Valproate came under fire when NICE revised the procedural guidelines for the treatment of bipolar disorder patients. NICE issued a warning against the use of valproate in pregnant women as it carried certain risks that can harm the fetus as well as the general health of the pregnant mother.

MHRA developed a toolkit that comprised of all the warning signs along with the explanation targeting the healthcare providers and the consumers.

Recently, Medicines and Healthcare Products Regulatory Agency (MHRA), launched a toolkit to apprise women regarding the teratogenic risks (congenital birth defects) associated with valproate use during pregnancy and provide additional guidance to clinicians, pharmacists and other healthcare providers regarding valproate use during pregnancy to ensure maximal safety and minimize hazardous side effects of the drug in female epileptic population.

Epilepsy is a chronic disorder and the fourth most common neurological disorder. People suffering from different forms of epilepsy are life-long dependent on anti-epileptic drugs. In females, especially during pregnancy, the risk of seizure precipitation can be manifold and so anti-epileptic drugs are inevitable, subjecting them to a condition where avoiding anti-epileptic drugs is no choice.

The need for toolkit arose as all anti-epileptic drugs are teratogenic in humans and the risk is manifold with valproate in comparison to any other anti-epileptic drug. The toolkit has been specially and specifically designed for female epileptic patients of child bearing age, female children, adolescent females, pregnant and breast feeding females.

Valproate is marketed under different brand names such as Epival, Depakote, Depacon, Epilim and Valprease and is categorized as an anti-epileptic drug (anti-convulsant), commonly used for different types of epilepsy but is also used for the treatment of mania associated with bipolar disorder (as a mood stabilizer) and for prophylaxis of migraine headaches. Common epilepsy forms for which the drug is mainly indicated, include:

Absence seizures, atonic seizure, focal (partial) seizures, focal (partial) seizures with secondary generalisation, infantile spasms, myoclonic seizures, myoclonic seizures in juvenile myoclonic epilepsy, tonic seizures, tonic clonic seizures, tonic clonic seizures in severe myoclonic epilepsy in infancy (smei or dravet syndrome).

Birth Defects: Research Studies Demonstrating Teratogenic Side Effects

Ever since the introduction of anti-epileptic drugs, they are known as teratogenic (causing birth defects) as demonstrated by various animal studies during clinical trials and the human embryo is far more susceptible to these teratogenic effects, thus, requiring regular therapeutic monitoring of anti-epileptic drugs during their use in pregnancy.

After the introduction of valproate in 1974, a number of scholarly articles have cited that the drug poses far more serious threats to fetus than other anti-epileptic drugs and precisely, the degree of anomalies is three-times more with valproate use during pregnancy.

A study by Dr Koch and his colleagues, of Children’s Hospital, Virchow Klinikum of the Humboldt University Berlin, Germany, published in the journal Acta Paediatrica, reported about the malformations studied in a set of 40 children who were exposed to different anti-epileptic drugs (phenobarbitone, phenytoin, valproic acid) in vitro.

The researchers found that amount or quantity of valproate acid in maternal blood at the time of fetal birth was significantly associated with the neonatal hyper excitability and later on led to the development of neurological dysfunction during childhood (around 2 years of age).

The congenital abnormalities are apparent at birth whereas the neurological symptoms manifest in the form of autistic spectrum disorder – a condition associated with behavioral and developmental disorder. The neurological symptoms are visible during late infancy (at 6 months to 1 year of age).

It appears that the dose and duration of valproic acid is mainly attributable to the development of teratogenic effects and should be used in minimal efficacious doses for least nominal period of time. The research also demonstrated that the major congenital malformation was spina bifida – a neural tube defect and the risk was highest during first trimester of pregnancy.

The North American Anti-epileptic Drug Pregnancy Registry also reported a study comparing the malformations associated with monotherapy valproic acid and with other anti-epileptic drugs. The report documented that among the offspring of 149 women with epilepsy who were exposed to valproic acid monotherapy during the first trimester of pregnancy at doses of approximately 1000 mg per day ,16 cases of congenital malformations occurred for a prevalence rate of 10.7%.

Three of the 149 offspring (2%) had neural tube defects and 6 of the 149 (4%) had less severe malformations. The malformation rate was 2.9% among epileptic women (1048 patients) who were exposed to other anti-epileptic drug monotherapies during pregnancy.

There was a 4-fold increase in congenital malformations among infants with valproic acid-exposed mothers compared with those treated with other antiepileptic monotherapies as a group”.

According to MHRA: “The risk of developmental disorders is up to 4 in 10 and the risk of birth defects is approximately 1 in 10”.

Congenital And Developmental Abnormalities Associated With Valproate

A term “fetal valproate syndrome” was suggested in 1984 for the major anomalies and dysmorphic features associated with valproate use.

