Sodium valproate

What is it?

Sodium valproate (Epilim®) and valproic acid (Depakote®, Convulex®) medicines are approved in the UK for the treatment of epilepsy and bipolar disorder, sometimes in combination with other medicines. These medicines are also sometimes used in the treatment or prevention of migraine. 

Why is it not safe to take sodium valproate in pregnancy?

Sodium valproate is harmful to babies in the womb. Taking sodium valproate in pregnancy can cause a condition called Fetal Valproate Syndrome (FVS) in the baby. Babies with FVS may have certain birth defects and lifelong alterations to learning and behaviour. Some babies with FVS have only a few features of the condition and are very mildly affected. Others may have more serious birth defects or learning difficulties. However, some babies of women who take valproate in pregnancy do not appear to have any features of FVS. 

The European Medicines Agency has therefore banned the use during pregnancy of valproate medicines for migraine or bipolar disorder, or for the treatment of epilepsy unless there is no other effective treatment available. For further information, visit the European Medicines Agency website.

This leaflet summarises the scientific studies relating to the effects of sodium valproate on a baby in the womb. It is advisable to consider this information if you are taking sodium valproate and are pregnant, or could become pregnant in the future, even if you are not currently planning on having children. If you can be treated with another drug that has been shown to be safer for an unborn baby than valproate, it is important that your doctor offers you this option. If you are not able to stop taking valproate then it is important that you are aware of the risks it poses to an unborn baby and of the importance of avoiding pregnancy.

Your doctor is the best person to help you decide what is right for you and your baby. 

What should I do if I have become pregnant while taking sodium valproate?

If you are taking sodium valproate, let your doctor know as soon as you realise that you are pregnant. Do not stop taking your medicine without first seeking advice from your doctor. Stopping valproate suddenly may be harmful to both you and your baby. If appropriate, your doctor will explain how to stop valproate as safely as possible. You may be advised to start a different medication to replace valproate. 

In some women with epilepsy, continuing treatment with valproate during pregnancy may be considered necessary. This decision should be made under the care of a specialist neurologist.  Women who need to continue taking valproate during pregnancy should be made fully aware of the possible risks to the baby. 

The bodily changes that occur as pregnancy progresses mean that the dose of valproate may need to be adjusted to ensure that epilepsy symptoms remain well-controlled. Women who need to continue taking valproate in pregnancy will therefore be offered monitoring to ensure they are taking the correct dose.

What should I do if take sodium valproate and could become pregnant in the future?

If you have not yet gone through the menopause, request an appointment with your doctor to review whether you can stop taking valproate. If you have to continue taking valproate, official guidance states that it can only be prescribed if you agree to a ‘pregnancy prevention programme’. The programme is designed to ensure that patients are fully aware of the risks, the need to avoid becoming pregnant, the need for pregnancy tests, and are using appropriate contraception.

Will taking high dose folic acid protect my baby against the harmful effects of valproate?

Sodium valproate can cause low folic acid levels. Folic acid is necessary for a baby’s growth and development in the womb. Women who have low folic acid levels in early pregnancy are much more likely to have a baby with a birth defect of the spine. It is therefore recommended in the UK that all women taking sodium valproate also take high dose folic acid (5mg/day) instead of the standard dose of 400ucg whilst trying to conceive and during the first trimester of pregnancy. High dose folic acid has to be prescribed by a doctor. 

There is not yet any scientific evidence to show that taking folic acid supplements at either high or standard doses can protect against the birth defects specifically caused by sodium valproate. However, until more scientific information is available, high dose folic acid is advised. For more information please see the folic acid bump leaflet. 

What is the chance of sodium valproate use in pregnancy causing birth defects in my baby?

A baby’s body and most internal organs are formed during the first 12 weeks of pregnancy. Taking sodium valproate during this time can affect the baby’s development and increase the risk of certain birth defects.

