Clinical Briefs

With Comments from John La Puma, MD, FACP

Vitamin C and E Supplementation and Pre-eclampsia

March 2000; Volume 3: 35-36

Source: Chappell LC, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial. Lancet 1999;354:810-816.

Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. Two hundred eighty-three women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery Doppler analysis or a previous history of the disorder. They were randomly assigned vitamin C (1,000 mg/d) and vitamin E (400 IU/d) or placebo at 16-22 weeks’ gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1] and placental dysfunction [PAI-2]) were measured every month until delivery. The ratio of PAI-1/PAI-2 is high in pre-eclampsia, and normal in normal pregnancies. Pre-eclampsia was assessed by the development of proteinuric hypertension, according to the International Society for the Study of Hypertension in Pregnancy Guidelines. Analyses were done by intention to treat in the cohort that completed the study.

Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, P = 0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio [OR] 0.39 [0.17-0.90], P = 0.02). Of those in the cohort who completed the study (81 placebo group, 79 vitamin group), the OR for pre-eclampsia was 0.24 (0.08-0.70, P = 0.002). Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease.


Pre-eclampsia still has little effective treatment: Diuretics, magnesium, zinc, fish oils, and antihypertensives have only modest effects, and sometimes none at all.

This well-done, impressive study was stopped at the interim analysis because the outcome ratio was already statistically different. The ratio could not be compared between groups: Some women were dropped at 24 weeks because of nonadherence, transfer of care, and unwillingness to continue. Only high-risk women were studied.

Vitamins C and E are considered Pregnancy Category A drugs in doses up to the RDA. There is a single case report linking anencephaly and high-dose vitamin C (and in this case, multiple other nutrients and drugs); I was unable to find case reports for infants harmed by vitamin E.

Whether supplementation reduces the incidence of pre-eclampsia in low-risk women; whether the timing and dosages are optimal; and whether food containing 1,000 mg of vitamin C has the same effect (food with 400 IU of vitamin E has way too many calories even for those eating for two) should be studied.


Women at high risk for pre-eclampsia should know about these results, and strongly consider supplementing with 1,000 mg vitamin C and 400 IU vitamin E in mid-pregnancy, if not before.