REVIEWS
Dietary supplements and disease
1
Division of Preventive
Medicine, Department of
Medicine, Brigham and
Women’s Hospital, Harvard
Medical School, Boston,
Massachusetts 02215, USA.
2
Institute of Environmental
Medicine, Karolinska
Institutet, 171 77
Stockholm, Sweden.
3
Department of Epidemiology,
Harvard T.H. Chan School
of Public Health, Boston,
Massachusetts 02215, USA.
4
Jean Mayer USDA Human
Nutrition Research Center
on Aging, Tufts University,
Boston, Massachusetts
02111, USA.
5
Division of Aging,
Department of Medicine,
Brigham and Women’s
Hospital, Harvard Medical
School, Boston,
Massachusetts 02215, USA.
Correspondence to J.E.M.
jmanson@rics.bwh.harvard.edu
doi:10.1038/nrendo.2016.54
Published online 6 May 2016
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 12 | JULY 2016 | 407
prevention — a global overview
Susanne Rautiainen1,2, JoAnn E. Manson1,3, Alice H. Lichtenstein4
and Howard D. Sesso1,3,5
Abstract | Dietary supplements are widely used and offer the potential to improve health if
appropriately targeted to those in need. Inadequate nutrition and micronutrient deficiencies are
prevalent conditions that adversely affect global health. Although improvements in diet quality
are essential to address these issues, dietary supplements and/or food fortification could help
meet requirements for individuals at risk of deficiencies. For example, supplementation with
vitamin A and iron in developing countries, where women of reproductive age, infants and
children often have deficiencies; with folic acid among women of reproductive age and during
pregnancy; with vitamin D among infants and children; and with calcium and vitamin D to ensure
bone health among adults aged ≥65 years. Intense debate surrounds the benefits of individual
high-dose micronutrient supplementation among well-nourished individuals because the
alleged beneficial effects on chronic diseases are not consistently supported. Daily low-dose
multivitamin supplementation has been linked to reductions in the incidence of cancer
and cataracts, especially among men. Baseline nutrition is an important consideration in
supplementation that is likely to modify its effects. Here, we provide a detailed summary of
dietary supplements and health outcomes in both developing and developed countries to
help guide decisions about dietary supplement recommendations.
Noncommunicable diseases are the most frequent causes among healthy participants and patients with a variety
of death worldwide, with a higher proportion of prema- of diseases reported increased mortality among those
ture deaths occurring in low-income and middle-income receiving supplements of β‑carotene and vitamin E2. In
countries than in high-income countries1. Thus, these addition, the USPSTF concluded that individual sup-
numbers underscore the urgent need for preventive strat- plements of β‑carotene, vitamin E, selenium, vitamin C,
egies and treatments on a global scale, and reductions of folic acid and vitamin D, or supplementation with a
current inequities within and among countries. combination of calcium and vitamin D, provided no
Dietary supplements comprise a broad array of beneficial effects for cancer and cardiovascular disease
products intended for ingestion to meet essential nutri- (CVD) prevention among nutrient-sufficient adults
tional requirements. These products are available in without prevalent disease at baseline3.
many forms (tablets, capsules, gelatin capsules, soft In this Review, we summarize the available evi-
gels, liquids, chewable preparations and powders) and dence on the potential role of dietary supplements in
can provide individual components or combinations the prevention of noncommunicable and communica-
of vitamins, minerals, herbs, amino acids, fatty acids ble chronic diseases from a global perspective. A huge
and other dietary components. Dietary supplements variety of supplements are currently available on the
of essential vitamins and minerals are important when market, with multiple chronic disease outcomes to be
nutritional requirements are not met through diet considered. Although observational studies — includ-
alone. Nevertheless, the role of dietary supplementation ing cross-sectional, case–control and cohort designs
when nutritional sufficiency has already been achieved — have important roles in hypothesis generation, their
remains vigorously debated, as potential deleterious inherent limitations (residual confounding by lifestyle;
effects of excessive intake have been identified for some collinearity of dietary and behavioural factors; and lack
micronutrients. A systematic review that summarized of randomization) limit conclusions on causal inference.
the effects of β‑carotene, vitamin A, vitamin C, vita- Consequently, we focus on randomized controlled tri-
min E and selenium supplementation on mortality als of essential vitamins, minerals and other common
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Key points 2013–2020 was, therefore, to promote a healthy diet,

• In developing countries, limited access or adaptation to a healthful, well-balanced
diet can cause micronutrient malnutrition, with irreversible health consequences
affecting morbidity and mortality
• Deficiencies in vitamin A and/or iron are prevalent among reproductive-aged
women, infants and children in developing countries, with therapeutic doses required
for treatment
• In developing and developed countries, reproductive-aged women or those who are
pregnant must ensure adequate intakes of folic acid, iron, calcium and iodine, which
might require supplementation
• In developed countries, adequate nutrient intake can usually be achieved through a
well-balanced diet and supplementation might not confer additional health benefits
(except among individuals with increased requirements)
• Postmenopausal women and elderly men could benefit from a combination
of low-dose calcium and vitamin D for bone health
• Use of a multivitamin supplement with low levels of essential vitamins and minerals
could be linked to reductions in the incidence of cancer and cataracts among men
dietary supplements (for example, n-3 fatty acids)
that have been evaluated in primary and secondary
prevention of noncommunicable and communicable
chronic diseases.
Global health challenges
Noncommunicable diseases have become a major global
burden in both developed and developing nations. An
estimated 36 million deaths (63% of the 57 million
that occurred globally in 2008) were caused by non­
communicable diseases, including CVD (48.0%), cancer
(21.0%), chronic respiratory disease (12.0%) and diabe-
tes mellitus (3.5%)1. The annual number of deaths from
CVD is expected to rise from 17 million to 25 million
between 2008 and 2030 owing to population growth
and increased longevity 1. A similar increase is expected
for cancer-related deaths in the same time frame (from
7.6 million to 13.0 million). Furthermore, in 2008, 80%
of all deaths from noncommunicable diseases occurred
in low-income and middle-income countries, with a
higher proportion of premature (≤70 years) deaths
recorded in middle-income countries than in high-
income countries (48% versus 26%)1. Thus, an urgent
need exists for simple and effective preventive strategies
and treatments that can be applied on a global scale.
Malnutrition
Malnutrition occurs when the nutritional requirements
for growth (calories and protein) are not met within
the context of either undernutrition or overnutrition.
This condition is a critical public health concern that
represents the largest single contributor to disease devel-
opment affecting quality of life in both developing and
developed countries4. Worldwide, ~805 million people
are chronically undernourished. In 2013, malnutrition
and communicable diseases accounted for 75% of all
deaths among infants aged 1–59 months, with 45% of
all such deaths in developing countries owing to under-
nutrition5. Unfortunately, improvements in nutrition
are unevenly distributed across affected areas6. One
key objective of the WHO Global Action Plan for the
Prevention and Control of Noncommunicable Diseases
with particular emphasis placed on maternal, infant and
early childhood nutrition6.
Malnutrition leads to deficiencies of essential micro-
nutrients, with damaging and sometimes irreversible
effects. Micronutrient malnutrition affects ~2 billion
people globally 7. Anaemia is one of the most frequently
reported conditions related to micronutrient defi-
ciency, affecting 43% of children, 38% of pregnant
women and 29% of nonpregnant women worldwide8.
The most common cause of anaemia is iron deficiency
(~50% of cases). Other nutritional factors implicated
in the development of anaemia include deficiencies in
vitamin A, vitamin B12, folate and riboflavin8. Vitamin
and mineral deficiencies are also prevalent among the
elderly owing to multiple factors — including difficul-
ties with chewing and swallowing, sensory loss and
comorbidities — that are superimposed on diminished
energy needs and reduced overall caloric intake9. Finally,
chronic poor food choices can lead to micronutrient
insufficiencies and deficiencies regardless of age and
demographic characteristics.
Prevalence of dietary supplement use
Global assessment of the prevalence of dietary sup-
plement use is problematic owing to variations in
inclusion criteria, assessment methods, definition of
supplement use and the time frame for data collection.
Consequently, most of the available information has
come from national surveys, although it should be noted
that population-level data are still not available for many
parts of the world.
Data on the prevalence of dietary supplement use
are summarized in TABLE 1. The prevalence of dietary
supplement use ranged from 22% to 53% in studies con-
ducted in the USA10, Canada11, Korea12, UK13, Sweden14,
Germany 15 and France16. Multivitamins with or without
minerals were the most frequently used supplements in
the USA10, whereas in Canada, vitamin C was the most
frequently used supplement overall, with vitamin D the
most prevalent supplement among women11. A compari-
son of dietary supplement use data among cohort studies
included in EPIC concluded that the frequency and type
of dietary supplement use varied widely across countries
and that the prevalence was higher in northern regions
of Europe than in southern regions17.
Major chronic disease outcomes
Noncommunicable diseases such as cancer, CVD,
chronic respiratory disease and diabetes mellitus are the
major causes of death globally 1.
Cancer
Optimum micronutrient intake could be crucial for can-
cer prevention, a theory that has been tested in many
randomized clinical trials conducted over the past few
decades. However, the timing of dietary supplementa-
tion for cancer prevention remains poorly understood
because cancer can take many years to develop and
long-term dietary supplement interventions are almost
impossible to accomplish. Indeed, for some nutrients,

