Prevention of Preeclampsia : Is it Still a Disappointment ?

Preeclampsia is a major cause of maternal mortality worldwide, with many preventive strategies tested. In this review we intend to provide a synthesis of available studies of these strategies that have been tested, including systematic reviews. We will not be performing systematic review of the studies here. Of these strategies tested only low dose acetyl salicylic acid (ASA) and calcium can be considered helpful for prevention at this time. A recent meta-analysis showed a benefi t of low dose ASA for both high (RR 0.75, 95% CI 0.66 to 0.85) and moderate risk groups (RR 0.86, 95% CI 0.79 to 0.95). Therefore, low dose ASA in high risk groups may be useful, with a possible smaller benefi t in moderate to low risk women. Another meta-analysis looking at calcium shows benefi t for both high and low risk groups with an overall reduction in the risk of preeclampsia (RR 0.48, 95% CI 0.33 to 0.69). As a result, prenatal supplementation of calcium may be benefi cial for the prevention of preeclampsia. However, vitamins C and E, zinc, fi sh oil, and magnesium supplementation have been discounted as potential preventive strategies. Nitric oxide, folic acid, and antithrombotics have not been well studied and there is insuffi cient data for reliable conclusions to be made. Areas of ongoing research that appear promising in the prevention of preeclampsia include modifi able metabolic factors, angiogenic proteins, angiotensin receptor antibodies, and syncytiotrophoblast microparticles. Strategies targeting these areas may provide opportunities for therapeutic interventions.


Introduction
Hypertensive disorders of pregnancy are major contributors to maternal mortality worldwide.In the United States, 17.6% of maternal deaths are attributed to hypertensive disorders of pregnancy. 1reeclampsia complicates 5%-8% of pregnancies. 2This is higher in the presence of certain risk factors such as nulliparity, multifetal gestation, chronic hypertension, chronic renal disease, diabetes mellitus, vascular or connective tissue disease, antiphospholipid antibody syndrome, obesity, age over 35, and African American race. 2 Also, women with a prior history of preeclampsia in an antecedent pregnancy are at high risk for a recurrence (7.5% to 65% in different studies) [3][4][5] in the subsequent pregnancy.These risk factors can be used to predict patients at increased risk, and thereby benefi t from prophylactic measures.
The etiology of preeclampsia is unknown, and pathophysiology is poorly understood.Therefore, any preventive strategies developed are mostly speculative.There have been many interventions tried, but very few have been well studied enough to reach any conclusion on risk and benefi t profi les.
We will provide a brief review of some of the most common preventive methods studied (antiplatelets, calcium, vitamins C and E, zinc, fi sh oil, magnesium, and nitric oxide), and emerging areas of interest.We will also summarize the most recent evidence.Though other strategies have been studied, including progesterone, anti-hypertensives, physical activity, and other dietary modifi cations, we will not review them here, as these have been addressed elsewhere, and there are no recent studies or updates that have clinical implications.We will not be performing a systematic review, but a synthesis of available data including systematic reviews.We will be focusing on meta-analysis, mainly the Cochrane reviews as they provide a more defi ned and structured analysis, and large individualized randomized studies when available.

Methods
We searched The Cochrane Library and MEDLINE.Cochrane systematic reviews and other up-to-date systematic reviews and individual randomized controlled trials (RCTs) were sought.Conclusions were based on the systematic reviews when applicable unless RCTs published after the systematic reviews prove otherwise.Searches were carried out up to January 2009.Since the Cochrane reviews contain trials identifi ed from monthly searches of MEDLINE and other sources, we restricted our MEDLINE search to after the date of the Cochrane systematic review when applicable.

