Sodium valproate

(Date: March 2018. Version: 2.2)

This factsheet has been written for members of the public by the UK Teratology Information Service (UKTIS). UKTIS is a not-for-profit organisation funded by Public Health England on behalf of UK Health Departments. UKTIS has been providing scientific information to health care providers since 1983 on the effects that medicines, recreational drugs and chemicals may have on the developing baby during pregnancy.

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.

In early 2018, official guidance was published banning the use during pregnancy of valproate medicines for migraine or bipolar disorder, or for the treatment of epilepsy during pregnancy unless there is no other effective treatment available. This report can be found on the European Medicines Agency website (click here).

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. Some babies of women who took valproate in pregnancy do not appear to have any features of FVS.

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 a pregnancy while taking valproate.

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 seeking advice from your doctor first. 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 continued 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 risks of taking valproate during pregnancy.

What should I do if I am taking 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. The new guidance states that valproate medicines must not be used in any woman or girl able to have children unless a pregnancy prevention programme is in place. The programme is designed to ensure that patients are made 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 that are 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 bumps 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.

Most studies suggest that overall, six to 10 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 on the underside rather than at the tip), 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.

Each woman’s personal risk of 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 scientific studies that have investigated this. 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 3000mg 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. 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 at higher risk 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. Because these results are from just one study, more research is required to confirm these findings.

Can taking sodium valproate in pregnancy cause stillbirth, or preterm birth?

A single small study found no links between sodium valproate use in pregnancy and stillbirth or preterm birth. However, many more women taking valproate in pregnancy need to be studied to confirm these findings.

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

No increased risk of the baby being smaller than expected for the stage of pregnancy was identified in one study of 410 babies born to women who took valproate in pregnancy. Another small study of 120 babies exposed to valproate in the womb showed that these babies were slightly lighter on average at birth (although their birth weights were still in the normal range) than babies not exposed to valproate. More research is required to confirm that taking sodium valproate in pregnancy does not increase the risk of low birth weight in the baby.

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

Withdrawal symptoms are thought to occur when a newborn baby’s body has to adapt to no longer getting certain types of medicines through the placenta.

Sodium valproate works in a similar way to other medicines that are known to cause neonatal withdrawal. There are reports of babies who were exposed to sodium valproate in the womb suffering from 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?

Most women will be offered a scan at around 20 weeks of pregnancy to look for birth defects as part of their routine antenatal care. Women who have taken sodium valproate during the first trimester should be offered more detailed anomaly scans from as early as around 12 weeks of pregnancy. It is, however, harder to see birth defects at this stage of pregnancy, which is why the main scan for birth defects is generally offered at around 20 weeks of pregnancy. It is important to understand that scans are not able to pick up all birth defects and cannot predict whether a baby will have problems with learning and behaviour. In general, women with epilepsy may be more closely monitored during pregnancy to ensure that they remain well throughout and that their baby is growing and developing as expected. 

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?

We would not expect any increased risk to your baby if the father took sodium valproate before or around the time you became pregnant.

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 paediatrician who will assess your child’s development and health, and will, if necessary, rule out other illnesses that may cause problems with development, some of which can be treated.

Spelling errors (mutations) in a person’s genetic code (DNA) can also cause similar problems to those seen in children with FVS. It is likely that your GP or paediatrician will therefore also suggest that your child is reviewed by a clinical geneticist, a type of doctor who specialises in assessing children for genetic conditions as well conditions caused by medicines such as valproate.

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.

General information 

Up to 1 out of every 5 pregnancies ends in a miscarriage, and 1 in 40 babies are born with a birth defect. These are referred to as the background population risks.  They describe the chance of these events happening for any pregnancy before taking factors such as the mother’s health during pregnancy, her lifestyle, medicines she takes and the genetic make up of her and the baby’s father into account.

Medicines use in pregnancy

Most medicines used by the mother will cross the placenta and reach the baby. Sometimes this may have beneficial effects for the baby.  There are, however, some medicines that can harm a baby’s normal development.  How a medicine affects a baby may depend on the stage of pregnancy when the medicine is taken. If you are on regular medication you should discuss these effects with your doctor/health care team before becoming pregnant.

If a new medicine is suggested for you during pregnancy, please ensure the doctor or health care professional treating you is aware of your pregnancy.

When deciding whether or not to use a medicine in pregnancy you need to weigh up how the medicine might improve your and/or your unborn baby’s health against any possible problems that the drug may cause. Our bumps leaflets are written to provide you with a summary of what is known about use of a specific medicine in pregnancy so that you can decide together with your health care provider what is best for you and your baby.   

Every pregnancy is unique. The decision to start, stop, continue or change a prescribed medicine before or during pregnancy should be made in consultation with your health care provider. It is very helpful if you can record all your medication taken in pregnancy in your hand held maternity records.

   

www.medicinesinpregnancy.org

Disclaimer: This information is not intended to replace the individual care and advice of your health care provider. New information is continually becoming available. Whilst every effort will be made to ensure that this information is accurate and up to date at the time of publication, we cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes following decisions made on the basis of this information. We strongly advise that printouts should NOT be kept for any length of time, or for “future reference” as they can rapidly become out of date.

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