Introduction

Valproate is a medication that comes in many forms including sodium valproate and valproic acid and is used to treat various neurological and psychiatric disorders. The medication was initially developed in 1882 as a derivative of a naturally occurring fatty acid, valeric acid. However, the anticonvulsant properties of valproate were discovered much later when the medication was shown to reduce the effect of electroshock seizures in mice.¹ Since then, valproate has proven effective in preventing the frequency of seizures in humans and has been largely prescribed in the treatment of epilepsy and other seizure-related disorders. It has also been especially successful as a treatment for bipolar disorder.

Although valproate has minimal side effects when taken for these disorders, it can cause serious problems if taken during pregnancy. Valproate can negatively affect the baby’s development, causing lifelong defects and learning disabilities. Despite these adverse risks, an alarming number of people assigned female at birth (AFAB) are still prescribed valproate during pregnancy. Sodium valproate was shown to have been prescribed to 247 people AFAB in England during their pregnancy between 2018 and 2021.² This article aims to provide information on the damaging effects of valproate exposure on fetal development and subsequently provide a risk assessment for taking this medication during pregnancy. 

Overview of valproate mechanisms

Valproate is a simple, branch-chained fatty acid that uses many mechanisms, some of which remain unknown, to treat neurological disorders effectively. Experimental evidence has shown that valproate increases the turnover of the neurotransmitter gamma-aminobutyric acid (GABA), which is thought to aid in controlling seizures. Valproate works through various mechanisms to alter the balance between inhibition and excitation in the brain which allows for it to regulate these neurological disorders.³ It is thought to block seizures caused by NMDA, a receptor of the neurotransmitter glutamate, which often causes seizures through the excitation of neurons.⁴

Prenatal exposure to valproate

Valproate falls into the category of “mood stabilizing” drugs that have the ability to freely pass to the baby through the placenta. The placenta is a barrier that acts as the connection point between mother and baby, providing the baby with necessary nutrients and oxygen. Although maternal and fetal blood never mix, valproate is able to diffuse through the placenta and enter into the baby’s bloodstream. Despite these control mechanisms that act to protect the baby, valproate’s prescription dosage is usually too high to be entirely counteracted. 

Risks associated with prenatal exposure

Approximately 10% of babies whose mothers continued taking valproate during pregnancy are born with a birth defect and up to 40% experience learning and growth problems later in life. The ways in which babies can be affected are numerous. 

Developmental effects

Valproate is a human teratogen, meaning that it is a drug whose exposure can cause developmental defects in the baby. One of the most common malformations caused are neural tube defects (NTD), which include any defect of the brain, spine or spinal cord, and can often cause spina bifida where the spine is malformed. Other common defects include cleft lip and palate as well as cardiovascular abnormalities.⁶ The physical abnormalities caused by the consumption of valproate are so characteristic that fetal valproate syndrome has coincided to describe the common set of symptoms involving facial disfiguration as well as developmental delay specifically involving language and communication.⁷

Neurodevelopmental outcomes

Taking Valproate during pregnancy increases the risk of having a child with neurodevelopmental disabilities by 4-5 times. Valproate has been associated with increasing the risk of having a child on the autism spectrum disorders, with attention deficit hyperactivity disorder (ADHD) as well as poorer educational outcomes.⁸

Risk assessment of discontinuation

Considering the associated risks of taking valproate during pregnancy, this drug is usually only prescribed for a condition if no other drugs work for treatment. For people AFAB not of child-bearing age, the risk of taking valproate is low. People AFAB of childbearing age are cautioned to use effective birth control methods to prevent accidental pregnancies and to consult their doctor if considering planning a family. In the event of a pregnancy, immediate discontinuation of the drug is not advised as this could also harm both the mother and the baby. The risks of discontinuation in general, even in a regulated manner, are worth assessing with a healthcare professional. 

In the context of epilepsy, a healthcare professional can advise switching to another form of treatment that may work and monitor closely to avoid discontinuation from all medication. However, if valproate is the only effective medication, discontinuation will be considered by assessing the severity of the specific patient’s epilepsy. Having a seizure during pregnancy can also restrict airflow to the baby, causing extreme developmental harm and even death. It is therefore essential that a doctor assesses all risks and possible switching of medications before discontinuation is advised.⁹ Moreover, in the cases where the risk of complete discontinuation outweighs continuation, the dosage of valproate may be lowered to a level that is less likely to affect the growing baby. 

For bipolar disorder, discontinuation comes with the risk of the mother experiencing symptoms such as depression, psychosis and mania. These symptoms can put the mother, and consequently the baby, in great danger. The effect of these symptoms can also affect the mother long after pregnancy, endangering her ability to look after the baby. Luckily, for bipolar disorder, many other effective treatments exist. The most crucial way to mitigate the adverse risks of discontinuation from valproate is to do so slowly and systematically while being overseen by a healthcare professional.¹⁰ 

Summary

Valproate is an effective medication for reducing seizures associated with epilepsy as well as acting as a mood stabilizer for bipolar disorder. However, when taken during pregnancy, it can cause abnormal development of the baby, such as spinal and facial disfiguration and neurodevelopmental issues. Discontinuing the drug, especially when done abruptly, can also harm both mother and baby through the onset of seizures and psychosis. Being aware of the risks associated with valproate during pregnancy and consulting a doctor before considering having a child while on treatment is the safest way to assess personal risk, whether continuing or stopping the medication. This also ensures monitoring of both mother and baby throughout. 

FAQs

What should I do if I think my child may have been affected by valproate?

The first thing to do is to speak to your family doctor who may refer you to a child medicine specialist if needed. There are many other support networks available for those affected by Valproate taken during pregnancy and their families such as Valproate Victims and Organisation for Anti-convulsant Syndrome.

Will other epilepsy medications negatively affect my baby?

Taking valproate comes with the highest risk of adverse effects on the baby. However, other forms of epilepsy medication can still pose a (lower) risk. Some epilepsy medications such as lamotrigine and levetiracetam are deemed safer to use during pregnancy as they have not been associated with increasing the risk of birth defects. The medications with the highest risk to the baby, next to valproate, are phenobarbital and phenytoin. However, the risk of taking other forms of medication can be lowered by controlling the dosage of the medication. Ultimately, consulting with a healthcare professional will help to choose a medication with the highest effect in treating epilepsy and the lowest risk of harming the baby.

Which healthcare professionals can be considered experts? 

When searching for a healthcare professional to consult, it is important to find someone with extended qualifications in epilepsy or bipolar disorder. Epilepsy specialist nurses can also be valuable in providing guidance to people AFAB taking valproate or concerned about taking valproate during pregnancy.

What do I do if the risk of seizures is too great and I cannot come off of valproate during pregnancy?

If no alternative medications with lower associated risks are suitable, you may choose to continue with the pregnancy while knowing the possible adverse outcomes and monitoring fetal progress often. However, if you do not wish to take the risk, surrogacy is a viable and recommended option to still be able to have biological children.