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High dose of epilepsy drugs linked to birth defects

Adrian O'Dowd

Monday, 6 June 2011

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Doctors can minimise the risks of taking epilepsy drugs by women who are considering pregnancy, claims a major international study published today in The Lancet Neurology.

An 11-year study gathering results from 33 countries has shown that taking four of the most commonly prescribed seizure-control drugs at the beginning of pregnancy is associated with a dose-dependent increased risk of major birth defects.

The findings claim to be the first to provide a multivariable analysis of the risks associated with individual drugs and their doses, so will help doctors identify the safest effective treatment for women with epilepsy who wish to become pregnant.

Between 0.3% and 0.7% of all pregnancies are in women with epilepsy and most of these women need to use antiepileptic drugs during pregnancy because uncontrolled seizures can harm the mother and fetus.

Previous research has suggested epilepsy drugs (particularly valproic acid) can increase the risk of birth defects, but until now, studies have not adequately compared the risks associated with different doses or assessed the influence of potential confounders such as a family history of birth defects or severity of epilepsy.

Researchers led by the Karolinska Institute in Sweden and the University of Pavia in Italy investigated the association between the use of carbamazepine, lamotrigine, valproic acid (valproate), and phenobarbital at different doses and the risk of major birth defects detected up to the end of the first year after birth.

They studied 3,909 pregnant women using data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP).

A total of 230 pregnancies associated with major birth defects were identified by the end of the first year after birth such as heart defects and spina bifida.

Analysis showed there was a growing rate of birth defects associated with increasing dose for all drugs.

The rate was lowest for low doses of the drugs lamotrigine (less than 300 mg per day) and carbamazepine (less than 400 mg per day).

The highest doses of valproic acid (1,500 mg per day or greater) and phenobarbital (150 mg per day or day or greater) posed the highest risk to the fetus, with particularly high rates of birth defects recorded in pregnancies exposed to valproic acid 1,500 mg per day or greater.

The authors said: “Our results show that dose selection is as crucial as the choice of drug…[and] gives the prescriber the possibility of assessing how teratogenic [ability to cause birth defects] risks at that dose compare with the risk associated with alternative treatments at various doses.”

They added a caution over the results, saying: “It should be emphasised, however, that, irrespective of which of the four investigated drugs was prescribed, the vast majority of women gave birth to perfectly healthy children.”

In an accompanying comment, Professor W Allen Hauser from Columbia University, New York, USA said: “The findings are important to the clinician treating people with epilepsy because they provide specific information not only on the drug but also on the dose.

“The data provide another reason for use of the lowest dose of a drug associated with optimum seizure control.”

DOI:10.1016/S1474-4422(11)70107-7
DOI:10.1016/S1474-4422(11)70129-6

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