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Drugs, chemicals, radiation & herbal products in pregnancy: Epilepsy drugs not equal in pregnancy

Valproic acid less safe than thought; Motherisk to issue new advisory based on results

By Kylie Taggart

TORONTO – How should physicians counsel women with epilepsy who want to have children?

Studies have shown that women on antiepileptic drugs have about two or three times the risk of having a child with major malformations compared with women without epilepsy.

On the other hand, epilepsy is not a disease that should be left untreated. What, then, is safe?

Three papers in a recent issue of Neurology shed new light on the issue. Two of the papers suggest valproic acid is less safe than previously thought and a Canadian expert said he will be changing the advice he gives to his patients based on the results. The third paper shows lamotrigine may be as safe as no treatment at all.

One of the papers on valproic acid is from the North American Antiepileptic Drug Pregnancy Registry, run out of Boston University school of medicine and Harvard Medical School.

Of 149 women exposed to valproic acid monotherapy in their first trimester, there were 15 pregnancies affected by malformations. Two women terminated the pregnancy (one of which involved twins) and there were 13 live births. All the 15 mothers had taken folic acid prior to their pregnancies, and their dose of valproic acid was not significantly greater than other mothers.

When compared with pregnant women exposed to other antiepileptic drugs in the first trimester, those on valproic acid monotherapy had a four times greater risk of malformations.

The malformations included congenital heart defects, hernias, club foot, spina bifida and hypospadias.

"Until now we told Canadian women that valproic acid was associated with a risk for spina bifida and other neural tube defects, and as a result of this we told women and physicians to test for spina bifida. The gospel was as long as there is no spina bifida the drug is probably OK," said Dr. Gideon Koren, director of the Motherisk program at the Hospital for Sick Children and the University of Toronto and Ivey chair in molecular toxicology at the University of Western Ontario in London. "What these studies show is very clearly that valproic acid causes other malformations, too."

Dr. Koren said Motherisk will respond with a new advisory. "Valproic acid is less safe than we thought," he said.

Dr. Koren noted that valproic acid is also used to treat some psychiatric disorders such as obsessive compulsive disorder.

Lower IQs

A second paper, this one from the Liverpool and Manchester Neurodevelopment Study Group, showed children exposed to valproic acid in utero were more likely to have lower IQs and poor memory compared with children exposed to other antiepileptic drugs.

"For many people this is the most important risk because even malformations can be treated surgically but once a child's cognitive function is lower then there's not very much you can do. And it is something you cannot predict on ultrasounds," said Dr. Eva Andermann, director of the neurogenetics unit at Montreal Neurological Hospital and Institute and professor in the departments of neurology, neurosurgery and human genetics at McGill University.

Cognitive outcome following exposure to antiepileptic drugs is an area of research people are becoming more interested in, Dr. Andermann said.

Her group conducted a large prospective study where they followed pregnant women on a monthly basis, looking at antiepileptic drug levels. The children were then given neuropsychological tests between the ages of six to 16. The results are expected to be published in the next few months, she said.

Lamotrigine monotherapy

In a third study, findings from the International Lamotrigine Pregnancy Registry suggest exposure to lamotrigine monotherapy in the first trimester carries a 2.9% risk of major birth defects, a rate similar to that seen in the general population. This finding was from 414 pregnancies, all of which were registered before the pregnancy outcome was known.

"Lamotrigine is a new drug so although there is a study showing it is relatively safe, the numbers are still small," Dr. Koren said.

"I think anybody who reviews the literature on this should look at the criteria for inclusion in any study," cautioned Dr. Warren Blume, professor of neurology in the department of clinical neurological sciences at London Health Sciences Centre and the University of Western Ontario, when asked to comment by the Medical Post.

He said good studies should have eliminated everyone with low folic acid levels, smokers "or anything else that is nefarious for fetal development."

Inform before pregnant

In general, the best management for women with epilepsy who want to have children is to send them to someone knowledgeable about the effects of drugs on the developing fetus.

"It is very important that you get to see them before they are pregnant. Once they are pregnant, by the time they know they are pregnant, it is already too late to do a lot of the things you can try and do to decrease the risk of malformation in the children," Dr. Andermann said.

If a medication has higher risk of malformations the best course is to take about a year to gradually switch them to another, safer medication such as carbamazepine, Dr. Andermann said.

Studies have shown monotherapy carries fewer risks, and Dr. Blume said most women can have their seizures managed with one drug.

Given enough time, other changes in management can reduce the risk of malformation of future offspring. Dr. Andermann said she tries to switch her patients to a slow-release form of the drug, or to spread a daily dose over several smaller doses throughout the day.

Dr. Blume said he also asks about lifestyle, and tries to help the patients minimize or better deal with stress in their lives.

Drs. Koren, Andermann and Blume all said going off medication was not the best option.

"Theoretically there are some patients who are ready to stay at home not doing too much during the first trimester, but it is fair to say this is not an optimal situation for every woman," Dr. Koren said.

Epilepsy no risk to fetus

The good news is that epilepsy itself is no risk to the developing child, Dr. Koren said.

Also, women with epilepsy do not have a greater risk of other complications during pregnancy and delivery, provided they have appropriate prenatal and postpartum care. Dr. Andermann and colleagues studied 414 women with epilepsy who delivered in a tertiary centre and compared them to more than 81,000 women without epilepsy who delivered at the same centre.

"I think this should be very reassuring for patients and for obstetricians that we found no increase in any complications of pregnancy," she said.

The findings corroborate with what Dr. Blume has seen in practice. "A real difficult worsening of seizures in pregnancy is unusual in my experience," he said.

Dr. Blume said he counsels all women with epilepsy of reproductive age about the risk of birth defects related to antiepileptic drugs.

This is probably wise given many antiepileptic drugs interfere with the effectiveness of oral contraceptives.

For those patients planning pregnancy, providing them with adequate information is key.

"We have to not frighten the woman and her spouse, but give them the information in a way they can understand it and tell them we are willing to follow them and help them make decisions—but they have to make the choices," Dr. Andermann said.

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