Vitamin E in Preeclampsia

LUCILLA POSTON,a MAARTEN RAIJMAKERS,a AND FRANK KELLYb

aMaternal

and Fetal Research Unit, Division of Reproductive Health, Endocrinology

and Development, Kings College Hospital, St. Thomas Hospital, London SE1 7EH,
United Kingdom
bSchool

of Health and Life Sciences, Kings College, London SE1 9NN,

United Kingdom

ABSTRACT: Preeclampsia is the disorder of pregnancy with the highest rate of

both maternal and neonatal morbidity and mortality. The maternal syndrome
is characterized by oxidative stress and activation of the vascular endothelium
that may originate from placental release of lipid peroxidation products, cytokines, and microparticles leading to an acute inflammatory response. The current understanding of the etiology has allowed the improvement of predictive
tests, tests that could make intervention possible from early pregnancy onwards. Although the large secondary intervention antioxidant trials in cardiovascular diseases did not show any beneficial effect of vitamin E and vitamin
C, either alone or in combination, knowledge of the nature of the pathogenesis
of preeclampsia offers hope for the beneficial use of antioxidants in the prevention of the disorder. Not only has our previous small trial shown that antioxidant prophylactics in high-risk women lowered the prevalence of preeclampsia,
but also new evidence has demonstrated multiple other actions of -tocopherol
(such as anti-inflammation and inhibition of NAD(P)H oxidase activation) besides its antioxidant properties that could be advantageous in the prevention of
the disorder. Several larger trials are under way to investigate the precise role
that vitamins C and E can play in the prevention of preeclampsia.
KEYWORDS: vitamin E; vitamin C; preeclampsia

Preeclampsia, a common and potentially serious complication of pregnancy, is responsible for the highest figures for maternal and fetal morbidity and mortality of all
pregnancy complications. The World Health Organization has estimated that 0.4
2.8% of all pregnancies in developed countries are affected by this disorder, a figure
that may rise to as much as 6.7% in developing countries. In total, as many as
8,370,000 cases worldwide occur every year.1 The simple clinical definition [gestational hypertension (>90 mmHg diastolic) occurring after the 20th week of gestation
with superimposed proteinuria (>300 mg/day)]2 belies the complexity of preeclampsia, which is often accompanied by multi-organ dysfunction. Maternal vascular endothelial activation and dysfunction is widely accepted as the common underlying
Address for correspondence: Professor Lucilla Poston, MFRU, Division of Reproductive
Health, Endocrinology and Development, St.Thomas Hospital, 10th Floor, North Wing, Lambeth Palace Road, London SE1 7EH, United Kingdom. Voice: (44) 207 188 3644; fax: (44) 207
620 1227.
lucilla.poston@kcl.ac.uk
Ann. N.Y. Acad. Sci. 1031: 242248 (2004). 2004 New York Academy of Sciences.
doi: 10.1196/annals.1331.024
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defect.3 In the cerebral circulation, this may lead to fits (that is, eclampsia) or stroke;
in the liver, to intense vasoconstriction and hepatic necrosis; and in the lung, to development of pulmonary edema. In the kidney, glomerular endotheliosis, a lesion peculiar to preeclampsia, may obliterate the glomerular capillary lumen and lead to
renal dysfunction and to proteinuria. Preeclampsia is considered to be a syndrome
or constellation of pathologies, because involvement of the different vascular beds
is highly variable from case to case. In developed countries, the greater part of antenatal care focuses upon early detection of preeclampsia (measurement of blood pressure and detection of proteinuria), and when diagnosis is made, the only cure is
delivery. Because preeclampsia may occur at any time from the late second trimester
onwards, it is one of the primary causes of pre-term delivery, accounting for as many
as 25% of all early births.1
The last decade has witnessed acceleration in our understanding of the etiology
of preeclampsia. In the current theory, oxidative stress plays a central role. The most
crucial event during placental development is establishment of an effective maternal
circulation, a process that requires conversion of the spiral arteries from highly tortuous and thick-walled vessels to flaccid conduits of low resistance.4 Failure or only
partial spiral artery conversion, as demonstrated by histological investigation of the
placental bed post delivery, is evident in the placentas of many women with
preeclampsia5 and results in reduced placental blood flow and abnormally high
uteroplacental resistance, which may be assessed by Doppler ultrasound of the uterine artery. Constriction and relaxation of the muscular walled spiral arteries or clot
formation and dissolution may lead to ischemia/reperfusion insults and subsequent
superoxide generation by the xanthine/xanthine oxidase pathway. The enzymes involved show increased expression in affected placentas.6 Evidence for this pathogenic pathway was recently provided by Hung and colleagues,7 who demonstrated
that an in vitro ischemia/reperfusion stimulus enhanced nitrotyrosine staining in
placental tissue and that this was prevented by addition of a free radical scavenger.
Recent studies also implicate NAD(P)H oxidase as a source of superoxide.
NAD(P)H oxidase activity is considerably enhanced in preeclamptic placentas,8
which may arise from activation by a preeclampsia-specific angiotensin II receptor
activating antibody.9,10 Increased superoxide generation by these processes is held
responsible for the frequently reported oxidative damage in placental trophoblast as
shown by enhanced lipid peroxidation, nitrotyrosine staining, and protein carbonyl
formation.1116
Several different theories are proposed for transfer of the preeclampsia signal
from the compromised placenta to the mother, all of which could be related to placental oxidative stress. These include deportation of placental apoptotic microparticles, lipid peroxides, placental cytokines, and activation of maternal leukocytes as
the maternal blood perfuses the affected placenta.17 Singly or together, these lead to
the activation of the maternal vascular endothelium and circulating neutrophils, such
that that the maternal disorder has all the hallmarks of an acute inflammatory state.
While normal pregnancy is associated with a mild inflammatory response, in preeclampsia this seems to be exacerbated,3 with enhanced neutrophil activation and an
increased Th1:Th2 ratio.18 There is extensive evidence that neutrophils isolated
from women with preeclampsia synthesize more superoxide upon activation than
those of normotensive pregnant women.1921 This appears to be mediated by
NAD(P)H oxidase.22 Increased superoxide generation not only leads to a vicious cir-

