A.D. Sadovnick–– Department of Medical Genetics and Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada; E. Dwosh–– Department of Medical Genetics, University of British Columbia, Vancouver, Canada; C.H. Guimond–– Department of Medical Genetics, University of British Columbia, Vancouver, Canada

Background

Multiple sclerosis (MS) is one of the most common neurological disorders, other than trauma, affecting young adults, especially during the period of their lives when reproduction is an option. Females are affected approximately twice as often as males.

Until the advent of laboratory tests for MS, in particular magnetic resonance imaging (MRI), it was not uncommon for the lag time (time from the onset of clinical signs and symptoms to clinical diagnosis of MS) to be years or even decades. Thus, in many situations, women had pregnancies after the onset of MS, but without knowing that they had the disease. The disadvantage (or possibly an advantage) stemmed from the fact that informed decisions about childbearing did not have to be made. Reproductive issues for males with MS were either never or very rarely addressed.

Now, especially with the use of the MRI and diagnostic criteria (Poser et al., 1983; McDonald et al., 2001; Polman et al., 2005), it is not uncommon for the diagnosis of MS to be made within months or even weeks of the clinical onset. In addition, disease-modifying therapies (DMTs) are now available and these are often initiated very early in the disease course. Therefore, on one hand, people are receiving the diagnosis of MS at younger ages and often during less severe stages of the clinical course and on the other hand, they must make many life decisions. Thus, today, the prototypic patient with MS is a young woman of childbearing age. Nevertheless, it is important to remember that approximately one in four patients with MS is a male for whom fathering a child is a major consideration.

What is Currently Known

Over the years, there have been many small studies and assumptions made about pregnancy in young women with MS. To date, the major study has been the Pregnancy in Multiple Sclerosis Study or “PRIMS” (Confavreux et al., 1999; Vukusic et al., 2004). Briefly, PRIMS was an analysis of 254 pregnant women with MS. The main study finding was a 70% decrease in clinical relapses in the third trimester and a 70% increase in the 3 months post-partum. At 2 years, there did not appear to be any effect of pregnancy or breastfeeding on relapses or disability. There are a number of gaps, however, in the PRIMS dataset including the following:

1. The PRIMS database was conducted in the era before DMTs were part of clinical practice and therefore no relevant data is available.
2. Relapses were defined in general, but pseudorelapses were notspecifically discussed.
3. No analysis of patient subsets with regard to low and high relapse rate prior to pregnancy (our own data from 100 patients suggests that the post-partum relapse activity reflects the pre-partum––Sadovnick, unpublished). The implication is that the post-partum relapse rate may be focused on a small subset of patients with a particular clinical course at the time of conception.
4. Forty-seven percent of PRIMS participants had probable rather than definite MS, according to diagnostic criteria (Poser et al., 1983)
5. Only eight PRIMS subjects had secondary progressive MS. No subject had primary progressive MS. Thus, no statement can be made on pregnancy and progressive subtypes of MS.
6. The issue of breastfeeding has not been resolved, either in terms of relapse rates (protection/initiation) or safety of taking DMTs or other therapies such as IVIG while breastfeeding.
7. The PRIMS study did not conduct any longitudinal follow-up of resultant live births.
8. No data were presented on males with MS who fathered children.

The decision whether or not to have a child must be made by the concerned couple (i.e., the person with MS and his/her partner). Thus, information on various topics must be considered in the “decision-making” process. Table 1 is a partial list of some questions commonly asked by males and females with MS when contemplating having children. In most instances, only partial answers to some of these questions are known and often evidence-based data are lacking (Devonshire, Duquette, Dwosh, Guimond, & Sadovnick, 2003; Dwosh, Guimond, & Sadovnick 2003; Dwosh, Guimond, Duquette, & Sadovnick, 2003). For example, while there are good data on the risks for children of persons with MS to also develop the disease (Sadovnick, Dircks, & Ebers, 1999) and on the non-genetic intrafamilial transmission of MS (Ebers, Sadovnick, Risch, & the Canadian Collaborative Study Group, 1995; Ebers et al., 2004), data on the safety of DMTs are largely based on “lack of evidence” rather than true facts (Waubant & Sadovnick, 2005). The extent of available information remains limited and discontinuation of DMTs, such as IFNB-1a (and any other DMT) prior to initiating pregnancy should remain the rule when possible. To date, however, there is no hypothesis- or data-driven argument to support induced abortion when pregnancy has been initiated before discontinuing DMTs (Waubant & Sadovnick, 2005; Sandberg-Wollheim et al., 2005; Boskovic, Wade, Wolpin, Bauer, & Koren et al., 2005).

