INTERVIEW WITH DR. KIMFORD MEADOR – AUGUST 2018 UPDATE – The Truth About Anti-epileptic Drugs And Pregnancy

“It is less the money than the focus of the money and what it is doing. You could throw money and waste it and not be using it well. I have very specific ideas about how that money could be spent.”

Your MONEAD study received continued funding?

We did get funded, so we are moving ahead with the study. We have completed all the pregnancies, now. Later this summer we will have finished the first point of cognitive testing with the kids which is two years of age. We will follow them to age six because it is the best predictor of outcomes.

The study is for four more years?

In terms of following through, yes. So, we have already published what the distribution of the drugs are in this group, which is quite different that it was at the turn of the century. The medicines that are shown to be not as safe are not getting used as much and people are using different kinds of drugs. There is a lot of information on other medications we do not know. This study is the first one that is going to have blood levels in the mothers to better estimate the fetal exposure. That is important because, for several of the drugs, metabolism changes in the mother during pregnancy dropped the levels. We have data we are analyzing now about the blood level changes and about the seizure changes during the pregnancy, risk of depression, OB complications; these kinds of things that we are working on publishing right now. We are continuing to test the children along the way, at the same time, so that we get more outcome data on the children.

Some of these women still are having seizures while pregnant even though they are on medication? They are just harder to control before they had a baby?

Oh, yes. If women are controlled before pregnancy, at least nine months before they get pregnant, they are controlled. They will have about an 85% chance of staying seizure-free. But if they are having seizures before pregnancy then they can have a seizure during pregnancy. Some women do worse during pregnancy. We are trying to figure out if that is because of these blood level changes that occur or other factors like, maybe, sleep deprivation because they are having trouble sleeping during the pregnancy or something like that. So, we are looking at those things and trying to figure out what might cause some women to do worse and some women to do better. There is one small study from Italy that suggests that women have catamenial epilepsy that is epilepsy that tends to cluster around there periods. Those women may actually do better during their pregnancy because they are not having periods. Maybe that is why they do better, but we are looking at that to see if we see that same pattern. We have not gone through those analyses, yet.

So, the study is going along very well and we hope to have a lot of information coming out over the next year in terms of results of the pregnancies themselves. Then we will move on to what is happening with the children after that.

This funding is for four more years, then?

Almost five years. We have to finish the last child and then we have to finish the analyses after the last child. So, it goes a little bit beyond the testing of the last child. The last child will be tested at six years of age. In a little over for years and we will finish up the rest of the year and so all the analyses which take a lot for this phase of the study.

Usually you are publishing along the way. You publish at least once a year, don’t you?

Well, actually, we are not publishing all the way through. You have to collect all the women and follow them out to get to the end of pregnancy. Then you have to make sure that the data is in good shape and then you can analyze it. Like in the NEAD study, most of the publications came after the first five years. So, we are going to have a lot of publications in the next five years. We have some before, but in the first part of the MONEAD we were enrolling people and following along to get to the end point and now we can start to publish. We finished the pregnancies, so we are going through and double checking all the data. We have had some preliminary results in abstract form. We have to make sure it has to be exactly right before we do the final publication. That is what we are doing, now, and we are headed that way in several different things; malformations, fetal deaths, seizures, OB complications, neonatal complications, depression in the mother, all these things we are looking at: also, the blood levels where blood-level changes in the babies during breast feeding. These kinds of things we are working on getting published.

You are collecting information on malformations. I did not know that was part of the study.

It is a minor part of the study. The study is not powered to look at malformations. These big registries are powered for that. We are reporting what we found in terms of malformations and in terms of fetal death just because we want to be open about all the data we have. It will not be definitive like the big registries with large number of women. You need a big number of women exposed to a drug to really understand what its risk are for malformations. It is probably around 400 pregnancies you need.  We do not have that many pregnancies for individual drugs. But our sample size is big enough to look at things like maternal outcomes. It is big enough to look at cognitive outcomes in the kids. We do not need as large a sample and you are better off with a smaller sample. We have all the details of what happened during the pregnancy. There are many things that can affect the baby’s cognition.  So, that is why we went to this format trying to enroll during pregnancy and then following the children of mothers out. We follow out at six years of age because at six years of age you get the best estimate of cognitive performance as it relates to adult performance. It is pretty high related at six years of age. Also, at six years of age that is the time you are starting school, so everything you are doing at that time is going to affect your school performance early on, which probably going to affect your school performance the whole way through. Because if you get behind at the front end, you are going to just kind of stay there. If you are having problems on the front end, they do not usually just suddenly disappear. Even with special education, things like that, that we try to implement early when we find things in our kids, we are referring these children to try and get early interventions. I believe the early interventions help, but they do not solve the entire problem even though they help.

You were talking about the funding. You said it was a standard reduction? Was everybody’s funding getting cut?

They were saying for certain kind of grants that they cut down. The NH funds a variety of different kind of research, some of it they call basic research. This research is largely in animals or cells in that kind of thing, lab-based kind of research. Then they fund clinical research. These are studies like ours in humans.  We are following humans along. Ours is an observational study. We are not randomizing women to certain drugs or anything. We are following along what happened to them when they are on certain drugs and what happened with them in terms of pregnancy outcomes and in their children’s outcomes. So that is a clinical study; clinical studies are much more expensive because they are more complicated. You cannot control it as well as you can in the lab. If we give the drug or do the intervention, these kinds of things. You have to get people to agree to it, you have to have them be willing to be in the study, and you have to have safeguards to make sure you are not doing anything that is bad for them. In our study we are not doing any interventions, so the only thing that could possibly happen is like we release somebody’s name or something. We have all kinds of safeguards not to do that. Some clinical trials, though, are randomized into certain treatments. Of course, they have to be careful but if you are going to get an answer about whether a certain drug works or not, for example, you need a randomization to it to be able to tell if it is better or not. They are more expensive, so the NH wants to stretch its money as far as it can. They give the clinical trials more money for individual trials. I think they may spend more money on basic science, I do not know for sure off the top of my head. But they said that for this type of trial, this type of clinical trial, they were reducing them a certain amount this year. So, that was disappointing. We had a pretty lean budget to begin with. It did not have a lot of fat in it. We will work on it and get as much done as we can. We will get the answers. They will just be a little bit harder without as much money, but we will get there.

