— ValproateVictims 🤰 #IMMDSreview #valproate (@facsjustice) August 11, 2019
Objective Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP).
Methods EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000–2005 (n = 4,760), 2006–2009 (n = 3,599), and 2010–2013 (n = 2,949).
Results There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000–2005 to 4.4% in 2010–2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy.
Conclusions There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.
Submission to the Cumberlege Review Concerning the Safety of Medicines and Medical Devices in the UK on behalf of the Organisation for Anti-Convulsant Syndrome (OACS Charity) and #FACSaware
” This document contains the legal and moral arguments for a Public Inquiry into medicine and devices regulation to focus on valproate as a case study.
The history of the licensing and regulation of valproate is particularly enlightening and highlights that we as patients were not informed of the risks associated with valproate and neither were many of our Doctors. “
Emma Friedmann, FACSaware
The Scope of this Submission
This submission is made on behalf of the Organisation for Anti-Convulsant Syndrome (known as OACs), the Foetal Anti-Convulsant Network (known as #FACSaware) and the individuals and families that both groups represent.
An outline of the essential work undertaken by these groups is provided below.
‘Firstly, the robustness and speed of the processes followed by the relevant authorities and clinical bodies to ensure that appropriate processes were followed when safety concerns were raised;
Secondly, whether the regulators and NHS bodies did enough to engage with those affected to ensure their concerns were escalated and acted upon;
Thirdly, whether there has been sufficient co-ordination between relevant bodies and the groups raising concerns; and
Fourthly, whether we need an independent system to decide what further action may be required either in these cases or in the future’. Mr Hunt explained; ‘This is because one of the judgments to be made is whether, when there has been widespread harm, there needs to be a fuller, or even statutory, public inquiry. Baroness Cumberlege will make recommendations on the right process to make sure that justice is done and to maintain public confidence that such decisions have been taken fairly’.
This submission relates to Sodium Valproate. It aims to help Baroness Cumberlege to consider these focal issues as they relate to Sodium Valproate.
The Purpose of this Submission
It is now well established by clinical researchers, in medical literature and across the regulatory community that Sodium Valproate is a teratogen; and that children exposed to this drug in utero suffer an increased risk of physical, developmental and neurological injuries. That cluster of injuries is known as ‘Foetal Valproate Syndrome’ (FVS).
With adequate warnings directed at both the users of Sodium Valproate preparations and their treating clinicians, FVS was, and is, an almost entirely avoidable injury. Yet, as at the date of this submission, as many as 20,000 individuals in the UK have been diagnosed with (or may suffer from) FVS.
In our submission the persistence of FVS as a diagnosis in the UK, and the number of individuals affected, is evidence of a long history of regulatory and legal failure in the prescription of Sodium Valproate as an anticonvulsant in the UK.
‘I am mourning my child now and will be mourning the death of her when she’s gone, this is the result of Valproate, no parent wants to see their child slowly die in front of them’
They do so without any acknowledgment on the part of the manufacturer or regulator of the role that they have played in creating and perpetuating the incidence of FVS in the UK; and crucially they do so without compensation.
Against that backdrop, this submission sets out; the legal case for a Public Inquiry into the regulatory and legal failings exposed by FVS and describes both the urgent need, and moral imperative, for compensation to be paid to all those affected by FVS in the UK.
To achieve that purpose this submission is divided into 3 chapters:
Chapter 1; provides the background on the clinical history and impact of Sodium Valproate in the UK;
Chapter 2; sets out the legal case for a Public Inquiry and is focussed upon dealing with the first three issues raised by Mr Hunt in his announcement on 21st February 2018: These are the Governmental, regulatory and legal failings that have resulted in FVS and have necessitated the 40-year old campaign for justice led by groups such as OACS Charity and FACSaware.
Chapter 3; sets out the moral imperative for the creation of a Compensation Fund, identifying the clinical and psychological needs of those affected by FVS and possible mechanisms through which such compensation could be awarded.
