Do Antioxidants Affect Preeclampsia?
Do Antioxidants Affect Preeclampsia?
September 2000; Volume 2; 70-72
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.
Background: Oxidative stress has been implicated in the pathophysiology of preeclampsia. This randomized controlled trial tested vitamin C and E supplementation in women at increased risk of preeclampsia (based on plasma markers of vascular endothelial activation and placental insufficiency or previous preeclampsia).
Methods: Two hundred eighty-three women at increased risk of preeclampsia by abnormal two-stage uterine artery Doppler analysis (or a prior history of preeclampsis) were randomized to placebo or 1,000 mg/d vitamin C and 400 IU/d vitamin E 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. Preeclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat (ITT) as well as in the cohort who completed the study.
Results: The group receiving supplemental vitamins C and E experienced a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% confidence interval 4-35, P = 0.015). In the ITT cohort, preeclampsia occurred in 24 of 142 (17%) women in the placebo group and 11 of 141 (8%) in the vitamin group (adjusted odds ratio [OR] 0.39 [0.17-0.90], P = 0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the OR for preeclampsia was 0.24 (0.08-0.70, P = 0.002).
Funding: Tommy’s Campaign and the Special Trustees for St. Thomas’ Hospital, London, UK.
Comments by Anthony R. Scialli, MD
I clearly remember the day the "cause" of preeclampsia was discovered. The year was 1974 and I was a medical student at St. Peter’s Hospital in Albany, NY. One morning, my resident came to work very excited. He had just read an article by a fellow named Page in which the pathophysiology of this enigmatic disease was clearly explained. According to Page, preeclampsia occurred as a self-perpetuating cycle in which release of placental thromboplastins led to intravascular coagulopathy, which led to deposition of fibrin in the microcirculation, which led to uteroplacental ischemia, which led to placental damage, which led back to release of placental thromboplastins.
The next quarter-century of my career was to show, of course, that Page’s eloquent description was just one of many eloquent descriptions of epiphenomena associated with this protean disorder of pregnancy. A large amount of effort has gone into identifying the cause of preeclampsia and into ways of preventing this potential cause of maternal and neonatal morbidity and mortality. In recent times, there has been considerable attention to prevention of the microangiopathy associated with preeclampsia. The use of calcium and aspirin prophylaxis went through respective phases of popularity, with early studies demonstrating a benefit. Larger trials were disappointing, showing no advantage of either therapy over placebo.
This latest study addressing the disordered vascular system in preeclampsia is a small randomized trial of vitamins C and E. The hypothesis is that free radicals promote endothelial malfunction, and that antioxidant vitamins can interrupt the process of endothelial damage and prevent laboratory and clinical manifestations of the disease. In this study, the laboratory manifestation of the disease is a ratio between PAI-1, which increases in preeclamptic women, and PAI-2, a placental product that decreases in the face of impaired placental function. Elevation of the PAI-1/PAI-2 ratio could, then, be taken as evidence of endothelial activation (increasing PAI-1) and placental dysfunction (decreasing PAI-2).
To test the hypothesis, Chappell et al identified women at high risk of preeclampsia using two methods. The first method used Doppler flow velocity studies of the uterine artery to identify women who failed to develop the expected decrease in resistance indices in the middle trimester. The second method relied on a history of preeclampsia in a previous pregnancy. Women identified by either method were randomized to receive both vitamins C and E or identical placebo vitamins. Women began supplementation at 16-22 weeks, but were excluded from the study at 24 weeks if their Doppler studies became normal. The results of the study were analyzed by ITT (that is, patients removed from the study were counted as though they had continued in their respective groups) and were analyzed separately for women who actually completed the study. Both methods of analysis showed a convincing improvement in the PAI-1/PAI-2 ratios, and a reduction in the incidence of preeclampsia.
This study was performed and reported in an extra-ordinarily competent manner. Chappell et al deserve applause for many excellent features, especially clear and accurate writing. The use of both vitamins C and E was bold but important; recognizing that these antioxidant vitamins work together, the investigators avoided the costly distraction of testing each vitamin alone, an error that has led investigators of other cardiovascular endpoints to conclude that antioxidant vitamins are ineffective. The use of resistance index by Doppler to identify women at high risk of developing preeclampsia was brilliant, and resulted in the identification of the exact population appropriate for the trial. Eliminating women whose resistance indices normalized further enriched the population with those at highest risk of preeclampsia. The analysis was carefully considered, with ITT and study-completion data displayed side-by-side.
The sole question is why women with a history of preeclampsia were grouped with women who had abnormal Doppler waveforms. Women with a history of preeclampsia are, in fact, at higher risk of developing preeclampsia in a subsequent pregnancy, but their risk is still rather low. Although inclusion of these women increased the sample size from 242 to 283, the cost could have been the introduction of a subgroup of women who would be at lower risk of preeclampsia and who might have jeopardized the power of the study to demonstrate a treatment effect. Because a treatment effect was clearly shown, it can be argued that inclusion of these women did not sabotage the study; still, one wonders whether these 41 women behaved differently from the others, a point not addressed by the authors.
As an accompanying editorial indicates, the results of this study are almost too promising. Replication in a larger, multicenter trial will be an important step in bringing us to a recommendation that pregnant women at risk, or perhaps all pregnant women, be supplemented with vitamins C and E. In the meantime, we are left with an intriguing question: Is preeclampsia a vascular disease, like some other vascular diseases, caused in whole or in part by a diet deficient in fruits and vegetables? Even before the question of vitamin supplementation is answered by a larger multicenter trial, recommending adequate fruits and vegetables in the diet of pregnant women appears to be a reasonable way to hedge the bet.
September 2000; Volume 2; 70-72
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