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Table 1 | National prevalence of dietary supplement use

Source Country Study Participants Exposure assessment Prevalence
Bailey et al. USA NHANES Noninstitutionalized US civilians Questionnaire assessing use of Any
(2011)10 aged ≥1 years (n = 18,758; 9,268 F vitamins, minerals, herbals and other • F: 53%
and 9,490 M) supplements during the past 30 days • M: 44%
(study period, 2003–2006)
MVM
• F: 36%
• M: 31%
Shakur et al. Canada CCHS 2.2 Nationally representative M and F Interview assessing vitamin and Any
(2012)11 aged ≥1 years (n = 34,381) mineral supplement use during the • F + M: 40%
past 30 days (study period, 2004)
MVM
• F + M: 28%
Vitamin D
• F + M: 28%
Lee et al. Korea KNHANES III Noninstitutionalized Korean Questionnaire assessing use of pill, Any
(2009)12 civilians aged ≥20 years (n = 4,775; capsule, coated tablet, drops or • F: 32%
2,792 F and 1,983 M) powder of a compound providing • M: 22%
nutritional value during the past year
(study period, 2005)
Lentjes et al. UK EPIC–Norfolk M and F aged 39–79 years Diet diary recording any use of Any
(2015)13 registered at 35 general practices vitamins, minerals or other food • F: 46%
in the east of England (n = 11,060) supplements over 7 days (study • M: 35%
period, 1993–1998)
Messerer Sweden Swedish Nationally representative Interview assessing use of any Any
et al. (2001)14 population sample of Swedish M and F aged dietary supplement (excluding iron) • F: 33%
16–84 years (n = 11,422; 5,826 F or ‘strengthening’ medicine during • M: 22%
and 5,596 M) the past 2 weeks (study period,
1996–1997)
Li et al. Germany EPIC–Heidelberg M aged 40–64 years and F aged Computer-interactive interview Any (regular use)
(2010)15 35–64 years living in Heidelberg assessing use of any dietary • F: 39%
and the surrounding areas supplements in the past 4 weeks • M: 29%
(n = 19,640; 10,672 F and 8,968 M) (study period, 1994–1998)

Pouchieu France NutriNet-Santé French residents aged ≥18 years Questionnaire assessing any Any
et al. (2013)16 with access to the internet dietary supplement use in the past • F: 46%
(n = 79,786; 60,388 F and 19,398 M) 12 months (study period, 2009) • M: 24%
Vitamin D
• F: 22%
• M: 25%
F, female; M, male; MVM, multivitamin supplement (with or without minerals).

supplementation might increase the rate of cancer pro-
gression, especially when taken in amounts that exceed
the recommended dietary allowance (RDA).
In 2013, the USPSTF presented a systematic review
on the effects of supplements in the primary prevention
of cancer among nutrient-sufficient adults without prev-
alent chronic diseases at baseline3 (BOX 1). Neither indi-
vidual supplements (β‑carotene, vitamin E, selenium,
vitamin C, folic acid and vitamin D) nor combined sup-
plementation (calcium plus vitamin D) exhibited bene-
ficial effects in cancer prevention. However, the USPSTF
concluded that the current evidence is insufficient to
assess the balance of benefits and harms of the use of
multivitamins based on evidence from two large-scale
trials (PHS II and SU.VI.MAX). Although PHS II and
SU.VI.MAX reported a reduction in cancer incidence
among men, the USPSTF concluded that because of the
lack of effect in women and the use of different supple-
ment formulations in the two trials the extrapolation of
findings to the general population is difficult.
To date, PHS II is the only large-scale trial to test a
multivitamin supplement that included essential vita-
mins and minerals at amounts approximating the RDA18.
This study included 14,641 male physicians and recorded
an 8% reduction in total cancer incidence among those
taking a daily multivitamin versus the placebo group.
The reduction in total cancer incidence seemed not to
be driven by any individual site-specific cancers. In addi-
tion, the effect was stronger among men with a history
of cancer than men without a history of cancer, with a
reduction in recurrent cancer of 27% versus 6%, respec-
tively 18. The SU.VI.MAX trial did not test a multivitamin
supplement but instead used low doses of ascorbic acid
(120 mg), vitamin E (30 mg), β‑carotene (6 mg), selenium
(100 μg) and zinc (20 mg)19. No overall effect on total can-
cer incidence was found among 13,017 French women
and men; however, a 31% risk reduction was found
in men. The observed risk reduction among men was
strongest for individuals with β‑carotene and vitamin C
blood concentrations of <0.30 μmol/l and <11.4 μmol/l,

