Transcript (Part 2)

The following is the unedited transcript (Part 2 of 3) of the Tuesday, December 7, 2004, Pregnancy and AEDs briefing, "Birth Defects and Anticonvulsant Drugs: Emerging Data Points to Differing Levels of Risk."
Posted: December 7, 2004

Dr. Morrell: Thank you. I want to tell you why this is so important. There are so many women who are taking antiepileptic drugs during their reproductive years, and this is not like an antibiotic, it's not something that's taken for a couple of weeks and then stopped.

Women with epilepsy and bipolar disorder have very serious conditions that require years or even a lifetime of treatment. So for these women, it is not an option to stop the medication. Now for the 18 years I have been caring for women with epilepsy, I have been in the same situation as my colleagues. The question is is it safe for me to take this during pregnancy? Will I hurt my baby?

And the answer that we've had is, well, we don't exactly know. And so much of our decision making has been based on poor data, our own experience, and this has really been uncomfortable for us, and more importantly, for our patients.

This is the first time that we have had real information to give our patients, and the information that we have thus far on Valproate, which is also known as divalproex sodium or valproic acid, is extremely concerning.

Let me say that Valproate is an excellent drug for treatment of many types of epilepsy, and it also has an indication as a treatment for headache and a treatment for bipolar disorder, all conditions which are very prevalent in women of reproductive age.

There are many women receiving this medication. For some of them it is appropriate. It is the only medication that will control their health condition. But in other cases there are options, and unless we make this information available, women who are already on this medication or who are considering starting this medication, will not know about those alternatives.

The other problem that we face is that the woman receiving an antiepileptic drug is often cared for by physicians who are not familiar with this information. They may be receiving their care from an obstetrician-gynecologist or from a primary care provider who doesn't have the opportunity to attend these meetings and to be aware of this breaking data.

We believe that means that the woman is in the best position to be her own advocate.

She is the one who is motivated to keep on top of this information and to make certain that all her health care providers are informed.

This is the role that you can play, and that is to educate the general public about these concerns.

This information will be of interest not only to the woman who is taking this medication but to her husband, her mother, her sister and her friends.

And so this network, once it's formed, will ensure that women go to their health care providers and say, Am I on the right medication? Are there choices I can consider? How can I further this public health agenda by making sure that I enroll in registries and that I support this public health effort?

And I think that pretty much covers my editorializing and statement that this is a very important issue and one that's only going to become more relevant as use of these medications continues to expand.

Dr. Barkley [?]: Just to give you some idea of numbers with women, we're talking about, there are estimated about 2-2.5 million people in the United States with epilepsy. The prevalence of bipolar disorder is about twice as common, so that's about 5 million people in the United States, and for migraine, the numbers of women, women with migraines, perhaps 15 percent, or maybe up to 20 percent of women have migraine between menarche and menopause.

So we're talking about large numbers of people in this country that may be appropriately prescribed these drugs. These are all indicated uses of these medications. So it's not off-labeled prescribing that we're talking about.

I think at this point we can open up the microphone to questions. Sally, do we want people to come to the microphone?

Ms. [?]: Yes.

Dr. Barkley: If you're in the room, come to the microphone so that the people on the phone can hear the question. Please.

Question: We keep hearing about the worst drugs that you possibly take, with Valproate, phenobarbital, carbamazepine. Well, what, based on the pregnancy registries—what drugs are the good drugs, in your opinion?

Dr. Barkley: The way the pregnancy registry works, we have a scientific advisory committee that answers your question, and I don't, sitting at a microphone today I cant do that. We know that we need 550 women enrolled on a drug, a single drug, to rule out a doubling of the frequency of major malformation. So it was easy to find 77 women taking phenobarbital or 149 taking Valproate, which lead to the release of those drugs.

It's taking us longer to get the sample size of the safer drugs up to the point where our committee, which meets tonight, could say, okay, ,let's release the data on drug X, drug Y, drug Z. So we think there's several, and I'm not a neurologist, but these folks that are would say "seem to be safer," and I would defer to them on what they've put in the list.

