Declining malformation rates with changed antiepileptic drug prescribing – An observational study

Reducing birth defects in women with epilepsy : prescribing responsively leading to results – Aug 2019

Abstract

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.

The shocking truth behind the widely used drug sodium valproate

Inside Out London, 22.01.2018 Full Version

We expose the government documents that we obtained concerning Sodium Valproate and the defect risk when taken during pregnancy and the worrying transgenerational link it will affect our grand children.

In a special edition of Inside Out London, Tarah Welsh investigates the shocking truth behind an anti-epilepsy drug which has harmed thousands of children. She uncovers new medical evidence suggesting that birth defects caused by the drug could be passed down through generations of the same family. Archives.

France : Renforcement des mesures de réduction des risques liés à l’exposition in utero aux antiépileptiques

L’Agence nationale de sécurité des médicaments et des produits de santé (ANSM) publie l’avis du comité d’experts (CSST) sur le renforcement des mesures de réduction des risques liés à l’exposition aux antiépileptiques au cours de la grossesse

Considérant le rapport de l’ANSM, les auditions des parties prenantes et le retour d’expérience sur le valproate, le CSST formule les recommandations détaillées ci-dessous afin de renforcer les mesures de réduction des risques malformatifs et neuro-développementaux suite à l’exposition in utero aux antiépileptiques autres que le valproate. Ces recommandations ont été établies après analyse des médicaments antiépileptiques selon les groupes de risque définis dans le rapport de l’ANSM.

En préambule, le CSST souligne la nécessité d’avoir une réflexion, lors de la prescription d’un traitement antiépileptique chez une jeune femme de plus de 10 ans, sur la possibilité qu’elle ait un jour un projet de grossesse et d’intégrer le choix de l’antiépileptique dans cette perspective.

1. Mise en place d’un carnet de suivi pour les patientes atteintes d’épilepsie à partir de l’âge de 10 ans

Le CSST recommande de mettre en place un carnet de suivi pour toutes les patientes atteintes d’épilepsie à partir de l’âge de 10 ans.

Ce carnet sera notamment destiné :

  • à informer systématiquement les patientes de la façon la plus claire possible sur les niveaux de risques malformatifs et neuro-développementaux des différents antiépileptiques. Il comportera également des informations scientifiques utiles pour les professionnels de santé ;
  • à documenter le suivi de la patiente (consultations, notamment pré-conceptionnelles, traitements, calendrier des crises, contraception, résultats d’examens…).
2. Mise en place de mesures spécifiques aux antiépileptiques à risque malformatif augmenté avéré

Pour les antiépileptiques dont l’augmentation du risque malformatif est avérée (carbamazépine, (fos)phénytoïne, topiramate, phénobarbital et primidone) sans relation dose-effet établie à ce jour et qui présentent par ailleurs un risque non exclu de troubles neuro-développementaux, le CSST recommande, chez les patientes atteintes d’épilepsie à partir de l’âge de 10 ans :

  • de mettre en place une consultation annuelle obligatoire par un spécialiste de l’épilepsie (neurologue, neuro-pédiatre ou pédiatre), afin de s’assurer régulièrement que le recours à ces médicaments est toujours nécessaire ;
  • de renforcer l’information des patientes sur ces risques au travers d’un document d’information signé par la patiente (ou son représentant légal) et le spécialiste de l’épilepsie ;
  • de conditionner la délivrance de ces médicaments à la mention sur l’ordonnance de la date de signature de ce document d’information.

Pour les médicaments antiépileptiques qui peuvent être prescrits dans d’autres indications (carbamazépine, phénytoïne, topiramate), cette mention devra également apparaitre sur l’ordonnance et conditionnera la délivrance.

