We read with interest the results of the trial by Xu et al titled “An international trial of antioxidants in the prevention of preeclampsia (INTAPP).” This is the sixth large clinical trial that has failed to demonstrate any benefit of vitamins C and E in preventing preeclampsia (PE). Hundreds of thousands (if not millions) of dollars, man hours, and other research resources have been expended on these studies. Yet, it should have become quite evident a few years back after the first couple of studies that vitamins C and E neither prevent nor ameliorate PE. We would like to explain why.

The single consistent pathological lesion in PE is defective trophoblastic invasion. Although there is strong evidence for a role for oxidative stress in PE, it is unlikely to be the cause of the defective invasion, but is more likely to act further downstream in the pathophysiology. It seems therefore self-evident that antioxidant therapy could not prevent PE, although theoretically it could ameliorate the disease.

Some fundamental questions should surely be addressed before a rush to potential therapeutic interventions. For example, the quality or quantity of the oxidative overload in PE is unknown, and therefore the potential quantity of antioxidant supplementation required to ameliorate disease activity would also be unknown. Lack of benefit of the vitamins C (500 mg) and E (400 mg) could simply reflect inadequate dosage. This is certainly the case if we extrapolate from animal experimentation, which has shown that oxidative stress plays a crucial role in oophorectomy-induced osteoporosis in mice, and that vitamin C, given intravenously at a dose of 1 mmol/kg, prevents the development of osteoporosis. Extrapolating to the human female, equivalent doses of vitamin C to attain antioxidant activity would be in the region of 10-15 g! Such high doses could not, intuitively, be given intravenously. Given by mouth, it seems highly unlikely that the required serum levels could be attained because of limited absorption, not withstanding the potential risks of hypervitaminosis.

The Cochrane review on this issue concurs with our view. The penny should by now have dropped. We do not for one moment dispute a role for oxidative stress in the pathophysiology of PE, or the possibility of amelioration of the disease by an antioxidant given at the right time and in the correct dosage; we simply wish to plead that the massive and expensive trials of vitamins C and E should cease!