campaigners have also identified evidence that in 1973 the Committee on the Safety of Medicines decided it was best not to mention the risk of birth defects in the information supplied with the medicine. Instead, doctors were informed of the risks and were expected to weigh up the benefits and risks of prescribing the drug and use their discretion in informing the patient about the side effects.
As more evidence became available of other risks to the unborn baby, firstly of developmental delay and later of autism, further warnings were repeatedly issued to prescribers over the next 40 years. By 2013, long-term follow up of affected children had provided clear evidence of the extent of the risks to babies in valproate pregnancies.
The Medicines and Healthcare products Regulatory Agency (MHRA) then began a Europe-wide safety review of valproate in pregnancy which concluded, in November 2014, that the benefits of valproate to women of childbearing potential could only be justified against the risks where no other drugs were effective in treating their epilepsy or bipolar disorder.
In March 2016, MHRA developed a valproate toolkit, containing information presented in various forms to help healthcare professionals, including GPs and pharmacists, share information with patients about the risks of valproate in pregnancy. However, despite coordinated efforts by the government and the MHRA to promote the use of the toolkit to encourage healthcare practitioners to raise awareness amongst patients, a survey by INFACT, the National Valproate Campaign, later discovered that 80% of patients had not received the toolkit booklet and 90% had not received the toolkit pharmacy card. In many cases GPs had not even been given the booklets to distribute but had been left to download them from the manufacturer’s website and the information was not reaching potentially vulnerable women.
Concerns about the limited impact of the toolkit in raising awareness in the UK led to a further EU safety review which strengthened the rules relating to safe prescription of valproate in potentially childbearing women. These new rules came into force in the UK in April 2018 when the MHRA changed the licensing rules controlling the prescription of valproate. The new rules banned the use of the drug for women of childbearing potential (whether or not they are currently sexually active) unless other drugs were not effective and they were using highly effective, (preferably user-independent) contraception via a pregnancy prevention programme (PPP). The regulations also required patients to have been told about and understand the risks of pregnancy, to be reviewed by their specialist at least once a year and to have signed a risk acknowledgement form.
Valproate campaign group, INFACT, carried out a further survey from December 2018 to February 2019. This revealed that despite the stringent requirements laid down by MHRA in April 2018, high percentages of women taking valproate were still not receiving information about the risk of pregnancy from their GPs and pharmacists. 40% had never discussed a pregnancy prevention programme with their doctor and more than 60% not been asked to sign an acknowledgement of risk form. This survey highlighted the ongoing failure by valproate prescribers and healthcare professionals, such as GPs and pharmacists, to comply with their obligations to inform and safeguard their patients against the risks of valproate-affected pregnancy.
What is being done to reduce harm to babies from valproate in pregnancy?
- Repeated warnings and drug safety updates to GPs and pharmacists
The MHRA continues to issue warnings and drug safety updates to pharmacists and doctors reminding them of their responsibilities towards patients and that they must comply with the new valproate licensing regulations.
- NICE easy reference summary guideline
In March 2019, the National Institute for Health and Care Excellence (NICE) issued a new summary guideline which brings together in one short, easy-reference, visual summary all the key information and advice on safe prescribing of valproate from various sources, including MHRA safety alerts, BNF (British National Formulary – a pharmaceutical reference book containing drug information used by GPs) and NICE’s own amended guideline following the April 2018 licensing changes.
- Valproate compliance now incentivised through GP contracts
NHS England’s General Practitioner (GP) contract framework – the GP contract – now includes a quality indicator for safe valproate prescribing to incentivise GPs to comply with their obligations.
- CQC inspections include valproate compliance
The Care Quality Commission now includes valproate compliance in its inspections.
- Studies into possible risks from paternal valproate
Studies are also being undertaken into the risks to the unborn baby caused by the father taking valproate following possible associations between birth defects and developmental disorders and paternal valproate use at the time of conception.
- Independent Medicines and Medical Devices Safety Review
In February 2018, following patient-led campaigns, the Department of Health and Social Care set up The Independent Medicines and Medical Devices Safety (IMMDS) Review to look into how the NHS handled complaints and emerging awareness of problems with three NHS treatments, one of which is sodium valproate. The review is led by Baroness Julia Cumberlege and is independent from government, the NHS, regulatory or public bodies, and the pharmaceutical industry.
The IMMDS review will assess the evidence surrounding the use of valproate, including:
- what was known about valproate;
- the decisions and actions taken by the manufacturers, regulators, clinicians and policy makers;
- whether proper consent (based on clear information) was taken from patients;
- whether the response to safety concerns raised by patients and others has been satisfactory;
- the licensing and treatment of women of childbearing age with valproate given the evidence of its teratogenicity (harmfulness to the unborn baby or fetus);
- how the knowledge of the drug’s potential effect on the fetus was or should have been communicated between manufacturers, regulators, healthcare practitioners and patients and acted upon.
In addition, the review will:
- clarify the characteristics of fetal valproate spectrum disorders and the implications of this condition so that those affected receive a proper diagnosis and assessment of their needs;
- make recommendations about what action is now required and who must take it.
It will publish its report later this year.
Will the IMMDS review give compensation to children affected by valproate in pregnancy?
No. The aim of the review is to help the healthcare system learn and improve. The review won’t allocate compensation to any individual but it may make recommendations if it concludes that there is a moral, social or ethical responsibility to consider a system of compensation if avoidable harm has been suffered.
If your child has suffered serious physical or developmental injuries as a result of negligent medical prescription of sodium valproate during pregnancy and you would like to find out more about bringing a claim, contact Boyes Turner’s birth injury experts by email at firstname.lastname@example.org.