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Box 1 | Supplementation during adulthood
• Low-dose calcium plus vitamin D supplementation might reduce risk of fractures and
BMD loss among postmenopausal women and men aged ≥65 years.
• Low-dose multivitamin supplementation seems to reduce the risk of incident cancer
(especially among men with baseline nutritional deficiencies or a previous cancer
diagnosis) and age-related cataracts. These effects remain to be confirmed in
large-scale trials (especially among women) and with baseline nutritional status taken
into account.
• Individual high-dose supplements of β‑carotene, vitamin E, selenium, vitamin C or
folic acid are not recommended for cancer or cardiovascular disease prevention.
• Harmful effects of high-dose supplementation with individual vitamins, including
β‑carotene, folate and vitamin E, have been reported.
respectively, emphasizing the potential importance of
taking baseline nutritional status into account 20. The
Linxian Chinese Cancer Prevention Trial included 29,584
adults from a population with documented subclinical
deficiencies of several nutrients. Low-dose supplemen-
tation with β‑carotene, vitamin E and selenium reduced
total cancer incidence by 13% and stomach cancer inci-
dence by 21%21. Thus, given the above evidence that low-
dose vitamin and mineral supplementation could prevent
cancer, a novel clinical trial (COSMOS; NCT02422745)
was initiated in 2016 to test a multivitamin supplement
comprising all essential low-dose vitamins and miner-
als among 12,000 women and 6,000 men with 4 years of
treatment and follow‑up. The results of COSMOS are not
expected for several years.
Despite the mounting evidence from observational
studies for an inverse association between the levels of
vitamin D and cancer risk22, no long-term large-scale
randomized trials of vitamin D supplementation with
cancer as the primary prespecified end point have been
completed. A systematic review of 18 predominantly
placebo-controlled randomized trials found that supple-
mentation with vitamin D₃ decreased cancer mortality
by 12% and vitamin D decreased all-cause mortality by
7% among adults; however, only 50,623 participants
were included and substantial dropout rates of 3.2% and
3.4% were recorded in the active and placebo groups,
respectively 23. Secondary analyses of previously com-
pleted trials have not yet provided support for a potential
role of supplemental vitamin D in cancer prevention24–28.
However, these trials assessed low doses of vitamin D
(typically <1,000 IU per day) and were probably under-
powered, with short durations of follow‑up. For exam-
ple, approximately one-third of the women enrolled in
the US Women’s Health Initiative (WHI) reported low
calcium intake (<800 mg per day) at baseline. After an
average of 7 years follow‑up, supplementation with vita-
min D (400 IU per day) and calcium (1,000 mg per day)
nonsignificantly reduced cancer deaths in this study
(HR, 0.89)24. The RECORD trial randomly allocated
5,292 UK individuals aged ≥70 years to daily vitamin D3
(800 IU), calcium (1,000 mg), vitamin D3 plus calcium,
or placebo for a period of 24–62 months, with 3 years
of follow‑up for fractures; no effect was found for either
total cancer incidence or mortality 27. Several large-scale
ongoing trials in the USA, UK, Finland and Australia will
test vitamin D at levels ranging from 1,600 IU per day
to 100,000 IU per month among up to 100,000 women
and men aged ≥50 years with 5 years of follow‑up29–31.
No primary prevention trials are currently availa-
ble for the effects (if any) of n-3 fatty acids on cancer.
However, trials of these compounds for secondary
prevention of CVD or among populations at increased
risk of CVD have reported no marked effects on cancer
incidence32–36. By contrast, the SU.FOL.OM3 trial raised
some concerns about the potential harmful effects of
n-3 fatty acids on cancer incidence among women (HR,
3.02)37. To date, VITAL is the only ongoing large rand-
omized trial testing n-3 fatty acids for the primary pre-
vention of cancer in a general population (25,874 men
and women in the USA)29.
Prostate cancer. Supplementation of individual vitamins
and minerals has been tested for prostate cancer preven-
tion, with largely equivocal results. SELECT randomly
allocated 35,533 men who were generally well-nour-
ished at baseline to receive selenium (200 μg per day),
vitamin E (400 IU per day), selenium plus vitamin E,
or placebo, with prostate cancer incidence as the pri-
mary end point; the trial ended early (after 5.5 years of
follow‑up) owing to ineffectiveness of the intervention38.
Nevertheless, the selenium formulation used in SELECT
has been criticized39. After 7 years of unblinded post-trial
follow‑up, increased risk of cancer was noted in the vita-
min E arm (HR, 1.17; P <0.05) but not in the selenium
arm (HR, 1.09; P >0.05) of SELECT40. Another trial tested
200 μg per day of selenium versus placebo among 423
men classified as being at high risk of prostate cancer;
no effect on Gleason score was found after 3 years of
follow‑up41. However, potential lowering of prostate can-
cer incidence associated with selenium supplementation
among men with low baseline plasma levels of selenium
(<106 ng/ml) was noted in this study. Neither vitamin E
nor vitamin C had any effect on the incidence of prostate
cancer in PHS II, contradicting the findings of SELECT42.
Moreover, low-dose antioxidant supplementation in
SU.VI.MAX reduced prostate cancer risk by 48% among
men with levels of prostate-specific antigen within the
normal range but nonsignificantly increased the risk by
54% among men with elevated levels of this biomarker
at baseline43.
Colorectal cancer. High doses of individual vitamins and
minerals have been hypothesized to have a preventive
role in colorectal cancer. In a combined analysis of ran-
domized trials for the secondary prevention of colorec-
tal adenomas, folic acid supplements (0.5–1.0 mg per
day) did not prevent the development of new colorectal
adenomas among women or men44. However, folic acid
was linked to reductions in mortality. When stratify-
ing patients by baseline plasma folate concentrations,
a statistically nonsignificant increased survival was
reported among individuals with the lowest concen-
trations (≤11 nmol/l), whereas those with the highest
concentrations (>29 nmol/l) had increased mortality 44.
By contrast, in WAFACS — a long-term trial of women
at high risk of CVD — supplementation with folic acid

