Episode 78 with Dr. Dessa Sadovnick on need for a pregnancy registry in MS
Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age, but a German neurologist runs the only MS pregnancy registry in the world. A multidisciplinary group of clinicians are calling for a North American pregnancy registry to properly assess reproduction and child health, including the impact of disease modifying therapies and the MS disease itself on pregnancy outcome.
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Host – Dan Keller
Hello, and welcome to Episode Seventy-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
A lot can be learned about pregnancy and MS by tracking pregnant women and their offspring over time. Dessa Sadovnick MD PhD, a professor of medical genetics and neurology at the University of British Columbia in Canada, has started such a registry with international colleagues. I spoke with her at the World Congress of Neurology in Santiago, Chile, in November, where she described these efforts and what a very focused registry can tell us.
Interviewee – Dessa Sadovnick
I'm not talking about a general registry. What I'm talking about is a pregnancy and outcome registry. So this is not just taking people who have MS and trying to keep track of them. This is looking at actual pregnancy outcomes and what happens to the children after. So it's a very specific type of registry.
Interviewer – Dan Keller
It seems like there's a multitude of variables you can look at. What sorts of things are you going to be tracking if you get this going?
Well, I think the important factor is that just because you have a disease such as multiple sclerosis doesn't mean you're immune from other factors that can affect pregnancy outcome and child development. So in addition to knowing about drug therapies, disease course, other exposures related to your MS, it's also important to know about your previous pregnancy history, your family history, your basic demographics, including your ethnic background, comorbid diseases which you may also have with the MS. All these factors can affect pregnancy outcome and child health.
Will you be looking at the mother's longitudinally? Or only the children?
Ideally, we'd like to be able to look at the mothers up to a year post-partum, and then follow the children longitudinally. Because there are situations where children do not have a certain disease that the mother may have, but over time, they might be found to have some late onset problems, for example, related to learning disabilities or something like that.
Can you separate those out by biological cause or environmental cause? They're in a household with people who have a disease and have to deal with it.
Well, we know for a fact in terms of MS that there is certainly no transmissibility within a household. We have done a lot of work over the years that show very clearly that the excess of MS you find within biological relatives of people who have MS is very clearly due to genetic sharing, not shared family environment. So from that point of view of the child inheriting MS, we're not looking at the family environment.
Obviously, there're many psychological issues and many socioeconomic issues related to having a parent who has a chronic disabling disorder. And the impact this could have on child development must, of course, be taken into consideration. But what I'm trying to look at here is more the general factors in terms of, if the mother is exposed to a disease-modifying therapy at the time of conception or in early gestation, and if there is an adverse outcome in the pregnancy, is that necessarily correlated? Or could that have happened for many other reasons?
Similarly, if the child develops problems down the road, could that be related, maybe, to the uterine environment because the mother has an autoimmune disease? Which does not mean the child gets an autoimmune disease, but maybe, in some way, it impacts the autoimmunity long-term?
How long would you have to track children? And how many would you have to track to get meaningful numbers?
Well, this is obviously always a concern, and you would have to track a sizable number. But when you consider how many people there are with MS in North America, and if you could do a centralized registry, I think it's realistic that you follow them at least for a few years after delivering. Once they start reaching their developmental milestones, you can get some ideas. But I think the main factor is that we're always saying, therapy is not indicated if you're contemplating a pregnancy. And this causes many issues for many people. But the evidence for this is so scarce. And my big concern is that, are we really being overly cautious? And we won't know this if every adverse outcome is automatically trying to be related to exposures either at conception or in the early parts of gestation.
Pregnancy itself is immunosuppressive, but it seems women have a rebound after delivery. So what goes on with treatment during pregnancy? Is it okay to stop treatment if they're naturally going to be somewhat immunosuppressed?