What the Evidence Shows Benefi cial in selected patients
Low dose aspirin Endothelial cell dysfunction is observed as a pathophysiologic change that attributes to most of the clinical features of preeclampsia.Mainly through increasing sensitivity to normal endogenous pressors, activating the coagulation cascade, and increasing vascular permeability. 6The observed imbalance between production of the vasodilator prostacyclin and the vasoconstrictor thromboxane led to the theory that low dose aspirin may alter this balance in favor of prostacyclin.[9][10][11][12][13][14] The most recent large RCT in nulliparous women published in 2003 14 showed that the aspirin (n = 1644) and placebo (n = 1650) groups did not differ signifi cantly in the incidence of preeclampsia (1.7% vs 1.6%; RR 1.08, 95% CI 0.64-1.83).However, a recent meta-analysis of 59 trials, including the above trial, showed benefi t for both high and low risk groups. 15There was a trend for the relative risk reduction to be greater in women at high risk of preeclampsia (RR 0.75, 95% CI 0.66 to 0.85) than those at moderate risk (RR 0.86, 95% CI 0.79 to 0.95).This meta-analysis concluded that administration of antiplatelet agents to women at risk leads to a 17% reduction in the risk of developing preeclampsia.Amongst women in the primary prevention trials, for every 72 women treated, one case of preeclampsia is prevented.However, for high-risk women, only 19 need to be treated to prevent one case.Overall, adverse effects appeared to be low.
There are some limitations to the interpretation of these meta-analyses; for example the timing of the initiation of the treatment, the dose, and the impact on different subgroups of patients.As preeclampsia is a disease process that likely starts at implantation, aspirin may need to be started before conception to improve outcome.The studies in the Cochrane meta-analysis were arbitrarily divided to the intervention being initiated before or after 20 weeks of gestation.Higher doses than the 100 mg dose may also have a different impact on the outcome, however the safety of higher doses needs to be further evaluated.Additionally, patients with certain risk factors may benefi t more from aspirin than other patients.
At this juncture, most authors recommend low dose ASA or in high risk groups, 2 and based on the above recent meta-analysis there may be benefi t in moderate to low risk women (Table 1).

Calcium
A low prevalence of preeclampsia had been reported in areas where the diet was rich in calcium. 16This observation led to the theory that calcium supplementation may be benefi cial for the prevention of preeclampsia.Numerous trials have evaluated the effect of calcium on the risk of preeclampsia, with the majority showing a non-statistically significant trend towards the reduction in the incidence of preeclampsia.However, a meta-analysis of 12 randomized trials shows  2 grams calcium daily taken as calcium carbonate Subgroups criteria used in the Cochrane systematic reviews. 15,17Prior history of preeclampsia, chronic hypertension, chronic renal disease, diabetes mellitus, vascular or connective tissue disease, antiphospholipid antibody syndrome.**Women with mean intake less than 900 mg per day.***Teenagers, prior history of preeclampsia, chronic hypertension, increased sensitivity to angiotensin II.benefi t for both high and low risk groups 17 with an overall reduction in the risk of preeclampsia (12 trials, 15,206 women: RR 0.48, 95% CI 0.33 to 0.69).This reduction in relative risk was greatest for women at high risk for preeclampsia (5 trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and for those with low baseline calcium intake (7 trials, 10,154 women: RR 0.36, 95% CI 0.18 to 0.70).
There is also some evidence to suggest that there may be a reduction in childhood systolic hypertension in the offspring of mothers who took calcium supplementation during pregnancy. 18alcium supplementation during pregnancy is simple, inexpensive, and there have been no reported side effects or adverse outcome in the mother or fetus.Therefore, selective prenatal supplementation for women with a low calcium diet (calcium consumption of less than 900 mg/ day) and those at high risk for preeclampsia (prior history of preeclampsia, chronic hypertension, chronic renal disease, diabetes mellitus, vascular or connective tissue disease, and antiphospholipid antibody syndrome) may be a way to reduce the incidence of hypertension and its consequences in the mother, fetus, and next generation.The Cochrane review describes the type of intervention as: supplementation with calcium from at the latest 34 weeks of pregnancy, compared with placebo treatment.However, when looking at the majority of the studies, especially the individual 3 large studies, the CPEP, Belizan, and the WHO studies, all had women recruited at Ͻ20 wks.[21] Still unproven (unknown, not enough evidence) Nitric oxide Nitric oxide is known to cause vascular relaxation and inhibit platelet aggregation, both of which are defi cient in preeclampsia.This led to nitric oxide donors being entertained in the possible prevention of preeclampsia.However, a meta-analysis of 4 trials including 170 women comparing nitric oxide donors or precursors to placebo found insuffi cient data for reliable conclusions about the effects on preeclampsia (RR 0.83, 95% CI 0.49 to 1.41). 22Moreover, due to the small numbers in these studies and the side effect of headaches, which led to discontinuing the treatment, more evidence using formulations with fewer side effects is needed to determine more clearly its role in the prevention of preeclampsia.

Multivitamins
Despite the fact that individual vitamins studied, such as vitamins C and E, have not been shown to affect the incidence of preeclampsia, there has been recent evidence to suggest that multivitamin supplementation in pregnancy can reduce the risk.A recent observational study of 2,951 pregnant women in Canada showed that supplementation of multivitamins containing 1 mg of folic acid was associated with a reduced risk of preeclampsia (adjusted odds ratio, 0.37; 95% CI 0.18 to 0.75). 23owever, randomized controlled trials are needed to confi rm this effect and its magnitude.This may be diffi cult and unethical since folic acid has been proven to improve pregnancy outcome, and folic acid supplementation has been recommended to prevent neural tube defects in the neonate.These fi ndings, however, may partially explain the recent decline in the rate of preeclampsia documented in a population based study of the incidence of hypertensive disorders of pregnancy. 24As more widespread awareness of the benefi ts of preconception folate supplementation, more folate consumption may have attributed to this trend.

