You are on page 1of 4

Review

Vitamin C as an antioxidant supplement in womens health:


a myth in need of urgent burial
Vikram Sinai Talaulikar *, Isaac T. Manyonda
Department of Obstetrics and Gynaecology, St Georges Hospital NHS Trust, Blackshaw Road, London SW17 0QT, United Kingdom
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2. The concept of free radicals and oxidative stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3. Antioxidants and the ght against free radicals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4. The promise of antioxidant therapies for human disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5. The myth of vitamin supplementation in the prevention of disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6. Why vitamin supplements may not be effective antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7. Where to now? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1. Introduction
In 1999 Chappell et al. [1] reported in The Lancet that the cheap,
simple, innocuous and ubiquitous vitamin C, by virtue of its
antioxidant properties and given orally at a dose of 1000 mg in
conjunctionwith400 mgvitaminE, couldprevent and/or ameliorate
pre-eclampsia (PE) in women at risk of the condition. Three years
later the group published data showing evidence of decreased levels
of markersof thediseaseinwomenat highriskof pre-eclampsiawho
were treated with the same vitamin supplements [2]. The race had
begun and various other centres joined in with their own trials,
including a WHO-supported international trial [3]. In 2005 Beazley
et al. [4] published the early results from a randomized trial,
followed in hot pursuit in 2006 by a much larger trial from the
original group [5]. Both studies reported negative ndings fromthe
use of the vitamins. Further studies [3,6,7] followed in rapid
succession, all showing a failure of benet fromvitamins C and E. In
2010 three papers also failed to show a benet: one in the New
England Journal of Medicine [8], the others in the American Journal
of Obstetrics andGynaecology[9] andTheLancet [10]. Thus a total of
eight large studies have reported that vitamins C and E neither
prevent nor ameliorate PE. Worse still, some of the studies have
reported potential harmin the treatment arm, including premature
rupture of membranes [6,9] low birth weight [5], increased
incidence of severe disease [6,7] and intrauterine fetal demise [9],
while a Cochrane review [11] has reported an increased risk for
European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 1013
A R T I C L E I N F O
Article history:
Received 4 November 2010
Received in revised form 14 February 2011
Accepted 20 March 2011
Keywords:
Antioxidants
Vitamin C
Pre-eclampsia
Womens health
A B S T R A C T
Epidemiological data suggest that diets rich in antioxidants protect against diseases associated with free
radical damage, including cancer, cardiovascular disease and diabetes. Early observations also suggested
that vitamin supplements with antioxidant properties, like vitamins C and E, could also prevent or
ameliorate pre-eclampsia, but most large randomized clinical trials have failed to show any benet.
Vitamin C given orally, even at high doses, does not achieve sustained serum levels that might be
required for effective antioxidant activity. This may explain the failure of the numerous clinical trials
involving its use in pre-eclampsia, cancers, cardiovascular diseases, etc. Vitamin C supplementation to
stave off pre-eclampsia, cancer and other diseases is a nutraceutical industry-driven myth which should
be abandoned. We do not dispute a role for oxidative stress in the pathophysiology of pre-eclampsia, nor
the possibility of amelioration of the disease by an anti-oxidant given at the right time and in the correct
dosage. We simply wish to make a case that the massive and expensive clinical trials of vitamins C and E
should cease until further rigorous scientic research is undertaken.
2011 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +44 020 8725 0359.
E-mail address: vtalauliker@gmail.com (V.S. Talaulikar).
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and
Reproductive Biology
j our nal homepage: www. el sevi er . com/ l ocat e/ ej ogr b
0301-2115/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2011.03.017
hospitalization for hypertension and for the use of antihypertensive
therapy, and increased incidence of abdominal pain in late
pregnancy.
Sadly, the story of vitamin C is not unique: once every fewyears
a new drug, therapy or intervention appears which captures the
imagination of the clinician and public alike. More often than not,
however, the initial enthusiasm quickly fades as the intervention
fails to live up to its promise in rigorous randomised clinical trials.
