Although a randomized clinical trial of vitamin D supplementation on primary MS prevention would provide more compelling evidence of causality than observational studies, challenges including cost, duration, and compliance make it unlikely that such a study will be done. As is often the case in medicine, recommendations have to be based on the best available observational evidence. Our study [1] contributed to a large body of literature supporting low vitamin D levels as a risk factor for multiple sclerosis (MS). [2]
Applying the Bradford-Hill guidelines for assessing causality, [3] the vitamin D and MS association meets many, including temporality, strength of association, dose-response, biologic plausibility, and consistency and coherence of study findings. A causal interpretation is further supported by the results of multiple Mendelian randomization studies. [4-5] Thus, when considered in the context of the current literature, a causal interpretation of the vitamin D and MS association is not inappropriate.
As discussed, one limitation to our study was lack of information on potential confounding variables, including smoking (information not collected in the Finnish Maternity Cohort). [1] However, we were able to measure serum cotinine (a biomarker of nicotine metabolism) and restrict the analyses to women negative for cotinine (60%) and the results were unchanged with a 50 nmol/L increase in 25-hydroxyvitamin D associated with a 45% reduced MS risk (RR=0.55 [95% CI]; 0.37-0.82).
1. Munger KL, Hongell K, Aivo J, et al. 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology 2017;89:1578-1583.
2. Ascherio A and Munger KL. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update. Semin Neurol 2016;36:103-114.
3. Hill AB. The environment and disease: Association or causation? Proc R
Soc Med 1965;58:292-300.
4. Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med 2015;12:e1001866.
5. Rhead B, Baarnhielm M, Gianfrancesco M, et al. Mendelian randomization
shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet 2016;2:e97.
For disclosures, please contact the editorial office at journal@neurology.org.
Although a randomized clinical trial of vitamin D supplementation on primary MS prevention would provide more compelling evidence of causality than observational studies, challenges including cost, duration, and compliance make it unlikely that such a study will be done. As is often the case in medicine, recommendations have to be based on the best available observational evidence. Our study [1] contributed to a large body of literature supporting low vitamin D levels as a risk factor for multiple sclerosis (MS). [2]
Applying the Bradford-Hill guidelines for assessing causality, [3] the vitamin D and MS association meets many, including temporality, strength of association, dose-response, biologic plausibility, and consistency and coherence of study findings. A causal interpretation is further supported by the results of multiple Mendelian randomization studies. [4-5] Thus, when considered in the context of the current literature, a causal interpretation of the vitamin D and MS association is not inappropriate.
As discussed, one limitation to our study was lack of information on potential confounding variables, including smoking (information not collected in the Finnish Maternity Cohort). [1] However, we were able to measure serum cotinine (a biomarker of nicotine metabolism) and restrict the analyses to women negative for cotinine (60%) and the results were unchanged with a 50 nmol/L increase in 25-hydroxyvitamin D associated with a 45% reduced MS risk (RR=0.55 [95% CI]; 0.37-0.82).
1. Munger KL, Hongell K, Aivo J, et al. 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology 2017;89:1578-1583.
2. Ascherio A and Munger KL. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update. Semin Neurol 2016;36:103-114.
3. Hill AB. The environment and disease: Association or causation? Proc R Soc Med 1965;58:292-300.
4. Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med 2015;12:e1001866.
5. Rhead B, Baarnhielm M, Gianfrancesco M, et al. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet 2016;2:e97.
For disclosures, please contact the editorial office at journal@neurology.org.