Transcript (Part 1)

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

Dr. Barkley: [In progress] — professor of neurology at Wayne State University. I am the Chair of the Professional Advisory Board of the Epilepsy Foundation and serve on the board of directors for the foundation. I'm also a member of the board of directors of the American Epilepsy Society and Chair of the Practice Committee.

I want to welcome you here today on behalf of Eric Hargis, president and CEO of the Epilepsy Foundation, and Suzanne Berry, who's the executive director of the American Epilepsy Society. The two organizations are working together to bring you this press conference on epilepsy/pregnancy registries and anticonvulsant drug effects on children born to women taking these drugs.

I also want to acknowledge the educational support in terms of a grant from the GlaxoSmithKline corporation to the Epilepsy Foundation to underwrite educational programs and help defray the costs of this press conference and to UCB Pharma for its support of the American Epilepsy Society's press room and press services during this conference.

The goal of this briefing is to provide public health service to women of child-bearing age who are taking anticonvulsant drugs, sometimes called antiepileptic or antiepilepsy drugs, and often abbreviated as AEDs. We want to increase awareness in women who take these medications about the possible risks of these drugs in pregnancy, and we hope that the message that comes forth today is—there are several messages. First is that most women who have children while taking these drugs have normal children. And while we're going to talk a lot about risk, I want to make sure that message does not get lost, because women who become pregnant always are fearful that something bad is going to happen to their baby. And we want to note—we want to then dispel some unsubstantiated fears.

On the other hand, we also want to try and give information that might help them have healthier babies, at least increase the odds of that happening.

We also want—while this is the American Epilepsy Society and the Epilepsy Foundation, we know that a large number of these women who take—a large number of women who take these medications do not have epilepsy. They're taking these drugs because they have headaches or they have mood disorders or they may be taking them for pain control. And so the population that we're speaking to is not just the two and a half million Americans who have epilepsy, which half of them are women, but a much larger slice of the American population.

We estimate that between 10 and 15 million prescriptions were written in the past year to women of child-bearing age for an anticonvulsant drug, so that the risk of this medication extends to a broad portion of the population.

The American Epilepsy Society and the Epilepsy Foundation have been working together for many years to try and increase awareness amongst the general population and the scientific and medical world about issues related to women's health, and this is just one of those many efforts.

What we're going to be talking about today, and particularly with the panelists who represent the North American registry, is some of the efforts that have been going on worldwide. There are five registries that have been established between 1992 and 1999 to provide post-marketing surveillance of the risk of anticonvulsant drugs. And those registries have been working together with the Epilepsy Foundation and the American Epilepsy Society to try and bring this information together in a way that will reach the most people possible. The registries that are working with us cooperatively are the Australian Pregnancy Registry of Women Taking Antiepileptic Drugs; the International Lamotrigine Pregnancy Registry Update; the European Registry of Antiepileptic Drugs, also known by its acronym, EURAP; the North American Antiepileptic Drug Pregnancy Registry, which is represented here; and the U.K. Epilepsy and Pregnancy Group.

One of the other important messages that we want to make sure is driven home is that we don't want women to abruptly stop taking a drug just because of the information that may be talked about today. This is an issue that is important to talk with between a woman and her physician. While there may be risks with any medication, we also recognize for epilepsy in particular that there are risks of having seizures, and those risks can be—including serious injury or even death. So abruptly stopping an anticonvulsant drug can be dangerous.

With that in mind, we would like to then—I think it's appropriate to now turn to our distinguished panel, and we'll introduce each panelist in turn and let them say a few words about the registry or their role in this effort. And then I'll open the floor to questions both from the members out here in the audience and to people calling in.

So first, on the far right, my far right, is Dr. Lewis Holmes, who is known internationally for his work in genetics and teratology. He is Professor of Pediatrics at Harvard Medical School and chief of the Genetics and Teratology Unit at the Pediatric Services at Massachusetts General Hospital in Boston. Dr. Holmes is the director of the North American Antiepileptic Drug Pregnancy Registry.

Dr. Holmes, could you say a few words about your registry, please?

Dr. Holmes: Yes. I'm delighted to have a chance to talk to you because one of our goals is to try to interest the press in this activity as we think more women, when they know about the option of calling a pregnancy registry, would indeed be more likely to do so.

To date, we have enrolled 4,000 women, which is a lot, but this group of 4,000 women is taking 21 different drugs as the single drug they're taking during pregnancy. So while we have at our exhibit here in the exhibit hall, which I urge you to visit, we have material on the two drugs whose findings we've released that are worrisome, phenobarbital and Valproate. Our goal is to try to get more information on a lot of the more recently marketed drugs. It's harder to prove that a drug is safer. Only 77 women taking phenobarbital clearly shows the significant risk from taking that old drug, and with Valproate the data findings on 149 women led to release.

Well, there are lots of more drugs than those, and the woman has to pick up the phone and make the decision in the privacy of her home and call the toll-free number. And we know from talking a lot to women that there's a reluctance to do that. And so our hope is that if we can interest the press in writing articles about a hospital-based registry [inaudible] in Canada or the U.S. can enroll in, that she's going to be doing that.

Right now our referrals come primarily from neurologists and obstetricians, and while we appreciate their help, we think that if you let everybody know who's taking these drugs for whatever reason, they're more likely to call and sign up.

So if you do write something, I hope you will put in the toll-free number because we've had a couple of articles written where that nitty-gritty issue wasn't included, and Kaitlin Riley Smith, who's just come in—she's in the back; she's our marketing person. And I'm sure she will also be willing to help you. Kaitlin, hold up your hand, so everybody will know who she is. Thank you.

Dr. Barkley: And your registry has interpreters for Spanish as well as English.

Dr. Holmes: Yes. A woman who calls is offered a menu of English, Spanish, or French.

