KeywordsPreeclampsia, eclampsia, prevention, low-dose aspirin, calcium supplementation, antioxidants, magnesium sulfate
Editors’ comment: The past two decades have seen many resources focused on the prevention of preeclampsia with minimal success (if prescribing low-dose aspirin to high-risk patients can be labeled a success), and even some are concerned that the small benefit attested to aspirin may be an artifact related to false positive significance associated with subset analysis, especially when not in the original study design. It is also fair to say that while the search for a better “preventive” goes on, some believe the dollar focus should be to better understand the causes, and only then think of prevention. The fourth edition introduces a new first author, Anne Cathrine Staff, who leads a premier preeclampsia research group in Oslo, Norway. She has suggested by her writings that redefining preeclampsia through placenta-derived biomarkers would hopefully be a better step towards eventual prevention.
Because of its sentinel position as a major cause of maternal and perinatal mortality and morbidity worldwide, and especially in developing countries, prevention of the hypertensive disorders of pregnancy has been an area of intense research interest. As discussed throughout this text, however, the etiology of the preeclampsia syndrome remains elusive. The preeclampsia syndrome appears in many clinical forms and may have several pathophysiological pathways, and thus the search for its prevention is considerably hampered. Most studies designed on theoretical bases to reduce the incidence of preeclampsia in either low- or high-risk women have been disappointing. Parallel to the quest for a preventive strategy, efforts have been made to develop a number of clinical, biophysical, or biochemical tests that would permit prediction or early detection of preeclampsia. Most of these have low sensitivity and positive-predictive value, and thus are not suitable for routine clinical use (see Chapter 11 ). Thus, prevention studies have previously concentrated on women with demographic, familial, medical, and obstetrical factors that are associated with an increased risk of preeclampsia, as listed in Table 12.1 .
|Advanced maternal age |
|Previous adverse obstetrical outcome|
|Gestational hypertension, especially preeclampsia|
|Fetal growth restriction|
|Abnormal midpregnancy uterine Doppler studies|
|Resistance index 0.58|
|Presence of diastolic notch|
|Obesity and insulin resistance|
The failure to find successful prevention for preeclampsia has not been from lack of effort. In the first edition of this book, Chesley chronicled the abusive dietary restrictions used during the 20th century. And following the low-salt diet and thiazide diuretic fads of the 1960s and 1970s, randomized trials have described the use of various methods to prevent or reduce the incidence and/or severity of preeclampsia. The purpose of this chapter is to review some of these clinical trials to gain insight into the problems that have frustrated research for prevention measures. Shown in Table 12.2 is a list of regimens that have been studied by randomized controlled trials.
|Fish oil supplementation|
|Ascorbic acid vitamin (C)|
|α-Tocopherol vitamin (E)|
Prevention is traditionally classified as primary, avoiding disease occurrence, secondary, diagnosing and treating extant disease in early stages, and tertiary, reducing the negative impact of existent disease by restoring function and reducing disease-related complications. As will be discussed in further detail below when dissecting individual studies to prevent preeclampsia, there have been many trials with many different approaches. We note here that the aims of such studies are not only to reduce the incidence of the disease but also to improve the clinical outcome for mother and offspring. One clinical primary prevention strategy used worldwide in 2014 is low-dose aspirin to women with high risk of preeclampsia, starting at the beginning of second trimester. The benefit of low-dose aspirin is modest at best, and some still question its efficacy, but its use has few risks. Also, magnesium sulfate is widely used to prevent eclampsia, and its efficacy is well documented, with substantial effects in reducing eclamptic convulsions. Most other intervention strategies are either not well documented or have proved to be without merit in randomized controlled trials (RCTs). As summarized from the recent UK NICE (National Institute for Health and Clinical Excellence) Guidelines on Hypertension in pregnancy (1), although several drugs, nitric oxide donors, progesterone, diuretics, and low-molecular weight heparin, and vitamin and nutrient supplements, vitamin C, vitamin E, folic acid, magnesium, fish oils, algae oils, and garlic, have been studied as preventive treatments for hypertensive disorders, these have not shown benefit and should not be given for this purpose. These are further discussed in the sections that follow, which included updated studies and meta-analyses done since the third edition of this book.
A challenge for any preeclampsia prevention and intervention study is how to identify the target population, to prevent preeclampsia in primiparous women, as well as recurrent preeclampsia in previously affected parous women. Preeclampsia is a heterogeneous syndrome, and clinical and laboratory prediction biomarkers in the general population are currently neither cost-effective nor sufficiently specific and sensitive, as reviewed in Chapter 11 .
