The ability to prevent hypertensive disorders of pregnancy is limited by lack of knowledge of its underlying etiology. Prevention is focused on identifying women at higher risk of developing pregnancy-induced hypertension or pre-eclampsia during pregnancy, followed by close clinical and laboratory monitoring to recognize the clinical symptoms of the disease in its early stages. These women and their pregnancies can then be selected for more intensive monitoring or delivery. Although these measures do not prevent the disease, they may be helpful for preventing some adverse maternal and fetal sequelae.
As part of many other nonpharmacological interventions, some dietary interventions have been proposed to prevent the development of pregnancy-induced hypertension and pre-eclampsia.
Nutritional advice in pregnancy The relevant literature was reviewed in order to assess the effects of advising pregnant women to increase their energy and protein intakes on the outcome of pregnancy, and maternal and fetal/infant morbidity and mortality. Nutritional advice was assessed on a Cochrane systematic review and appears to be effective in increasing pregnant women's energy and protein intake, but the implications for fetal, infant, or maternal health cannot be judged from the available evidence. Pre-eclampsia prevention was assessed only in one small trial involving 136 women with no beneficial effects.
Protein/energy supplementation The effect of balanced protein/energy supplements for pregnant women on gestational weight gain and pregnancy outcomes was also evaluated. Pre-eclampsia prevention was assessed in three trials involving 516 women, with no significant beneficial effects. However, these trials had methodological flaws, so the results should be interpreted cautiously. In another pre-specified subgroup, only one trial involving 782 women evaluated pre-eclampsia prevention when isocaloric balanced protein/energy supplements were given to underweight pregnant women, showing no effect.
Energy/protein restriction for obese pregnant women Excessive weight gain during pregnancy has long been recognized as a risk factor for edema and impending pre-eclampsia. Epidemiological studies suggested that high maternal weight was positively associated with the risk of pre-eclampsia.
Energy/protein restriction for high weight-for-height or weight gain during pregnancy was another subgroup assessed in this systematic review. Pre-eclampsia was evaluated in two trials (284 women), which showed no reduction in the risk of occurrence. Similarly, there was no influence on pregnancy-induced hypertension (3 trials, 384 women). The limited evidence available suggests that protein/energy restriction of pregnant women who are overweight or exhibit high weight gain is unlikely to be beneficial and may be harmful to the developing fetus. Although weight reduction may be helpful in reducing or preventing high blood pressure in nonpregnant women, there is no effect on preventing pre-eclampsia, even in obese women. Clinicians frequently ask pregnant women to restrict their food intake in an attempt to prevent pre-eclampsia, despite the absence of evidence that such advice is beneficial.
Salt restriction Even in the early phase of pregnancy, marked hemodynamic changes occur including a fall in vascular resistance and blood pressure and a rise in cardiac output. To compensate for the increased intravascular capacity the kidney retains more sodium and water. Apparently, the set point of sodium homeostasis shifts to a higher level at the expense of an expansion of extracellular volume. In nonpregnant individuals, a strong positive association of sodium intake with blood pressure has been established, but the relationship between sodium intake and blood pressure in human pregnancy remains obscure to date. For decades a low-salt diet has often been recommended as treatment for edema, in the hope that restricting salt intake would treat, and also prevent, pre-eclampsia. Recently, this practice has been questioned, and even a high sodium intake has been proposed for pre-eclampsia treatment and prevention.
The concerns about the effect of a low-sodium diet during pregnancy on maternal nutritional status led researchers to investigate if such changes could alter other nutrient intake. It was shown that the reduction in sodium intake also caused a significant reduction in the intake of energy, protein, carbohydrates, fat, calcium, zinc, magnesium, iron, and cholesterol. Even though the majority of clinicians no longer advise women to alter their salt intake during pregnancy, this is still current practice in many countries worldwide.
A recently published Cochrane systematic review evaluates the effect of the advice about low dietary salt intake during pregnancy. The review includes two trials with data reported for 603 women. Both trials compared nutritional advice to restrict dietary salt with advice to continue a normal diet. Women with established pre-eclampsia were not enrolled, so this review provides no information about the effects of advice to restrict salt intake for treatment of pre-eclampsia. No effect was found in preventing pre-eclampsia or pregnancy-induced hypertension (1 trial, 242 women). Women's preferences were not reported, but the authors presumed that a low-salt diet was not very palatable and was therefore difficult to follow.
Calcium supplementation A role for altered calcium metabolism in the pathogenesis of pre-eclampsia is suggested by epidemiological evidence linking low dietary levels of calcium with increased incidence of the disease. In agreement with these observations, several modifications in calcium metabolism have been observed in pre-eclamptic women and in calcium supplemented mothers.
A Cochrane systematic review of calcium supplementation during pregnancy has been published. Authors prespecified comparison groups taking into account the women's risk of hypertensive disorders of pregnancy (low versus increased), and the women's baseline dietary calcium intake (low: <900mgday_1 versus adequate: >900mgday_1).