This is one of the big areas that we really don't have information, and we need good information. Obviously, if you look at a series of women, what seems to happen is especially in the third trimester, they seem to do better. And then, of course, once you deliver and their hormonal changes take place, there's an increase of relapses after delivery within the first three months. That's not to say women can't have relapses while they're pregnant. That is not to say that women are going to have relapses necessarily after delivery. But if you look at large numbers, this is the pattern. The question then comes up, if you have a relapse while you're pregnant, how severe is the relapse? And how should it be treated? There're no set guidelines. The same way as after delivery, a big factor is whether the mother's breastfeeding or not breastfeeding. In today's society, you're really encouraged to breastfeed, but that could have impacts on how you treat a relapse.
The other big issue in terms of pregnancy-related relapses is something that we also experience when we look at people who have MS and they're going into menopause. And that is, are the symptoms really an MS relapse? Or could they be pregnancy-related? If you have a symptom, say you have urinary problems, say you have balance problems, say you have fatigue, how do you measure if this is specifically an MS relapse versus just part of either the later stages of pregnancy, the early stages of pregnancy, or living with a newborn child? There is really nothing concrete on how to measure what's a true relapse, what's a pseudo-relapse. And there are no really specific guidelines on how to treat these symptoms during gestation and immediately after delivery. This is an area that we really need to develop.
One of the things that we have been able to do is a lot of people are interested in this topic, but it's never been looked at in a formalized manner using experts from many different areas. So about a year and a half ago, I put together a meeting of a group of people who are interested in reproduction and child health. And we received some funding to have a two-day meeting from the Canadian Institute of Health Research, as well as some money from Teva Neurosciences and Biogen Idec. And what we did is we had a two-day workshop basically saying, is there a need to learn more about this area? And if there is, how can all these specialists work together to try to develop knowledge-based information?
So we gave our little virtual network, which has no ongoing funding; it's basically people just working voluntarily. We've given it the name of MS CERCH, which is Center of Excellence for Reproduction and Child Health. And we've put together a voluntary working group. And where we're at right now is we've actually just had a paper published in Obstetrics and Gynecology, the American main journal. They also call it a Green Journal, but it's not neurology. Just talking about limitations, guidelines, what we know and what we don't know about reproduction and child health. So this was published the end of 2014.
We're currently working with the American College of Obstetrics and Gynecology to try to have our paper turned into some guidelines for people with multiple sclerosis. We've also just recently as a group published a paper talking about why there is a need for a disease-specific registry rather than a treatment-specific registry.
We are also just submitted a manuscript looking at all the issues dealing with males with MS in terms of reproduction and child health, because the focus, of course, is on females. But there're still a lot of males out there, and they face many issues that have not been addressed. And we're in the process of trying to get some funding for the first-ever grant to look prospectively at the occurrence of peripartum depression in both mothers and fathers who have multiple sclerosis, a topic that's never been looked at before. So from our two-day meeting, which was quite casual and informal, we have been able to move forward, and as a group, had some concrete outcomes. And we're hoping that we're be able to move forward with this group, hopefully obtain appropriate funding, and we're be able to, maybe, really come up with some knowledge-based information for people with MS who are contemplating reproduction.
Another major area of concern is we're more frequently now identifying the pediatric population with multiple sclerosis. The focus on this population has largely been the recognition that MS does occur in the pediatric population. But what's happening is as years are progressing, this pediatric population is evolving into a population who are capable of reproduction. How diagnosis of pediatric MS can impact not only reproductive ideas, but also just behavior in teenagers, and how all this is interrelated is not known as well. So it's a whole other area that we really need to understand.
Are you looking for buy in from clinicians in all of North America? Or restricted to Canada? Or worldwide?
Ideally, we'd like worldwide. Realistically, right now in our group, we're basically clinicians who are in Canada and the US. We have some buy in from some clinicians in Europe, and it's the obvious problem when you don't have resources, the buy in has to be voluntary. So we do have strong connections between Canada and the US, and we're working forward to try to make this a topic that is more at the forefront.
