Why we should offer routine vitamin D
supplementation in pregnancy and childhood
to prevent multiple sclerosis
Department of Neurology, Institute of Neurological Sciences, 1345 Govan Road, Glasgow G51 4TF, UK
Received 14 June 2004; accepted 24 June 2004
and disables young people. The disease is more prevalent in the geographic areas that are farthest from the equator.
No form of treatment is known to be effective in preventing MS or its disabling complications. A number of
epidemiological studies have shown a protective effect of exposure to sunlight during early life and a recent
longitudinal study confirmed that vitamin D supplementation reduced life-time prevalence of MS in women. Very little
is known regarding the role of vitamin D on the developing brain but experimental data suggest that cerebral white
matter is vitamin D responsive and oligodendrocytes in the brain and spinal cord and express vitamin D receptors. It is
possible that differentiation and axonal adhesion of oligodendrocytes are influenced by vitamin D level during brain
development and a relative lack of vitamin D may increase oligodendroglial apoptosis. The age effect of migration on
susceptibility to develop MS could be explained by a role of vitamin D on brain development. In areas of high MS
prevalence, dietary supplementation of vitamin D in early life may reduce the incidence of MS. In addition, like folic
acid, vitamin D supplementation should also be routinely recommended in pregnancy. Prevention of MS by modifying
an important environmental factor (sunlight exposure and vitamin D level) offers a practical and cost-effective way to
reduce the burden of the disease in the future generations.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that runs a chronic course
c 2004 Elsevier Ltd. All rights reserved.
The cause and the exact pathogenesis of multiple
sclerosis (MS) are unknown . The pathological
hallmark of MS is confluent and multi-focal demye-
lination in association with progressive neuronal
loss. In the past, most researchers assumed an auto-
immune mechanism of demyelination in MS driven
by T-lymphocytes sensitised to one or more target
epitopes in the myelin protein [2,3]. However, it
is acknowledged even by the ardent followers of
autoimmunity that there exists no reproducible
and specific immunological marker for MS .
Experimental allergic encephalomyelitis (EAE) is
an animal model of demyelination induced by artifi-
cial T-cell sensitisation to myelin basic protein.
Clinically and pathologically, EAE bears only super-
ficial resemblance to MS and most treatments that
work in EAE are not considered to be safe or effec-
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Medical Hypotheses (2005) 64, 608–618
tive in the human trials of MS . Morbidity and
occasional mortality from immunological treat-
ments in MS are of significant concern, especially
because these treatments do not prevent the dis-
ease or its progression over the years. Pathological
findings in newly forming acute demyelinating le-
sions may be characterised by virtual absence of
lymphocytes or myelin phagocytes that bear no
resemblance with the histology of EAE . There
is a growing controversy at present whether the pri-
mary disease process in MS is autoimmune [5,6].
One of the most valid criticisms of the autoim-
mune mechanism and the EAE model in MS is that
these assumptions cannot explain either the geo-
graphic distribution or the effect of early life
migration on the prevalence of MS. Exposure to
sunlight during early life is considered to have a
protective effect on the disease . Seasonal fluc-
tuations in the vitamin D level have been associ-
ated with MS relapses [8,9] and a prospective
longitudinal study in women recently found that
dietary vitamin D supplementation significantly re-
duced the incidence of MS . Here, I suggest that
vitamin D supplementation in pregnancy and early
life may prevent the symptomatic manifestation
of MS later in life. Vitamin D supplementation in
pregnant women should be considered as a public
health policy similar to maternal folic acid supple-
mentation that is currently recommended to pre-
vent neuralp tube defects.
The present review is based on our reading of
the existing medical texts and a search of
the PubMed and Medline for articles combining
(a) multiple sclerosis and vitamin D; (b) season
of birth and multiple sclerosis; (c) migration
and multiple sclerosis; (d) vitamin D and popu-
lation; and (e) myelin and/or oligodendrocytes
and vitamin D and/vitamin D receptor pub-
lished by March 2004. Only articles in English
were considered and where appropriate, orig-
inal articles cited in the published reference
lists were traced.
Physiology of vitamin D
Vitamin D (Fig. 1) is a steroid hormone in structure
and function. The dietary form of vitamin D is an
essential nutrient only if humans are not suffi-
ciently exposed to sunlight. With adequate expo-
sure to solar ultraviolet B radiation, vitamin D is
synthesised in the skin and no dietary supplement
is needed. The biologically active form of vitamin
D requires successive hydroxylations in the liver
and kidneys before it enters the circulation. Active
vitamin D, i.e., 1,25 dihydroxyvitamin D3, is recog-
nised by target tissues that possess a specific nucle-
ar receptor (vitamin D receptor or VDR). VDR is a
member of the steroid superfamily of receptors.
Interaction between VDR and active vitamin D re-
sults in the phosphorylation of the 1,25 dihydroxy-
vitamin D3-VDR complex. This phosphorylated
complex then combines with the retinoic acid
receptor to form a heterodimer that, in turn, inter-
acts with a specific vitamin D responsive element in
the target nuclei, leading to the mRNA synthesis for
proteins such as osteopontin and osteocalcin.
The bioactive form of vitamin D (1,25 dihydrox-
yvitamin D3) is produced not only in the kidneys but
also in the placenta during pregnancy. Receptors
for 1,25 dihydroxyvitamin D3are present in bone
and the best understood function of vitamin D is
in relation to its role in calcium and phosphate
homeostasis and to bone formation and mainte-
nance. Other than bone, VDR is expressed widely
in the intestine, skin, kidneys, pituitary, parathy-
roids, pancreatic beta cells, gonads, skeletal mus-
cles, circulating monocytes and activated T and B
As compared to the knowledge of vitamin D in
calcium homeostasis and skeletal growth, very lit-
tle is known about its role in the central nervous
system. The evidence for a neurobiological effect
of vitamin D came in 1991 when the regulatory ef-
fect of 1,25 dihydroxyvitamin D3on nerve growth
factor was first reported . Studies have since
shown that bioactive vitamin D may modulate the
production of neurotrophins, growth factors and
neurotransmitters in the mammalian brain .
Dietary requirement of vitamin D
It is not a current recommendation, at least in the
United Kingdom, that vitamin D supplementation
should be routinely offered either during pregnancy
or childhood unless there are concerns about nutri-
tional deficiency or malabsorption. It is generally
accepted that simple vitamin D deficiency can be
prevented by dietary supplementation of 400 units
(800 units in Asians and in the elderly) every day
. In England, a daily requirement of 100 units
was considered adequate in the adults on the basis
of its effect in only 7 women all of whom had se-
vere nutritional osteomalacia . However, a dai-
ly intake of 200 units of vitamin D, the currently
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