In the September 1999 issue of The Lancet researchers from The Fetal Health Research Group, at Guy's, King's and St Thomas' School of Medicine reported the results of a randomized clinical trial of the effects of antioxidant supplements on the occurrence of preeclampsia in women identified as having an increased risk of preeclampsia. The rationale for the study was based on the hypothesis that free radicals, particularly superoxide anions, may promote maternal vascular malfunction. The authors briefly summarized published studies suggesting that in preeclampsia the placenta is in a state of oxidative stress. Articles cited in the Lancet report included evidence of elevated levels of markers of lipid peroxidation (malondialdehyde and 8-epiprostaglandin-F2α) in the plasma of women with preeclampsia and low concentrations of antioxidant in the plasma and placenta. The authors hypothesized that early supplementation with antioxidants could be beneficial.

Methods:

The study was a randomized double-blind controlled trial of early supplementation with vitamins C and E in women at increased risk of preeclampsia. Study endpoints included the diagnosis of preeclampsia (development of proteinuric hypertension) and markers of endothelial and placental function explained below:

a) plasminogen-activator inhibitor-1 (PAI-1) - the level should increase during normal pregnancy but the level is higher in preeclampsia than in normal pregnancy.

b) plasminogen-activator inhibitor-2 (PAI-2) - the level also increases with normal pregnancy but instead is decreased with reduced placental function during preeclampsia. The ratio of PAI-1 to PAI-2 should decrease in normal pregnancy as the placental mass increases. However it is high in preeclampsia due to endothelial cell activation and placental insufficiency. The ratio (adjusted for the baseline measure) was used as an index of disease process. Eligible participants were classified as at risk of preeclampsia based on: an abnormal Doppler waveform in either uterine artery at 18-22 weeks gestation, or a history in a preceding pregnancy of: preeclampsia requiring delivery before 37 weeks, or HELLP Syndrome. After screening 283 women were randomized to receive both vitamin C (1000 mg) and vitamin E (400 mg) or to receive placebo tablets starting at 16-22 weeks gestation.

Results:

Analyses were carried out on the 141 vitamin users and 142 placebo users. 13 placebo and 14 vitamin group patients dropped out before the end of the pregnancy but were included in the evaluation. Odd's ratios were adjusted for DBP, smoking, ethnic origin and chronic hypertension.

The PAI-1/PAI-2 ratio was reduced among the vitamin group by 21% (95% CI 4-35%) during gestation, indicating better placental function. The frequency of preeclampsia was reduced from 17% in the placebo group to 8% in the vitamin group - the adjusted odd's ratio was 0.39, representing a decreased risk of 61% (95% CI of 10-83%, p=0.02). The beneficial effect was even stronger in the group of women completing the study. The authors concluded that vitamin supplementation may prove beneficial in high risk pregnancies.

References

• Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of preeclampsia in women at increased risk: a randomized trial. Lancet 1999;354:810-816.