A protocol for reproductive counseling has been developed (Dwosh, Guimond, & Sadovnick, 2003). This is designed to incorporate current knowledge (and lack thereof) into a format so that a couple, one or both of whom have MS, can discuss their concerns with a health care professional (e.g., MS neurologist, MS nurse practitioner, genetic counselor, etc.). Table 2 lists the general topics to be covered during a reproductive counselling session. The reproductive counseling protocol is presently being prepared as an interactive Web site for health care professionals. This is part of the MS North American Pregnancy Project (MS-NAPP).

Future Directions

To date, there are no well designed or well-controlled dataset(s) on large numbers of women available to address about MS and reproduction with any certainty. Our long-term goal is to establish a North American MS Pregnancy Register that will have sufficient prospective data to answer many questions being asked by persons with MS including those outlined in Table 1. As a first step, it is necessary to determine reproductive practices and the reasons for decision-making for North American patients with MS (male and female). It is not known whether, over the last 15 years with the advent of earlier diagnosis and disease modifying therapies, these have changed. Three pilot studies, to be conducted as part of “MS-NAPP,” are designed to identify what has happened in the past among patients with MS with respect to reproduction, whether the pattern of practice has changed with the advent of DMTs, and what reasons are behind reproductive choices among persons with MS. The three pilot studies to be conducted over the next 12 months are:

1. Reproduction questionnaire to be sent to patients with MS attending selected Canadian and American MS clinics/centers.
   With appropriate ethics approval, the clinic/MS center personnel will identify male
   and female patients with MS who were diagnosed while still in the likely reproductive years (e.g., 18 to 45 for females; 18 to 60 for males). Minors (currently under the age of 18 years) will be excluded. Each participating MS clinic/center will send out letters asking eligible persons among the total caseload to complete an enclosed
   questionnaire which has been approved by the appropriate ethics review boards. Specifically, the short questionnaire will ask questions about reproductive decisions and whether or not these were related to the diagnosis of MS. The replies will be returned to the authors of this paper in an anonymous format.
2. Anonymous analyses of relevant field in the North American Research Committee on Multiple Sclerosis (NARCOMS) database.

   NARCOMS has anonymous (no identifying information) data on demographics and family structure for its enrolees. NARCOMS personnel will conduct an anonymous analysis of these data to provide a background picture of reproductive patterns for persons with MS, controlling for factors such as gender, year of MS diagnosis, and age at diagnosis. This information will be strictly statistical and will not include any direct
   information from individuals enrolled in NARCOMS.

3. Reproduction questionnaire to be sent to volunteer patients with MS identified through NARCOMS.

   The questionnaire will be sent to active American participants in NARCOMS (ages as outlined in item #1) with a request to complete this and return it to the authors of this paper in an anonymous format. This will be a one-time mailing through NARCOMS and the investigators will make no direct contact with the NARCOMS
   enrollees. The questionnaire will be the same described in item #1.

Relevance to Persons With MS

The findings will be relevant to the clinical management of patients with MS considering reproductive options, specifically in terms of pharmaceutical management. In many cases, to paraphrase from the psychiatric literature, MS health care professionals often find themselves between a “therapeutic rock and a teratogenic hard spot” with respect to reproductive decisions by patients with MS.

It is anticipated that the long-term overall results of this pilot and the resultant registry will ameliorate this situation. The overall objective of this work is to improve the delivery of service to persons with MS who are contemplating reproduction, bearing in mind the medical welfare of both the parent with MS and the resultant child(-ren).

