American Journal of Obstetrics and Gynecology (2005) 192, 5201

www.ajog.org

Vitamin C and E supplementation in women at

high risk for preeclampsia: A double-blind,
placebo-controlled trial
Dorothy Beazley,a Robert Ahokas,b Jeffrey Livingston,c Mary Griggs,b
Baha M. Sibai, MDd,*
Department of Obstetrics and Gynecology, Tufts-NEMC, Boston, Mass,a Department of Obstetrics and Gynecology,
University of Tennessee, Memphis, Tenn,b Department of Obstetrics and Gynecology, Carilion Hospital, Roanoke, Va,c
Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohiod
Received for publication May 7, 2004; revised September 2, 2004; accepted September 2, 2004

KEY WORDS
Preeclampsia
Pregnancy
Vitamin C
Vitamin E

Objective: We sought to determine the effect of supplemental antioxidant vitamins C and E on

the rate of preeclampsia in high-risk pregnant women.
Study design: Women at risk for preeclampsia (previous preeclampsia, chronic hypertension,
pregestational diabetes, or multifetal gestation) were recruited at 14 to 20 weeks gestation and
randomly assigned to receive either 1000 mg of vitamin C and 400 IU of vitamin E or placebo
daily in addition to their regular prenatal vitamins. The primary outcome was the occurrence of
preeclampsia. An estimated sample size of 220 women in each arm was determined to be
necessary to demonstrate a 50% reduction in the rate of preeclampsia.
Results: Funding was terminated after 109 women had been recruited; 9 were lost to follow-up or
withdrew. We analyzed data from the remaining 100 women to look for differences in outcome
and to estimate the required sample size for future studies. The rate of preeclampsia was not
different: 17.3% in women who received supplemental vitamins C and E, versus 18.8% in the
placebo group. Assuming a baseline rate of preeclampsia in the placebo group between 15% and
20%, we can estimate that 500 to 950 women in each arm will be required to show a clinically
important reduction in the rate of preeclampsia.
Conclusion: The potential benefit of vitamin C and E supplementation to prevent preeclampsia in
women with clinical risk factors is smaller than we estimated. Future studies of antioxidant
vitamin supplementation in this population will require more than 500 women in each arm.
2005 Elsevier Inc. All rights reserved.

Presented at the Twenty-Third Annual Meeting of the Society for

Maternal-Fetal Medicine, San Francisco, Calif, February 2003.
* Reprint requests: Baha M. Sibai, MD, Department of Obstetrics
and Gynecology University of Cincinnati, 231 Albert Sabin Way,
Cincinnati, OH 45267.
E-mail: baha.sibai@uc.edu
0002-9378/$ - see front matter 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.09.005

Preeclampsia is a multisystem disorder of pregnancy

that is seen more frequently in women with prior
preeclampsia, chronic hypertension, renal disease, insulin-dependent diabetes mellitus, and multiple gestation, and in women with abnormal uterine artery
Doppler scans.1 Despite numerous attempts at early
diagnosis and treatment, eorts to prevent preeclampsia

Beazley et al
have been disappointing. Recently, it has been proposed
that preeclampsia is a disorder of increased oxidative
stress, oering the possibility of targeted therapy aimed
at oxidative stress reduction with antioxidants.2 There is
only 1 randomized trial evaluating the eects of vitamin
C plus E supplementation on the rate of preeclampsia.3
This trial was conducted in women identied to be at
risk for preeclampsia because of abnormal uterine artery
Doppler scan at 18 to 20 weeks and 24 weeks gestation.
In this study, the rate of preeclampsia was reduced from
17% to 8% (54% reduction; P = .02) in the intent-totreat cohort. Our objectives were rst to evaluate the
eects of antioxidant vitamin supplementation with
vitamin C 1000 mg and vitamin E 400 IU for the
prevention of preeclampsia in an inner city population
at high risk of preeclampsia.

Materials and methods

This is a double-blind, randomized clinical trial of
vitamin C 1000 mg and vitamin E 400 IU supplementation versus placebo in pregnant women at high risk of
preeclampsia. The primary outcome was development of
preeclampsia.
Inclusion criteria were pregnancy at 14 weeks 0 days
to 20 weeks 6 days with a history of prior preeclampsia,
chronic hypertension, insulin-requiring diabetes mellitus, or multiple gestation. To determine sample size, we
assumed a rate of preeclampsia of 20% in this population.3 On the basis of a proposed reduction in
preeclampsia of 50% with vitamin C and E supplementation,3 we calculated that a total of 220 women need to
be randomly assigned in each group to have a power of
80% with an alpha of .05. Because of cessation of
funding, the trial was terminated early after 109 women
were randomly assigned.

Results
Pregnancy outcomes are listed in the Table. There were
no pregnancy losses before 20 weeks gestation in either
group. Overall, 18 women had preeclampsia develop, 9
in each group. Of these, 6 women had severe preeclampsia develop (3 in each group), 5 had mild
preeclampsia, and 7 had superimposed preeclampsia
develop. The rate of preeclampsia was 17.3% in the
vitamin supplement group and 18.8% in the placebo
group (relative risk = 0.92; 95% CI, 0.4-2.13).

Comments
The ndings of our study reveal that antioxidant
supplementation with vitamin C 1000 mg and vitamin

521
Table

Pregnancy outcome

Delivery age (wk)

Birth weight (g)
!2500 (%)
!10 (%)
Delivery !37 wk (%)

Placebo*
(n = 48)

Vitamins C and E*
(n = 52)

37.2 G 3.9
3050 G 1021
12 (25)
4 (8.3)
14 (30)

36.8 G 3.6
2911 G 901
13 (25)
2 (3.8)
20 (38.4)

Mean G SD.
* No significant differences between groups.

E 400 IU had no eect on the rate of preeclampsia in

a high-risk patient population. However, we must
caution that our study was terminated prematurely and
the sample size was inadequate to answer this question.
Nevertheless, considering the marginal dierences in the
rate of preeclampsia found between the 2 groups (17.3%
vs 18.8%) even if the study was continued, it would have
been unlikely to demonstrate a 50% reduction in rates of
preeclampsia with vitamins C and E.
Our randomized trial has limitations and may be
improved in 2 ways. First, we terminated the trial
prematurely because of inadequate funding. Second,
the most serious limitations of this study is what we have
learned from this trial. On the basis of the results of only
1 previous trial3 on this subject, we calculated our
sample size on the basis of a 50% reduction in rate of
preeclampsia with vitamin supplementation (from 20%
in placebo to 10% in vitamin group). Therefore, a 50%
reduction is unrealistic with vitamin supplements. A
more realistic expectation should have been a 33% or
even 25% reduction in rates of preeclampsia. This
would have required at least 500 to 950 women in each
arm to show a meaningful reduction in preeclampsia.
Thus, we recommend that future trials base their
calculated sample size on these realistic expectations.
In addition, adequate funding should be available before
initiation of any randomized clinical trial.

References
1. Caritis SN, Sibai B, Hauth J, Lindheimer MD, Klebano M,
Thom E, et al, for the National Institute of Child Health and
Human Development Network of Maternal-Fetal Medicine Units.
Low-dose aspirin to prevent preeclampsia in women at high risk.
N Engl J Med 1998;338:701-5.
2. Roberts JM, Hubel CA. Is oxidative stress the link in the two-stage
model of preeclampsia? Lancet 1999;354:788-9.
3. Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, et al.
Eect of antioxidants on the occurrence of pre-eclampsia in women
at increased risk: a randomized trial. Lancet 1999;354:810-6.