Sodium Valproate medicines are used to treat various conditions such as epilepsy, the manic phase of bipolar disorders (since 2009) and severe migraines (this application is off label use in some EU countries).
In the UK the primary use of Sodium Valproate is, and has always been, in relation to epilepsy as an anticonvulsant (AED).
There is little doubt that Sodium Valproate is an effective medication in treating patients at risk of epilepsy associated convulsions.
Sodium Valproate is marketed internationally under a range of brand names. In the UK, Epilim is by far the most dominant Sodium Valproate preparation available.
Epilim was first licensed for usage in the UK in 1973. The company responsible for manufacturing and marketing the drug in the UK is now known as Sanofi.
It is now accepted across the clinical and regulatory community by, for example, the National Institute for Health and Clinical Excellence (NICE), the MHRA and European Medicines Agency (EMA) that Sodium Valproate is a teratogen and that wherever possible prescription should be avoided in female patients of childbearing age.
The congenital birth defects associated with in utero exposure to Sodium Valproate include:
Neural tube defects (NTDs), such as spina bifida
Cleft lip and palate
Facial and skull malformations
Heart, kidney, urinary tract and sexual organ malformations
Autism Spectrum Disorders (ASDs)
Attention Deficit Hyperactivity Disorder
Ear malformations and auditory processing
Arthritis in older children
Effects on the endocrine system
Sexual identity problems (which occur due to a mismatch between genital development and neural / sexual identity development).
Withdrawal symptoms – associated with prenatal Sodium Valproate exposure.
It is important to understand that this list is not exhaustive.
When these congenital abnormalities, either singularly or in combination, are identified in children exposed to Sodium Valproate in utero they are diagnostic signifiers of FVS.
The controversy surrounding Sodium Valproate is focused upon the teratogenic potential of the drug and the historic failure of the regulator and manufacturer to communicate that potential to clinicians and patients.
It is submitted that by the early 1980s the regulator/manufacturer was in possession of sufficient information to conclude that Sodium Valproate was a teratogen which increased the risk of congenital abnormalities above the risks associated with epilepsy in general or where alternative AEDs were used.
However, this information was not communicated directly to patients until as late as 2005; whilst, in our submission, appropriate care pathways for women of child-bearing age using Sodium Valproate were not instituted by the regulator/manufacturer until as late as 2016.
That failure of the regulator/manufacturer constituted a dereliction of their statutory duties under the Medicines Act 1968, and successive legislation, to safeguard patients and warn of the adverse risks associated with medications.
That failure also created a fundamental ‘Information Gap’ between regulator/manufacturer-clinician/patient out of which the tragedy of FVS has developed.
An info-graphic describing this ‘Information Gap’ is provided at Appendix B and in Chapter 2 of this submission. The case for a Public Inquiry into medical product regulation in the UK is made with reference to the creation and maintenance of this ‘Information Gap’ which is exposed through the history of FVS in the UK.
Those affected by FVS and their families have complex care needs and are in the unusual position of having to cope with children with often profound disabilities whilst dealing with the fact of their own epileptic and or mental health condition.
For many of the mothers with epilepsy who are caring for children affected by FVS, stress is a trigger for their epileptic convulsions; the fact that they have been unheard and uncompensated for so long, despite their persistent campaigning, has often exacerbated their own clinical condition – this has added injury to injury.
We describe, in Section 15, the Double Disability which the mothers of FVS children experience; the fact of their own epilepsy in addition to the problems experienced by their children with FVS, a condition brought about by the Epilim which has enabled them to live normal lives. This imposes a significantly greater burden on these women than would be the case if they did not suffer from epilepsy.
Setting aside the emotional and psychological costs; the physical care needs of those affected by FVS place significant financial demands on the individual families affected and upon the NHS and/or Local Authority, who have been left to shoulder the significant cost burden associated with FVS.