The tragedy with the vitamin C story is that it has required eight
large studies for the penny to drop if it has done so yet lessons
could have been learnt from experience with other vitamins, as
well as by taking on board some basic considerations existing prior
to the studies which could have saved large sums of money, time
and other research resources.
2. The concept of free radicals and oxidative stress
Oxidative damage is caused by free radicals chemicals or
compounds which, by virtue of having unpaired electrons, are
unstable, highly reactive and seek to stabilize themselves by
stealing electrons from other chemicals or compounds (includ-
ing proteins, carbohydrates, lipids and DNA), thereby oxidising the
latter (Fig. 1). In the process they create more free radicals,
sparking off a chain of destruction. The results of free radical
damage or oxidation include cell injury, making the cells more
vulnerable to infection and degenerative disease, and DNA
damage, interfering with normal cell division and resulting in
mutations. Thus oxidative damage accompanies most, if not all,
diseases and has been implicated in the pathogenesis of cancer,
diabetes, heart disease, arthritis, neurodegenerative disorders,
atherosclerosis, osteoporosis, pancreatitis and, specic to womens
health, pre-eclampsia.
While free radicals are produced during normal respiration and
metabolism, their production can also be triggered by exposure to
air pollutants, sun exposure, radiation from X-rays, drugs, viruses,
bacteria, parasites, dietary fats, stress and injury.
3. Antioxidants and the ght against free radicals
An antioxidant is a molecule capable of slowing or preventing
the oxidation of other molecules by being oxidized itself. As stated
above, oxidation reactions can produce free radicals, which start
chain reactions that damage cells. Antioxidants neutralize free
radicals by donating one of their own electrons, ending the
electron-stealing reaction. The antioxidants do not become free
radicals when they donate an electron because they are stable in
either form. They act as scavengers, helping to prevent cell and
tissue damage. Antioxidants are often reducing agents such as
thiols, ascorbic acid or polyphenols. Although oxidation reactions
are crucial for life, they can also be damaging; hence plants and
animals maintain complex systems of multiple types of antiox-
idants, such as glutathione, vitamin C and vitamin E, as well as
enzymes such as catalase, superoxide dismutase and various
peroxidases. Low levels of antioxidants, or inhibition of the
antioxidant enzymes, cause oxidative stress and may damage or
kill cells. Therefore the potential for antioxidants in preventing
disease has attracted much attention.
4. The promise of antioxidant therapies for human disease
It has been known for a long time that diets rich in fruits and
vegetables appear to protect against the types of diseases
associated with free radical damage, including certain types of
cancer, heart disease, dementia, diabetes and stroke. The attractive
supposition has been that fruits and vegetables are a rich source of
antioxidants that can neutralize free radicals. Green plants are
especially vulnerable to oxidative stress since they produce pure
oxygen during photosynthesis, and therefore need to manufacture
a range of potent antioxidants to protect themselves. Thus the
concept that fruits and vegetables contain antioxidants that could
also be given as supplements or in fortied foods gained ground
and spawned what is now a multi-billion dollar nutraceutical
industry that vigorously promotes the sale and consumptions of
capsule-packaged pure antioxidants in pursuit of the prevention/

Unstable oxygen
f d l
Sources of free radicals
Trauma
free radical
lacking an electron
Radiaon
Microbes
Heat
Stress Stress
Immune injury
Toxins
Free radicals seek to stabilize themselves by stealing an
electron from other compounds or molecules such as lipids /
DNA / mitochondria which in turn become a free radical which
steals an electron : a damaging chain reacon is thus created.
Donates electron
Anoxidant
Anoxidant
Stabilised radical
Anoxidant remains stable despite
of loss of electron
(Endogenous superoxide dismutases, glutathione etc
Exogenous - Vit C, Vit E,beta carotene etc)
Fig. 1. Interaction of oxygen free radicals and antioxidants.