Antithrombotics
Heparin emerged as a possible prophylactic strategy when the placentas of preeclamptic pregnancies were found to have infarcts.There have been no randomized trials thus far that have been published on using heparin in the prevention of preeclampsia.There are a few case series and cohort studies on the effect of anticoagulation with heparin on the development of preeclampsia.These reports mainly include patients with a history of adverse pregnancy outcome or a thrombophilia. 25,26 study evaluating thromboprophylaxis with low molecular weight heparin plus low dose aspirin suggested improved pregnancy outcome in women with previous severe preeclampsia. 26More studies are needed to confi rm these fi ndings.

Discounted as preventative option for preecplampsia
Vitamins C and E supplementation Oxidative stress has been described in the pathogenesis of preeclampsia.There is evidence that preeclampsia is associated with decreased levels of vitamins C and E, which are known for their anti-oxidant roles. 27This provides the rationale for using vitamins C and E supplementation in pregnancy for the prophylaxis of preeclampsia.There have been many studies [28][29][30] evaluating the effect of different antioxidants on preeclampsia risk and are summarized in meta-analyses. 31,32These Cochrane reviews assessed different antioxidants (vitamins C, E, selenium, lycopene) alone and in combination and found antioxidants were associated with no significant decrease in the risk of preeclampsia (9 trials with a combined total of 5,446 women).This is in agreement with another systematic review that included recent large randomized trials [33][34][35] to assess the effects of the combination of both vitamins C and E on preeclampsia and perinatal outcomes, and demonstrated no signifi cant differences between the vitamin and placebo groups on the risk of preeclampsia.
The results of a more recent randomized controlled trial of antioxidant vitamins to prevent serious complications associated with pregnancy related hypertension in low risk nulliparous women have been published in abstract form at the 29th SMFM Annual meeting in January 2009.This study is a RCT of 10,154 low risk primiparous women from 2003-2008 and differs from previous studies in that treatment is started earlier, between 9-17 weeks of gestation, and the primary outcome is adverse outcomes associated with preeclampsia rather than its incidence.This study concluded that "therapy initiated with the antioxidant vitamins C and E prior to 17 weeks gestation in nulliparous low risk women does not reduce the frequency of serious complications associated with pregnancy related hypertension, nor does this treatment reduce the diagnosis of preeclampsia." 36t this point, vitamins C and E supplementation in pregnancy do not appear to prevent preeclampsia and are not recommended.In fact, it may be harmful, since one study showed that vitamins C and E supplementation were associated with an increased frequency of gestational hypertension, low birth weight, and stillbirth. 35

Fish oil
The hypothesis that fish oil could prevent preeclampsia developed from epidemiologic studies that suggested a lower incidence of preeclampsia in populations that consumed more fish. 379][40] A Cochrane review of 4 trials, involving 1,683 women assessed the effi cacy of a marine oil supplement in reducing the incidence of preeclampsia.There were no clear differences in the incidence of preeclampsia (4 trials, 1,683 women: RR 0.86, 95% CI 0.59 to 1.27) between marine oil treated and control groups. 41Therefore, fi sh oil is not recommended for preventing preeclampsia.

Zinc
Low maternal serum zinc levels have been found to be associated with preeclampsia. 42,43Nonetheless, a systematic review of 7 randomized trials including 2,975 women showed no signifi cant difference in the pregnancy hypertension or preeclampsia between the zinc and no zinc groups (RR 0.83, 95% CI 0.64 to 1.08). 44gnesium Some observational studies reported that magnesium supplementation might be associated with a decreased incidence of preeclampsia.Yet a metaanalysis of 2 randomized controlled trials that included 474 patients 45,46 did not demonstrate any benefi t of magnesium supplementation on the risk of preeclampsia. 47

Future directions
Areas of interest that are emerging and appear promising include the role of metabolic factors, angiogenic proteins, angiotensin receptor antibodies, and syncytiotrophoblast microparticles.

