15 August 2003

A life-threatening condition that can occur with very little warning, pre-eclampsia is one of the commonest complications of pregnancy, affecting 4 per cent of all pregnant women. It affects the mother's blood vessels, leading to raised blood pressure, fits, strokes or injury to the lungs, liver and kidneys.

At present, the only cure is delivery of the baby. Since pre-eclampsia can set in from 26 weeks onwards, this may severely compromise the baby's health. Problems associated with premature births - many of which can persist into adulthood - include immature organs, respiratory problems due to underdeveloped lungs, blindness, deafness and susceptibility to infections. Up to 60 per cent of very premature babies will have low IQ or learning disabilities.

Pre-eclampsia also has major economic implications. It costs around £10 000 per week to look after a premature baby in neonatal intensive care - and pre-eclampsia is responsible for 7000 or so premature babies every year. To these must be added the costs of hospital admissions for the mother, and of the frequent check-ups all pregnant women receive, even though they may be feeling perfectly well, to make sure they haven't developed pre-eclampsia. In total, these costs put a heavy strain on the healthcare system.

The picture looks bleak on all sides, yet hope may not be far away. Recent research suggests that the incidence of this devastating condition could be significantly reduced by a cheap and beautifully simple intervention: vitamin supplements.

Just over three years ago, Professor Lucilla Poston and colleagues at Guy's, King's and St Thomas' School of Medicine in London discovered that the cells lining the walls of tiny blood vessels were abnormal in women with pre-eclampsia. This, and evidence from other labs, suggested that the blood vessels were being damaged by reactive forms of oxygen - 'free radicals'. If so, something that mopped up the free radicals might prevent the condition developing. As vitamin C and vitamin E were both known to be highly effective dousers of free radicals, as well as safe and easy to administer, they were ideal candidate treatments to test.

The group pressed on with a small study, giving vitamin C and E supplements to women at risk of pre-eclampsia. "We looked at 283 women who had abnormal blood flow to the placenta, which we identified by an ultrasound scan, or who had pre-eclampsia in a previous pregnancy," says Professor Poston. The results, published in the Lancet in 1999, showed that vitamin supplements halved the risk of pre-eclampsia in such women.

Fighting free radicals

How can vitamins make a difference? "Although the cause of pre-eclampsia is still being debated," explains Professor Poston, "the most popular theory is that the disease occurs due to inadequate blood-vessel development in the placenta, which leads to the production of large numbers of oxygen free radicals." The key appears to be intermittent blood flow in the placenta; tissues are alternately starved of oxygen then replenished as blood flow resumes. But when the oxygen supply returns, there is a burst of cellular metabolism that, as a byproduct, generates dangerous oxygen free radicals.

Free radicals are unstable molecules with one electron too many or too few. To stabilise themselves they 'grab' an electron from a neighbouring molecule, making it unstable in turn. This can set off a chain reaction that wreaks havoc on cells: free radicals damage cell membranes and genetic material and inactivate enzymes.

The free radicals produced in the placenta gain access to the mother's blood vessels and attack the layer of cells forming the blood vessel walls. These endothelial cells play a critical role in maintaining circulation, regulating blood clotting and controlling the contraction and relaxation of the blood vessel wall. Damage to these cells causes intense narrowing of the blood vessels, clot formation and activation of white blood cells. Blood vessels in the liver and kidneys are also affected, causing the kidney to leak protein into the urine - a classic sign of pre-eclampsia. Constriction of blood vessels in the brain can lead to the fitting associated with pre-eclampsia, while problems with blood clotting may lead to strokes.

Antioxidants, such as vitamins C and E, alleviate these symptoms by mopping up free radicals in the mother's bloodstream. Antioxidants are able to supply the missing electron, or remove the extra one, without becoming unstable themselves.

The trials

Professor Poston and her colleagues now hope to confirm their earlier findings in a large-scale, countrywide randomised placebo-controlled trial, funded by the Wellcome Trust. The trial, which will be the largest study of its kind in the UK, started in July 2003. "Over the coming 23 months, midwives will recruit pregnant women from 22 hospitals in ten geographical locations across the UK," says Professor Poston. "This time we want to look at a much broader group of women, to make sure we include all the risk factors for pre-eclampsia, including obesity, diabetes, high blood pressure, blood clotting problems and kidney problems."

