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Antioxidant supplementation in pre-eclampsia: Commentary  
  The Lancet April 8 2006; 367:1119-1120
Marshall D Lindheimer a and Baha M Sibai b
a. Departments of Obstetrics & Gynecology and Medicine, University of Chicago, Chicago, IL 60637, USA
b. Department of Obstetrics and Gynecology, University of Cincinnati,
Cincinnati, Ohio, USA
Preventing pre-eclampsia or decreasing its severity would considerably reduce maternal-fetal morbidity worldwide, bringing as it would substantial decrements in maternal-fetal demise, premature births, and other serious immediate and long-term consequences of this multisystem disorder. Thus for over a decade now, many large and expensive multicentre randomised trials have failed to show significant reductions in the incidence of pre-eclampsia, or, when positive results occurred, the significance was small and the number to treat large.1,2 All the trials were based on seemingly plausible hypotheses and/or promising results from small trials, or their likelihood of success was suggested in systematic reviews. First came the aspirin studies (more than 30 000 patients, randomised in over 30 trials1), and then the calcium supplementation trials (over 15 000 patients randomised in 12 studies2).
Today's Lancet contains the latest focus on pre-eclampsia prevention, the VIP study by Lucilla Poston and colleagues.3 VIP was a well-conducted trial in which 2410 women with clinical risk factors predisposing them to develop pre-eclampsia were randomly allocated in blinded fashion to receive antioxidant supplementation (1000 mg vitamin C and 400 IU vitamin E) or placebo before gestational week 22. This intervention not only failed to decrease the incidence of pre-eclampsia, but might also have been responsible for an increase in adverse events. Pre-eclampsia appeared 8 days earlier and may have been more severe in the supplemented group, as significantly more of these women required either parenteral antihypertensives and/or magnesium sulphate. Supplementation was also associated with more gestational hypertension and fetal jeopardy. Birthweight was significantly lower and there were significantly more unexplained deaths after gestational week 24, higher rates of cord-blood acidosis, and lower 5-min Apgar scores in supplemented women.
Another trial of similar size, but in nulliparous women, has been completed in Australia and will hopefully be reported soon. The VIP results have been communicated to the data and safety monitoring committees of several ongoing trials, including the large National Institute of Child Health and Development's Maternal-Fetal-Medicine-Trials Network, in which about 5000 of their intended 10 000 nulliparous women have been randomised. Thus we will shortly know much more about these latest revelations. But what else can we learn from the VIP trial?
About a decade ago, we noted the limited resources allocated to pre-eclampsia research, and suggested that studies focus on the basic science needed to understand this disease before costly trials started.4,5 The results from VIP do not alter this view. The VIP study was based on an interesting but still not established hypothesis (ie, the roles of antioxidant excess and the exaggerated systemic inflammatory response in the causation of pre-eclampsia) that seemed to have considerable supporting data but was not without its critics. VIP had been preceded by positive results from a small trial that used a biochemical ratio in the circulation (PAI-1:PAI-2) as its endpoint, and other support came from the conclusions of a limited systematic review.1,3 Of interest, in VIP, and supporting the rationale behind the study, vitamin C levels were significantly lower in the pre-eclamptic women in both study arms. However, samples were obtained in less than half of the participants and longitudinally in only about 10%, while confounding variables perhaps related to other aspects of poor nutrition in the pre-eclamptic woman with lower vitamin C levels might have aetiological significance.
VIP focused on high-risk patients, a popular approach because these populations manifest a high incidence of pre-eclampsia, with, more often, severe disease. Thus fewer women need be recruited. However, such study populations are also heterogeneous (here they included women with diabetes, chronic hypertension, renal disease, previous pre-eclampsia, antiphospholipid syndrome, obesity, and multiple births). We know from the old reports on renal biopsy that diagnosis of superimposed pre-eclampsia by clinical criteria alone is often erroneous in these groups, especially in multiparous women or in those with proteinuria at baseline.6 Further, the preventive intervention might affect the disease subgroups differently. Thus, in pre-eclampsia, studies of nulliparous women remain the gold standard even if the trials are larger and more costly.
The cause of pre-eclampsia might be multifactorial, in which case the effect of a single intervention would be diluted. If so, identification of markers to determine what should be blocked or development of a "preventive cocktail" for all possible causes would be needed before developing future trials. In essence, although there have been logarithmic leaps recently towards understanding pre-eclampsia, the disease is still somewhat mysterious,7,8 and one should not be convinced too easily and rush to trials while angels fail to get their grants funded. Our limited resources should focus more on basic research, with human studies stressing prediction markers combined with ancillary studies to help define mechanisms (and, of course, the safety and efficacy of therapy).
It appears surprising that administration of vitamins in amounts that did not exceed maximum daily tolerable allowances should be associated with adverse effects, but the VIP data are not the first time that vitamin or nutrient supplements administered to populations already consuming considerable amounts of the supplement's content in their diets have had adverse effects. This brings to mind some of the problems when vitamins A and D are ingested by well-nourished populations, as well as one of the earliest supplementation trials in which adverse results were associated with high protein-supplementation in women who were not protein deficient.9 There is also the reverse side of the coin when investigators showed a small but important effect of calcium supplementation-ie, a decrease in the severity of adverse outcomes-in a population with deficient intake of calcium.2 Thus it would not be surprising if two ongoing trials involving antioxidant supplementation in areas of developing nations where nutrient deficiencies are rampant produced results differing from those here (ie, a multicentre WHO trial and one in Brazil).
We declare that we have no conflict of interest.
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