Dr. Barkley: What's important to recognize about these registries is that as a physician we can only recommend that the woman call. I have a poster of Dr. Holmes' registry that right's above my head in my office. But if I picked up the phone and dialed and said, here, talk to the registry, that would be coercion. So we can only suggest that women call in. And we'll maybe talk a little bit later about some of the issues we've done to ensure privacy, too.

Next let's have Dr. Kimford Meador speak. He's the Melvin Greer Professor of Neurology at the University of Florida where he serves as the director of both the epilepsy program and the clinical Alzheimer program. His areas of research include (?) -ization, dementia, epilepsy, mechanisms of attention and memory, neglect syndrome, psychoimmunology, pharmacology, and physiology of cognition. Dr. Meador is the lead researcher in neuro-, neuro-, neurodevelopmental effects of antiepileptic drugs study—easy for me to say. Actually, I'm one of the investigators at the [inaudible] site. And, Dr. Meador, would you tell us about the NEADS study and what's involved?

Dr. Meador: The NEADS study is an NIH-funded study. It's a multicenter study with 25 centers. And our goal is quite distinct from Dr. Holmes' North American registry, which is looking at anatomical defects. We're looking at behavioral, cognitive defects, and our study is looking at it in the four most commonly used drugs in monotherapy in epilepsy centers around the United States and England. Our centers are both in the United States and England. And the four drugs are [inaudible], lamotrigine, phenytoin, and Valproate. And the study is designed to follow these children out to six years of age where we can really do detailed cognitive and behavioral testing. But in the process of going through the study, we've been following adverse events, serious adverse events with these children.

At this point, most of our children are under three years of age. They're still quite young at this point. We have not done [inaudible] cognitive testing in most of the children.

The three serious adverse events that we've reported here that we're looking at were did the babies die in utero, fetal death; did the baby have a major malformation that could be related to one of the drugs, the drug they were taking; or did the baby have gross developmental delay after they were born. And in our study, one in four of the children taking Valproate had one of these serious adverse events. It was around 9 to 10 percent for [inaudible] and phenytoin and about 1 percent for lamotrigine.

While our study is not definitive, it certainly raises serious concerns. If you take our study and put it in the context of six other studies, I think you can make a statement. Dr. Holmes' registry shows the difference between Valproate and the general population. The statistics, the confidence intervals do not reach the state where he can make a definitive statistical statement that it's less—that it's different than other drugs. However, it does have the highest rate—Valproate has the highest rate of congenital malformation in his study. The U.K. registry, the highest rate of congenital malformation is Valproate. The Australian registry, the highest rate of congenital malformation is Valproate. Plus there's three studies that looked at cognitive outcomes in children exposed to in utero anticonvulsant drugs during a mother's pregnancy, and they include two from Liverpool, England, University of Liverpool, where they looked at a cohort under six years of ago and a cohort six to 16 years of age. And in both those cohorts, the Valproate group had the poorest cognitive development, and the group that they could do IQ testing [inaudible] point difference.

Finally, a prospective study of a small arm of patients exposed to Valproate in Finland comparing them to a much larger arm that was exposed to [inaudible] showed a statistical difference with Valproate impairing verbal IQ. [inaudible] different studies, different populations, different methodologies, even different outcomes. All seven studies, Valproate is worse, and I think this is enough evidence that I would agree with the statement made in the last year by the medical advisory board in England, the [inaudible] council, that said that Valproate should not be used as first-line drug in women with epilepsy.

Now, that's not to say that Valproate shouldn't be used and women on Valproate should suddenly stop the medicine. As Dr. Barkley mentioned, it's extremely difficult—it's very dangerous, and it's a difficult issue taking care of women with epilepsy because we have two difficult issues, the seizures and the drug effects on the child. The seizures can kill the mother. The risk of death is higher in women with epilepsy, and it's usually due—during pregnancy, and it's usually due to seizures. And, in addition, those seizures could kill the child if the mother dies or even cause miscarriage. In addition, [inaudible] case studies show that those convulsions can impair the child's cognition if the mother has more than [inaudible] convulsions during the pregnancy.

So this is a difficult issue which physicians are grappling with, with some information but not enough information to make good decisions. And that's what's so important here. These initial findings here that we have really suggest that these registries can make a tremendous difference in how we make decisions and advise women about the treatment [inaudible] epilepsy and also, as Dr. Barkley mentioned, for other diseases for which these drugs are used and understand the differential risks and reduce the number of bad outcomes in this regard. But to get there, we need our patients to partner with us. This is not something we can do on our own. We need their help. We need them to call in and register in the North American registry.

Now, while my prospective study has completed enrollment and will be following these children for several more years, we also have a retrospective study. We're still [inaudible] trying to enroll children in from six to 16 who were exposed to anticonvulsive drugs during their mother's pregnancy. And to add additional—we're trying to add additional [inaudible] information. I encourage women with epilepsy to consider enrolling in these two studies here in the United States and in the registries overseas that are available.

Dr. Morrell is the chief medical officer at Neuropace as well as a clinical professor of neurology at Stanford University, and she is the American Academy of Neurology, which is the AAN, liaison to the American Epilepsy Board of Directors.

Dr. Morrell has held leadership positions in the epilepsy section at the American Academy of Neurology, at the Epilepsy Foundation, and also here for the American Epilepsy Society.

Prior to July of this year, Dr. Morrell was the Kaitlin Kinen Doyle [ph] professor of clinical neurology at Columbia University and director of the Columbia Comprehensive Epilepsy Center at New York Presbyterian Medical Center in New York City.

Dr. Morrell has written extensively about issues of women's health, in particular, about epilepsy and pregnancy issues.

Dr. Morrell.

Continue to Part 2.