During the trial, 2400 women will be randomised into separate groups, and will either take vitamins C and E or a placebo. The research team also wants to establish that the vitamins do no harm to the baby, so any effects on the birthweight of each baby, a robust marker of the child's health, will also be recorded.

Across the Irish Sea, at the Royal Victoria Hospital in Belfast, Dr David McCance and colleagues will be conducting a more focused study of the effects of vitamins C and E on pregnant women with diabetes. In diabetes, high levels of glucose and insulin in the bloodstream also increase the production of free radicals, which then attack the mother's blood vessels. "Diabetes is an important risk factor for pre-eclampsia," explains Dr McCance. "Around 20 per cent of pregnant women with type 1 diabetes develop it."

Although there have been a number of studies testing the impact of vitamins C and E on diabetes, there is a dearth of randomised controlled trial data about the impact of this intervention on the outcome of diabetic pregnancy. Against the background of Professor Poston's initial findings, and funded by the Wellcome Trust, Dr McCance and colleagues are therefore embarking on one of the largest randomised studies of type 1 diabetes in pregnancy.

Around 800 women with type 1 diabetes, who are dependent on insulin for their survival, will be recruited from 16 centres in Northern Ireland, Scotland, and the north of England - and, as in Professor Poston's parallel trial, given supplements of vitamins C and E or a placebo. "There were no women with diabetes in Professor Poston's earlier study. We want to find out whether a similar benefit - reducing the occurrence of pre-eclampsia by half - will be found in the presence of diabetes," he explains.

Two further, international studies should yield important data to complement these two UK-based projects. In the USA, the NIH Maternal Fetal Medicine Network is conducting a trial looking at the effect of vitamin supplements on pregnant women in their first pregnancy with no risk factors for pre-eclampsia - a study that will provide a valuable benchmark for comparative analysis.

Meanwhile, the World Health Organization (WHO) will be looking at the effect of vitamin supplements on pregnant women at risk of pre-eclampsia in women in developing countries - where every year, 100 000 women die from pre-eclampsia. The WHO study, scheduled to begin in November 2003 and which will be collaborating with Professor Poston's team, will recruit 1750 women from Peru, Vietnam and India to find out whether vitamins C and E work in different environments, and with different forms of antenatal care.

These trials have far-reaching implications. If the results prove as favourable as Professor Poston's preliminary study suggests they might, they could offer a simple and cheap way of not only saving and improving the lives of mothers and children, but also significantly reducing healthcare costs across the globe. "Until now this devastating disease has been unpreventable," says Professor Poston. "But now we have a real opportunity to make a difference."

See also

• Preventing premature births (Press release: 15 July 2003)

External links

• Professor Lucilla Poston at Guy's, King's and St Thomas' School of Medicine, London: Research interests

Further reading

Chappell L C, Seed P T, Briley A L, Kelly F J, Lee R, Hunt B J, et al. (1999) Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomized trial. Lancet, 354: 8106.

Chappell L C, Seed P T, Kelly F J, Briley A, Hunt B J, Charnock-Jones S, et al. (2002) Vitamin C and E supplementation in women at risk of pre-eclampsia is associated with changes in indices of oxidative stress and placental function. Am. J. Obstet. Gynecol., 187: 777-84.

Hubel C A. (1999) Oxidative stress in the pathogenesis of pre-eclampsia. Proc. Soc. Exp. Biol. Med., 222: 22235.

Roberts J M, Lain K Y. (2002) Recent insights into the pathogenesis of pre-eclampsia. Placenta, 23: 359-72.

Zhang C, Williams M A, King I B, Dashow E E, Sorensen T K, Frederick I O, et al. (2002) Vitamin C and the risk of pre-eclampsia results from dietary questionnaire and plasma assay. Epidemiology, 13: 409-16.