V.S. Talaulikar, I.T. Manyonda / European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 1013 11
amelioration of diseases associated with oxidative stress. The
popular range of antioxidants includes vitamin E, vitamin C,
carotenoids (including beta carotene and lycopene) and poly-
phenols (including avonoids), although the full list of compounds
with antioxidant properties is extensive. Vitamin E is the most
abundant fat-soluble antioxidant in the body and one of the most
efcient chain-breaking antioxidants available, and therefore a
primary defender against oxidation. Vitamin C is the most
abundant water-soluble antioxidant in the body and acts primarily
in cellular uid, being especially effective in combating free-radical
formation caused by pollution and cigarette smoke. In the western
world and especially in America it is estimated that up to 50% of the
adult population take antioxidant pills on a daily basis to promote
health and stave off disease. The question is whether these
supplements are effective.
5. The myth of vitamin supplementation in the prevention of
disease
The epidemiologic evidence of the benets of antioxidants on
staving off cancer, cardiovascular and other diseases of ageing
spawned a series of preventative studies. Although there have been
conicting data published by various study groups, the results of
recent large studies using vitamin E supplements have been almost
universally disappointing, with one study even suggesting that
vitamin E might increase the risk of heart failure. Other studies
failed to nd a benet for vitamin E against cancers or the
progression to Alzheimers disease in people with mild cognitive
impairment. There is even evidence that vitamin E supplements
could be harmful [12], although the report has been challenged. In
a study focussing on beta carotene and its potential for protecting
against lung cancer, 29,133 male smokers 5069 years of age from
southwestern Finland were randomly assigned to one of four
regimens: alpha-tocopherol alone, beta carotene alone, both
alpha-tocopherol and beta carotene, or placebo. Follow-up
continued for ve to eight years and, unexpectedly, a higher
incidence of lung cancer was observed among the men who
received beta carotene than among those who did not [13]. Apart
from failing to show benet in the prevention or amelioration of
PE, vitamin C has not fared well elsewhere, with reports suggesting
that it may accelerate atherosclerosis in some people with
diabetes, and fail to confer benet in patients with advanced
cancer [14] despite early promise. However, while it should nowbe
fully accepted that vitamin C does not prevent or ameliorate PE in
its current form and dose, it should also be recognized that overall
the jury is still out on a role for vitamin antioxidant therapy for a
range of diseases, since a PubMed search for 2010 still yields a
mixed bag of recent positive and negative studies.
6. Why vitamin supplements may not be effective antioxidants
That many vitamins, including E and C, are antioxidants and
exhibit vigorous antioxidant activity in the test tube is beyond
dispute. Why then, when packaged in pure form in a capsule and
swallowed in large quantities, do these vitamins fail to prevent
disease? There are several potential explanations. Firstly, the
antioxidants in fruit and vegetables may be tightly bound within
the tough brous material of these foodstuffs and may exert their
antioxidant activity not in the blood or tissues but in the
gastrointestinal tract where free radicals are constantly generated
from food [15] Supplements, on the other hand, are probably
digested too quickly to replicate the effect. Elegant studies by Lean
et al. [16] showed that oxidative stress plays a crucial role in
oophorectomy-induced osteoporosis in mice, and that vitamin C
will prevent the development of osteoporosis when given
intraperitoneally at a dose of 1 mmol/kg twice a day. The human
equivalent of the vitamin C dose they used is 20 g per day. The
equivalent serum levels of vitamin C cannot be achieved if the
supplement is given by the oral route, since there is an upper limit
for absorption of vitamin C of about 500 mg, which is why this is
normally the highest dose given. Any more vitamin C stays in the
gut and may cause osmotic diarrhoea and other gastrointestinal
upset [17]. In contrast, plasma levels up to 70 times greater can be
achieved by parenteral administration [18]. Finally, antioxidants
such as glutathione are present in cells at huge (millimolar)
concentrations, and vitamin C prevented oxidant-induced bone
loss in the work described by Lean et al. [16] because a sufcient
dose was given to normalize antioxidant levels. In contrast, while a
dose of 5001000 mg (used in the clinical trials involving pre-
eclampsia) is sufcient to full the need for a cofactor in collagen
synthesis, it may be far too small a proportion of a cells antioxidant
reserve to exert a detectable antioxidant effect.
