Colleen Guimond

Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review

Objective: To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). Methods: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Results: Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Conclusion: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study.

Objective Pregnancy has a well documented effect on relapse risk in multiple sclerosis (MS). Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months postpartum. However, it is unclear as to whether there are any long term effects on disability. Methods Data were collated from clinical records and family histories systematically collected from the University of British Columbia MS Clinic. Results Clinical and term pregnancy data were available from 2105 female MS patients. MS patients having children after MS onset took the longest time to reach an Expanded Disability Status Scale (EDSS) score of 6 (mean 22.9 years) and patients having children before MS onset were the quickest (mean 13.2 years). However, these effects were not related to term pregnancy and were fully accounted for by age of MS onset. Conclusions Pregnancy had no effect on the time to reach an EDSS score 6. As MS predominantly affects women of childbearing age, women with MS can be reassured that term pregnancies do not appear to have any long term effects on disability.

Reproductive decision making after the diagnosis of multiple sclerosis (MS)

Objective: This study aimed to determine reproductive practices and attitudes of North Americans diagnosed with multiple sclerosis (MS) and the reasons for their reproductive decision making. Methods: A self-administered questionnaire on reproductive practices was mailed to 13,312 registrants of the North American Research Committee on Multiple Sclerosis (NARCOMS) database who met inclusion criteria for the study. Completed questionnaires were then returned to the authors in an anonymous format for analysis. Results: Among 5949 participants, the majority of respondents (79.1%) did not become pregnant following diagnosis of MS. Of these, 34.5% cited MS-related reasons for this decision. The most common MS-related reasons were symptoms interfering with parenting (71.2%), followed by concerns of burdening partner (50.7%) and of children inheriting MS (34.7%). The most common reason unrelated to MS for not having children was that they already have a “completed family” (55.6%). Of the 20.9% of participants who decided to become pregnant (or father a pregnancy) following a diagnosis of MS, 49.5% had two or more pregnancies. Conclusion: This study indicates that an MS diagnosis does not completely deter the consideration of childbearing in MS patients of both genders.

Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance.

When contemplating a pregnancy, women treated for multiple sclerosis (MS) with a disease-modifying drug must decide to discontinue their medication before conception or risk exposing their unborn child to potential drug toxicity. Few studies exist as reference for patients and physicians, and of those available, the majority are less than ideal due to real-world constraints, ethical issues and methodological shortcomings. The authors provide a brief summary of existing animal and human data with current recommendations regarding the safety of IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod and teriflunomide during pregnancy and lactation in women with MS. We also assess the quality, strengths and limitations of the existing studies including challenges with study design. The investigation of outcomes such as spontaneous abortion and congenital anomalies are highlighted with potential methodological improvements for future studies on drug safety in pregnancy suggested. The authors explore the pharmacokinetics and pharmacodynamics of the MS disease-modifying drugs for their possible mechanistic role in fetal harm and discuss the potential role of clinical trials. Future pharmacovigilance studies should continue to pursue multicenter collaboration with an emphasis on appropriate study design.

Age of Onset in Concordant Twins and Other Relative Pairs With Multiple Sclerosis

The ages of onset in multiple sclerosis cases span more than 7 decades. Data are presented for affected relative pairs from a Canadian population base of 30,000 multiple sclerosis index cases (1993–2008). The effects of genetic sharing, parent of origin, intergenerational versus collinear differences, and gender on the ages of onset were evaluated in the following concordant pairs: monozygotic twins (n = 29), dizygotic twins (n = 10), siblings (n = 614), first cousins (n = 405), half siblings (n = 29), parent/child (n = 285), and aunt/uncle/niece/nephew (avunculars) (n = 289). Fishers z test assessed intraclass correlation (r) for ages of onset. Correlations for monozygotic twins, dizygotic twins, full siblings, and first cousins were 0.60, 0.54, 0.20, and 0.10, respectively. Dizygotic twins resembled monozygotic twins more than siblings. The age-of-onset correlation for maternal half siblings (r = 0.37) was higher than that for paternal half siblings (r = 0.26), consistent with other observations suggesting an intrauterine environmental effect on multiple sclerosis risk. Intergenerational comparisons are complicated by substantial increases of multiple sclerosis incidence over time. Genetic loading (familial vs. sporadic cases) did not generally influence the age of onset, but correlation of age of onset in multiple sclerosis relative pairs was proportional to genetic sharing. A maternal parent-of-origin effect on the age of onset in collinear generations was suggested.

Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors

Background: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence. Objective: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada. Methods: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases. Results: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 – 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019). Conclusion: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.

