Introduction 

Valproate, also known as valproic acid or sodium valproate, is a drug licensed in the UK as an anticonvulsant to treat epilepsy, and as a mood stabiliser to treat bipolar disorder. It may also be prescribed for “off-license” conditions, such as the preventative treatment of migraines. Epilepsy is a neurological condition characterised by abnormal electrical activity in the brain, resulting in seizures. Bipolar disorder is a psychiatric condition characterised by cycles of mania (elevated mood) and depression. Valproate is teratogenic, meaning it can pass from the gestational carrier to the foetus during pregnancy. 

Valproate prescribing guidelines

Valproate is a prescription-only medication, and extra precautions are taken when prescribing to those assigned females at birth who are of childbearing age. In the UK, this involves a consent process required by law with the patient, the prescribing doctor and the parent/carer if relevant. 

The decision of whether or not to prescribe valproate is made based on individual medical history, but is typically only prescribed once other medications have proven ineffective. Alternative medications, such as lamotrigine for epilepsy, are typically prescribed instead, as they do not pose the same risk of congenital abnormalities. Valproate must not be prescribed for bipolar disorder during pregnancy, and must be agreed by two independent specialist doctors for the treatment of epilepsy. 

Those assigned female at birth of childbearing age are screened for pregnancy before starting on valproate, and whilst taking the medication are typically required to use a form of contraception. Ideally, this should be a ‘user-independent’ form of contraception, such as an intrauterine device or implant inserted, rather than a contraceptive pill, which depends on the person adhering to the instructions. Individuals are also required to take a high dose of folic acid from at least 6 weeks prior to conception to reduce the risk of neural tube defects.¹

Note: valproate should never be discontinued without medical supervision. 

Foetal valproate syndrome

Foetal valproate syndrome is a rare congenital condition caused by exposure to valproate during pregnancy. The term ‘foetal valproate spectrum disorder’ encompasses the range of different disorders that come with exposure to valproate in utero. According to figures from France, only 450 children between 2004 and 2016 were born with foetal valproate syndrome. The MHRA (medicines and healthcare regulatory agency) in the UK reported that the risk of congenital defects in pregnant people who take valproate is around 11%, increasing to 24% at higher doses. The risk of congenital abnormalities is around 2-3% in the general population, so although the risk associated with valproate use in pregnancy is significantly higher, the overall prevalence of foetal valproate syndrome is still relatively uncommon.²

Valproate is most teratogenic during the first trimester, with the risk of neural tube defects such as spina bifida almost 20 times higher compared to other antiepileptic drugs. Neural tube defects are a group of embryonic abnormalities in the neural tube, which is the origin of the nervous system the brain and the spinal cord.  Valproate exposure during pregnancy also significantly increases the risk of cleft lip and palate, polydactyly (having extra fingers and/or toes), cardiovascular abnormalities,  developmental delay (e.g. missed milestones), endocrinological (hormonal) disorders, and limb defects.³ Facial defects are also observed, including a prominent metopic ridge, where the two halves of the skull do not fuse normally, forming a prominent bony ridge across the forehead. Another facial abnormality is the under-development of the middle of the face, including the nose, nasal passages and upper jaw. This may lead to breathing difficulties if the nasal passages are not large enough. Children may also have difficulties in speech and reading and have lower IQs (less than 70). Foetal valproate syndrome is also associated with an increased risk of autism spectrum disorder.⁴

Circulatory system 

When blood is oxygenated in the lungs, it is transported to the heart, which then pumps it out into the arteries. The aorta is the major artery leaving the heart, which then branches off into smaller arteries to go to the rest of the body. In the bloodstream, oxygen and other nutrients in the blood are carried to the different organs. As the blood is transported around the body, the blood can pick up carbon dioxide, which is then transported back to the lungs to be exhaled in the veins. Other waste products are filtered out in the kidneys. 

The placenta is an organ that forms during pregnancy. It sits in the womb and is attached to the foetus by the umbilical cord. The maternal blood enters the placenta, and as it does, oxygen and other nutrients can move from the maternal blood into the foetal blood. Oxygen, for example, moves via a process called diffusion, where the substance moves from an area of high concentration to a low concentration. Where the maternal blood has higher oxygen levels, oxygen can move from the gestational carrier to the foetus. The maternal blood can then pick up carbon dioxide from the foetal blood, which is transported to the lungs for exhalation.⁵

The diagrams below demonstrate how circulation occurs at the placenta. 

File:Placenta.svg - Wikipedia 2010. https://commons.wikimedia.org/wiki/File:Placenta.svg (accessed January 6, 2025).

Pathophysiology

Valproate also passes from the pregnant person to the foetus via the placenta, primarily via diffusion in the blood. The ability for a substance to pass to foetus and cause structural or functional abnormalities during pregnancy is known as teratogenicity. Not all drugs are teratogenic, but some medications, such as valproate and lithium, which is also used for bipolar disorder, are teratogenic.

Once valproate enters the foetus, it damages the DNA of the cells. DNA is inherited material replicated from the egg and sperm cells after fertilisation. DNA is made of individual units called bases. Genes are sections of DNA (multiple bases), which encode for the production of a protein in the body. There are many genes within the DNA; some are “switched on" and therefore expressed, and others are “switched off” and not expressed. The study of how the genes are expressed due to hereditary or modifiable risk factors is called epigenetics. 

Two epigenetic processes are DNA methylation, where a methyl group is added, and histone acetylation, where an acetyl group is added to histones- proteins bound to DNA. Valproate can influence these processes via chromatin remodelling, influencing the expression of genes. 

One protein that valproate damages is chromatin. The function of chromatin is to bind the DNA into the tightly bound chromosomes (of which there are 23 pairs in human cells). Chromatin can either bind the DNA such that it is accessible and easily translated, or in a way that prevents the DNA being ‘read’. When the chromatin is altered, it alters which genes are ‘read’. Valproate inhibits the enzyme that removes acetyl groups from histones within the chromatin, altering the chromatin’s function.^{6, 7}

Valproate can also result in the formation of highly reactive molecules called reactive oxygen species (ROS) and induce a state of oxidative stress. ROS can react with the DNA and alter it. If it changes what the DNA is coding for, then it can result in an abnormal function being carried out. 

Summary

Valproate is a drug mainly prescribed for epilepsy and bipolar disorder. If taken during pregnancy, it can be passed on from the pregnant person to the foetus via the placenta. Valproate causes the most damage if taken during the first trimester, as it is an important period for the development of foetal organs. Valproate alters the DNA of the cells; it can influence reactions within the cell to alter the DNA itself or can cause changes to how the genes are expressed. It can “switch on” genes which are not normally expressed or “switch off” genes that should be. 

Foetal valproate syndrome is the name of the condition that a baby is born with following exposure to valproate in utero. Foetal valproate syndrome affects individuals differently, but can result in a number of abnormalities, including cleft lip and palate, limb abnormalities, intellectual impairments, heart defects, and hormone imbalances. As a congenital syndrome, there is no “cure” for foetal valproate syndrome. Usually those assigned female at birth who are taking valproate are prescribed contraception and high-dose folic acid, and are made fully aware of the risks of taking valproate during pregnancy. Those who do become pregnant should speak to a doctor before altering the dose of valproate.