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cle of endothelial cell and neutrophil activation, but results also in generalized oxidative stress, a hallmark of the disease. Indeed, several studies have reported
elevation of makers of lipid peroxidation in the maternal circulation.23

ROLE OF ANTIOXIDANTS AND VITAMIN E IN PREECLAMPSIA

Numerous studies have investigated antioxidant capacity in the placenta or the
maternal circulation in preeclampsia through investigation of total antioxidant capacity, the concentration of specific antioxidants, or the activity of antioxidant enzymes. The consensus opinion arising from these various studies suggests that
antioxidant capacity is decreased in women with preeclampsia.23 The investigations
of antioxidant capacity in the maternal circulation have mainly been focused on the
most important soluble antioxidants and have consistently reported a reduction in
cellular and plasma glutathione concentrations24,25 and in plasma concentrations of
vitamin C.2629 In contrast, the findings on vitamin E are ambiguous, and reported
concentrations vary widely amongst the different studies,23 which may be explained
by the fact that measurement of plasma vitamin E is a far from satisfactory estimate
of the focal site of vitamin E activity, namely the cell membrane. Although elevation
of total cholesterol and triglycerides is a characteristic of preeclampsia,30 concentrations of lipid-soluble vitamin E have not always been adjusted for plasma cholesterol
and triglyceride concentrations.31,32 We and others have reported a modest increase
in plasma vitamin E concentrations with gestation,29 reflecting the pregnancy-related increase in plasma lipoproteins. It is striking, however, that in the reports describing either lowered or elevated levels of vitamin E in preeclamptic plasma, diversion
from normal values correlated with severity of disease, with the largest difference
from values in normotensive control women being found in women with more severe
preeclampsia.26,27,33,34 To our knowledge, there is no study in which red cell vitamin E concentrations have been estimated or indeed those in any other tissue in
women with preeclampsia.
The substantive evidence for oxidative stress in preeclampsia has prompted the
suggestion that antioxidant prophylaxis may have therapeutic benefit in the treatment of preeclampsia. Two early studies in which vitamin E was given either alone
(100300 mg/day)35 or in association with vitamin C and allopurinol (800 IU/day,
1000 mg/day, and 200 mg/day, respectively)36 showed no benefit in women with established preeclampsia. In the latter study, however, there was a trend for a reduction
in plasma concentrations of uric acid, a biomarker of disease severity, probably
caused by the inhibition of xanthine oxidase by allopurinol. We carried out a small,
randomized trial37 in which we combined 400 IU/day vitamin E (RRR--tocopherol) with 1000 mg/day vitamin C prompted by the reported synergy between
these two antioxidants.38 Women at known risk of preeclampsia, either on the basis
of previous preeclampsia or because of a high resistance profile of the uterine artery
Doppler waveform, entered the study at 1622 weeks gestation and took the antioxidant cocktail (or placebo) until delivery. The primary outcome measure of the study
was endothelial cell activation, measured as the plasminogen activator inhibitor-1
and -2 (PAI-1/PAI-2) ratio, and the secondary outcome was the frequency of preeclampsia. The trial was stopped early, because interim analysis showed a highly significant difference between placebo and treatment groups for the primary outcome.

