Introduction 

Fetal valproate syndrome (FVS)

Fetal valproate syndrome is a rare, congenital disease present in the form of physical and developmental fetal abnormalities.¹ It is by large a teratogenic disease - the main cause of it is fetal in-utero exposure to valproate/valproic acid. Valproate is a main ingredient in many psychiatric medications and is widely used for the treatment of epilepsy.² Maternal exposure to valproate during pregnancy may result in the fetus developing FVS. Therefore it is paramount to understand the factors that predispose one to developing FVS and to develop strategies for prevention, diagnosis and treatment of this disease. This article aims to explore the genetic and epigenetic mechanisms that contribute to the development of FVS and discuss their clinical significance. 

What is valproate/valproic acid?

Valproate (also known as valproic acid) is a potent, active ingredient that is widely used in formulating medication for a range of psychiatric conditions. Its common uses include treatment and management of seizures associated with epilepsy, bipolar disorder and migraines.² Valproate acts by altering neurotransmission (brain activity) and hence acting as an anticonvulsant. 

Fetal valproate syndrome 

Whilst valproate is a useful medication, exposure to it during pregnancy may result in serious damage to the developing fetus. Fetal valproate syndrome is associated with a range of symptoms that sometimes is a result of maternal exposure during crucial periods of fetal development in pregnancy (i.e. during the first trimester). 

The symptoms include:

• Congenital malformations:
  • Neural tube defects - such as spina bifida 
  • Heart defects - ventricular septal defect 
  • Distinct facial dysmorphisms 
  • Oral clefts 
  • Genital abnormalities (hypospadias).¹  
• Neurodevelopmental problems:
  • Developmental delays
  • Abnormal cognition
  • Autism spectrum disorders
  • Attention deficit disorders
• Growth retardation

Which symptoms appear depends from case to case and is often based on the amount, duration and time during pregnancy when the exposure took place. However, this disease is very rare - it is estimated that in the US fewer than 50,000 people have this disease. 

Interestingly, valproic acid does not always result in fetal development of this disease. Many babies are born healthy following in-utero exposure to valproate. Therefore there must be specific alterations already present in the genes of the fetus or in the mother that predispose them to developing this disease. 

Genetic and epigenetic factors in the development of FVS 

Exposure to valproate may cause genetic mutations which lead to the pathophysiology of the syndrome. These mutations may be in the enzymes involved in the metabolism of valproate, or in specific regulatory genes involved with the development itself. Epigenetic factors (factors that are not involved in changing the genetic code) altered in FVS include changes in DNA methylation pattern - how much DNA is available to be “read” by machinery that translates it to protein. Genetic alterations may be intergenerational (passed down from parents to offspring). 

Summary

Valproate is a pharmaceutical drug that is involved in treating a variety of psychiatric conditions. However, it also may result in severe side effects if used by pregnant women - which includes abnormal fetal development via fetal valproate syndrome. Exposure to valproate alters genetic or epigenetic mechanisms which give rise to the symptoms of the syndrome. It’s essential to understand the mechanisms by which valproate works to educate pregnant women about its use when pregnant.