How much did they cut it?

Well, they cut it I think it was about 18%. That is a pretty good cut. They asked us on the front end to make a lower budget. Eighteen percent is all relative. If you have a lot of fat in your system and you cut 18%, OK. But if you made it pretty lean and there is not a lot of fat, then you have to figure out what you are going to do and how you are going to do it with that kind of cut. It did not affect us much this year. It will affect us more in the future years. We will figure it out. We are still working on how we are going to deal with that budget cut going down the road, but we will have to do more with less. It was kind of disappointing because the budget for the IH this year was quite good. Probably looking ahead on how they spend their money in the future and they are trying to be good stewards. I do not agree with them in this case, but I understand what they are trying to do. Maybe if we go to them and say that we are really in trouble. But I have not seen the government show up and give me money they had left over anytime recently!

The last time we met, there were some studies that you knew about doing the same thing you are doing, investigating different medications for women with epilepsy and how they affect the children and the mothers during pregnancy, but they were not getting funded.

I think you are referring to my reference to the fact that it would be very helpful to have the basic science investigations that parallel the human investigations. There is a model for prediction of the cognitive deficit that we see, and it comes from a model that was used for alcohol exposure. There was a very pivotal paper around 2000 showing that the alcohol exposure in immature animal brains caused death of the nerve cells, but more importantly, it caused the remaining nerve cells not to work quite right. That is really the problem – the remaining cells. They do not lose that many cells that you could not recover, but the remaining cells do not work right. So, that probably leads to the major deficits in fetal alcohol exposure. They postulate with that paper that because some of the ways it was doing this that maybe some of the seizure medicines would do something similar. Sure enough, when they tested those, it was. Some of the seizure meds do cause the same kind of neuronal death, cell death, and dysfunction.  It is fairly predictive the ones that shown in the animal, are exactly the ones we saw in humans, what is disappointing is that there is not ongoing funding to do that across all the drugs. There are many drugs that have not been tested in this model. It would be very helpful to have that information. It looks like it will be predictive. It needs to be confirmed in humans, but that would be the fasted way to get new information about whether the medicines are at risk for this. Then confirm it in humans and see if it keeps lining up like we see. That kind of research has not funded well. People have tried to put in grants: they just have not gotten funded.  I remember years ago there was somebody doing this research, a Dr. Reese that inspired me, his basic work, inspired me to do the clinical work. He was doing anticonvulsant drugs and then he had trouble getting funded and he switched over to doing drugs of abuse. He was getting well-funded for that! He shifted to that because he could not get funded for the anticonvulsant drugs. It is kind of sad because these are medications women have to take, not that women, necessarily, with addictions are not driven to take the addictive drugs, but the simplest thing there is that they do not get the drugs of abuse. It is not that simple because of the addictive qualities and those factors. But here women do not have a choice, they have to take it when they have really severe epilepsy. They have to take the medication. Yet, we are not pushing that research to understand those drug exposures. This is one of the most common drugs. This can cause birth defects and cognitive problems that are given to women at child-bearing age and it should be a higher priority of research, in my opinion. There should be a higher priority of research, in my opinion, for that basic science to understand the underlying components; that then would allow us to do the human research better and would allow us to take care of the human patients better if we had this information. It may also allow us to understand the underlying mechanisms, understand if there are other ways to prevent it or treat it once it occurs.

If you could wave a magic wand, how much more money, do you think, needs to go into this kind of research?

A lot more!

Come on! How many more million? 25 million? 30 million? 100 million?

It is less the money than the focus of the money and what it is doing. You could throw money and waste it and not be using it well. I have very specific ideas about how that money could be spent. This is one of them (the answer above) looking at this component. Another one would be for us to have the CDC and the government legislate that these have to be reportable conditions. If someone has malformations, we should know. That should be reported, and we should know what drugs they were exposed to during the pregnancy. If we had that in place, then we would have discovered these associations with the bad drugs much before we did. We do not have that in the U.S. We have that for some diseases like TB, but I think these malformations caused by drugs probably pose at least as large a health risk as TB does in the U.S., right now. So, I think they ought to be reportable with systematic screening for the drugs in animals for these kinds of defects before they come on the market and we are to have a program to back and test the old ones that are already on the market. Some that are not that old, but we have not information on them. We ought to be routinely following cohorts so that we can understand, like we are doing, so we can understand what happens to the children from these exposures. We are getting part way there. Some groups in other countries that are doing some research that way, in England and in Scandinavia. Scandinavia has population-based data. So, they are able to go back and look at large groups and the data from pregnancy. They have a reportable system for malformations. So, they can look at malformations across the whole country along with the drug exposures. All of that is collected. If we had this in the United States, we would probably be able to figure things out faster and be able to avoid more catastrophes for these children that are exposed when we do not know.

I like hearing this for the second time around. I would like to make a visit to my state senator, Kamala Harris. I think this is very important. When you talk to me, I have facts to back up what I say.