Pauline Anderson

December 09, 2016

HOUSTON — Patterns of antiepileptic drug (AED) prescriptions for patients during pregnancy have changed dramatically over the past 15 years, at least at tertiary centers in the United States, new research shows.

At the turn of the last century, the four most popular monotherapy AEDs for this patient population were carbamazepine, lamotrigine, phenytoin, and valproate.

Today, the two most common monotherapy AEDs in pregnancy "by far" are lamotrigine (41.9%) and levetiracetam (37.7%), Kimford Meador, MD, professor of neurology and neurological sciences, Stanford Comprehensive Epilepsy Center, Palo Alto, California, told Medscape Medical News.

There's a "fair amount" of polypharmacy when it comes to AED use among pregnant women, with almost half of this involving lamotrigine and levetiracetam, he said.

"So if you put all this together, you see the vast majority of women are getting treated with those two drugs, either alone or in combination," he said.

Their results were presented in separate presentations here at the American Epilepsy Society (AES) 2016 Annual Meeting.

Best Safety

The reason these two drugs are so popular in this patient population "is that we have the best safety data for them in pregnancy."

For example, he said, they have "low malformation rates, and we have good data showing that children have good cognitive and behavioral outcomes with those two drugs."

The new information on prescribing trends comes from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

Other than the two main drugs, there were fewer than 20 women in each of the other nine drug groups. "Carbamazepine and phenytoin and valproate are markedly reduced," said Dr Meador. "I think we had one mother on valproate and she was on polytherapy."

Enrollment for the MONEAD study began in late 2012 and was completed about 5 or 6 months ago. The study incudes pregnant women with epilepsy at 20 centers in the United States.

The study includes a total of 565 women. In addition to the 351 pregnant women with epilepsy, it also includes 2 "fairly well-matched" control groups: 105 pregnant women without epilepsy and 109 nonpregnant women with epilepsy.

About two thirds (73%) of the women with epilepsy in the study were receiving monotherapy. And about two thirds of these had focal epilepsy; the rest had generalized seizures or seizures that were "unclassified," that is, the women had convulsions but it was unclear whether they were focal or primary generalized, said Dr Meador.

Although quite a lot of evidence is now available about the maternal and offspring risks in lamotrigine and levetiracetam, much less is known about other AEDs in pregnancy, said Dr Meador.

That's aside from valproate, which is now well down on the list of prescribed drugs during pregnancy because of its known adverse outcomes; it's been linked to malformations and cognitive deficits in offspring. American Academy of Neurology/American Epilepsy Society guidelines for treatment of epilepsy during pregnancy released in 2009 already recommend against use of valproate.

A similar conclusion was reached by Dr Meador and colleagues in a study reported that year in The New England Journal of Medicine.

Also down on that list is lacosamide, but not because of known risks. "People have shied away from it because it's new, and we don't have data about malformations and cognitive outcomes yet," said Dr Meador.

He also noted that carbamazepine use has fallen over the years (to 5.4% according to the new data). "This is ironic because this is rather a good drug in terms of the child's cognitive performance and in terms of malformations," he said.

Push the Envelope

Experts need to know more about drug combinations during pregnancy, said Dr Meador. "We're trying to push the envelope and figure out what the risks of various combinations of drugs are."

The MONEAD study is breaking ground in that it's also gathering blood levels of the various drugs during pregnancy, said Dr Meador. "This is important because some drugs change their clearance dramatically during pregnancy.

Dr Meador cautioned that these prescribing trends pertain to tertiary care centers and that the trends may not be the same elsewhere.

He noted that a paper he and his colleagues published a few years ago showed that in a Florida Medicaid population, valproate prescriptions had dropped for the pregnant epilepsy population but had actually increased slightly among pregnant women with a psychiatric indication.

Dr Meador and his team aim to follow the children in the study out to 6 years to assess them cognitively and behaviorally.

The MONEAD study is also looking at maternal outcomes, such as seizures, depression, and cesarean deliveries. According to Dr Meador, evidence indicates that the cesarean delivery rate in pregnant women with epilepsy is relatively high, but it's not clear why.

Responding to a query from a delegate about the admonition not to breastfeed while taking the AED zonisamide, Dr Meador said he views such recommendations as "poppycock" without evidence to back it up.

He stressed that breastfeeding is good for both the mother and the child. "Give me some evidence that this drug is causing harm; otherwise I think you're actively denying the positive effects of breastfeeding."

Another delegate said he would like to get more information on the use of new drugs such as lacosamide in pregnancy. Dr Meador noted that it's difficult to study a drug if it's not being used.

The study was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health and Human Development.

American Epilepsy Society (AES) 2016 Annual Meeting. Poster 1.211, Platform Session C.03. Presented December 3 and 5, 2016.

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