Introduction

What is Foetal Valproate Syndrome?

A teratogenic agent possesses a known risk to foetal development and may cause significant abnormalities. Valproate is a medication used in the treatment of epilepsy, bipolar disorder, and migraine attacks. It is also a known teratogen and is not recommended to those who are pregnant or who wish to become pregnant in the short term.  

Although many babies that are exposed to valproate during pregnancy are born healthy, studies have indicated that there is an increased risk of Foetal Valproate Syndrome (FVS) in the developing embryo after exposure to valproate during pregnancy.¹ There is a spectrum of the clinical presentation and symptoms presented by FVS and individuals may exhibit major or minor abnormalities. Congenital abnormalities, facial dysmorphism, and neurodevelopmental challenges are all associated with FVS. Individuals experiencing a wide array of symptoms require a multidisciplinary care plan to navigate the management of FVS.² The true number of individuals affected by FVS in the UK remains a mystery, but some investigators have estimated that it is around 20,000.³ In the UK, many women of reproductive age still rely on sodium valproate to manage their symptoms of epilepsy. Therefore, it is imperative that the government explores new avenues to minimise the risk of valproate affecting future generations. 

The History of Valproate in the UK

In 1972, Epilim was licensed in the UK as an anticonvulsant to be used in the treatment of epilepsy. Its main ingredient is Sodium Valproate. The effectiveness of Epilim as an anticonvulsant ensured that the drug gained widespread popularity to the detriment of pregnant people. 

Over time, studies identified teratogenic concerns related to the use of sodium valproate during pregnancy.⁴ However, the public remained oblivious to these findings due to the drug company and their marketing team choosing not to disclose the teratogen status of sodium valproate.³ Until 2005, the public was not made aware of the link between congenital abnormalities and sodium valproate usage. Unfortunately, many people were unable to make an informed decision regarding the use of the drug, resulting in many babies being affected by FVS and many preventable deaths. 

Evidence sourced from archives indicate that the drug regulator and manufacturer possessed sufficient data, from as early as the 1980s, to conclude the teratogenic effects of sodium valproate use during pregnancy.³ Occulting this knowledge directly contradicts the duty of healthcare professionals to ‘first do no harm’.

Since the risks have been uncovered, the NHS has introduced programmes to inform the public about the safety concerns around sodium valproate.⁵ These include:

• Visible warnings on the medication packet indicating a risk associated with the medicine to pregnant people 
• Distribution of a letter informing the person about the risks of the medication to individuals of child-bearing age who have a prescription for sodium valproate 
• Monitoring the number of people who have taken sodium valproate at some point during pregnancy and subsequently given birth 

The lack of safeguarding for patients by the government and the regulatory body during this scandal has resulted in a call for compensation for those affected by FVS.³ 

Clinical Features and Symptoms of Foetal Valproate Syndrome

Physical Abnormalities

There is a vast array of physical abnormalities that may manifest themselves in FVS. Some recognisable facial features of FVS include:⁶  

• A broad nasal bridge 
• A long and slight upper lip
• Epicanthal folds: Skin of the upper eyelid that forms a groove covering the inner corner of the eye 
• A small mouth 
• A flat philtrum (the space between your nose and upper lip)

Further case studies have noted some common limb and skeletal anomalies present in babies exposed to valproate in-utero, and these include:⁷ 

• Unusually long and thin fingers and toes
• Underdeveloped finger and toe nails
• Overlapping fingers and toes 
• Club foot 

Other physical abnormalities that may be exhibited by a few individuals are: 

• Microcephaly: An abnormally small head 
• Cryptorchidism: The absence of at least one testicle in males
• Hypospadia: When the opening of the penis is located on the underside of the penis
• Tracheomalacia: The softening of the trachea (windpipe) 
• Cardiac anomalies such as atrial or ventricular septal defect
• Spina Bifida: A neural tube defect which causes a gap in the spine

Neurodevelopmental Difficulties Related to FVS

Clinical reports have noted that FVS increases the likelihood of an individual to suffer from a range of neurodevelopmental abnormalities.⁸ These include:

• Autism Spectrum Disorder (ASD)
• Attention Deficit Hyperactivity Disorder (ADHD)
• Poor academic performance
• Memory impairments 
• Speech and language delays 
• Decreased social and adaptive behaviour skills

Although many studies indicate a high dose-dependent relationship between valproate and the risk of suboptimal neurodevelopment, it remains unclear if there is a dose-dependent relationship between valproate and neurodevelopmental challenges due to the lack of statistical analysis.⁸ 

Diagnosing FVS

Diagnosing FVS is not straightforward. Unfortunately for medics, there is no FVS specific biomarker that can be used for a diagnosis. A process of exclusion is used to rule out other medical conditions with overlapping clinical presentation and symptoms to FVS.⁶ 

Prenatal ultrasounds can be used to detect physical abnormalities including neural tube defects and organ anomalies. Assessment of cognitive and neuropsychological abnormalities can be carried out during childhood to support the process of diagnosing FVS. 

Clayton-Smith et al have published a table highlighting criteria to make an FVS diagnosis. The table is divided into ‘essential’ (Must be present for an FVS diagnosis), ‘suggestive’ (Significantly increased frequency in FVS), and ‘supportive’ (Slightly more common in FVS). The identification of the essential characteristics alongside a history of in-utero valproate exposure aids a clinical diagnosis being made. 

Raising Awareness and Prevention 

INFACT is a campaign group responsible for keeping the pressure on the government with regards to the sodium valproate tragedy. This led to the Cumberlege Review and resulted in the published 9 key recommendations issued to the government. The recommendations are:

• Apology
• Patient Safety Commissioner
• Financial Redress
• Redress Agency
• Specialist Centres
• Overhaul of MHRA
• Database 
• Declaration of Interest
• Taskforce 

In January 2024, the government updated the drug safety report of Valproate including educational and safety materials to try to minimise the risk posed. 

Conclusion

In summary, sodium foetal valproate syndrome is a consequence of in-utero exposure to the epilepsy drug sodium valproate. The risks of valproate were not made widely available to the public for many years even though the data and knowledge was there. Therefore, many people suffer from the consequences of valproate exposure due to the lack of information provided to their parents. There is a wide range of clinical presentations of FVS, including facial dysmorphism, limb abnormalities, neural tube defects, and neurodevelopmental difficulties. Diagnosing FVS is not straightforward, and often a process of elimination is used to arrive at a conclusion. 

Frequently asked Questions

What is Valproate? 

Valproate is a medication most commonly used to treat epilepsy. It may also be used as a treatment in bipolar disorder and migraine. 

How is foetal valproate syndrome acquired? 

If a pregnant individual is prescribed sodium valproate and consumes it whilst pregnant, their unborn child is at a high risk of suffering from foetal valproate syndrome symptoms. 

What are the facial abnormalities seen in FVS? 

Some of the facial features seen in FVS are: wide nasal bridge, thin upper lip, small mouth, small head, and epicanthal folds. 

What are other clinical presentations of FVS?

Spina bifida, absence of testicles, cardiac defects, and abnormal fingers and toes. 

How is FVS diagnosed?

There is no definitive diagnostic test for FVS. Your doctor will look at your symptoms and history of valproate consumption. Prenatally, your clinician may use ultrasound to identify neural tube defects and organ anomalies. After birth, tests are used to rule out any other medical disorders with overlapping symptoms to FVS.