<Acknowledgements

The authors would like to thank various personnel from the following organizations for their ongoing intellectual and technical expertise and well as the organizations themselves each providing start-up funding for this project:

1. National MS Society (NMSS)
2. MS Society of Canada (MSSC)
3. Consortium of MS Clinics (CMSC), including the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry.
4. Additional funding for MS-NAPP is provided by unrestricted grants from the Edward Bronfman Family Foundation, Teva Neurosciences, and Berlex Canada.

References

Boskovic, R., Wade, R., Wolpin, J., Bauer, G., & Koren, G. (2005). The reproductive effects of beta interferon therapy in pregnancy: A longitudinal cohort. Neurology, 65, 807-811.

Confavreux, C., Hutchinson, M., Hours, M., Cortinovis-Touriaire, P., Grimaud, J., & Moreau, T. (1999). Multiple sclerosis and pregnancy: Clinical issues. Reviews in Neurology, 155, 186-191.

Devonshire, V., Duquette, P., Dwosh. E., Guimond, C., & Sadovnick, A. D. (2003). The immune system and hormones: Review and relevance to pregnancy and contraception in women with multiple sclerosis. International MS Journal, 10, 44-50.

Dwosh, E., Guimond, C. G., & Sadovnick, A. D. (2003). Reproductive counselling for multiple sclerosis: Rationale. International MS Journal, 10, 52-59.

Dwosh, E., Guimond, C., Duquette, P., & Sadovnick, A. D. (2003). The Interaction of Multiple Sclerosis and Pregnancy: A Critical Review. International MS Journal, 10, 38- 42.

McDonald, W. I., Compston, A., Edan, G., Goodkin, D., Hartung H. P., Lublin F. D. et al. (2001). Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals in Neurology, 50, 121- 127.

Ebers, G. C., Sadovnick, A. D., Risch, N. J., & the Canadian Collaborative Study Group (1995). Familial aggregation in multiple sclerosis is genetic. Nature, 377, 150-151.

Ebers, G. C., Sadovnick, A. D., Dyment, D. A., Yee, I. M. L., Willer, C. J., & Risch, N. for the Canadian Collaborative Study Group (2004). A parent of origin effect in multiple sclerosis: Observations in half siblings. Lancet, 363, 857-850.

Polman, C. H., Reingold, S. C., Edan, G., Filippi, M., Hartung, H. P., Kappos, L. et al. Diagnostic criteria for multiple sclerosis; 2005 revisions to the “McDonald Criteria”. Annals in Neurology, Nov 10; [Epub ahead of print]

Poser, C. M., Paty D. W., Scheinberg, L., McDonald, W. I., Davis, F. A. Ebers, G. C. et al. (1983). New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals in Neurology, 13(3), 227 231.

Sadovnick, A. D., Dircks, A., & Ebers, G. C. (1999). Genetic counselling in multiple sclerosis: Risks to sibs and children of affected individuals. Clinical Genetics, 56(156), 118-122.

Sandberg-Wollheim, M., Frank, D., Giesser, B., Lopez-Bresnahan, M., Stam-Moraga, M., Chang P. et al. (2005). Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology, 65, 802-806

Vukusic, S., Hutchinson, M., Hours, M., Moreau., T., Cortinovis-Tourniaire, P., Adeleine, P., Confavreux, C., & Pregnancy In Multiple Sclerosis Group (2004). Pregnancy and multiple sclerosis (the PRIMS study): Clinical predictors of post-partum relapse. Brain, 127, 1353-60; Erratum in: Brain, 127, 1912

Waubant, E., & Sadovnick, A. D. (2005). Interferon babies. EDITORIAL. Neurology, 65, 788-789.

This entry was posted on Thursday, February 23rd, 2006 at 5:21 pm and is filed under All Articles, Clinical Issues, Primary Progressive MS, Relapsing-progressive MS, Relapsing-remitting MS, Secondary Progressive MS. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.