Everybody that is a neurologist knows the drugs that are commonly used and those women are enrolling on a registry, and what we're hoping is that with more women enrolling faster, we'll get to the point where we can start releasing the data on the safer drugs.

Dr. Morrell.

Dr. Morrell: The North American registry is—

[Audio goes out momentarily.]

Moderator: —those participants on the phone, if you'd like to ask a question, please press star one.

Dr. Morrell: —also rigorous, and information from those registries were released at this meeting, and they include the United Kingdom registry, the Australia registry, and the GlaxoSmithKline-sponsored registry for lamotrigine.

At this point it's very reassuring that the data is quite consistent and it appears that lamotrigine, across all the registries, is a medication that does not increase the risk of major malformation above that of the medically normal population, recognizing that somewhere around 3 percent of women will have a child with a major malformation.

The number reported for women receiving lamotrigine is not different. We will continue to gather information on this but I think that the fact that the numbers from all these registries are the same is very compelling and reassuring.

Dr. Barkley: We don't know with some of these other drugs, just because they may not be used as much, and the enrollment has not been as great, whether they are going to fall into that same risk factor as lamotrigine, or that they may be more like phenobarbital or Valproate.

So this is all the—what we can say is that we have some things that we do know and we have a lot of questions we still have not answered, which is why we hope that in your articles, that you encourage people to register.

And then we're just talking about monotherapy. These drugs are also used in combination and there may be particular combinations which are ones that definitely should be avoided, and there may be combinations that are not riskier than either drug—the drug by itself. We don't have any information on that either yet.

A question from the phone?

Moderator: From Sal Boyles [?] with WebMD. Please go ahead.

Question: Thank you. So is it too strong to say the message you're trying to get out is that Valproate should not be used as a first-line drug in women of child-bearing years, with any of these conditions?

Dr. Barkley: Dr. Meador, would you—

Dr. Meador: That's my opinion, yes. Now there's not class one evidence in the sense of a randomized clinical trial. We're never going to have that for this particular type of a patient population. But what is the probability that seven different studies of seven different populations, with seven different methodologies and seven different—not seven different outcomes but somewhat different outcomes across those studies, one drug comes out worse? And already, in England, the NICE [?] council [?] has made this recommendation and in my opinion this should be the approach.

That doesn't mean it shouldn't be used, it should not be used as first-line drug, consideration of other drugs. Women that are presently on the drug should certainly not just suddenly stop the drug and not necessarily should be taken off the drug, they should talk to their physician about this to make a decision as to what would be best for them.

Dr. Barkley: Right. Remember that valproic acid is a drug that is effective for some of the most-difficult-to-treat epilepsies, and so while it may not necessarily be the drug for first-line epilepsy, there may be individual patients in which this is the best drug because it's either taking valproic acid or having intractable seizures, or taking valproic acid and having bipolar disorder become uncontrolled, then you may wish to do that and take appropriate contraceptive medications, or try and avoid pregnancy in other ways.

Question: Can I follow up?

Dr. Barkley: Sure.

Question: Do we have any sense of how many women out there are taking this drug as a first-line therapy, when they could be taking something else?

Dr. Barkley: Well, I don't have that answer and I don't know if any of the other panelists do. It's very hard for physicians to know that information, in particular.

We do know that, for valproic acid, that the majority of its use is for reasons other than epilepsy, primarily for bipolar and other kinds of mood disorders and for treatment of headaches.

So we can say that with confidence, that most of its use is not for epilepsy.

Dr. Morrell: I think it's fair to say that for every condition for which valproic acid or Valproate is used, that there are other agents, and for bipolar disorder there are several other antiepileptic drugs that have indications for treatment, and certainly with epilepsy and with migraines.

And so it is, I think it is reasonable and it is recommended that any woman taking Valproate talk to her physician about whether it is appropriate to continue.