Le CSST recommande par ailleurs de prévoir des dispositions permettant :

  • la délivrance de la quantité minimale de traitement antiépileptique si l’ordonnance ne mentionne pas la signature du document d’information, afin de ne pas exposer les patientes aux risques liés à une interruption de traitement ;
  • de s’affranchir de la signature du document d’information par les patientes lorsqu’il existe des raisons indiquant qu’il n’y a aucun risque de grossesse. Seul le médecin signe alors ce document en précisant les raisons pour lesquelles la patiente ne le signe pas et mentionne sur l’ordonnance « document d’information non requis ».
3. Concernant les antiépileptiques à risque malformatif potentiel ou pour lesquels la fréquence globale de malformation ne semble pas augmentée

Pour ces médicaments, en l’état actuel des connaissances, le CSST recommande :

  • d’avoir recours au carnet patient préconisé ;
  • que l’avis d’un spécialiste de l’épilepsie soit recherché pour tout projet de grossesse chez une patiente épileptique traitée par plusieurs médicaments antiépileptiques (polythérapie),
4. Adaptation des pictogrammes sur les boites

Les pictogrammes concernant la grossesse figurant sur les boites d’antiépileptiques devront être adaptés et harmonisés au niveau de risque détaillé dans le rapport de l’ANSM.

5. Mise en place d’un registre national de surveillance des grossesses sous antiépileptiques

Ce registre a pour objectif de surveiller les effets tératogènes et foetotoxiques des médicaments antiépileptiques. Dans cette perspective, il devra intégrer a minima les mêmes données que celles du registre européen EURAP auquel il devra être lié. Il devra par ailleurs permettre également de colliger des informations sur le suivi, à plus long terme, des enfants exposés in utero aux anti-épileptiques afin de poursuivre les investigations notamment sur les troubles neurodéveloppementaux.
Les sociétés savantes devront pouvoir accéder à ces données

6. Poursuite du suivi renforcé de l’ANSM

L’ANSM devra mettre à jour régulièrement son rapport ainsi que l’information sur ces risques et adapter, si nécessaire, les mesures de réduction des risques selon l’évolution des connaissances.

La mise en place de ces mesures devra être accompagnée d’actions de communication afin d’informer les patientes et les professionnels de santé sur les risques des médicaments antiépileptiques pendant la grossesse mais également sur l’importance d’une épilepsie bien équilibrée.

Primodos, Sodium Valproate, Surgical Mesh : Baroness Cumberlege Talks

UK Parliament, House of Lords Hansard, 28 February 2019

“For the families involved, it is life-changing and extremely distressing. For those women who took Primodos and sodium valproate, there is an intense feeling of guilt. They took the medication and they blame themselves. However hard one tries to persuade them that it was not their fault, the guilt remains.”

“That tells me something is seriously wrong; the system is not working as it should. People who have been harmed should not have to fight to be heard or to access the care they need.”

More information

Lords debate Safety of Medicines and Medical Devices

UK Parliament, House of Lords Hansard, 28 February 2019

Lords debates medicinal safety in ref to the public health scandals involving the hormone-based pregnancy test drug Primodos, the use of vaginal mesh implants and the anti-epilepsy drug sodium valproate.

  • Interventions from Lord O’Shaughnessy, Lord Hunt of Kings Heath, Baroness Walmsley, Baroness Masham of Ilton, Baroness Cumberlege 36:28 , Lord Brennan, Lord Carrington, Lord Bethell, Baroness Bryan of Partick, Lord Alton of Liverpool 1:17:29 , Lord Suri, Baroness Finlay of Llandaff, The Earl of Dundee, Baroness Jolly, Baroness Thornton, The Parliamentary Under-Secretary of State, Department of Health and Social Care (Baroness Blackwood of North Oxford).
  • Read the Lords Hansard transcript.
  • Parliamentary news, research briefing.
  • Parliament news, press release.
  • Video source, Parliament Tv.

More information

Harms in Healthcare: Primodos, Vaginal Mesh Implants and Sodium Valproate

How concerned should we be about treatment side-effects, innovation and regulatory failures?

Prof Carl Heneghan discusses the evidence about three NHS treatments undergoing government review:

  • Primodos,
  • vaginal mesh implants
  • and the anti-epilepsy sodium valproate.

Oxford University Department for Continuing Education,
Open Event Dec 2018.

Prof Carl Heneghan is Director of the Centre for Evidence-Based Medicine. Information about the postgraduate courses and qualifications in EBHC can be found here.

More information

Sodium Valproate Review : Who knew What and When ?