The only intervention that completely nullifies the risk of preeclampsia is to avoid pregnancy, which is not an option for most women.
Because edema appeared to be an important component and even a forerunner to preeclampsia, it was natural that attempts would be made to prevent its progression. Mechanical methods, e.g., positional elevating of the feet, had been used, but a devoted following of salt restriction developed in the 1940s. This historical chapter was eclipsed by the introduction of chlorothiazide in 1957, when the use of diuretic agents for preeclampsia was advocated. Regarding sodium restriction, Steegers et al. found no convincing evidence that it reduces the incidence of preeclampsia. Later, Knuist et al. performed a randomized multicenter trial and found no benefits of prescribing a low-sodium intake in reducing the rate of preeclampsia. As of 2014, none of the major guidelines, including those of the World Health Organization, National Institute of Health and Clinical Excellence, and the American College of Obstetricians and Gynecologists, recommend salt restriction during pregnancy to prevent gestational hypertension or preeclampsia.
The use of various fish oils to prevent or ameliorate a number of “diseases of civilization” has an interesting history that dates back to finding a link between certain types of fatty acids that mediate “inflammation.” In this scheme, the atherogenic fatty acids are responsible for many of the ills that plague modern man in industrialized countries. As the diet drifted away from the hunter-gatherer to modern habits, so did the consumption of some heretofore protective fatty acids. The latter were found in oils of some fatty fishes in the diets of people from Scandinavian countries and in American Eskimos.
The fatty acid cascade begins with arachidonic acid, which follows a complex metabolic pathway of oxidation and decarboxylation. The variety of fatty acids produced is dependent on which precursors are incorporated, and many of their physiological properties stem from the position of the first double carbon bond in relation to the terminal CH group – this group is termed the “omega” carbon because it is furthest from the COOH – “alpha” – group. Thus, fatty acids with the first double bond located three carbon atoms away from the end are termed “omega minus 3” fatty acids – this is commonly written “omega-3.” The average industrialized diet consists of a small percentage of omega-3 fatty acids, with the two most common being eicosapentaenoic acid (EPA), present in fish oil, and alpha-linolenic acid (ALA), derived from the omega-6 linoleic acid found in vegetable oil and some animal fats.
Proclamations soon followed that supplementation with omega-3 oils would prevent inflammation-mediated vascular disease, e.g., atherogenesis. Thus, it was not a quantum leap to posit that their ingestion might prevent preeclampsia as well as other adverse vascular disorders of pregnancy, such as fetal-growth restriction or even preterm delivery. Initial reports of beneficial effects of fish oil on lowering the incidence of preeclampsia arose from observational studies and a few small randomized trials. Beneficial effects of omega-3 fatty acids are typically ascribed to inhibition of platelet thromboxane A production with simultaneous production of limited amounts of physiologically inactive thromboxane A. Endothelial production of prostacyclin (PGI) is not inhibited, thus shifting the balance toward reduced platelet aggregation and increased vasodilatation. Another theoretical mechanism is through diminished vascular sensitivity to infused angiotensin II (Ang II). Adair et al. evaluated the effects of omega-3 fatty acid supplementation on vascular sensitivity in 10 normotensive pregnant women between 24 and 34 weeks. Angiotensin infusions were performed before and 28 days after supplementation with 3.6 g per day of EPA. The effective pressor dose of angiotensin II was significantly increased after EPA supplementation – 35.8±15.9 vs. 13.6±6.3 ng/kg/min ( p =0.001).
There have been three randomized trials to study the effects of fish oil supplementation in women at high risk of preeclampsia. In none was there a reduction in the incidence of preeclampsia. Olsen et al. conducted a European multicenter trial to compare fish oil to olive oil in women with previous preeclampsia or multifetal gestation. As shown in Table 12.3 , they found no significant differences between the groups in rates of either gestational hypertension or preeclampsia. Olafsdottir et al. conducted a Cochrane review and reported no reduction in the incidence of gestational hypertension or preeclampsia with fish oil supplementation. Finally, Makrides et al. reported results of a prospective study of the relationship between high consumption of marine fatty acids and hypertensive disorders during pregnancy. They found that consumption of large amounts of fish oil in early pregnancy actually increases the risk of hypertensive disorders. Thus, fish oil supplementation is not recommended for the prevention of preeclampsia, which is reflected in recent NICE guidelines.
