What is Fetal Valproate Syndrome?

Fetal Valproate Syndrome (FVS) is a rare condition that develops in unborn babies during the first 3 months of pregnancy.¹ It is caused by exposure to valproic acid, an ingredient of Valproate. Research has found that the risk of FVS developing is 11% when the mother takes Valproate during the first trimester.² Once the child has been born, they will face developmental abnormalities, congenital defects and facial dysmorphic features.² The severity of these symptoms differs across individuals. 

The prevalence of FVS differs between regions and is impacted by the awareness of the effects of valproate use during pregnancy, and the dosage taken. Research has found that the risk of FVS developing is 11% when the mother takes Valproate during the first trimester.² It has been suggested that more than 20,000 children in the UK could currently be affected by FVS. Here, we will discuss the cognitive impairment and developmental delays caused by FVS.

FVS may impact the affected individuals and their families emotionally, financially and socially. 

Overview of Valproate, its uses, and diagnosis

Valproate is a prescription medication used to treat epilepsy, bipolar disorder and migraines.³

Epilepsy

Seizures are caused by bursts of electrical activity in the brain (nerve signals). Valproate works by inhibiting nerve signals in the brain, preventing a large burst of electrical activity. Due to its anticonvulsant properties, valproate normalizes the movement of nerve signals in the brain, stopping seizures before they happen or treating them.⁴ Valproate is highly effective in both controlling and preventing a wide variety of seizures, making it a common choice for the management of epilepsy. 

Bipolar disorder

As a mood stabilizer, valproate works on the symptoms of mania in bipolar disorder. Mania is characterized by feelings of overexcitability, overactivity and distractedness. Valproate reduces feelings of excitement, regulating mood stability. Valproate works by preventing the breakdown of a chemical in the brain (GABA) that is responsible for calming nerve excitability in the brain. By blocking the breakdown of the chemical, more nerve signals can be calmed. Thus, the excited nerve signals previously mentioned are reduced to a normal level.⁵ Valproate is effective in treating manic episodes of bipolar disorder, thereby stabilising mood swings. Alongside it, other medication may be taken to treat the other symptoms of bipolar disorder, such as depression.

Migraines

Less is known about the mechanism of action of valproate in the treatment of migraines. It has been suggested that the increase of GABA levels in the brain suppresses migraines.⁶ Valproate has been effective in the prevention of migraines.

There is no current diagnosis for FVS. Instead, a diagnosis of exclusion will be made.² This means that other conditions with similar symptoms must first be ruled out, and observations of the symptoms of FVS need to be made, for example, identifying a characteristic facial abnormality. Alongside this, it must be established that the mother is taking Valproate during pregnancy. Thus the diagnosis of FVS relies on a comprehensive approach.

Possible side effects

Like all medications, valproate can cause side effects. The severity and duration of these effects differ between people and can range from mild to severe. 

Some of the milder symptoms include:³

• Nausea
• Weight gain
• Diarrhea.
• Tremors (shakes) in parts of the body
• Headaches
• Vomiting
• Fatigue
• Thinning hair
• Irregular periods
• Dry mouth

More serious side effects can include:

• Suicidal thoughts
• Jaundice (yellowing of the skin)
• Yellowing of the eyes
• Acute pancreatitis
• Excessive bruising
• Abnormal bleeding

Fetal Valproate syndrome: causes and mechanisms

It is believed that valproate causes FVS as it can pass through the placenta, and interfere with the development of the fetus in the womb¹, thus causing fetal abnormalities. 

Maternal use of Valproate during pregnancy 

Maternal use of valproate during pregnancy is responsible for valproic acid (VPA). Consequently, it is often advised that while using the drug, women do not try to get pregnant. Alternatively, they may safely stop taking the drug when they wish to become pregnant and throughout their pregnancy.

However, it is not always possible to stop taking the drug. A specialist neurologist may decide that it is in the best interest of the mother to continue the medication during pregnancy. During this instance, the mother must be made aware of the risks of taking the drug while pregnant to herself and her unborn baby.⁷ In men, it is advised that contraception is used when taking valproate. Additionally, they should stop taking valproate 3 months before they wish to try for a baby, but before, advice from a doctor must be given.³

There is a dose-effect relationship between taking the drug and the effects this has on the baby. Higher doses of the drug mean more exposure of valproic acid to the baby, resulting in a higher likelihood of fetal abnormalities, or FVS. In contrast, lower doses pose a smaller risk of fetal abnormalities, however, this does not mean they will not occur.¹

Timing between doses has no impact on FVS prevention or development. Taking any dosage of valproate at any time during pregnancy increases the likelihood of FVS. 

Cognitive impairment in FVS

Cognitive impairments at the hands of FVS can come in different forms, including intellectual disabilities, memory deficits, attention and difficulties.

