Preeclampsia is a common condition of pregnancy that threatens the life of mother and baby. One of the justifications for prenatal care is to decrease the risks of preeclampsia. Over the past century, prenatal care has included a variety of imaginative if useless strategies, including avoidance of cold drafts and decrease in salt intake, for preventing preeclampsia. 1 More recently, some have suggested that preeclampsia is not preventable; prenatal care should aim simply to manage the disease carefully once it has occurred. 2 Still, the possibility of preventing preeclampsia continues to be pursued, and there may well be important factors yet to be discovered. As a paper in the present issue of Epidemiology suggests, a new clue for nutritional prevention of preeclampsia may be emerging.
In this issue, a team from Seattle reports on a case-control study of vitamin C in preeclampsia. 3 The authors assessed exposure to ascorbic acid through measurement of plasma levels and also by means of a dietary intake questionnaire. Both methods suggest that preeclamptic women had a reduced level of ascorbic acid intake. Women in the lowest decile of plasma ascorbic acid were nearly four times as likely to develop preeclampsia. This finding of an association specific for vitamin C follows a recent randomized trial of supplementation by two antioxidants (vitamins C and E). In that trial, which was conducted among 283 high-risk women, preeclampsia was substantially reduced among women who received antioxidant supplements (adjusted odds ratio [OR] = 0.4; 95% confidence interval [CI] = 0.17–0.90). 4 Also, the intervention was associated with a 21% decrease (95% CI = 4%–35%) in the ratio of plasminogen activator inhibitor 1 to 2, a surrogate marker for preeclampsia.
With the further epidemiologic support for this association, the possibility of preventing preeclampsia through dietary intervention becomes an exciting possibility. However, this result must be placed in the context of past nutritional interventions that, at one time, also seemed promising. These interventions are legion, and include both additions to and subtractions from the diet.
“Over the past century, prenatal care has included a variety of imaginative if useless strategies for preventing preeclampsia. . .”
In the prevention of preeclampsia, the most extensively researched dietary supplement must be calcium. A Cochrane Review identifies 28 trials, of which one is ongoing; 17 were deemed uninformative, and 10 were retained for the final overview of 6604 women. 5 Results depended on the baseline calcium intake. In the six trials carried out among populations with low intake, the risk of preeclampsia was reduced by two-thirds in the supplemented women (relative risk [RR] = 0.3; 95% CI = 0.21–0.49]). There was a weaker trend towards lower risk among high-intake populations (RR = 0.9; 95% CI = 0.71–1.05). One follow-up study found lower rates of childhood hypertension in the intervention group.
The second well researched candidate is fish oil, which has been the object of studies since before the Second World War. Fish oil is a plausible candidate for prevention, owing to the known effects of n-3 fatty acids on the prostacyclin/thromboxane-A2 balance in preeclampsia. In a clinical trial of 1938–1939, 5644 women were randomized, and a 31% reduction in preeclampsia was observed in the supplemented arm. 6 Unfortunately, recent randomized clinical trials of fish oil supplementation have been less conclusive. In six multicenter trials, there was a modest decrease in recurrence risk of preterm delivery, but no decrease in preeclampsia. 7 The authors concluded that “although some of these [fish oil] interventions are promising, to date none have been clearly shown to have clinically worthwhile benefits”.
Other nutritional factors have been suggested but are less extensively studied. For example, in Hungary, researchers found an association between the rate of preeclampsia and the magnesium content of drinking water. 8
Abstaining from salt (presumably because of the edema that is part of the preeclamptic syndrome) was for years a standard recommendation for the prevention of preeclampsia. The two small trials included in the Cochrane review on salt intake could not show benefit or risk from a low-salt diet. 9
If salt is not a culprit, perhaps sugar will become a new candidate for banishment. A dietary cohort study showed an adjusted odds ratio for preeclampsia of 3.6 (95% CI = 1.3–9.8) with high sucrose intake. 10 However, the Cochrane review of low-energy diets (in women who were either overweight or exhibited high weight gain earlier in gestation) did not show any effect of reduced weight gain on pregnancy-induced hypertension or preeclampsia. 11
The Next Move
Given the disappointing interventions of the past, there are three possible options. One is the disillusioned—none of this will work. Another is the pragmatic—let’s recommend that pregnant women have a nice breakfast of orange juice, cocoa (for magnesium), a handful of almonds and hazelnuts (for vitamin E), smoked salmon (for the n-3 fatty acids), and cheddar (for the calcium), but hold back on those sweets and added salt. This pragmatic stand is being offered by at least one teaching hospital. 12 The third option is to mount a large, multicenter randomized trial of antioxidants, ideally with a sufficient group of at-risk women (with both a history of preeclampsia and a poor diet). The time has probably come for such a trial.
As investigators consider a new nutritional trial, one suggestion may be in order. In the real world, food remains very much a pleasure. 13 A good meal might be more tempting than a multivitamin tablet. So why not try three arms: placebo, tablet, and good food supplementation?
1. Loudon I. Some historical aspects of toxaemia of pregnancy. A review. Br J Obstet Gynaecol 1991; 98: 853–858.
2. Moutquin J-M, Garner PR, Burrows RF, et al
. Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy. CMAJ 1997; 157: 907–919.
3. Zhang C, Williams MA, King IB, et al
. Vitamin C and the risk of preeclampsia–results from dietary questionnaire and plasma assay. Epidemiology 2002; 13: 409–416.
4. Chappell LC, Seed PT, Briley AL, et al
. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–816.
5. Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (Cochrane Review). Cochrane Database Syst Rev 2000; 3: CD001059.
6. Olsen SF, Secher NJ. A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: indications from a 50-year-old trail. Br J Nutr 1990; 64: 599–609.
7. Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ, Gluud C. Randomised clinical trials of fish oil supplementation in high risk pregnancies. Fish Oil Trials In Pregnancy (FOTIP) Team. Br J Obstet Gynaecol 2000; 107: 382–395.
8. Melles Z, Kiss SA. Influence of the magnesium content of drinking water and of magnesium therapy on the occurrence of preeclampsia. Magnes Res 1992; 5: 277–279.
9. Duley L, Henderson-Smart D. Reduced salt intake compared to normal dietary salt, or high intake, in pregnancy (Cochrane Review). Cochrane Database Syst Rev 2000; 2: CD001687.
10. Clausen T, Slott M, Solvoll K, Drevon CA, Vollset SE, Henriksen T. High intake of energy, sucrose, and polyunsaturated fatty acids is associated with increased risk of preeclampsia. Am J Obstet Gynecol 2001; 185: 451–458.
11. Kramer MS. Energy/protein restriction for high weight-for-height or weight gain during pregnancy. Cochrane Database Syst Rev 2000; 2: CD000080.
12. Szabo J, Pal A, Szabo-Nagy A. Preventing toxaemia. Lancet 2001; 357: 2140.
13. Rozin P, Fischler C, Imada S, Sarubin A, Wrzesniewski A. Attitudes to food and the role of food in life in the U.S.A., Japan, Flemish Belgium and France: possible implications for the diet-health debate. Appetite 1999; 33: 163–180.