DOCTOR: I'd comment on that too. In our study in epilepsy centers in the U.S. and England, Valproate is the third-most commonly used drug in women with epilepsy.

Dr. Barkley: Can I ask the WebMD caller a question?

Question: Yes.

Dr. Barkley: One of our frustrations is that naturally your questions are focusing on bad news about Valproate and I can understand that, but we'd love it if you have a stringer, a line of, a couple a lines in any article you write that tells about the AD pregnancy registry and puts in the toll-free number, because women are going to read that and that's what's missing. We're not getting—

Question: And help me understand why the registry is so important.

Dr. [?]: It is the way to get data on all the drugs taken by women in North America who are taking them for either epilepsy or other reasons and we're compiling data on all the drugs, to now only show that there's concern about Valproate, we're just publishing that in the journal called Neurology, but we're also trying to get information on the alternative drugs to provide the women and their doctors information on their presumed better safety.

Dr. [?]: The reason why these registries are important is because the women register before they've had their child, so that the danger of looking at all children with birth defects is that will naturally look to the ones that had birth defects and miss some of the normal children, so it makes the numbers skewed in a way, that by collecting the information before the child is born, we now have a prospective study and we're carrying forward from a baseline where we presume every child is going to be normal.

That gives us a much more solid scientific basis to the results by doing it this, in this fashion, and that's why these registries are so vitally important. We cannot do any kind of prospective study of women, say take this drug, get pregnant, see what happens. That would be unethical; it will never happen.

So while we have information that has been obtained from animal studies on all these medications, there are differences between species, and the only way we can know what the human situation is, to gather data prospectively and see what happens. Anti-convulsive drugs, when they're under development, just like any other drug, are not given to women who might become pregnant because we don't even know if the drugs work at that point.

So the only way to follow drugs and their effects is after they've been approved for use, where they've been shown to be a safe drug for human use, and effective for the conditions they are being used for.

The other issue I want to point out is that we've talked about bipolar disorder. We can't say any—we don't know Valproate acid risk to women with bipolar disorder may be worse, or higher or lower than some of the other drugs that are used to treat bipolar disorder. So one has to take some caution in interpreting and expanding the results to say that you shouldn't use valproic acid in bipolar disorder because of the pregnancy risk, when it may be that some of the other alternatives may be even worse.

Question: I just wanted to follow up on something Dr. Holmes said. You said—you keep talking about the 800 number. Do you attribute people not calling in because the number's not getting out, or do you think it's something, what Dr. Barkley talked about in terms of wondering about privacy?

Dr. Holmes: There are two issues. Actually, it's an 888 number, (888) 233-2334. We think it's not getting out, is the number one concern, and we've had little snippets of information in the past where we had it included in an article in Glamour Magazine several years ago, and that one little line that mentioned it in two or three sentences with the 888 number led to 25 women calling and enrolling, which makes us think that getting it out would increase enrollment.

But the larger issue is women are afraid, and we of course have no way to know why a woman won't pick up the phone, but among the women who do, they often express concern about will the data I give you—and she's giving us information about her health and her child's health—will an insurance company get that information and use it against me or my baby? And we try as best we can to assure her that the data on her is entered into a computer with a study number. There's no way anybody could get into our computer and find her.

But I think you've got sort of a free-floating anxiety out there that insurance companies can't be trusted, and it will be held against her. And so we're competing against that, and we don't have a chance to talk to her. You know, obviously, if she called we have a chance to engage her and reassure her, but we assume there are a lot of women who just simply don't pick up the phone because of these fears, and the only way we have a chance to reach her and speak to that concern is obviously through folks writing articles that she would read.

Dr. [?]: Along those lines, these are no-risk studies in regards to the women. We're not randomizing them to a drug. We're doing nothing really invasive to these women at all.

And along the lines of the risk for the disclosure of the information, the new government standards under the HIPAA regulation would really strictly control the flow of this data, and it would be extremely unlikely that any of this data is going to be breached in any way. It would be a violation of federal law.

Continue to Part 3.