Prevalence of MS in Iranian immigrants to British Columbia, Canada.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by myelin loss, varying degrees of axonal pathology and progressive neurological dysfunction [6]. The cause of the disease is not yet conclusively understood. We thus read with interest the report of Smestad and colleagues showing that immigrants who relocated from the Middle East to Oslo, Norway had a markedly higher prevalence of MS compared to other migrant groups [10], highlighting the fact that both genetic and environmental factors are important in disease susceptibility [2]. As part of the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS), 2,673 patients with clinically definite MS residing in British Columbia (BC), Canada were interviewed between 1997 and 2008 [9]. Information on ethnicity and migration was collected to assess risks of those born in ‘‘low’’ to ‘‘moderate’’ risk countries and now residing in the ‘‘high’’ MS risk region of BC [1, 7]. Forty-two Iranian-born MS patients had migrated to BC between 1976 and 2008. The average age of MS onset was 29.5 years of age (range: 12–46 years) and the gender ratio was 2.8 females to 1 male (31 F:11 M). The 42 probands had 82 siblings (all born in Iran), of whom four were affected with clinically definite MS yielding a crude sibling risk of 4.9%. Information on onset age and year of migration to BC was available for thirty-four of the 42 probands (80%). Of these, 18 had onset of symptoms in Iran and 16 had onset in BC. A total of 20,150 Iranians reside in BC (BC Census 2006). The crude prevalence of MS in the group of Iranian migrants with onset in BC was therefore 79/100,000 (95% confidence interval = 41/100,000–118/100,000), similar to the figure of 85/100,000 obtained by Smestad and colleagues [10]. The MS prevalence in Iran is 43/100,000 [8] and thus prevalence in the BC and Oslo patient groups is approximately double. It is likely that Iranians carry MS susceptibility genes (notably HLA-DRB1*15) at a greater frequency than other migrant groups [10] and consanguinity between migrants may elevate risk. However, it is more likely that environmental factors endemic to temperate climes are primarily responsible for substantially increasing background risk to MS. A study of environmental MS risk factors (e.g. sun exposure, Vitamin D [5], Epstein–Barr Virus [4], smoking [3]) in Iranian migrants is C. Guimond M. Criscuoli I. M. Yee A. D. Sadovnick Department of Medical Genetics, University of British Columbia, Vancouver, Canada

Genetic Counseling for Early-onset Familial Alzheimer Disease in Large Aboriginal Kindred from a Remote Community in British Columbia: Unique Challenges and Possible Solutions

A novel, pathogenic presenilin 1 (PS1) mutation has recently been identified in a large Aboriginal kindred living in dispersed communities throughout British Columbia, Canada. Disseminating genetic information and ensuring that appropriate genetic counseling services are provided to all concerned relatives have posed several unique challenges. These challenges include knowledge exchange and continuity of care in a geographically remote and culturally distinct community. To our knowledge, this is the first time a specific genetic counseling approach has been needed for early-onset familial Alzheimer disease (EOFAD) in a North American Aboriginal community.

A Novel PS1 Gene Mutation in a Large Aboriginal Kindred

BACKGROUND There is currently little information on the genetic epidemiology of Alzheimer disease (AD) among North American Aboriginal populations. No cases of familial AD (FAD) in these populations have been published to date. METHODS Here, we describe a large North American Aboriginal kindred with early onset FAD (EOFAD) in which genetic testing was done. RESULTS AND CONCLUSIONS A novel Presenilin 1 (PS1) gene mutation (L250F) has been identified. In contrast to the three previously reported families with PS1 codon 250 mutations, affected members of this kindred demonstrate neither myoclonus nor seizures. Furthermore, the identification of a PS1 mutation in a North American Aboriginal kindred presents several unique challenges with respect to knowledge transfer and continuity of care in a geographically remote and culturally distinct community.

Disease onset in familial and sporadic primary progressive multiple sclerosis

The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration which is believed to start early in the disease process, even before the onset of clinical symptoms. Symptomatic onset then occurs when this process reaches a threshold after which the axonal loss can no longer be compensated. A preliminary study showed that patients with familial PPMS had an earlier clinical onset than patients with sporadic disease, suggesting a hereditary component to the disease process of PPMS. In this study, we combined data from two large, population-based, longitudinal MS databases to investigate disease onset in familial and sporadic PPMS. We examined 411 patients with PPMS. There were no differences in gender distribution or onset symptoms between familial and sporadic PPMS. Patients with familial PPMS were significantly younger at disease onset (n = 84, median age: 37.6 years) than patients with sporadic disease (n = 327, median age: 42.7, p = 0.007). This difference was due to a greater proportion of familial cases with a disease onset before the age of 30 and a smaller proportion with disease onset between 40 and 50 years of age (p = 0.002). Gender had no significant effect on the age at disease onset. Further analyses showed that these findings were unlikely to be due to ascertainment bias towards an earlier diagnosis in familial cases. Our findings suggest a hereditary component to the disease process of PPMS. It would be worthwhile to identify patients with familial PPMS for future research on disease modifying genes in MS.