• Intellectual disability - Individuals with FVS are likely to have a low IQ score. This will reflect how they learn skills throughout their life; delayed and limited. Academic performance is often stunted
• Memory deficits - these can be both short-term and long-term memory deficits. Short-term memory difficulties can include having trouble remembering faces or lists.² This makes it harder to learn information and skills, hindering the child in their education as well as in their social lives. Recalling long-term information may be a struggle for some individuals
• Attention deficit - individuals may struggle to focus on a task at hand, or things happening around them. This will affect their education and work life. The inability to concentrate could be the result of an inability to filter out unnecessary stimuli, or an inability to focus on something in general. A diagnosis of Attention Deficit Disorder (ADD) may be the result of this behaviour¹

Brain structure abnormalities could be causing neurodevelopmental issues. Evidence has been found that suggests enlarged cerebral ventricles, hypoplasia of the corpus callosum and an abnormal septum pellucidum can cause cognitive impairments.⁸

Standardised cognitive tests will be carried out to diagnose cognitive impairments. There are a variety of tests that may be carried out, each specific to a different aspect or combination of cognition, such as the Stanford-Binet Intelligence Scales which tests for Knowledge, Quantitative Reasoning, Visual-Spatial Processing, Working Memory and Fluid Reasoning.⁹ The combined scores from these tests are referred to as the IQ score.

Clinical evaluations must also be carried out to assess the overall health of the individual, specifically looking for any characteristics of FVS. Evaluations can take many forms, including looking into the individual's medical history, physical examinations, and behavioural and developmental assessments.

Developmental delays in FVS

Like cognitive impairments, FVS causes different developmental delays, including delays in motor skills, language, and communication.

• Motor skills - children with FVS typically reach milestones at a slower rate than other children. Milestones such as sitting, crawling, cruising and walking. They may also face problems with their fine motor skills such as writing, drawing or moving an object. Several physical abnormalities could be responsible for their difficulty carrying out motor skills, such as spina bifida, thin fingers and toes, discolouration of the hip, and weak muscle tone¹
• Language -speech delays are prevalent in individuals with FVS. Speech therapy can improve language deficiencies, improving the individual's ability to talk to others
• Communication - 6-15% of individuals exposed to valproate are diagnosed with Autism Spectrum Disorder.² The main symptom experienced will be difficulty in communicating and interacting with others¹

Development screening tools are used to monitor a child's development. They observe the development of language, movement, behaviour, emotions and thinking in children. Screening tools can take the form of questionnaires or checklists created based on research on children's development. These can be carried out by parents, doctors or nurses. A child exposed to valproate may need to undergo development screening more often than an unexposed child.¹⁰

Development monitoring is used to monitor whether a child is reaching important milestones in learning, speaking, moving, playing and behaviour.¹⁰ These are more informal than developmental screening and can be carried out more frequently. 

It is important to remember that all children reach milestones at different speeds, and no two children are the same.

Interventions and management strategies

Early developmental therapies can address developmental delays early on, allowing children to reach their full potential. Early intervention is imperative in the successful treatment of developmental delays as it aids children in leading normal lives. Occupational, physical, speech and behavioural therapy are often recommended. 

Educational support is required for individuals with FVS. Individualised Education Programs (IEPS) are effective programmes tailored to the specific needs of individuals with disabilities.¹¹ By tailoring the programme to each individual, children are given the support they require to reach their full potential. 

Classroom accommodations should be made for schoolchildren. The classroom must be accessible to any physical needs they have, as well as cognitive. For example, unnecessary noise should be minimised to reduce distractions. 

Medication may be required for symptoms of FVS. 

• Stimulants - Methylphenidate may be offered to children and adults showing signs of ADD. As a stimulant, it increases activity in the areas of the brain that control attention, thus increasing focus¹²
• Antidepressants - some individuals may feel anxious or depressed due to their delayed development, so sometimes antidepressants are required to improve mood

A multidisciplinary approach is required to treat FVS due to the large number of symptoms it can cause. Such an approach ensures all symptoms are addressed comprehensively.

Prognosis

Using a collaborative approach to treatment results in a better prognosis, especially when parents are involved in the treatment. This is because of the large influence parents have over their child's development. Like most diseases, the prognosis is improved with awareness. Teaching parents the danger of taking Valproate whilst pregnant can prevent FVS. Knowing the symptoms of the syndrome allows early intervention by medical professionals. 

Awareness is also important as it teaches compassion and empathy in others, enabling encouraged development in children. 

FAQs

What is cognition?

Cognition refers to all of the conscious and unconscious processes that are involved in how we think, perceive and reason. These can include thinking, learning, remembering, and making judgments and language.¹³

Summary

Fetal Valproate Syndrome presents a complex array of challenges, affecting cognitive, motor, and behavioural development in children exposed to valproate during pregnancy. Due to the complexity of its nature, FVS cannot be treated alone. It requires a comprehensive, multidisciplinary approach, which combines expertise from a range of healthcare professionals, including neurologists, paediatricians, psychologists, therapists, and teachers. Continued research is essential to raising awareness of the dangers of taking Valproate during pregnancy. 

Using a collaborative approach to treatment results in a better prognosis, especially when parents are involved in the treatment. This is because of the large influence parents have over their child's development. 

Early diagnosis is of profound importance as it allows quick and effective intervention by implementing the appropriate treatment.