Studies suggest that overall, nine to 13 out of every 100 babies exposed in the womb to sodium valproate during the first trimester have a birth defect. This is higher than in the general population where major birth defects occur in two to three out of every 100 babies. The birth defects that have been linked to exposure to sodium valproate in the womb include spina bifida, heart defects, cleft lip and palate, hypospadias (where the hole in the penis is in the wrong place), and abnormalities of the fingers. Some valproate-exposed babies may have just one of these malformations, while others have more than one, or none at all. 

The likelihood of any individual woman who is taking valproate having a baby with birth defects will depend on a number of things, including the dose of valproate that she is taking and her and her baby’s genetic make-up (see below).

What is the chance that taking sodium valproate in pregnancy will affect my child’s learning and behaviour?

A baby’s brain continues to develop right up until the end of pregnancy. It is therefore possible that taking certain medicines at any stage of pregnancy could have a lasting effect on a child’s learning or behaviour.

A large number of studies have shown that children who were exposed to sodium valproate in the womb are more likely to have problems with co-ordination, movement, learning and behaviour compared to children not exposed to valproate. Studies have also shown that children exposed to valproate in the womb have a higher chance of having autism spectrum disorder (ASD) and possibly attention deficit hyperactivity disorder (ADHD). These effects on learning and behaviour have been observed in children both with and without birth defects or other features of fetal valproate syndrome.

It is difficult to work out the overall chance of a child’s learning or behaviour being affected by exposure to valproate in the womb from the available scientific studies. This is because these studies used different tests and have assessed slightly different aspects of learning and behaviour. It is therefore often not possible to directly compare their results. Three studies have shown that between two and six out of every 10 children exposed to valproate in the womb require extra help at school, but because of the way that these studies were carried out, we cannot say for sure that these figures are accurate, and more research into this subject is required.

Is there a safe dose of valproate that won’t cause FVS in the baby?

There is no known safe dose of valproate. However, it is clear that as the dose of valproate a woman takes increases, so does the likelihood of her baby having FVS. For example, in one study eight out of 100 women who took 500mg valproate a day had a baby with a birth defect, whereas 62 out of 100 women who took 3,000mg a day had a baby with a birth defect. This shows that although high doses present the highest risk, lower doses of valproate may still cause FVS in some pregnancies.

There is much less information on how the dose of valproate taken in pregnancy relates to a child having learning or behavioural difficulties after birth. The few studies that are available suggest that learning and behavioural problems are more common than would be expected in the general population with doses above 800-1,000mg per day during pregnancy, but further research is required to confirm this.

Is slow release valproate or taking multiple smaller doses of valproate in a 24-hour period okay during pregnancy?

No. There is no evidence that slow release valproate or taking multiple smaller doses of valproate is less likely to result in Fetal Valproate Syndrome. ALL medicines that contain valproate should be avoided in pregnancy unless the mother has epilepsy that cannot be controlled with any other medicine. 

Do not alter the dose of any medicine you are taking without first speaking to your doctor. Making changes to your medicine yourself may be more harmful to both you and your baby than continuing to take that medicine as prescribed.

Is it true that women who have had a child with FVS are more likely to have another child with FVS?

Two small studies have both suggested that unborn babies who are exposed in the womb to valproate have a higher chance of being born with FVS if they already have a brother or sister with FVS. Together, the studies showed up to six out of every 10 pregnant women who had a previous child with FVS had another baby with FVS in their next pregnancy. In contrast, fewer than two out of every 10 pregnant women whose previous child had not had FVS (even though they took valproate in pregnancy) then had a baby with FVS. This suggests that certain genes carried by the mother and/or her children may influence how valproate affects an unborn baby. It is hoped that future research will help to develop a way of identifying women and girls who are at high risk of having a baby with FVS before they start a family.

Is taking sodium valproate with other epilepsy treatments more harmful to the baby than taking it on its own?

Sodium valproate is sometimes taken in combination with other medicines to treat epilepsy. Most studies have not found that women taking sodium valproate in combination with other antiepileptics were had a higher chance of having a baby with a birth defect than women who took only sodium valproate. If you are taking more than one medicine to control epilepsy you should discuss any concerns that you may have with your doctor.  