High blood pressure with or without proteinuria was evaluated in 9 trials involving 6604 women. Overall, there was less high blood pressure with calcium supplementation (relative risk (RR) 0.81; 95% confidence interval (CI) 0.74-0.89), but there was a variation in the magnitude of the effect across the subgroups. The effect was considerably greater in women at high risk of developing hypertension (3 trials, 297 women: RR 0.35; 95% CI 0.21-0.57) than in those at low risk (6 trials, 6307 women: RR 0.84; 95% CI 0.76-0.92). Taking into account the women's calcium intake, the effect was also greater in those with low baseline dietary calcium (5 trials, 1582 women: RR 0.49; 95% CI 0.38-0.62) than in those with adequate calcium intake (4 trials, 5022 women, RR 0.90; 95% CI 0.81-0.99).
There was a reduction in the risk of pre-eclampsia when evaluated from 10 trials involving 6864 women (RR 0.70; 95% CI 0.58-0.83). When predefined subgroups were considered, there was a significant reduction in women with low baseline dietary calcium intake (6 trials, 1842 women: RR 0.32; 95% CI 0.21-0.49), but not in those with adequate calcium intake (4 trials, 5022 women: RR 0.86; 95% CI 0.71-1.05). Pre-eclampsia was considerably reduced in women at high risk of hypertension (4 trials, 557 women: RR 0.22; 95% CI 0.11-0.43), and less consistently in those at low risk of hypertension (6 trials, 6307 women: RR 0.79; 95% CI 0.65-0.94).
The results from the largest trial conducted by the National Institutes of Health (NIH), which studied low-risk women with adequate baseline calcium diet, and in whom all women in both groups received low-dose calcium supplementation as part of their routine antenatal care, showed no significant effect on hypertension and that pre-eclampsia.
Based on this, authorities from developed countries where adequate dietary calcium intake is common, discourage the use of routine calcium supplementation during pregnancy. Evidence from this review support the view that calcium supplementation might benefit women at high risk of gestational hypertension and women with low dietary calcium intake are at risk of developing pre-eclampsia, and current guidelines suggest supplementing calcium intake in these groups.
This recommendation is currently being evaluated in a large (8300 women), double-blind randomized controlled trial by the World Health Organization (WHO), conducted in seven locations around the world where calcium intake is low (<600mgday_1) in which pregnant women received an extra 1.5gday_1 of calcium carbonate or a placebo from the 20th week of gestation. Results should be available in 2005.
Iron and folate supplementation Numerous trials involving various populations of pregnant women with normal hemoglobin levels have evaluated the effects of iron and/or folate supplementation on several outcomes, some of them including hypertensive disorders of pregnancy. A Cochrane systematic review of 2 trials involving 87 women with normal hemoglobin levels in which iron and folic acid were compared with no treatment showed no effect on the occurrence of gestational hypertension. Pre-eclampsia was not evaluated. In another Cochrane review of two trials involving 696 pregnant women already receiving iron, where some women were allocated to receive folic acid and others received no treatment/placebo, again there was no effect on the prevention of gestational hypertension.
Although evidence shows that iron and folate supplementation is not effective in preventing hypertensive disorders during pregnancy, they should be prescribed for other established beneficial effects on pregnancy such as prevention of anemia.
Magnesium supplementation Magnesium is one of the essential minerals needed by humans in relatively large amounts. Magnesium works with many enzymes regulating body temperature and synthesizing proteins as well as maintaining electrical potentials in nerves and muscle membranes. Magnesium occurs widely in many foods; dairy products, breads and cereals, vegetables, and meats are all good sources. It is therefore not surprising that frank clinical magnesium deficiency has never been reported to occur in healthy individuals who eat standard diets. However, dietary intake studies during pregnancy consistently demonstrate that many women, especially those from disadvantaged backgrounds, have intakes of magnesium below recommended levels. Observational studies based on medical records reported that magnesium supplementation during pregnancy was associated with a reduced risk of fetal growth retardation and pre-eclampsia and that magnesium intake was associated with increased birth weight. Stimulated by these encouraging epidemiological studies, randomized clinical trials have been undertaken to evaluate the potential benefits of magnesium supplementation during pregnancy on pregnancy and neonatal outcomes.
A Cochrane systematic review of these randomized controlled trials was carried out in order to assess the effects of magnesium supplementation during normal or high-risk pregnancies on maternal, neonatal, and pediatric outcomes. Results from two trials (474 women) showed no apparent effect of magnesium treatment on prevention of pre-eclampsia. However, these results may have been confounded by the fact that in the largest trial all women (both magnesium supplemented and placebo groups) received a multivitamin and mineral preparation containing low doses of magnesium. Several of the trials also have poor methodological quality, especially related to concealment of allocation, which could give biased results. These authors conclude that dietary magnesium supplementation of pregnant women cannot be recommended for routine clinical practice because of the poor methodological quality of the current evidence.