Cumulative meta-analysis gives extra insights

2018 Abstract

Sodium valproate is licensed in the EU for treating generalised, partial or other forms of epilepsy. It has also been used to treat bipolar disorder and to prevent migraine. In February of this year, the European Medicines Agency recommended that sodium valproate should not be used during pregnancy unless no other effective treatment is available, and that it must not be used in women able to have children, unless the conditions of a pregnancy prevention programme are met. These measures to protect women and their children are welcome, but we argue that they should have been instituted several years ago, as the evidence was clear as far back as 1990 that there were risks of congenital malformations in women exposed to valproate.

Our analysis shows the value of cumulative meta-analysis, which, in our view, should be performed as standard in systematic reviews when any concerns about harms arise during the use of medications. …

…, we consider that drug companies, journal editors, prescribers and systematic reviewers have all acted too late. We, therefore, consider that from 1990 individuals should have been offered the opportunity to switch to treatments with lower risks, where they existed, and given minimum effective doses of valproate if alternative treatments were not available or advisable. In the intervening years, many women’s children will have been harmed. Manufacturers and regulators should be responsible for ensuring that cumulative analyses are carried out as part of postmarketing risk management plans.

Failures in reproductive health policy: overcoming the consequences and causes of inaction

Inaction and its consequences in Reproductive Health

Achieving safer pregnancies and thriving babies is within reach here and now. The key is finally taking robust action on these public health measures. The next generation deserves no less.

The focus of this Journal of Public Health article, published 18 August 2018, is on public health actions that should have been implemented in Scotland (and the rest of the UK) years ago, but were not.

Overview

  • Profiles in procrastination
    1. Case 1: Not fortifying flour with vitamin B9
    2. Case 2: Minimizing the existence and importance of foetal alcohol harm
    3. Case 3: Failing to control access to, and gain informed consent about, valproate prescribing for women of reproductive age
  • The price of passivity
  • The causes of inaction
  • Replacing inaction with accomplishment
  • Replacing inaction with accomplishment

Abstract

It is assumed that long-established research findings and internationally accepted evidence should, and will, be translated into policy and practice. Knowledge about what prevents harm and promotes health has, in fact, guided and resulted in numerous beneficial public health actions. However, such is not always the case.

The authors examine three notable, and unwelcome, exceptions in the UK—all in the field of reproductive health and all focused on the period prior to pregnancy. The three examples of counterproductive inaction discussed are:

  1. fortifying flour with Vitamin B9 (folic acid);
  2. preventing foetal alcohol spectrum disorders;
  3. and reducing risks and better regulating a highly teratogenic medication (valproate).

The adverse consequences, as well as the causes, of inaction are analysed for each example. Reasons for optimism, and recommendations for overcoming inaction, are also offered, in particular, greater priority should be accorded to preconception health, education and care.

Assisting Baroness Cumberlege in ref Review into Primodos, Sodium Valproate, Vaginal Mesh

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

Introduction

” 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.

This submission is made to Baroness Cumberlege in her role as chair of the Government ordered Review announced by the Secretary of State for Health, Jeremy Hunt, on 21 February 2018. The purpose of this Review is to consider – in the context of medicinal products/devices identified as, Primodos, Sodium Valproate and Vaginal Mesh:

  1. ‘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;
  2. Secondly, whether the regulators and NHS bodies did enough to engage with those affected to ensure their concerns were escalated and acted upon;
  3. Thirdly, whether there has been sufficient co-ordination between relevant bodies and the groups raising concerns; and
  4. 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.

Those affected by FVS continue to pay the highest price for that failure:

‘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:

  1. Chapter 1; provides the background on the clinical history and impact of Sodium Valproate in the UK;
  2. 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.
  3. 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.

Executive Summary

  • 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
    • Limb defects
    • Developmental delay
    • Autism Spectrum Disorders (ASDs)
    • Attention Deficit Hyperactivity Disorder
    • Ear malformations and auditory processing
    • Skeletal malformation
    • 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).
    • Psychomotor issues.
    • 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.

 

Valproate Medicine : Chronology of Research, Regulation and Knowledge

Fetal Valproate Syndrome : The “Information Gap”, Infographic by FACSaware

Infographic showing the chronology of what happened and when.

It exposes the gaps in who received information and the lack of additional regulation.

Sources FACSaware group on Facebook.