Can taking sodium valproate in pregnancy cause miscarriage?

One small study has shown that women who took daily sodium valproate doses of 750mg or more were about three times more likely to have a miscarriage than women not receiving epilepsy treatments during pregnancy. One further small study found that for women taking valproate at doses of less than 1,000 mg per day, use of folic acid supplements was linked to a reduced chance of miscarriage. However, folic acid did not seem to make any difference to the chance of miscarriage in women taking more than 1,000 mg/day valproate. 

Taken together, the results of these studies suggest that higher doses of valproate increase the chance of miscarriage and underscore the importance of taking folic acid in early pregnancy. However, because each of these results is from just one study, more research is required to confirm these findings.

Can taking sodium valproate in pregnancy cause stillbirth?

Several small studies do not raise concern that sodium valproate use in pregnancy is linked to stillbirth. However, many more women taking valproate in pregnancy need to be studied to confirm these findings.

Can taking sodium valproate in pregnancy cause preterm birth?

Studies of almost 3,000 pregnant women taking valproate do not overall, raise alarm of a link with preterm birth.

Can taking sodium valproate in pregnancy cause my baby to be small at birth (low birth weight)?

Studies that have assessed whether exposure in the womb to sodium valproate might affect the baby’s growth have produced mixed findings. Although two small studies reported lower birth weights following valproate exposure, one much larger and therefore more reliable study showed no effects on the baby’s birth weight. While this is reassuring, further studies are ideally required.

Can taking sodium valproate in pregnancy cause withdrawal symptoms at birth (‘neonatal withdrawal’)?

Withdrawal symptoms are thought to occur when a newborn baby’s body has to adapt to no longer getting medicines that affect the brain and central nervous system through the placenta. 

There are reports of babies who were exposed to sodium valproate in the womb experiencing withdrawal symptoms at birth. Close monitoring of your baby for a few days after birth may be therefore advised if you have taken sodium valproate regularly in the weeks before delivery. Monitoring of your baby may be particularly important if you have taken sodium valproate in combination with other antiepileptic medicines or medicines that act on the brain. 

Will my baby need extra monitoring?

As part of their routine antenatal care most women will be offered a scan at around 20 weeks of pregnancy to look for birth defects and to check the baby’s growth. Women with epilepsy are likely to be more closely monitored during pregnancy to ensure that they remain well throughout and that their baby is growing and developing as expected.  

Because there is a possibility that sodium valproate taken in the first trimester might increase the chance of birth defects in the baby, your doctor may offer you the option of having more detailed anomaly scans. 

If you have taken sodium valproate around the time of delivery your baby may require extra monitoring after birth because of the risk of neonatal withdrawal.

Are there any risks to my baby if the father has taken sodium valproate?

Sodium valproate can reduce a man's fertility, although it usually goes back to normal once the drug is stopped. In addition, one study has suggested that children born to men taking valproate may be slightly more likely to have problems with learning and behaviour. This finding needs to be confirmed but as a precaution, UK guidelines suggest that valproate should be avoided in males who might wish to have children in the future. Men who take valproate and who are planning to father a pregnancy should speak to their GP or neurologist. It is important to continue taking valproate unless a doctor has advised that it is safe to stop or switch medication.

What should I do if I am concerned that my child has Fetal Valproate Syndrome?

There is no simple test to diagnose fetal valproate syndrome. If you took valproate during pregnancy and are concerned that it may have caused problems in your child, it is best to speak to your GP. They will arrange for your child to be referred to a specialist who will assess your child’s development and health, and will, if necessary, rule out other illnesses (including some genetic disorders) that may cause birth defects and problems with development. 

Who can I talk to if I have questions?

If you have any questions regarding the information in this leaflet, please discuss them with your health care provider. They can access more detailed medical and scientific information from www.uktis.org.