Metabolic factors
Metabolic disturbances, such as maternal obesity and insulin resistance, increase a woman's risk of developing preeclampsia. 48,49The mechanisms by which these metabolic derangements predispose to preeclampsia are still poorly understood.Maternal prepregnancy obesity is one of the strongest modifi able risk factors for the development of preeclampsia.There is evidence that the associated infl ammation in obese patients predisposes them to preeclampsia. 50It has also been postulated that the additive insults of insulin resistance and alteration in angiogenesis may lead to preeclampsia. 49Further insight into the relationships between these metabolic derangements and preeclampsia may shed more light on the pathogenesis of preeclampsia.Interventions that may correct these metabolic derangements such as good glycemic control and prepregnancy weight reduction deserve further study for the prevention of preeclampsia.A randomized trial of metformin in pregnant patients with polycystic ovary syndrome demonstrated a signifi cant reduction in pregnancy complications including preeclampsia. 51These results appear promising, however, before metformin is prescribed throughout pregnancy for these PCOS patients, further data is necessary in regards to confi rming these fi ndings, proving its safety and providing information on follow-up of the offspring of these pregnancies.

Angiogenic proteins
A significant imbalance has been discovered between the proangiogenic (vascular endothelial growth factor [VEGF] and placental growth factor [PIGF]) and antiangiogenic factors (soluble fmslike tyrosine kinase [sFlt-1] and soluble endoglin [sEng]) in preeclampsia patients.High serum levels of sFlt-1 and sEng and low serum VEGF and PIGF have been observed in preeclampsia patients. 52,53Their pathogenic role in preeclampsia was further illustrated by the exogenous administration of sFlt-1 into pregnant rats via adenovirus mediated gene transfer resulting in increased arterial pressure and proteinuria, and decreased plasma free VEGF and PIGF concentrations similar to that observed in the preeclamptic patients. 54VEGF infusion has also been shown to attenuate the increased blood pressure and renal damage observed in pregnant rats overexpressing sFlt-1. 55urther research into correcting this imbalance by either blocking these antiangiogenic factors or replacing the proangiogenic factors offers potential for a preventive strategy or even a cure.

Angiotensin receptor-activating autoantibodies
Recent studies have found that women with preeclampsia have autoantibodies that activate the angiotensin receptor and result in biologic responses that are relevant to the pathophysiology of preeclampsia. 56The introduction of these angiotensin receptor activating antibodies into pregnant mice resulted in classic features of preeclampsia including hypertension, proteinuria, and increased production of sFlt-1. 57It has recently been demonstrated that these autoantibodies can be blocked by a 7-amino-acid peptide, and thus may provide an opportunity to prevent this disease. 57

Syncytiotrophoblast microparticles
In preeclampsia there has been found to be increased circulation of syncytiotrophoblastderived debris compared with normal pregnancy. 58hese microparticles may play an important role in stimulating the systemic infl ammatory response.In-vitro preparations of trophoblast microparticles have been demonstrated to lead to an antiangiogenic state that would contribute to the clinical features of preeclampsia. 59Further research is required to determine the role of these microparticles in the pathogenesis of preeclampsia, and possible interventions that may block their effect, thereby preventing this disease process.

Genomics, proteomics, and matabolomics
Studies evaluating the genetics, proteomics, and metabolomics of different disease processes have been reported and appear promising.As the development of preeclampsia appears to involve several different mechanisms, the use of these data-generating approaches has the potential to contribute significantly to future research in preeclampsia and aid in our understanding of this condition.This may, in turn, offer opportunities for new diagnostic and preventive strategies.

Conclusions
Although the interventions for the prevention of preeclampsia thus far are still imprecise, it has not been a complete disappointment.There has been signifi cant progress made.Further research into the pathogenesis of preeclampsia is needed, as this will offer more opportunities in finding effective preventative strategies.We advocate the next wave of research to focus on better understanding the pathophysiology of preeclampsia at the cellular level.Funding these areas of research may be more cost effective than universal implementation of interventions that are of minimal benefi t.As preeclampsia is a multifactorial disease process, multidisciplinary and collaborative research between different disciplines, and between basic and clinical researchers, is highly recommended.Also, collaboration with the pharmaceutical industry, along with other potential partners, may help develop novel therapeutic strategies to prevent preeclampsia.The preventive interventions that have already been studied may need to be reexamined from different aspects.This includes identifying what specifi c subgroups may benefi t more from each strategy.Reexamination of previous strategies should also include earlier timing of the intervention than in past trials.In most previous trials the interventions were later in pregnancy than the early placentation period, and thus may have been too late for the intervention to show a benefi t.It would also be benefi cial to fi ne tune drugs that already work in terms of formulations, dosing, and see what effect their combination may have, such as ASA and calcium.Further research into nitric oxide and folic acid would also be of interest.

Table 1 .
Recommendations for select patients.