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This was associated with a significant reduction in the number of cases of preeclampsia in the treatment vs. placebo group (8% vs. 26%, P < 0.02). We also reported
that reduced plasma vitamin C concentrations compared to those of low-risk controls
antedated the development of the disease. Moreover, antioxidant treatment resulted
in a return to normal of vitamin C values, similar to those of low-risk controls, and
reduced the abnormally raised plasma markers for oxidative damage (e.g., 8-epiprostaglandin F2) and placental function (e.g., leptin).39 As a result of this study,
much larger trials using the same antioxidant regimen are under way in several other
countries.
The use of -tocopherol and vitamin C, either alone or in combination, in several
clinical studies of cardiovascular disease, have shown ambiguous clinical outcomes.
Although supplementation enhanced plasma vitamin status, meta-analysis failed to
show a beneficial effect of the use of vitamin C and/or vitamin E in the amelioration
of preexisting cardiovascular disease.40,41 The largest secondary prevention study to
date consists of 20,536 subjects with preexisting cardiovascular disease or diabetes
that were randomized to antioxidants (600 mg vitamin E, 250 mg vitamin C, and 20
mg -carotene daily) or matching placebo. Treatment for more than 5 years did not
show an improvement in outcome in the vitamin group.42 In the Womens Angiographic Vitamin and Estrogen (WAVE) trial, postmenopausal women with coronary
disease who received two daily doses of 500 mg of vitamin C and 400 IU of vitamin
E also showed no improvement in outcome compared to the placebo group; in fact
treatment suggested a potential harm.43 These studies contrast with the Antioxidant
Supplementation in Arterioscleroses Prevention (ASAP) study, which documented a
reduction in progression of arterioscleroses in subjects who received a combination
of 250 mg slow-release vitamin C and 136 IU vitamin E twice daily with a meal in
a randomized trial of 520 subjects studied over a period of 6 years.44 Moreover, it
was shown that subjects who had low baseline plasma vitamin C concentrations benefited most from antioxidant supplementation.
Although these large secondary intervention trials in subjects with established
cardiovascular disease have not provided convincing evidence in favor of vitamin
supplementation, this does not rule out the possibility that primary antioxidant intervention may be effective in disorders that are more acute. For instance, small, randomized trials in heart transplant recipients have shown a reduction of transplantassociated arteriosclerosis in patient who received a combination of vitamin C and
vitamin E.45,46 Furthermore, one report has suggested that a combination of vitamin
C and vitamin E may be effective in improving endothelial function as demonstrated
in hyperlipidemic children taking part in the Endothelial Assessment of Risk from
Lipids in Youth (EARLY) study.47 These studies suggest that in the early pathogenic
stages of cardiovascular diseases, the damaging effect of oxidative stress on endothelial dysfunction is reversible by antioxidants.
Although controversies of vitamin E and vitamin C prophylaxis are apparent in
secondary intervention of cardiovascular diseases, antioxidant prophylaxis from early gestation onwards might be beneficial for the prevention of preeclampsia. Recent
investigations have shown encouraging evidence in favor of the beneficial effect of
vitamin E and vitamin C in the prevention of preeclampsia.37,48,49 Two recent in vitro studies, of particular relevance to work from our unit, have been performed in placental tissue. Perfusion of preeclamptic placental tissue with 500 M vitamin C
returned elevated lipid peroxidation potential to values found in placental tissue of

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control women,49 whereas another study demonstrated that vitamin C and vitamin E
either alone or in combination achieved complete inhibition of lipid peroxidation in
human placental mitochondria.48 More important, this effect was much more pronounced when a combination of vitamins C and E was used, compared to the influence of each antioxidant alone.
In addition, the non-antioxidant properties of -tocopherol have also become
more widely appreciated. For example, it has been discovered that -tocopherol may
reduce inflammatory mediators, lower the expression of cell adhesion molecules,
and increase peroxisome proliferatoractivated receptor- (PPAR-) expression.50,51
These properties are all highly relevant to women with preeclampsia in whom concentrations of several cytokines (such as IL-6 and TNF)3 and several soluble cell
adhesion molecules are raised (such as sICAM-1 and sVCAM-1)52 and in whom
PPAR- is reduced.53 The reported anti-apoptotic properties of -tocopherol are also
of interest in view of the suggestion that deportation of trophoblast in preeclampsia
may occur as a result of activation of apoptotic pathways.7 The report that -tocopherol can prevent PKC activation and the translocation of the p47phox subunit of
NAD(P)H oxidase to the plasma membrane, thereby preventing activation of the enzyme,54 is pertinent to the recent recognition of the role this enzyme plays in superoxide generation in the preeclamptic placenta.17 It will be of considerable interest to
determine in the clinical trials under way whether biomarkers of inflammation as
well as those of oxidative stress are reversed by the antioxidants. Two in vitro studies
have already suggested that -tocopherol can reverse inflammatory processes (activation of NFB, ICAM-1, and IL-6) induced by incubation of preeclamptic plasma
with cultured human umbilical venous endothelial cells.55,56

SUMMARY
Preeclampsia, a state of oxidative stress intimately associated with an inflammatory response, offers considerable potential for intervention with -tocopherol.
None of the trials in progress have a factorial design that would assess the potential
value of vitamin E alone. Nonetheless, the studies will determine whether supplementation of vitamin E and vitamin C together may have a role to play in the prevention of preeclampsia.
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