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EDITORIAL
Got Milk?
he article by Mirzaei and colleagues1 is another
thoughtful and clever use of the Nurse’s Health
Study. The evaluation of the mother’s data from this
study is carefully conducted with an innovative approach
to taking self-reported outcomes and validating their
approach to estimating actual serum 25(OH)D levels.
Further, by focusing on the gestational period, the problems of telescoping and sequencing effects in retrospective studies are mitigated to a degree. There are careful
considerations in the handling of design issues and the
authors acknowledge the obvious limitations of such
studies, such as differential recall bias by cases vs controls. Acknowledging it, of course, does not eliminate it,
but there is equally no evidence to demonstrate the findings result from recall bias. Thus, the authors should be
congratulated on a very thoughtful and well done work.
Nevertheless, we want to express some cautions, limitations, and overinterpretations of the data. It is easy to see
the potential headlines that could result from this work
or the public health perceptions that all pregnant mothers should be consuming greater amounts of milk to prevent multiple sclerosis (MS). These concerns can be
directly traced to language in the paper such as ‘‘33% of
the MS cases among mothers who drank less than 2
glasses of milk per day could have been hypothetically
prevented.’’1 While this is carefully worded and analytically correct in its statement, it is too easy to take the
current fervor for vitamin D and a cross-sectional retro-
T
spective analysis and demand pregnant women not drink
or smoke, and now drink more milk.
The concern over an overly simplistic message is
opposite the article’s extremely complex nature and analyses of the evidence. It incorporates not only direct variables, but also covariates that may be highly correlated. It
is difficult to assess the interrelated variables and isolate
their impact on the results. For example, milk consumption has north to south gradients.2 The Northeast on average consumes 335ml per day; North Central 291ml/
day; West 276ml/day, and the South 214ml/day. While
the authors adjusted for location at birth, they did so as
North, Middle, South, which may have left unadjusted
some of the milk consumption and latitudinal effects in
a combination that with highly correlated environmental,
genetic, and vitamin D effects give rise to an association
with the milk consumption data. The evidence for the
vitamin D effect is mostly through a gradient as individual levels of milk consumption are not significantly different except at the highest levels of consumption. Furthermore, the gradient effect may not be the appropriate
paradigm for the impact on disease. With rickets, as with
many other nutritional diseases, it is a threshold that is
key and while there is some evidence for this, the basic
association rests with the gradient.
In addition, what is the biological basis by which
the estimated level of vitamin D associated with the selfreported intake could work to prevent, in utero, subsequent MS? It is not totally clear what level of vitamin D
intake is required to sustain an adequate serum level.
FIGURE 1: Distribution of month of birth for NARCOMS cohorts. NARCOMS 5 North American Research Committee on
Multiple Sclerosis.
C 2011 American Neurological Association
V
3
ANNALS
of Neurology
Some authors have argued that intakes of 1,000IU per
day are insufficient.3 If each glass of milk were 16oz, the
amount of vitamin D supplementation would only be
240IU.4 Thus, how the additive effect of even 2 glasses
per day would provide this protective effect in utero is a
bit unclear. It seems unlikely that mothers would be
drinking more than 2 to 3 glasses of milk per day, thus,
one might ask for what is this milk consumption a surrogate? While sunlight and vitamin D have been an intriguing explanation for the latitude effects seen in MS prevalence, it is not firmly established as causative. Nevertheless,
if a residual of the effect results from the North, Middle,
and South covariate adjustment, then we are identifying in
a complex model, the fact that there is a greater risk of
MS in Wisconsin than there is in Alabama, but presented
in a way that gives pregnant women 1 more thing to
worry about and an overly simple solution.
We agree that there is growing evidence for a role
of vitamin D in MS and find the potential that vitamin
D might be associated with the etiology of MS worthy
of epidemiological and experimental research. The effects
of vitamin D on the fetus have been suggested by studies
in Northern latitudes consistent with lower daylight and
thus ultraviolet (UV) exposures, but these have not been
replicated in the United States. In a veterans population
the season of birth effects have been described, but data
from the North American Research Committee on
Multiple Sclerosis (NARCOMS) registry could not
reproduce any month of birth effect (ie, increased MS
derived from winter months gestations).5 When the data
were restricted to latitudes above 42 degrees, the pattern
differs from the below 42 degrees and more closely
resembles the pattern seen in Great Britain and Canada
(Fig).6 Thus, the current work suggests that dietary vitamin D is somehow quite potent, but one wonders
whether the use of covariates, the interest in Vitamin D
and the collinearity of the various variables has somehow
4
cooperated to provide these intriguing and provocative
results. Our main intent of this editorial is to caution
against the simple notion that milk consumption in and
of itself might reduce this disease.
Potential Conflicts of Interest
Nothing to report.
Gary Cutter, PhD, and Amber Salter, MPH
Department of Biostatistics
University of Alabama
Birmingham, AL
References
1.
Mirzaei F, Michels KB, Munger K, et al. Gestational vitamin D and
the risk of multiple sclerosis in the offspring. Ann Neurol 2011:70:
31–41.
2.
National Cancer Institute. 1997. Estimated exposure and thyroid
doses received by the American people from iodine-131 fallout following Nevada atmospheric nuclear bomb tests. Washington, DC:
U.S. Department of Health and Human Services, National Institutes
of Health, National Cancer Institute. Available at: http://rex.nci.nih.
gov/massmedia/Fallout/index.html. Accessed June 10, 2011.
3.
Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D
supplement doses and serum 25-hydroxyvitamin D in the range
associated with cancer prevention. Anticancer Res 2011;31:
607–611.
4.
U.S. Department of Agriculture, Agricultural Research Service.
2010. USDA National Nutrient Database for Standard Reference,
Release 23. Nutrient data laboratory home page. Available at:
http://www.ars.usda.gov/ba/bhnrc/ndl. Accessed June 10, 2011.
5.
McDowell TY, Amr S, Langenberg P, et al. Time of birth, residential solar radiation and age at onset of multiple sclerosis. Neuroepidemiology 2010;34:238–244.
6.
Salter AR, Cofield SS, Vollmer T, Cutter GR. Timing of birth
in United States-born MS population. Mult Scler 2010;16:
S210–S211.
DOI: 10.1002/ana.22507
Volume 70, No. 1
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