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(2.5 mg), vitamin B6 (50 mg) or vitamin B12 (1 mg) had
no appreciable effect on the incidence of colorectal can-
cer 45 or colorectal adenoma46. These results emphasize
the importance of taking baseline nutritional status
into account when testing vitamin and mineral sup-
plements in disease prevention. Given the widespread
folate fortification of the food supply in the USA and
other countries, the finding of a potential adverse effect
in the secondary prevention of colorectal adenomas is of
concern and requires clarification.
Vitamin D has been suggested to be an important
nutrient in the prevention of colorectal cancer develop-
ment; however, to date, no completed primary prevention
trials have tested this hypothesis. Secondary analysis of the
WHI did not report an appreciable effect of a low-dose
combination pill including calcium and vitamin D com-
pared with placebo on the incidence of invasive colorectal
cancer 25. A trial of 2,259 patients with newly diagnosed
adenomas found that administration of 1,000 IU of vita-
min D daily had no effect on recurrent colorectal adeno-
mas47. A similar absence of benefit for recurrent colorectal
adenomas was reported in another trial48.
Breast cancer. Few randomized trials have tested indi-
vidual or multivitamin supplements for the prevention of
breast cancer. In the WHI, administration of a combined
calcium and vitamin D supplement was not associated
with the incidence of invasive breast cancer among post-
menopausal women26. In two separate meta-analyses that
combined small randomized trials testing folic acid49 or
β-carotene50 supplements, neither reported a statistically
significant effect on breast cancer.
Lung cancer. Antioxidant supplementation was hypothe-
sized to prevent lung cancer because this organ is chroni-
cally exposed to high levels of oxidative stress, especially
among smokers and workers exposed to asbestos. The
ATBC study randomly allocated 29,133 individuals who
smoked to receive vitamin E (50 mg daily), β‑carotene
(20 mg daily), vitamin E plus β‑carotene or placebo.
Vitamin E had no appreciable effect on lung cancer
risk, whereas β‑carotene increased the risk by 18%51. An
increased risk of lung cancer (HR, 1.46) was detected in
CARET, a study that enrolled 18,314 smokers, former
smokers and individuals exposed to asbestos in the work-
place who were administered a combination pill compris-
ing β‑carotene (30 mg) and retinol (25,000 IU)52. Notably,
other trials among populations with a lower proportion
of smokers than in ATBC and CARET reported no effect
of β‑carotene on lung cancer risk53–56.
Cardiovascular disease
Observational studies have consistently reported an
inverse association between the risk of CVD and high
intakes of fruit, vegetables, fish and other foods, which
suggests that specific individual vitamins and minerals
might be responsible for these effects. However, large-
scale, long-term randomized controlled trials have yet
to provide definitive evidence that dietary supplements
match the purported cardiovascular benefits of a food-
based approach. Consequently, the USPSTF concluded
there was insufficient evidence to support any beneficial
or harmful effects of multivitamin supplements or indi-
vidual nutrient supplements on the primary prevention
of CVD among nutrient-sufficient adults3. That said, the
USPSTF did recommend against the use of β‑carotene
and vitamin E supplements for CVD prevention owing
to potential harmful effects reported in large-scale tri-
als2,51,52. Vitamin E supplementation has been extensively
tested in randomized trials with CVD as the primary end
point but no beneficial effects have been reported57–59.
Furthermore, a meta-analysis of randomized trials testing
vitamin E reported a 22% increased risk of haemorrhagic
stroke but a 10% reduced risk of ischaemic stroke60.
B vitamins. Several trials have investigated whether folic
acid, vitamin B12 and vitamin B6, which are all important
regulators of homocysteine metabolism, reduced CVD
among participants at high risk of developing these con-
ditions. Although the levels of homocysteine were low-
ered in response to ingestion of these vitamins61–65, no
corresponding effect on CVD has yet been reported61–70.
The China Stroke Primary Prevention Trial reported
that folic acid supplementation (0.8 mg per day) reduced
stroke incidence by 21%, mainly through reductions in
ischaemic stroke among adults with hypertension66. In
this trial, the beneficial effect was strongest among the
participants with the lowest baseline folate concentra-
tions (<5.6 ng/ml). No effect on major CVD events was
observed in WAFACS, which tested higher amounts
of folic acid (2.5 mg per day) than the China Stroke
Primary Prevention Trial together with vitamin B6
(50 mg per day) and vitamin B12 (1 mg per day) among
female health-care professionals at high risk of CVD but
with low risk of folate deficiency 67. The NORVIT trial
tested various daily vitamin B combinations of folic acid
(0.8 mg), vitamin B12 (0.4 mg) and vitamin B6 (40 mg)
versus placebo among patients with acute myocardial
infarction62. Although the combination of these vita-
mins reduced homocysteine concentrations, there was
a 22% increased risk of further major CVD events, which
resulted in early termination of another trial running in
parallel after reporting no effect of B vitamins on CVD68.
Finally, the SU.FOL.OM3 trial tested vitamin B supple-
mentation for the secondary prevention of major CVD
events and reported no effect 70.
Taken together, trials testing supplements of
homocysteine-lowering B vitamins have reported
inconsistent findings for CVD risk, which might partly
be explained by differences in baseline nutritional status.
Vitamin D. No completed trials have specifically tested
the effect of vitamin D supplementation with CVD
as the primary end point. However, four ongoing large-
scale trials conducted in the USA, Europe and Australia
will enrol up to 100,000 participants and are likely to
provide definitive answers in the years to come29–31.
Secondary analyses of trials tested use of a combina-
tion pill comprising low-dose vitamin D (400–1,000 IU
daily) and calcium (1,000 mg daily), mainly among post­
menopausal women24,27,71–73. To date, the results from
these completed trials do not support a role for vitamin D

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supplementation, either alone or in combination with Hypertension

