Antiepileptic drugs and birth defects

“Epilepsy drug link to birth defects found” is the headline in The Guardian . Research into the drug topiramate, which is also used for people with migraines, has shown an increased risk of birth defects if the drug is taken during pregnancy. Babies were “more likely to have cleft palates, cleft lips and genital abnormalities”, the newspaper says.

It is well known that a number of antiepileptic drugs, including topiramate, carry a risk of harming the developing foetus. Women who are currently prescribed these drugs are advised of the risk and about the need to take adequate contraception. Women who take antiepileptics and are considering starting a family should always inform their doctor of their wish to become pregnant so that they can receive specialist care and advice. If they become pregnant while taking the drugs, they should receive appropriate care, counselling and screening for birth defects.

Where did the story come from?

Dr Stephen Hunt of the Department of Neurology, Royal Group of Hospitals, Belfast, and colleagues, carried out this research. The study was funded by the Epilepsy Research Foundation and by using a number of educational grants from pharmaceutical companies. It was published in the peer-reviewed medical journal: Neurology .

What kind of scientific study was this?

This was an observational study in which the researchers report on the safety of topiramate use during pregnancy. Topiramate is used to treat epilepsy, either alone or in combination with other treatments. More recently, it has also been licensed for the treatment of migraine. Unlike other more established antiepileptic drugs, the exact risk to the developing foetus from exposure to topiramate is unknown, although it has been shown to harm the developing foetuses of animals.

This study looked at 203 pregnant women who were exposed to topiramate during the first 12 weeks of pregnancy (the time period when foetal development is most at risk). Seventy women used topiramate only, and the rest were exposed to topiramate plus at least one other antiepileptic drug during pregnancy. The researchers obtained data using the UK Epilepsy and Pregnancy Register (originally set up to monitor the safety of antiepileptic drugs taken in pregnancy) up until August 2007. In order to be included, the women had to have been referred to the trial before the outcome of their pregnancy was known. The researchers excluded cases in which an abnormality was detected during antenatal screening, or when the foetus had been lost through abortion or miscarriage.

The researchers collected outcome data three months after the expected date of delivery by sending a questionnaire to the mother’s GP. The main outcome that they looked at was any major congenital malformation (MCM), defined as “an abnormality of an essential embryonic structure requiring significant treatment, and present at birth or discovered during the first six weeks of life”. They looked at the rate of MCM across the total pregnancies.

What were the results of the study?

Of the 203 topiramate-exposed pregnancies, 87.7% (178) resulted in a live birth, of which 17.4% (31) had some form of birth defect. Sixteen (9% of the total) of these were major congenital malformations (MCMs); three from exposure to topiramate on its own, and 13 from exposure to topiramate taken in combination with other antiepileptic medication.

The MCMs that were found among the studied pregnancies included cleft lip and palate, hypospadius (abnormal position of the urethral opening on the underside of the penis), hernia, pyloric stenosis (narrowing of the lower part of the stomach causing projectile vomiting), tracheoesophageal fistula (abnormal connection between the trachea and oesophagus), anal atresia (absent opening of the lower end of the intestinal tract), hydronephrosis (swelling and stretching of the kidney due to obstructed urinary flow), and dislocated hips.

For the three cases using topiramate only (two cases cleft lip and palate; one hypospadius), the average dose was 400mg. In the 13 other MCM cases (topiramate in combination with other drugs), the average dose was 238mg. Comparing these figures with known rates of MCM in the general population, the risks for cleft lip and palate were 11 times higher, and for hypospadius, 14 times higher.

What interpretations did the researchers draw from these results?

The rate of major congenital malformations in pregnancies exposed to topiramate is within the range seen with other antiepileptic drugs. The rate of malformation was greater when there was additional exposure to another antiepileptic drug.

What does the NHS Knowledge Service make of this study?

This preliminary research has followed a small number of cases exposed to topiramate during pregnancy. The findings are unsurprising and reflect what is already well-known to the medical profession – that a number of antiepileptic drugs carry a risk of harming the developing foetus. Obtaining data on outcomes from a larger number of pregnancies could provide a better quantification of the risk from topiramate alone or in combination with other drugs. As the researchers note, they did not have information on the weight of the mothers, and this could have a possible interaction with the drug and the outcome. Additionally, all of the women in this study had epilepsy, and it is important that information is collected on the pregnancy outcomes of women who take topiramate for migraine, as there may be a difference between these patient groups.

Women who are currently prescribed antiepileptics are advised of the risk and the need to take adequate contraception. Women who take antiepileptics and are considering starting a family should always inform their doctor of their wish to become pregnant so that they can receive specialist care and advice. If they become pregnant while taking the drugs they should receive appropriate care, counselling and screening for birth defects.