Sanofi, the manufacturer responsible for Sodium Valproate, has made very significant profits as a result of its marketing of Sodium Valproate in the UK without shouldering any of the consequential costs of FVS injuries.
Litigation initiated against Sanofi on behalf of those affected by FVS and their families was discontinued when the Legal Aid Agency decided to withdraw legal aid funding in 2010, three weeks before Trial: Consequently, FVS sufferers have been denied access not only to compensation but also the opportunity to bring the fact of the manufacturer’s and regulator’s failures into the public domain.
This contrasts with the experience of FVS sufferers in other jurisdictions.
In 2016 the French Government instituted payments to FVS sufferers through a centrally constituted Compensation Fund.
The recent reparative actions of the French Government in respect of FVS, contrast with the historic inaction of successive UK Governments: This contrast is noteworthy given that both jurisdictions have had to deal with:
the same drug (Sodium Valproate)
the same injuries (FVS)
the same manufacturer (Sanofi); within
the same legislative framework- by virtue of the European wide Product Liability Directive.
The scale of the task of compensating UK FVS sufferers is hard to estimate; however, the moral imperative to facilitate such compensation is abundantly clear:
‘I can tell you from my experience of 32 years that there has never been enough support/facilities within the community to cover the needs of my daughter or any other person with learning difficulties/special needs or disabilities. There has been a continuous lack of understanding of the complexities of FVS’
In summary, this submission seeks the following outcomes:
A compensation and care package for all those affected by FVS;
A Judge led Public Inquiry into the regulation and licensing of medical products within the UK, focussing upon FVS as a case study; and
Scrutiny of how consumers can be better safeguarded and, if necessary, compensated, in a revised regulatory framework post-Brexit.
Download the whole document via FACSaware group on Facebook.
Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years
2015 Study Abstract
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate).
In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales.
Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD.
The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.
Sources and more information
Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years, Epilepsy Behav. NIHMSID: NIHMS 539674, PMCID: PMC3902100, 2014 Nov 1.
This is to inform you of important new information and strengthened warnings related to safety of medicines related to valproate (sodium valproate, valproic acid [brand leader: Epilim] and valproate semisodium [brand leader: Depakote]), following completion of a Europe-wide review:
children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases)
valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated
valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder
carefully balance the benefits of valproate treatment against the risks when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant
you must ensure that all female patients are informed of and understand:
risks associated with valproate during pregnancy
need to use effective contraception
need for regular review of treatment
the need to rapidly consult if she is planning a pregnancy or becomes pregnant
Valproate is associated with a dose-dependent risk of abnormal pregnancy outcomes, whether taken alone or in combination with other medicines. Data suggest that when valproate is taken for epilepsy with other medicines, the risk of abnormal pregnancy outcomes is greater than when valproate is taken alone.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).
Given these risks, valproate for the treatment of epilepsy or bipolar disorder should not be used during pregnancy and in women of child-bearing potential unless clearly necessary ie in situations where other treatments are ineffective or not tolerated.
Carefully balance the benefits of valproate treatment against the risks when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant.
If you decide to prescribe valproate to a woman of child-bearing potential, she must use effective contraception during treatment and be fully informed of the risks for the unborn child if she becomes pregnant during treatment with valproate.
Treatment during pregnancy
If a woman with epilepsy or bipolar disorder who is treated with valproate plans a pregnancy or becomes pregnant, consideration should be given to alternative treatments.
If valproate treatment is continued during the pregnancy:
the lowest effective dose should be used and the daily dose should be divided into several small doses to be taken throughout the day – the use of a prolonged release formulation may be preferable to other treatment forms
initiate specialised prenatal monitoring in order to monitor the development of the unborn, including the possible occurrence of neural tube defects and other malformations
folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies; however the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure
The Cochrane review published in November 2014 assessed 22 prospective cohort studies and 6 registry studies. The review supported findings from the European review that children exposed to valproate in utero were at an increased risk of poorer neurodevelopmental scores compared to the general study population both in infancy and when school aged.