calcium, for the prevention of CVD; however, new evi-
dence will emerge in the coming years to clarify the pos-
sible effect of individual supplementation with vitamin D
on CVD and other chronic diseases.
n-3 fatty acids. Levels of triglycerides were substantially
lowered by n-3 fatty acids in some clinical trials74; how-
ever, n-3 fatty acids have not shown beneficial effects on
other biomarkers of CVD risk, including levels of LDL
cholesterol. Moreover, trials testing the effect of n-3
supplementation on CVD risk have been limited to sec-
ondary prevention trials or have enrolled participants at
increased risk of CVD, with inconsistent results. Three
trials reported that n-3 supplementation (1.0–1.8 g)
reduced total CVD or coronary events by 8–19%32,33,75.
However, trials testing n-3 supplements (0.4–2.3 g) in
high-risk groups or among patients after myocardial
infarction reported no effect on CVD34–36,70,76. Baseline
n-3 fatty acid intake and concurrent use of lipid-lowering
medications could partly explain the null findings. Little
is known about the efficacy of n-3 supplements for the
primary prevention of CVD. As such, VITAL will provide
important insights as to whether supplementation aids the
primary prevention of CVD among men aged ≥50 years
and women aged ≥55 years29.
Multivitamins. The use of a low-dose multivitamin sup-
plement comprising essential vitamins and minerals as an
approach to prevent CVD has not been extensively tested,
which is surprising given the widespread use of multi­
vitamin preparations worldwide. The only available clin-
ical trial evidence is from PHS II, which was conducted
among male physicians aged ≥50 years. This study found
that administration of a multivitamin supplement had no
effect on major CVD events but did confer a lower risk
of fatal myocardial infarction (HR, 0.61), although these
results should be interpreted with caution because of
multiple comparisons and a low number of incident cases
developing during the trial77. The effect of multi­vitamin
supplementation on major CVD events was modified by
age with a statistically nonsignificant lowered risk of CVD
among men aged ≥70 years (9%). Determining whether
baseline nutritional status might modify the effect would
greatly improve understanding of which individuals
might (or might not) benefit from multivitamin use for
CVD and other chronic disease end points.
Conceptually similar to PHS II, the SU.VI.MAX trial
conducted among French adults tested a limited low-dose
combination of ascorbic acid (120 mg), vitamin E (30 mg),
β‑carotene (6 mg), selenium (100 μg) and zinc (20 mg) and
found no effect on ischaemic CVD among either men or
women19. The Linxian Chinese Cancer Prevention Trial,
which investigated a multivitamin supplement comprising
vitamins and minerals at doses above the RDA among
adults with oesophageal dysplasia, found a statistically
nonsignificant 38% reduction in cerebrovascular deaths
in this nutrient-insufficient population78. Finally, the on­
going COSMOS trial is expected to provide further insight
as to whether multivitamin supplementation has any role
in CVD prevention.
Hypertension is considered a major risk factor for CVD,
and it is well-established that a diet characterized by high
amounts of fruit, vegetables and fish plus low amounts of
saturated fatty acids and sodium can lower blood pres-
sure and reduce risk of hypertension79,80. Nevertheless,
whether vitamin and mineral supplementation might
help to lower blood pressure and so reduce the risk of
hypertension is less well studied. Neither blood pres-
sure nor hypertension have been considered as primary
end points in many trials of supplements conducted
to date. A meta-analysis of vitamin C supplementa-
tion reported short-term reductions in blood pressure
(−3.84 mm Hg for systolic and −1.48 mm Hg for dia­
stolic). When trials with high baseline concentrations
of ascorbic acid (>60 μmol/l) were excluded, somewhat
stronger effects were reported (−4.16 mm Hg for systolic
and −2.21 mm Hg for diastolic). However, long-term
trials have yet to confirm these effects or any impact on
hypertension prevention81.
Vitamin D has been suggested to lower blood pressure
and prevent hypertension on the basis of observational
studies that consistently link low blood concentrations
of vitamin D with increased blood pressure levels82.
However, a growing body of clinical trials evidence sug-
gests that vitamin D has no effect on short-term changes
in blood pressure. Two trials that tested 4,000 IU per day
to 100,000 IU every 3 months of vitamin D supplemen-
tation among women and men with low blood levels of
25‑hydroxyvitamin D (<30 ng/ml) at baseline found no
overall effect on 24 h ambulatory blood pressure measure-
ments83,84. By contrast, in a trial conducted among patients
with hypertension, vitamin D supplementation (3,000 IU
per day) reduced 24 h systolic (−4 mm Hg) and diastolic
(−3 mm Hg) blood pressure when analyses were restricted
to 92 women and men with blood 25‑hydroxyvitamin D
levels <32 ng/ml at baseline85. Another trial among 148
elderly women with blood levels of 25‑hydroxyvitamin D
<20 ng/ml reported reductions in clinically measured
systolic blood pressure (−5 mm Hg) in the group receiv-
ing vitamin D supplementation (800 IU) with calcium
(1,200 mg) after 8 weeks of follow‑up86. A meta-analysis
of small trials of vitamin D supplementation reported no
effect on blood pressure87. However, in these trials, nei-
ther blood pressure nor hypertension was the primary
end point, and many of the participants were already
taking antihypertensive medications.
Gestational hypertension is one of the leading causes
of maternal morbidity and mortality and this condition
has been linked to an increased risk of preterm birth and
fetal growth restriction88. A systematic review reported
that calcium supplementation during pregnancy among
women with low calcium intake (defined differently
among the included trials) reduced the risk of elevated
blood pressure by 35% (12 trials) and preeclampsia by
55% (13 trials)89 (BOX 2). Nonetheless, these results should
be interpreted with caution because the individual trial
cohorts were small. Clearly, the need exists for large-scale
trials to investigate whether supplementation with cal-
cium or other micronutrients might have a role in the
prevention of gestational hypertension and preeclampsia.

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Box 2 | Supplementation during pregnancy
• Folic acid supplementation is recommended among reproductive-aged women
and during at least the first trimester of pregnancy to prevent neural tube defects.
Folic acid might be important for the prevention of other outcomes; however, more
studies are needed to address this point.
• Vitamin A supplementation during pregnancy is recommended in areas where
vitamin A deficiency is highly prevalent for the prevention of night blindness.
However, vitamin A is teratogenic when consumed in excess.
• Iron supplementation is used among women with low haemoglobin and/or
ferritin levels during pregnancy to prevent and treat anaemia. Little is known
about the effect of iron supplementation on outcomes in the offspring.
• Iodine supplementation is recommended in areas where iodine deficiency
is prevalent to reduce the risk of congenital hypothyroidism. However,
supplementation is not recommended among women with optimum
iodine status.
• Calcium supplementation among pregnant women with low calcium intake
seems to reduce the risk of gestational hypertension and preeclampsia. However,
there is a need for large-scale trials to confirm this effect.
• The effects of supplementation with n-3 fatty acids, vitamin D and multivitamins on
maternal and child health requires further study.
Type 2 diabetes mellitus
A well-balanced and nutritionally adequate diet is
thought to be critical for the prevention and treatment
of type 2 diabetes mellitus90. Nonetheless, the effect of
different vitamin and mineral supplements in diabetes
prevention and glycaemic control among both diabetic
and nondiabetic participants is less well studied. The
majority of evidence is based upon results from second-
ary analyses of clinical trials testing individual vitamins
and minerals at amounts substantially above the RDA.
The Women’s Antioxidant Cardiovascular Study indi-
cated a statistically nonsignificant reduced risk of type 2
diabetes mellitus with vitamin C (500 mg per day),
increased risk (HR, 1.13) with vitamin E (600 IU taken
every other day) and no effect with β‑carotene (50 mg
taken every other day)91. Vitamin E had no effect on
type 2 diabetes mellitus in the WHS and ATBC trials92,93.
In a secondary analysis of WAFACS, no effect on type 2
diabetes mellitus was detected for high doses of folic acid
(2.5 mg per day), vitamin B6 (50 mg per day) and vita-
min B12 (1 mg per day)94. A meta-analysis of randomized
trials testing vitamin D supplementation, administered
either alone or in combination with calcium, concluded
that there was no evidence for an effect of vitamin D
supplementation (interquartile range: 1,000–5,536 IU)
on glucose homeostasis or diabetes mellitus prevention,
with follow‑up times ranging from 4 weeks to 7 years95.
Finally, several small-scale clinical trials testing magne-
sium supplements have reported statistically significant
improvements in insulin sensitivity and prevention of
type 2 diabetes mellitus96–99.
Bone health
Deposition of bone mineral commences in utero, with
bone mineral content increasing 40‑fold from birth until
adulthood100. Calcium and vitamin D are key nutrients in
skeletal health101. Vitamin D can be synthesized in the skin
from UVB radiation; however, at latitudes >33°, including
North America and Europe, the sun is only an effective
source of vitamin D during the summertime102. Dietary
sources of vitamin D are limited and predominantly
comprise fatty fish.
Calcium and vitamin D
Clinical trials investigating combined supplementation
for the prevention of fractures or changes in BMD among
postmenopausal women and men aged ≥65 years have
predominantly reported promising results103–111 (BOX 1).
Nevertheless, pooling data from 11 randomized trials
indicated that administration of ≥800 IU vitamin D daily
lowered the risk of both hip fracture and nonvertebral
fractures by 10% and 7%, respectively, among individuals
aged ≥65 years111.
Routine vitamin D supplementation is currently rec-
ommended for infants in the USA and some European
countries to prevent rickets, especially among those who
are exclusively breastfed100,112,113 (BOX 3). Nutritional rick-
ets is still prevalent among children in parts of Africa,
Asia and the Middle East. The dose, duration and critical
period for vitamin D supplementation remains debated,
with recommendations varying by country 114. Intake
of calcium and vitamin D in youth and adolescence is
also important, although ensuring sufficiency might not
require supplementation if adequate levels of these nutri-
ents are derived from dietary sources100. Moreover, vita-
min D fortification is implemented in countries of both
North America and Europe115, although little is known
about the long-term nonskeletal health implications of
this policy 116.
Vitamin K
Vitamin K is also an important nutrient for bone health;
however, any role for supplementation on fracture risk
or markers of bone formation and resorption remains
unclear. Clinical trials testing vitamin K supplements have
been performed among postmenopausal women but offer
mixed results for fracture and changes in BMD117–124.
Vitamin K1. Beneficial effects were noted for fracture risk
but not BMD in a randomized trial that tested daily vita-
min K1 supplementation (5 mg) for 2–4 years among 440
postmenopausal women with osteopenia117. A Scottish
trial that included 244 nonosteoporotic postmenopausal
women tested daily administration of vitamin K1, vita-
min D and calcium at levels close to the RDA (200 μg,
400 IU and 1,000 mg, respectively)118. In this trial, sus-
tained increases in both BMD and bone mineral content
were observed over a period of 2 years. A trial of 181
Dutch postmenopausal women tested 1 mg of vitamin K1
with low doses of vitamin D (8 μg), calcium (500 mg),
zinc (10 mg) and magnesium (150 mg) for 3 years, and
reported increased BMD in the femoral neck but not in
the lumbar spine119.
Vitamin K2. Several studies support a beneficial effect of
vitamin K2 on bone health121,122,124. One trial conducted
among 244 healthy postmenopausal women found that
daily administration of low-dose vitamin K2 (180 μg
menaquinone‑7) for 3 years reduced bone loss121. In
addition, a trial among 325 postmenopausal women