7. Where to now?
A careful pre-trial consideration of what was already known
about vitamin C could have provided hints that vitamin C in its
current dose and form was highly unlikely to be the holy grail in
combating pre-eclampsia, and it may not have required so many
largeinternational clinical trials toarrive wherewearetoday. Wedo
appreciate that research studies with negative ndings add to the
existing knowledge on the subject and that they are critical for
acceptance/refusal of novel healthcare interventions. Nevertheless,
the propagation of the same fundamental aw of assuming benet
from intervention has cost huge amounts of precious research
resources. The need of the hour is for robust laboratory scientic
research to explore new routes of administration or doses of novel
antioxidants, before any more large trials are planned for future.
Role of funding source
No funding was received for this review.
Disclosure of interest
None of the authors reports any conict of interest concerning
this review.
References
[1] Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of
pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;
354(9181):8106.
[2] Chappell LC, Seed PT, Kelly FJ, et al. Vitamin C and E supplementation in
women at risk of preeclampsia is associated with changes in indices of
oxidative stress and placental function. Am J Obstet Gynecol 2002;187(3):
77784.
[3] Villar J, Purwar M, Merialdi M, et al. World Health Organisation multicentre
randomised trial of supplementation with vitamins C and E among pregnant
women at high risk for pre-eclampsia in populations of low nutritional status
from developing countries. BJOG 2009;116(6):7808.
[4] Beazley D, Ahokas R, Livingston J, et al. Vitamin C and E supplementation in
women at high risk for preeclampsia: a double-blind, placebo-controlled trial.
Am J Obstet Gynecol 2005;192(2):5201.
[5] Poston L, Briley AL, Seed PT, et al. Vitamins in pre-eclampsia (VIP) trial
consortium. Vitamin C and vitamin E in pregnant women at risk for pre-
eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:
114554.
[6] Spinnato 2nd JA, Freire S, Pinto E Silva JL, et al. Antioxidant therapy to prevent
preeclampsia: a randomized controlled trial. Obstet Gynecol 2007;110(6):
13118.
[7] Klemmensen A, Tabor A, sterdal ML, et al. Intake of vitamin C and E in
pregnancy and risk of pre-eclampsia: prospective study among 57 346 wom-
en. BJOG 2009;116(7):96474.
[8] Roberts JM, Myatt L, Spong CY, et al. Vitamins C and E to prevent complications
of pregnancy-associated hypertension. N Engl J Med 2010;362(14):128291.
[9] Xu H, Perez-Cuevas R, Xiong X, et al. An international trial of antioxidants in
the prevention of preeclampsia (INTAPP). Am J Obstet Gynecol 2010;202(3):
239.e1239.e10.
V.S. Talaulikar, I.T. Manyonda / European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 1013 12
[10] McCance DR, Holmes VA, Maresh MJA, et al. For the Diabetes and Pre-
eclampsia Intervention Trial (DAPIT) Study Group. Vitamins C and E for
prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a
randomised placebo-controlled trial. Lancet 2010;376:25966.
[11] Rumbold A, Duley L, Crowther CA, et al. Antioxidants for preventing
pre-eclampsia. Cochrane Database Syst Rev 2008 Jan 23;1:CD004227.
[12] Miller 3rd ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage
vitamin E supplementation may increase all-cause mortality. Ann Intern Med
2005 Jan 4;142(1):3746.
[13] The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The
effect of vitamin E and beta carotene on the incidence of lung cancer and other
cancers in male smokers. N Engl J Med 1994;330(April (15)):102935.
[14] Wittes RE, Vitamin C. cancer [Editorial]. N Engl J Med 1985;312:1789.
[15] Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn
from cell culture and in vivo studies? Arch Biochem Biophys 2008 Aug
15;476(2):10712.
[16] Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in
estrogen-deciency bone loss. J Clin Invest 2003;112:91523.
[17] Dietary reference intakes for vitamin C, vitamin E, seleneium and carotenoids,
Report of the Food and Nutrition Board, Institute of Medicine. Washington, DC,
USA: National Academy Press;2000. P161.
[18] Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications
for oral and intravenous use. Ann Intern Med 2004;140:5337.
V.S. Talaulikar, I.T. Manyonda / European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 1013 13

You might also like