The major congenital abnormalities include cleft palate, small fingers and toes, physiological and anatomical abnormalities in vital organs such as heart, kidneys, urinary tract, sexual organs and limb defects and develop in utero during organogenesis stage of pregnancy (6-10 weeks) whereas the developmental abnormalities involve appearance of autism spectrum disorder, anti-deficit hyperactivity disorder ADHD, being late in learning to walk and talk, poor speech and language skills, memory problems and lower IQ scores than other children of the same age and appear during late infancy period(around 6 to 9 months or 1 year of age).

Cause Of Teratogenicity

The proposed mechanisms that underlie these congenital and developmental disorder lie in the fact that valproate blocks the folate receptors, thus blocking the access of folate to its receptors, and instead bind to the receptors itself, depriving the fetus of supremely essential vitamin, leading to the development of neural tube defect in valproate exposed fetuses.

Therefore, folic acid intake is imperative before conception even in normal pregnancies and in female epileptic patients, folic acid is indispensable and a prerequisite.

The other mechanism that serves as a contributor to teratogenicity is the inhibition of an enzyme-histone deacetylase by valproic acid and fetal oxidative stress. By acting as an inhibitor of histone deacetylase, valproic acid alters the gene expression resulting in characteristic “fetal valproate syndrome”.

The fetal oxidative stress is induced by generation of reactive oxygen species which exert their deleterious effects on cellular elements mainly on DNA, RNA, lipids and proteins.

These teratogenic effects are induced during organogenesis stage of pregnancy – the stage in which the organs are developing and the most susceptible stage to risk factors associated with external factors such as toxins and drugs.

Necessity For Toolkit

Both, FDA and NICE have certain rules and guidelines regarding valproate use during pregnancy. Both regulatory authorities state that valproate should be avoided to a maximal extent and other safe alternatives (most commonly lamotrigine) be used instead. A studyantiepileptic drugs during pregnancy in primary care: A UK population based study”, in 2012 reported: “Lamotrigine has been increasingly prescribed in pregnancy over older AEDs namely carbamazepine and sodium valproate”.

Moreover, if valproate use is inevitable, the drug should be used in minimal effective doses and for a shortest period of duration. Additionally, patient should be provided with all the necessary information (benefits and risks) associated with the drug use.

The 2012 clinical guidelines from the National Institute of Health and Clinical Excellence (NICE) advised caution on the use of sodium valproate in pregnancy. The British National Formulary (BNF) also emphasizes that therapy with valproic acid should only be considered if in pregnancy the “risk of harm to the mother and fetus from a convulsive seizure outweighs that of continued therapy”.

The Toolkit Contents

The toolkit by Medicine and Healthcare Products Regulatory Agency serves the purpose of providing comprehensive information regarding birth defect risks along with valproate use.

The toolkit checklist comprises of certain statements to be reviewed by both the patients and the practitioner/prescriber.

The prescriber should conform to the statement that the requirement for valproate is imperative for the patient, since the patient is not able to adequately respond or tolerate other medical treatments for epilepsy or bipolar disorder.

Moreover, the prescriber should assign the statement that he has informed the patient about the high risk of birth defects associated with valproate use and has suggested the minimum effective dose to the patient, has counseled the patient about effective and long-term contraception methods if the patient is of child bearing age, will regularly review the need for therapy and handed over the patient booklet information.

The patient will assign the checklist stating that she understands the high rate of birth defect risks associated with valproate and why the treatment with valproate is considered necessary for her, that she has been advised about taking contraceptive measures if not planning pregnancy and the therapy will be regularly reviewed and should request an urgent review if attempting to conceive.

Valproate Patient Guide

The patient guide describes in detail the malformations and developmental skill delays associated with valproate therapy, which should only be taken if nothing else works, advises to use effective contraception methods, to inform on urgent basis if the patient has conceived, not to withdraw from therapy without informing the prescriber, a list of things to remember while taking valproate.

Health Professionals Guide

The guide for healthcare providers/professionals (HCPs) provides a detailed information about the birth defect risks associated with valproate containing drugs to the prescribers and gives detailed information as to how to treat females of different ages (female child, female adolescents of child bearing age but not planning pregnancy or those planning pregnancy or in case patient has conceived during treatment), effective contraception methods to be adopted, the need for regular monitoring of therapy in such patients and forbid patients withdrawing on their own from the therapy.

Patient Card

The patient card states two important objectives as a reminder to the patient; The risks of birth defects and the need for effective contraception. The safety card is a sort of continuous reminder for the patient about the serious hazards associated with the use of the drug to the fetus.

Current Advice

The current advice by MHRA is to not to use the valproate alike or containing drugs unless absolute necessity (if other treatment options fail) and the use of effective contraceptive measures to be taken and not withdrawing from the drug without the prescriber’s consent and urgent meeting with the prescriber if conception (unplanned pregnancy) occurs.