You have a pretty good system of linked databases in Canada. Can that help you with this? I mean, you know diagnoses and pharmacy and death records and hospital visits and everything else.
Linked databases are a very important resource, but they are exactly what they are: linked databases. You're not dealing with the actual people. You're dealing with how the information has been recorded. So while for some purposes linked databases are extremely important, and there's been a lot of work published out of Canada, including with our group in British Columbia using the BC record linkages. They are informative. But it's not the same as actually dealing with the actual people, because record linkage cannot tell you everything you need to know about the person.
Just to use an example in terms of pregnancy outcome. You can identify a woman who has MS. You can look at when she had prescriptions filled for her disease-modifying therapy, for example. You can look at if any birth defects were registered for the child. But what you don't know is, did this mother have previous pregnancy losses? Registries only have live births. Does the mother have a family history of some relative with a certain disease? Could the mother have comorbid diseases that for some reason are not linked into her medical history? Maybe she's moved from another country. Maybe she doesn't have the health coverage. So there's a lot of issues with record linkage. And I think it's very important to know that it has strengths and limitations. But it's not the actual end of everything.
The other issue with record linkage is it's someone's interpretation. For example, if it's recorded through record linkage that you have a given disease, it's assumed that all the appropriate diagnostic tests have been done. But is that necessarily the case? Could the person who's actually doing the coding reading from the records make that assumption? So you have to be careful.
Years ago when I started in clinical genetics, we had a BC health surveillance registry. And the idea was to basically identify any children who had been within the hospital system in the first seven years of their life. And it was a provincial recording system. But the truth of the matter was is when we went back, and I spent a lot of time working with colleagues going back and reviewing the actual forms from which the data was collected, and the amount of errors you would find. Even in something as simple as MS, looking at cause of death.
If you look at record linkage, sometimes it doesn't always note the cause of death the person had MS. Sometimes if there's asphyxia, the question is, was it just asphyxia? Is it related to the MS? Is it from something else? Another issue is very often people who have a specific disease like multiple sclerosis and they die, the real cause of death is ignored. Very often we know that cancer, for example, is underdiagnosed in a person with a specific disease like MS. Just because you're having bladder problems, it's often attributed to MS, where in fact, you could actually have bladder cancer, as an example, or bowel cancer. So if you look at all these data, I think it's important to realize that record linkage is a very useful tool, but it is not the only tool that should be used.
Finally, where does this all stand? You mentioned that you have people doing it on a voluntary basis. Do you foresee something more formal?
We're trying to get something more formal in North America. Obviously, funding is the issue. And right now we're trying to get the drug companies to realize that, if they would work together to have a proper pregnancy registry, it might be in everybody's interest, rather than just assuming that the drugs are not advised during pregnancy or when trying to conceive.
The problem with all these registries is that where does the money come from? In Canada, we have a very interesting scenario right now where they're trying to put together a registry of people who have multiple sclerosis in Canada. This has nothing to do with pregnancy. This is just, who has multiple sclerosis in Canada? A registry with minimal data sets. And this started with the Canadian Institute of Health Informatics. This has been going on for quite a few years, and I'm on both the technical and the medical advisory committee for this. But the problem is, who's going to fund it? The concept was to enlist the ministries of health to get involved and fund it, but each ministry of health has its own issues in each province, and their interests are different. So even though the concept there was to try to get a cross-Canada registry for people who have MS, funding after many years of trying is still a major obstacle.
It's a big issue, but this is why I'm hoping at least if we can focus on the idea of pregnancy, maybe through some research funding or company funding, we'll be able to at least get a pilot started that will start to answer some of these questions. A lot of money is being spent by each drug company looking at their treatment-specific pregnancy registries. And if we could get them to realize that if they all work together, we might get somewhere. It would be nice.
Thank you for listening to Episode Seventy-eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
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For Multiple Sclerosis Discovery, I'm Dan Keller.