A dose-related risk of developmental disorders was reported for valproate in 6 of the 28 studies included in the Cochrane review. However, based on the available data, it is not possible to establish a threshold dose below which no risk of developmental disorders exists.
Usage during pregnancy in the UK
Data from the Clinical Practice Research Datalink suggest that approximately 35,000 women aged 14 to 45 per year had a prescription for sodium valproate between 2010 and 2012, the majority for epilepsy. Of these, at least 375 per year had a prescription for sodium valproate while pregnant.
Pharmaceutical companies holding licences for valproate containing medicines must monitor the usage of these medicines to assess the effectiveness of these new measures on reducing the number of pregnant women taking valproate. We will continue to monitor valproate usage using the Clinical Practice Research Datalink. We will also work with stakeholders such as clinical guideline bodies to develop tools to aid decision-making for healthcare professionals and patients. We have already developed information booklets for healthcare professionals and patients (see further information below).
The product information will now be updated to reflect our current understanding of the available evidence and to make information as clear as possible.
Educational materials are available to healthcare professionals and patients in order to inform about the risks associated with valproate in female children, female adolescents, women of childbearing potential and pregnant women (see further materials below).
Anti-epileptic drugs during pregnancy affects babies’ brain
A new research suggests that children whose mothers took anti-epileptic drugs during pregnancy might suffer from brain impairments.
Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.
Approximately 40 per cent of the 48,000 children born in the UK to mothers taking Epilim since it was introduced in 1973 have developed either mental or physical disorders, with many suffering both
Approximately 40 per cent of the 48,000 children born in the UK to mothers taking Epilim since it was introduced in 1973 have developed either mental or physical disorders, with many suffering both.
That is according to the Daily Mail, which states that drug is now being blamed for causing more harm to children than Thalidomide.
Epilim is one of the registered trade names for sodium valproate, which has been at the centre of a media storm in recent weeks following the publication of new research into its effects on unborn children and a special BBC documentary.
The anti-epileptic drug controls electrical activity in the brain and is one of the most effective means of halting seizures.
However, Emma Murphy, founder of the Independent Fetal Anti-Cunvulsant Trust, told the news provider: “This is bigger than Thalidomide and it will not just be epileptic mothers whose babies are harmed. Epilim is prescribed to pregnant mothers with depression, bi-polar disorders and even for pain relief.”
Nearly 20,000 Children Harmed By Epilim (Sodium Valproate), EpilepsyResearchUK, News, Feb 26 2013.
The drug that’s harmed more children than Thalidomide, DailyMail, article-2284425, 26 February 2013.
To: Rt Hon Stephen Dorrell MP, Chair of the Health Select Committee
We are appealing to you on behalf of the Fetal Anti Convulsant Trust and all people affected by Fetal AntiConvulsant Syndromes.
Please could you request a public Inquiry as to why Sodium Valproate (Epilim) has been given out for over 30yrs and is still being given out to women with Epilepsy and other conditions like Bi-Polar, manic Depression, Persistant Headaches, and many more, when there is a chance that they may want to start a family. There needs to be more awareness of the fact that research shows conclusively that there is a 12% risk of the child having Neuro Developmental Problems, with the highest incidence being of an Autistic Spectrum Disorder, and that the risk increases to 15% if on a second medication.The risk factor then rises to 40% if you take into account all physical and cognitive impairments also. Some physical impairments are so severe the child doesn’t survive into adulthood.
This film uses the failed fetal anti-convulsant litigation against a multinational pharmaceutical company to critique UK law, and medicine regulation. It further addresses the economic effects of this failed litigation, and questions decisions within government regarding spending cuts within the public sector—particularly the legal aid budget. Is austerity the answer? Do short-term savings result in long-term costs?