More Evidence Links Vitamin D Deficiency to MS

Pauline Anderson

September 14, 2017

Results of a large new study reinforce the view that vitamin D deficiency may be a risk factor for multiple sclerosis (MS).

The study, which compared vitamin D levels in blood donated by pregnant women without MS, showed a twofold increase in MS risk among those considered vitamin D deficient compared with those who had adequate levels.

While numerous previous studies have shown similar findings, this was the largest longitudinal investigation yet to directly assess whether vitamin D levels in healthy individuals predict their risk for MS.

"Previous studies had fewer than 20 MS cases, and here we had over 1000 women with MS, so it was a very large study," lead author, Kassandra L, Munger, ScD, research scientist, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, told Medscape Medical News.

The study was published online September 13 in Neurology.

Dr Munger and her colleagues used the Finnish Maternity Cohort, which comprises over 800,000 women who have provided a blood sample for routine prenatal testing, typically between 10 and 14 weeks' gestation. There are over 1.8 million stored serum samples, covering over 95% of pregnancies in Finland since 1983.

In 2004, Finland formally recommended that pregnant women take vitamin D supplements.

Using linked national databases, researchers identified women with a sample who were subsequently diagnosed with MS. On average, serum samples were collected 9.3 years before the MS diagnosis.

The analysis included 6200 serum samples from 1092 cases as well as 2123 age- and residence-matched controls.

Vitamin D Deficiency

For the study, researchers defined vitamin D deficiency as levels of 25-hydroxyvitamin D (25[OH]D) less than 30 nmol/L. Insufficient levels were 30 to less than 50 nmol/L, and adequate levels were 50 nmol/L or greater.

Women in the study collectively had relatively high levels of vitamin D deficiency and insufficiency, said Dr Munger. This may be because Finns, living in a northern hemisphere, historically have had low vitamin D levels. Also, the Finnish Maternity Cohort dates back to 1983, before many of the recommendations surrounding prenatal vitamins came into play.

Multivariate-adjusted analyses showed that a 50-nmol/L increase in 25(OH)D was associated with a 39% reduced risk for MS (relative risk [RR], 0.61; 95% confidence interval [CI], 0.44 - 0.85; P = .003, adjusted for gravidity, parity, and time of sample collection).

Compared with women with adequate vitamin D levels, those with deficient levels had a 43% increased risk for MS. Compared with women with insufficient levels, those who were deficient had a 27% increased MS risk (adjusted RR, 1.27; 95% CI, 1.07 - 1.50, P = .005).

In an analysis of quintiles, women in the bottom two quintiles (<26.8 nmol/L or extreme deficiency) had a 53% to 66% increased risk for MS compared with women in the top quintile (41 nmol/L or greater). The overall trend of increasing MS risk with decreasing 25(OH)D was statistically significant.

The researchers also looked at the association between vitamin D levels and MS risk in 511 MS cases and 831 matched controls who had two or more serum samples. Such an analysis should be less affected by random variation than that based on a single measurement, the researchers note.

The association here was even stronger; there was a two-fold higher risk for MS in women with 25(OH)D less than 30 nmol/L compared with women with levels 50 nmol/L or greater (RR, 2.02; 95% CI, 1.18 - 3.45; P = .01).

Because the serum samples were collected nearly a decade before the MS diagnosis, reverse causation as an explanation of the results was reduced, the authors write.

A limitation of the study was that it could not adjust for other MS risk factors, such as smoking, body mass index in adolescence or early adulthood (a relatively newly uncovered possible risk factor), human leukocyte antigen status (a possible genetic risk factor), and Epstein-Barr virus infection. As well, the study included mostly white participants.

Although the current study included only women, the authors noted that previous research found decreased MS risk with increasing 25(OH)D levels in both men and women.

The women in the current study "just happened to be pregnant," commented Dr Munger. "It was a cohort that we could access; pregnancy itself is kind of irrelevant in this study."

Despite the accumulating research, it's still not clear what the optimal vitamin D level is to prevent MS.

"We still don't have a good handle on the best time — and if there is a best time — for people to supplement with vitamin D to reduce MS risk, or the actual dose, or level that is most beneficial," said Dr Munger.

"Studies are indicating that it seems that the more vitamin D you can get, the lower your risk seems to go, but we haven't identified a threshold level yet."

She noted that researchers have not been able to look much beyond the 100 nmol/L level. In this study, only 15 participants had vitamin D levels above 75 nmol/L, she said.

Time for Active Prevention?

In an editorial accompanying the publication, Ruth Ann Marrie, MD, PhD, University of Manitoba, Winnipeg, Canada, and Christopher A. Beck, PhD, University of Rochester Medical Center, New York, explore the question of whether, based on this study and other evidence, it is time to undertake more active prevention of MS.

"Overall, this study adds to the biologic data and epidemiologic body of evidence supporting a causal role for vitamin D in MS," they write. "Collectively, 3 studies in adults now show an association between 25(OH)D levels and risk of developing MS years later; the risk appears to be greatest among those with levels in the deficient range, but levels beyond those typically considered sufficient (0.99 nmol/L) may exert protective effects."  

They go on to weigh the pros and cons of undertaking a universal recommendation for vitamin D supplementation as a public health strategy to prevent MS. In terms of limitations, they point out that first, most of the available studies are in white populations from Europe and the United States, so "studies conducted in other racial groups and in other regions are needed."

"Second, it is uncertain whether supplementation would be needed lifelong or whether supplementation during a critical period would be adequate," Dr Marrie and Dr Beck write. "Third, we lack evidence from a randomized controlled trial. However, such a trial would not be feasible due to the need for large samples, long duration of follow-up, and costs."

Conversely, they examine the potential benefits of going ahead now with a strategy of vitamin D supplementation.  

"Vitamin D supplementation is a simple intervention that would be highly cost-effective even if it prevents only a proportion of MS cases," they write. "Harm from such a strategy is unlikely; doses of up to 4,000 IU/day are safe for adults even in pregnancy, so they could be used through late adolescence and adulthood as such doses would be adequate to achieve vitamin D sufficiency in most individuals."

It may also produce other benefits; they note; for example, supplementation during infancy has been shown to be associated with greater bone mass among girls aged seven to nine years.

"It is time to take an active approach to preventing MS, at a minimum targeting those individuals with an elevated risk of MS, including smokers, the obese, and those with a family history of MS," they conclude.

Commenting on the study for Medscape Medial News, Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, said it "nicely lends support" to prior studies showing that elevated vitamin D levels were associated with a reduction of MS risk.

Dr Jung Henson noted that the study also suggests that vitamin D replenishment in reproductive-age women may be beneficial in reducing the risk for MS.

"This has implications in those who may be at higher risk of developing the disease." 

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr Munger has received grant funding from the National Multiple Sclerosis Society. Dr Marrie serves on the Editorial Board of Neurology and receives research funding from Canadian Institutes of Health Research, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Multiple Sclerosis Society, Rx & D Health Research Foundation, and Crohn's and Colitis Canada, and has conducted clinical trials funded by Sanofi-Aventis. Dr Beck serves as a biostatistical reviewer for Neurology and has received research support from Abeona Therapeutics, Boehringer Ingelheim Pharmaceuticals, Boston Scientific, Auspex Pharmaceuticals, PCORI, the Food and Drug Administration, and the National Institutes of Health. Dr Jung Henson has disclosed no relevant financial relationships. 

Neurology. Published online September 13, 2017. Abstract, Editorial

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