Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses

Background The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases. Methods We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by 12 (defined as large for I-2 >= 50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results). Findings Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sderosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0.05 and 11 at p values less than 0.001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0.001) induded more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (12<50%), small-study effects (p for Egger's test >0.10), or excess significance (p>0.05). These were IgG seropositivity to Epstein-Barr virus nudear antigen (EBNA) (random effects odds ratio [OR] 4.46,95% CI 3.26-6.09; p for effect size=1.5 x10(-19); I-2=43%), infectious mononucleosis (2-17,1-97-2.39; p=3.1x10(-50);I-2=0%), and smoking (1.52,1.39-1.66; p=1.7 x 10(-18); I-2=0%). Interpretation Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association.