Fish oil supplementation Studies of non-pregnant subjects suggest that fish oil, rich in long-chain n-3 fatty acids, has a moderate effect on blood pressure in normotensive as well as hypertensive individuals. A meta-analysis of controlled clinical trials of the effect of fish oil on blood pressure has demonstrated a significant reduction in systolic and diastolic blood pressure in untreated hypertensive non-pregnant individuals, but found no significant effect on normotensives. Fish oil has been shown to modify prostaglandin metabolism, and its effect on blood pressure has often been assumed to be due to such interference. Epidemiological studies suggested that marine diets could have a preventive effect on early delivery and hypertensive disorders of pregnancy.
Fish oil supplementation during pregnancy was evaluated in 1995 in a systematic review of 2 trials (5135 women), showing no effect on pregnancy-induced hypertension (2 trials, 5135 women) RR: 0.98, 95% CI 0.91 to 1.04. There was a statistically significant but modest reduction in the rate of pre-eclampsia (RR: 0.81, 95% CI 0.69 to 0.93). However, this reduction is strongly influenced by a single large trial conducted in 1942. Four other trials of fish oil supplementation involving more than 2000 women have been published recently none of which demonstrates any differences in the incidence of hypertension and pre-eclampsia between groups. Based on current evidence, fish oil supplementation is not recommended during pregnancy for the prevention of pre-eclampsia.
Zinc supplementation Zinc is proposed as playing an important role in many biological functions, including protein synthesis and nucleic acid metabolism. There is controversy in the literature in demonstrating the relationship between low serum zinc levels and abnormalities of pregnancy outcomes such as pregnancy-induced hypertension, prolonged labor, post-partum hemorrhage, preterm or post-term pregnancies, small-for-gestational age babies, or poor perinatal outcomes.
The role of routine zinc supplementation during pregnancy on outcomes for both mother and newborn was assessed in a Cochrane systematic review. Routine zinc supplementation in pregnancy had no detectable effect on gestational hypertension (four trials, 1962 women). However, there appears to be inconsistency among trials regarding the effects from other pregnancy outcomes. This may be related to variable population characteristics of women recruited in the various trials, as some included normal pregnant women with no systemic illness, other studies specifically selected women at high risk of low-zinc status, and in one study, participants were selected on the basis of proven low plasma zinc levels. There is at present no evidence of overall benefit from routine as opposed to selective zinc supplementation in pregnancy in pregnancy-induced hypertension or pre-eclampsia.
Vitamin (A, E, and C) supplementation An oxidant/antioxidant imbalance has been suggested among the possible pathogenic factors involved in pre-eclampsia. As vitamin E is one of the most important antioxidants, its levels and their relation with circulating levels of lipid peroxides in pre-eclamptic women has been intensively studied in recent years. As with other antioxidants, several studies found decreased vitamin E levels in serum from women with gestational hypertension and pre-eclampsia compared with controls. However, these findings could not be demonstrated in other studies. Increased ascorbate radical formation and ascorbate depletion were also found in plasma from women with pre-eclampsia. Recently, a randomized controlled trial involving 283 women at very high risk of developing pre-eclampsia was conducted. Women were randomly assigned to receive vitamin C (1000 mg day"1) and E (400IU day"1) or placebo at 16-22 weeks of gestation. The authors found a significant reduction in the risk of developing pre-eclampsia in the vitamin-supplemented group compared to controls (RR: 0.46; 95% CI 0.24-0.91). The authors concluded that supplementation with vitamins C and E may be beneficial for preventing pre-eclampsia in women at increased risk of the disease. However, these findings come from a single trial of 283 women and need to be further assessed in different settings and populations, as well as in low-risk women. The preventative potential of vitamins C and E is currently being evaluated in three large multicentre double-blind randomized trials in North America, in several institutions in the UK and in a new WHO multicentre trial in India, Peru, and Vietnam. Results are expected during 2006.
The role of vitamin A in pregnancy-induced hypertension and pre-eclampsia is another subject of controversy. It was proposed as a chain-breaking antioxidant in the free radical cascade. Some studies found significantly reduced serum vitamin A levels in pre-eclamptic and eclamptic women when compared to levels in healthy women in the third trimester. No trials have been published to date to assess the effect of vitamin A supplementation on pregnancy-induced hypertension or pre-eclampsia. A double-blind cluster randomized trial of low-dose supplementation with vitamin A or beta-carotene carried out in Nepal in 44 646 married women showed a 40% reduction in maternal mortality related to pregnancy in vitamin A supplemented women. However, differences in cause of deaths, including pre-eclampsia and eclampsia, could not be reliably distinguished between supplemented and placebo groups. Use of vitamin A supplements for the prophylaxis and management of pregnancy-induced hypertension and pre-eclampsia needs to be evaluated further before it can be recommended.
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