(Date of issue: May 2015. Version: 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®) is used to treat epilepsy, sometimes in combination with other medicines. Sodium valproate and another form of the same medicine called valproic acid (Depakote®, Convulex®) are also used in the treatment of mania, bipolar disorder, and to prevent migraine.
Is it safe to take sodium valproate in pregnancy?
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.
Sodium valproate should therefore not be used to treat girls or women who have not yet gone through the menopause unless other medicines that are thought to be safer for an unborn baby have been tried but did not work, or cannot be used for another reason.
If you are a female under 50 years of age and you need to decide whether or not to take sodium valproate, it is very important that you and your doctor weigh up how necessary sodium valproate is to your health against the possible risks to you and your baby if you were to become pregnant. These risks are individual and will be affected by factors such as the dose of sodium valproate you need to take, the severity of the medical condition for which you are being treated, and whether or not you are already pregnant.
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.
Your doctor is the best person to help you decide what is right for you and your baby.
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 if I have already taken sodium valproate during pregnancy?
If you are taking sodium valproate it is vital that you inform your doctor that you are pregnant as early in your pregnancy as possible. Your doctor will prescribe high dose folic acid and will refer you to a specialist who is experienced in caring for pregnant women who take medicines such as valproate. It is also very important that you do not suddenly stop taking sodium valproate as this could be dangerous to you, and also to your baby if you are already pregnant. Do not make any change to your medication without first talking to your doctor.
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.
Why has my doctor advised changing to slow release valproate or taking multiple smaller doses in a 24-hour period?
During pregnancy your doctor might recommend that instead of taking your valproate in a single daily dose, you take smaller doses multiple times per day (‘divided doses’), or a slow release form of valproate. This is to try and prevent the levels of valproate in your blood that reach the unborn baby from being very high at any one time. The only study which has looked at whether women who took a single daily dose of valproate were at increased chance of having a baby with birth defects compared to women who took divided doses did not see any difference. However, until more research into this subject is carried out, divided doses or slow release preparations are advised in pregnancy. If you are thinking of changing to multiple doses it is important that you remember to take all your doses. Forgetting to take your pills could put both you and your baby at risk. For some women, tablets that slowly release valproate over the day and therefore only need to be taken once in a 24-hour period may be the best option.
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 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 as 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.