Epilepsy drugs 'raise birth defect risk'

A study has found that pregnant women with epilepsy who take high doses of drugs to control seizures are particularly at risk of having a baby with birth defects, reported The Daily Telegraph.

The study behind this news report analysed almost 4,000 pregnancies that were exposed to four common antiepileptic drugs: carbamazepine, lamotrigine, valproic acid or phenobarbital. The researchers looked at the rate of birth defects in pregnancies exposed to different doses of epilepsy drugs. They found that, overall, major problems were identified in only 6% of the babies by one year of age. The risk increased with higher doses of the drugs, and certain drugs were associated with greater risk than others.

Antiepileptic drugs are already known to be linked to a greater risk of birth defects. However, pregnant women with epilepsy usually need to continue taking these drugs as having a seizure in pregnancy could have serious consequences for mother and baby. Women who are taking antiepileptic medication and who are thinking of having children should discuss this with their doctor. This report and similar studies will help doctors and their patients make fully informed decisions about how to minimise risks to mother and baby. See the Pregnancy care planner for more information on epilepsy and pregnancy.

Where did the story come from?

The study was carried out by researchers from the Karolinska Institutet in Sweden and other research centres in Europe and Australia. The study received support from Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, Stockholm County Council and ALF. The journal paper states that the sponsors had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

The study was published in the peer-reviewed medical journal The Lancet Neurology.

What kind of research was this?

This prospective cohort study, called the EURAP study, looked at how different epilepsy drugs taken at different doses affected the risk of pregnant women having babies with birth defects.

There has been a suspicion since the 1960s that antiepileptic drugs are associated with an increased risk of birth defects, and since then there has been growing evidence to support this. However, stopping taking the drugs is also associated with risks, as a seizure could harm the mother and baby.

Several studies in the past 10 years have looked at the risks associated with the different drugs. A recent systematic review that compared the effects of the drugs concluded that “it is highly probable” that exposure to valproic acid early in pregnancy leads to “a higher risk of major congenital malformations compared with carbamazepine, and possibly compared with phenytoin or lamotrigine”.

However, the researchers say that many of the studies did not include sufficient numbers of women to be able to find differences between those taking different doses of individual drugs. This study aimed to do this by looking at a large amount of data collected from 42 countries.

As these drugs are known to present a risk to unborn babies, it would not have been ethical to randomly assign pregnant women with epilepsy to take different anti-epileptic drugs or doses. In situations such as this, researchers need to rely on observational studies, like this one, to investigate the risk. They need to take into account factors other than antiepileptic drug use that could potentially affect the risk of birth defects.

What did the research involve?

The researchers collected data over 11 years on pregnant women taking four commonly used antiepileptic drugs: carbamazepine, lamotrigine, valproic acid and phenobarbital. These women were followed up to determine the outcome of their pregnancy. The researchers then compared the risk of birth defects in pregnancies exposed to different doses of these four drugs.

The participants included women from 42 countries. To be eligible, the women had to have been receiving treatment with antiepileptic drugs at the time they conceived, and had to have been enrolled before the 16th week of their pregnancy and before the health of the foetus was known. Eligible women were identified by their doctors, who entered information into an online registry about the women’s medical and family history, smoking, alcohol use and drug treatment. The doctors then collected data on the women once during each trimester, at the time of birth, and 12 months after the birth.

Pregnancies were excluded if they resulted in miscarriage or chromosomal or genetic abnormalities, if the women did not have epilepsy or changed their epilepsy medication in the first trimester, if the women were taking more than one epilepsy drug or if they had diseases or were taking other treatments that could affect the outcome of their pregnancy.

Of the 14,461 pregnancies registered by June 9 2010, 4,540 were found to be eligible, and 3,909 pregnancies in 3,521 women were exposed to the four commonly used antiepileptic drugs being assessed. This included data on 1,402 pregnancies exposed to carbamazepine, 1,280 to lamotrigine, 1,010 to valproic acid, and 217 to phenobarbital. The doses received were divided into:

carbamazepine: less than 400mg daily, 400mg to under 1,000mg daily, or 1,000mg or more daily
lamotrigine: less than 300mg daily, or 300mg or more daily
phenobarbital: less than 150mg daily, or 150mg or more daily
valproic acid: less than 700mg daily, 700mg to under 1,500mg daily, or 1,500mg or more daily

The researchers were mainly interested in the prevalence of major congenital malformations detected by 12 months after birth. This included malformations detected before birth that led to elective termination or stillbirth. In their analyses, the researchers took into account 10 factors that could affect the risk of birth defects, including family history of congenital malformations, occurrence of seizure during pregnancy, type of epilepsy and maternal age.

What were the basic results?

Of the 3,909 pregnancies that were analysed, 67% (2,625) were seizure-free throughout pregnancy. Of those analysed, 6% were affected by major congenital malformations. Women with a family history of major congenital malformations had four times the odds of having a major congenital malformation identified in their children.

The researchers found that taking higher doses of any of the four drugs at the time of conception was associated with an increased risk of malformation in the foetus compared to taking a lower dose.

The lowest rates of malformation at up to one year were in women taking less than 300mg of lamotrigine daily (2% [17 events], 95% confidence interval [CI] 1.19% to 3.24%) or less than 400mg of carbamazepine daily (3.4% [5 events], 95% CI 1.11% to 7.71%). The highest rates were seen in women taking 1,500mg or more of valproic acid daily (24.2% [24 events], 95% CI 16.19% to 33.89%), and 150mg or more of phenobarbital daily (13.7% [7 events], 95% CI 5.70% to 26.26%).

Valproic acid and phenobarbital at any of the doses assessed were associated with an increased risk of malformation compared to lamotrigine alone at doses less than 300mg daily. Carbamazepine at doses higher than 400mg daily was also associated with an increased risk of malformation compared to lamotrigine alone at doses less than 300mg daily.

How did the researchers interpret the results?

The researchers concluded that “the risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables”. They say that their findings should be taken into account when deciding how to treat epilepsy in women of childbearing age.

Conclusion

This large multinational study adds to what is known about the risks associated with different antiepileptic drugs, and how this risk varies with different doses. There are some points to note:

This study cannot tell us how these figures would compare to the rate of congenital malformations in pregnant women with epilepsy who are not taking these drugs. However, such a control group is unlikely to be readily available.
The women were categorised according to the dosage of drugs they were taking at conception. However, it is possible that women changed their doses in pregnancy, which might have affected the results.
The identification of any major congenital malformations relied on the participating doctors who submitted data on their patients’ outcomes and the outcomes of the babies. There may have been some inaccuracies or inconsistencies in how these were reported or classified. Doctors were asked to report anything they thought abnormal to minimise the chance that any malformations were missed.
As with all studies of this type, there may have been differences between the groups, other than their antiepileptic use, which could have influenced the results. The researchers took into account several potential confounding factors to reduce this risk, but there may have been others.
The study included women from many different countries. The way in which these drugs are prescribed, how women are managed in pregnancy and background rates of congenital malformations may differ between these countries. This could have potentially influenced the results. However, the researchers suggest that this factor may improve the ability to apply these findings in different countries.

Antiepileptic drugs are already known to be associated with a greater risk of birth defects. However, pregnant women with epilepsy usually need to continue taking these drugs as having a seizure in pregnancy could have serious consequences for the mother and baby.

Women who are taking antiepileptic medication and who are thinking about having children should discuss this with their doctor. This report and similar studies will help doctors and their patients make fully informed decisions about how to minimise risks for mothers and their babies. See the Pregnancy care planner for more information on Epilepsy and pregnancy.