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Box 3 | Supplementation among infants and children
• The WHO recommends vitamin A supplementation for infants aged 6–59 months in
areas where vitamin A deficiency is a public-health problem to reduce morbidity and
mortality. This approach also applies to children infected with HIV.
• Vitamin D supplementation can be used to prevent rickets among infants.
• Iron supplementation can be considered to prevent anaemia and iron deficiency
among infants aged 6–23 months in areas where anaemia is prevalent or where
intakes of foods fortified with iron are low. Little is known about the effects on
morbidity, mortality or developmental outcomes.
• Supplementation with n-3 fatty acids among children with attention deficit
hyperactivity disorder or autism spectrum disorders could reduce symptoms;
however, well-designed large-scale randomized trials are needed.
• Multivitamin supplementation might reduce duration of hospital admission for
diarrhoea and respiratory infections, but little is known about effects on other
health outcomes.
reported substantial effects on bone health after 3 years
of follow‑up in response to supplementation with vita-
min K2 (45 mg per day of menaquinone‑4)122. A Japanese
study of 48 postmenopausal women tested a vitamin K2
supplement (45 mg per day of menaquinone‑4) and
found appreciable improvements in bone quality, as
shown by decreasing blood concentrations of under-
carboxylated osteocalcin and pentosidine124. By con-
trast, two other trials reported no effect of vitamin K2
supplementation on bone health120,123.
Eye disease
Visual impairment and blindness are major public health
problems that affect quality of life and incur large soci-
etal costs125. Cataracts, age-related macular degeneration
and malnutrition-related eye conditions among children
(for example, vitamin A deficiency) are the leading
causes of blindness worldwide. Individuals in develop-
ing countries account for ~90% of all visual impairment
on a global scale, yet 80% of cases are considered to be
preventable and/or treatable125.
Cataracts and macular degeneration
Oxidative stress is involved in the pathophysiology of
both cataracts and age-related macular degeneration.
Consequently, supplementation with antioxidant vita-
mins and minerals was hypothesized to slow disease
progression.
To date, clinical trials of individual vitamins at lev-
els exceeding the RDA have not reported a beneficial
effect on age-related cataracts126–131. By contrast, studies
investigating the use of multivitamins, comprising essen-
tial vitamins and minerals at RDA levels, have reported
marked slowing of cataract progression132–134. In PHS II, a
9% reduction in the incidence of cataracts was observed
with long-term daily multivitamin use134.
Randomized trials investigating the effects of individ-
ual or multiple nutrients on age-related macular degen-
eration at levels above the RDA have reported mixed
results135–141. The AREDS trial tested a combination of
vitamin C (500 mg), vitamin E (400 IU) and β‑carotene
(15 mg) with zinc (80 mg) and reported marked
reductions in the progression of advanced age-related
macular degeneration that persisted for 5 years after the
intervention136. In WAFACS, a combined pill of folic
acid (2.5 mg per day), vitamin B6 (50 mg per day) and
vitamin B12 (1 mg per day) reduced age-related macular
degeneration by 34%139. By contrast, long-term multi-
vitamin use, which included all essential low-dose vita-
mins and minerals, had no effect on age-related macular
degeneration in PHS II134.
Loss of vision and night blindness
In 2011, the WHO published a report evaluating the
effect of vitamin A supplementation during pregnancy
among women in developing countries who were at risk
of vitamin A insufficiency 142. This report concluded that
parental vitamin A supplementation conferred no effect
on maternal or child mortality; however, preventable
effects on night blindness were noted. Current recom-
mendations for vitamin A supplementation are up to
10,000 IU per day or 25,000 IU per week during a min-
imum of 12 weeks of pregnancy until delivery in areas
where vitamin A deficiency and night blindness are fre-
quent among women and children142 (BOX 2). Increased
risk of vomiting and fontanel bulging have been noted
as adverse effects in trials testing therapeutic doses of
vitamin A among infants143,144.
Infectious diseases
Pneumonia causes 2 million deaths annually among
children aged ≤5 years in developing countries. Together,
pneumonia and diarrhoea are the main causes of mor-
bidity and mortality among both infants and children,
particularly those infected with HIV145.
Vitamin A
A systematic review of trials investigating the effect of
vitamin A supplementation on mortality related to infec-
tious diseases among populations deficient in this nutri-
ent revealed substantial reductions in diarrhoea-related
mortality (28%) and new episodes of diarrhoea (15%);
however, no effects were observed for mortality associ-
ated with measles or respiratory disease143 (BOX 3). High
doses of vitamin A (100,000–200,000 IU) have often
been used in clinical trials, raising concerns that supple-
mentation might promote adverse effects. A systematic
review of three trials indicated that chronic supplemen-
tation with high-dose vitamin A increased the risk of
vomiting (risk ratio, 2.75)143. Moreover, vitamin A tox-
icity has been documented at the doses used in previous
trials, and teratogenic effects have been reported when
consumed in high amounts during pregnancy 146.
HIV
Estimates suggest that 35 million people worldwide are
infected with HIV5,147. The prevalence of new cases of HIV
infection declined by 33% from 2001 to 2012 as a result of
increased access to antiretroviral therapy and public-health
prevention strategies. Conversely, the proportion of indi-
viduals living with HIV has increased dramatically as
deaths from AIDS have dropped. Thus, HIV has become
a manageable chronic disease, although the long-term con-
sequences of persistent viral infection and medication use
have been associated with adverse effects147.

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Multivitamin supplements have been tested among
children and adults with HIV. A systematic review indi-
cated marked reductions in the duration of hospital
admission owing to diarrhoea and respiratory infections
among children148 (BOX 3). By contrast, a trial conducted
among HIV-positive children reported reductions in
diarrhoea and acute upper-respiratory tract infections
for those receiving zinc but not a multivitamin; how-
ever, a statistically nonsignificant increase in mortality
was reported for the zinc treatment arm149. Further trials
are needed to understand the short-term and long-term
effects of multivitamin supplements among children and
adults infected with HIV. Moreover, individual vitamin D,
zinc and selenium supplements have yet to be thoroughly
investigated for any effects in these populations149.
defects160. Maternal iron supplementation might also
reduce the risk of low birth-weight and preterm birth,
although the data were not statistically significant 160.
Childhood iron deficiency anaemia has been linked
to increased childhood morbidity and impaired cog-
nitive development and educational performance.
Although trials of iron supplementation have reported
improvements in haemoglobin concentrations and risk
reduction of anaemia and iron deficiency (BOX 3), few
have investigated the consequences on mortality, mor-
bidity, developmental outcomes and adverse effects161.
Of note, the USPSTF concluded that further research is
needed to assess the benefits and harms of routine iron
supplementation to prevent anaemia among pregnant
women and infants162.

Birth defects and child growth Iodine

Adequate nutrition is crucial among reproductive-aged
women, particularly for those planning a pregnancy or
already pregnant. Several micronutrient deficiencies
have been linked to adverse effects among mothers and
their offspring.
Folate
Estimates from 2012 projected that 270,358 deaths
worldwide (equivalent to 3.3 deaths per 1,000 live births)
were attributable to congenital anomalies and neural tube
defects that developed during the first 28 days after con-
ception owing to folate insufficiency 150. Children born
with neural tube defects are extremely likely to experi-
ence lifelong physical and mental handicaps, and only a
few will function independently as adults151. Folate and
folic acid supplementation prevents the development
of neural tube defects among women with inadequate
folate intake (BOX 2); however, little is known about the
effects of these nutrients on other birth defects152. Thus,
in many developed countries, folic acid is recommended
for routine use for women of reproductive age and dur-
ing pregnancy 153,154. However, many European countries
report low compliance with such supplementation during
pregnancy 153,155–157. Moreover, many countries have also
implemented a national food fortification policy. Some
potential concerns have been raised about an increased
risk of wheezing and asthma among children with
mothers who took folic acid supplements during preg-
nancy but clinical trials have yet to clarify this issue158. In
addition, given the high prevalence of folic acid supple­
mentation during pregnancy, surprisingly little is known
about the short-term and long-term effects on health
outcomes in either mother or child. However, it would
be difficult to ethically conduct a placebo-controlled trial
testing folic acid supplementation.
Iron
Iron supplementation is frequently administered to
pregnant women because the levels of haemoglobin
tend to decrease during pregnancy 159. A systematic
review concluded that iron supplementation reduced
the risk of maternal anaemia and iron deficiency among
iron-insufficient women by 70% and 57%, respectively;
however, little effect was seen for preventing birth
Severe iodine deficiency during pregnancy has been
linked to congenital hypothyroidism and irreversible
brain damage in the offspring. Countries such as Australia,
New Zealand, Belgium and Denmark have national pol-
icies to reduce iodine deficiency through supplementing
salt; however, both mild and moderate iodine deficiency
remain prevalent globally 163. Insufficient iodine intake
during the neonatal period affects intellectual develop-
ment164. Randomized trials are needed to evaluate the effi-
cacy and safety of iodine supplementation in pregnancy
and various childhood developmental outcomes165.
Vitamin D
Optimal maternal vitamin D status has been suggested
to prevent low birth-weight and preterm delivery. A sys-
tematic review concluded that vitamin D supplemen-
tation at various doses during pregnancy reduced the
risk of low birth-weight by 60% and of preterm birth
by 64%166. However, no trial has investigated whether
vitamin D supplementation in pregnancy reduced the
risk of other developmental outcomes.
n-3 fatty acids
Maternal supplementation with n-3 fatty acids could
ensure optimal status of this nutrient and health among
children; however, randomized trials among women with-
out preeclampsia, twin birth or a history of pre-term birth
have reported mixed results for preterm birth, neonatal
outcomes and death before term167. Supplementation
with n-3 fatty acids might also offer benefits for the pre-
vention of bronchopulmonary dysplasia and necrotiz-
ing enterocolitis when extremely preterm neonates are
specifically targeted168.
Psychological disorders
Cognitive function
Slowing the development of dementia and maintaining
a high quality of life represent major challenges among
older adults (age ≥65 years) as life expectancy increases
globally 169,170. Vitamin B12 deficiency is highly prevalent
among older adults (age ≥65 years), which is not only
a result of poor diet but also diminished absorption
associ­ated with age171 (BOX 4). Several secondary analyses
of clinical trials have investigated the effects of dietary

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Box 4 | Supplementation during old age
• Deficiencies of vitamin B12, as well as other vitamin and mineral deficiencies, are more
frequent among older adults (age ≥65 years).
• Multivitamin supplements might modestly reduce the incidence of cancer among
men but trials among women are still needed.
• Short-term reductions in cognitive decline have been reported with multivitamin
supplementation. Large-scale trials are needed to confirm these results.
• Little is known about the impact of dietary supplements on functional status or
quality of life.
supplements (either individual vitamins and minerals
or combinations of these nutrients) on cognitive func-
tion. Folic acid, vitamin B6 and vitamin B12 are the most
extensively studied vitamins to date. Trials conducted
among initially healthy elderly adults or those with cog-
nitive disorders (for example, Alzheimer disease) have
reported mixed results, with inconclusive evidence
regarding a role for folate, vitamin B6 or vitamin B12
supplementation in preventing cognitive decline, or how
baseline nutritional status might affect the results172–181.
Clinical trials testing vitamin  C, vitamin  E and
β‑carotene at doses above the RDA have yet to support a
preventive role against cognitive decline182–187. In PHS II,
β‑carotene supplementation for 1 year among men who
were apparently healthy at baseline had no effect on cog-
nitive performance, whereas long-term supplementation
(mean duration, 18 years) exhibited appreciable benefits
versus placebo185.
Clinical trials of n-3 fatty acids among patients with
cognitive impairment or Alzheimer disease have largely
reported no effects on cognitive function188–191. Studies
that investigated n-3 fatty acids among mentally healthy
older adults reported little or no effect 192–195.
Other nutrients such as calcium and vitamin  D
are less well studied196,197. In a secondary analysis of
the WHI, long-term low-dose supplementation with
calcium and vitamin D had no significant effects on
cognitive performance197.
Randomized trials investigating the use of multivita-
min supplements also report mixed results. A secondary
analysis of SU.VI.MAX found that a combination of five
low-dose vitamins and minerals substantially improved
verbal memory 198. Multivitamin use for a period of
12 months benefited cognitive function in MAVIS199.
Finally, in PHS II, long-term daily multi­vitamin use
conferred no cognitive benefits compared with placebo200.
Depression and depressive symptoms
Several vitamin and mineral supplements have been
evaluated in relation to changes in depression and
depressive symptoms, which are highly prevalent and
leading causes of disability, contributing to both mor-
tality and high health-care costs201,202. In secondary
analyses of WAFACS, no effect of a combination of folic
acid (2.5 mg per day), vitamin B6 (50 mg per day) and
vitamin B12 (1 mg per day) was observed among women
without a history of depression203. Other trials conducted
among initially healthy populations204,205 and a second-
ary CVD prevention trial206 reported similar results.
By contrast, daily supplementation with folic acid (2 mg),
vitamin B6 (25 mg) and vitamin B12 (0.5 mg) for an aver-
age of 7 years of follow‑up reduced the risk of major
depression by 52% among stroke survivors207.
The n-3 fatty acids have a critical part in the devel-
opment and function of the central nervous system,
and supplementation might prevent or reduce depres-
sive symptoms208. In meta-analyses of small-scale trials
evaluating the effect of n-3 fatty acid supplementation
on depressive symptoms, no effect was found for partic-
ipants overall although there was a potential beneficial
effect among the participants with depression (stand-
ardized difference in a random-effects model, 0.56)209,210.
Trials testing vitamin D211,212 or a multivitamin213–215 have
reported mixed results.
ADHD
Attention deficit hyperactivity disorder (ADHD) is
characterized by attention dysfunction, hyperactivity
and impulsive behaviour among children that is associ-
ated with long-term social, academic and mental-health
problems216. Insufficient amounts of polyunsaturated
fatty acids might underlie the onset of attention deficit
hyperactivity disorder. A systematic review of trials con-
cluded that there was insufficient evidence as to whether
supplementation with polyunsaturated fatty acids bene-
fits children and adolescents who already have ADHD217.
Given the variability of selection criteria, different types
and dosages of polyunsaturated fatty acids supplements
used, and the short duration of follow‑up, it is difficult
to draw any firm conclusions. Two small-scale trials test-
ing a combination of n-3 fatty acids and n-6 fatty acids
reported marked improvements in ADHD symptoms,
but little is known regarding the role in the prevention
of this condition217 (BOX 3).
Autism spectrum disorders
Autism spectrum disorders are characterized by dys-
functions in social interaction and communication, as
well as restricted repetitive behaviours, interests and
activities with an age of onset <3 years218. Nutritional
deficiencies during pregnancy have been implicated
in the development of autism spectrum disorders but
little is known about the effects of maternal micronu-
trient supplementation219. A large prospective study of
Norwegian mothers found that folic acid supplementa-
tion during the first trimester reduced the risk of autism
spectrum disorders among their offspring220. Moreover,
a systematic review concluded that the therapeutic
effects of polyunsaturated fatty acid supplements on
autism spectrum disorders have been poorly studied in
randomized trials221.
Conclusions
A well-balanced diet remains the optimal approach
to ensure adequate intake of essential micronutrients.
However, there are many instances when supplementa-
tion has an important role in treating vitamin and min-
eral deficiencies and insufficiencies. Supplementation
for individuals who are already nutritionally sufficient
remains debated; its effectiveness and necessity have

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been questioned and potential adverse effects have yet to
be fully evaluated. Several trials have reported potential
adverse effects from supplementation with high-doses
of β‑carotene and vitamin E, raising concerns about
dietary supplementation at much higher levels than the
RDA. Thus, existing and future trials should carefully
monitor both beneficial and adverse effects on different
health outcomes.
The developing and developed worlds face differ-
ent challenges in meeting nutritional requirements.
Macronutrient and micronutrient deficiencies are seri-
ous public health problems in developing countries that
lead to irreversible health consequences when not pre-
vented or treated. Malnutrition remains a major cause of
death among children5. Furthermore, reproductive-aged
women and their offspring are highly vulnerable groups
among whom vitamin A, iron and iodine deficiencies
remain common142,143,160,161,165. Developed countries can
lay claim to achieving greater access to, and prevalence
of, adequate nutrient intake during pregnancy and child-
hood. However, women in both developing and devel-
oped countries who are either planning to conceive or
who are already pregnant might experience difficulties
meeting nutritional requirements of folate, iron, calcium
and iodine. Moreover, older adults might be at increased
risk of nutritional insufficiencies and malnutrition owing
to lowered energy intake, lack of variety in the foods con-
sumed, difficulties with chewing and swallowing, sen-
sory losses, and pertinent comorbidities9. However, the
effectiveness of vitamin and mineral supplementation to
ensure optimal nutritional status and any impact on health
outcomes is less well studied. Self-medication of dietary
supplements to prevent or treat a medical condition is also
prevalent. This practice can be very problematic if it delays
seeking medical help when needed, replaces prescribed
drugs or interacts with concurrent drug treatment.
In this Review, we focused on randomized clinical
trials because they can overcome the issues of residual
confounding associated with observational studies,
which can yield biased estimates. However, it is important
to note that observational studies are also needed because
they bring useful and complementary information from
‘real life’ settings. Moreover, observational studies add
important data when ethical concerns hinder the design
of clinical trials. Thus, both randomized trials and obser-
vational studies are essential to advancing our under-
standing of the role of dietary supplement use in disease
prevention, as well as in assessing complex nutrient–
environmental interactions. Ongoing and future research
on promising dietary supplements in at-risk populations
will hopefully help to fill the existing research gaps and
inform future public-health recommendations.

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Acknowledgements
S.R. has received funding from COFAS 2 Marie Curie Fellowship,
Stockholm, Sweden. J.E.M. has received grant or research sup-
port from the NIH (HL34594, CA138962 and
HHSN268201100001C) for the for the VITamin D and
OmegA‑3 TriaL (VITAL) and other research studies. A.H.L has
received funding from USDA 1950-51000-072-02S, USDA/
N I FA / A F R I 2 0 11 - 0 3 3 8 9 a n d A H R Q / C o n t r a c t
HHSA290201200012I. H.D.S. has received grant support from
the NIH (R01 HL102122) related to work on the VITamin D and
OmegA‑3 TriaL (VITAL).
Author contributions
S.R. researched the data for the article. All authors provided a
substantial contribution to discussions of the content. S.R.,
J.E.M., A.H.L. and H.D.S. contributed equally to writing the
article. All authors contributed equally to review and/or editing
of the manuscript before submission.
Competing interests statement
J.E.M. declares that she has received investigator-initiated grant
support and/or donation of study pills from Mars
Symbioscience, Pfizer Inc., PharmaViteProNova and
BioPharma/BASF. H.D.S. declares that he has received investi-
gator-initiated grant support (including donations of study pills)
from the Council for Responsible Nutrition Foundation, Mars
Symbioscience and Pfizer Inc. S.R. and A.H.L. declare no com-
peting interests.
Review criteria
We conducted a MEDLINE and PubMed search for English-
language, full-text articles published through January 2016 of
randomized clinical trials testing the effects of supplements of
vitamins, minerals or polyunsaturated fatty acids on communi-
cable and noncommunicable diseases. The reference lists of
identified articles were searched for additional papers.