|Risk Factor and Study Group||Gestational Hypertension No. (%)||Preeclampsia No. (%)|
|Prior gestational hypertension|
|Fish oil ( n =167)||55 (32.9)||11 (7.2)|
|Olive oil ( n =183)||61 (33.3)||17 (10.1)|
|Fish oil ( n =274)||38 (13.9)||14 (5.7)|
|Olive oil ( n =279)||29 (10.4)||6 (2.4)|
The relationship between dietary calcium intake and pregnancy-associated hypertension has been of interest since the 1980s. In their review, Belizan et al. reported an inverse association between calcium intake and maternal blood pressure, as well as the incidence of preeclampsia syndrome. Possible mechanisms by which calcium might prevent preeclampsia are unknown but these authors suggested that supplementation reduces maternal blood pressure by influencing parathyroid hormone release and intracellular calcium availability.
To test these hypotheses, a number of clinical studies have been designed to compare calcium supplementation during pregnancy with no treatment or a placebo. Protocols have varied considerably, and some studies compared women at low risk with those at high risk; there were varied types of randomization, placebo use, and blinding; gestational ages at enrollment ranged from 13 to 32 weeks; and calcium doses ranged from 156 to 2000 mg daily. In addition, these studies differed regarding the definition of hypertension and preeclampsia, and several did not differentiate between the two.
A total of 10 randomized trials that studied the incidence of preeclampsia were placebo-controlled. Results from these are shown in Table 12.4 . Of importance, the three trials with enrollment sizes exceeding 1000 healthy nulliparous women demonstrated no significant reduction in the incidence of preeclampsia with calcium supplementation. In two of these three, there was a beneficial effect with calcium supplementation to lower the incidence of maternal hypertension overall. Supplementation also had a salutary effect on the incidence of preeclampsia in a subgroup of women with probable calcium deficiency. In the largest study, secondary analysis with a composite morbidity index suggested that calcium supplementation had reduced the incidence of both severe disease and very adverse outcomes, although the number needed to treat to obtain an effect was high. By way of contrast, there were no effects on the incidence of maternal hypertension or preeclampsia in any of the subgroups analyzed by calcium intake in the NICHD Maternal Fetal Medicine Network trial of over 4500 women.
|Study||Risk Factors||Enrollment (wks)||Intervention (No.)||Preeclampsia (%)|
|Lopez-Jaramillo et al.||Nulliparas||24||55||51||3.6||24 *|
|Lopez-Jaramillo et al.||Positive roll-over test||24–32||22||34||0||24 *|
|Villar & Repke||Nulliparas (85%)||24||90||88||0||3.4|
|Belizan et al.||Nulliparas||20||579||588||2.6||3.9|
|Sanchez-Ramos et al.||Positive roll-over test and A-II sensitivity||24–28||29||34||14||44 *|
|Purvar et al.||Low-calcium diet||<20||97||93||2.1||11.8|
|Levine et al. a||Nulliparas||13–21||2295||2294||6.9||7.3|
|Lopez-Jaramillo et al.||Nulliparas||20||125||135||3.2||16|
|Crowther et al.||Nulliparas||<20||227||229||4.4||10|
|Villar et al. b||Low-calcium diet||<20||4151||4161||4.1||4.5|
These randomized trials have also been the subject of two systematic reviews. In a Cochrane review by Hofmeyr and Atallah that included 15,206 women, for those assigned to treatment with calcium the relative risk of preeclampsia was 0.48 (95% CI 0.33–0.69) compared with nontreated women. These authors also concluded that calcium supplementation appeared to reduce the risk of severe hypertensive disorders, particularly in populations with poor calcium intake. In contrast, Trumbo and Elwood reported an evidence-based review by the United States Food and Drug Administration. They concluded that “the relationship between calcium and risk of hypertension in pregnancy is inconsistent and inconclusive, and the relationship between calcium and the risk of pregnancy induced hypertension and preeclampsia is highly unlikely.”
A Cochrane systematic review from 2010 concluded that calcium halved the risk of preeclampsia. A later meta-analysis (2011) showed that calcium supplementation during pregnancy is associated with a reduced risk of gestational hypertension, preeclampsia, neonatal mortality and pre-term birth in developing countries. Another meta-analysis (2012) favors an additional intake of calcium during pregnancy to reduce the incidence of preeclampsia in populations at high risk of preeclampsia due to ethnicity, gender, age, or high BMI and in those with low baseline calcium intake.
In summary, in the third edition of Chesley’s book we reached a conclusion that remains valid currently in that preeclampsia prevention with calcium supplementation is unlikely to be achieved except perhaps in high-risk populations that are chronically calcium-deficient. Even in the latter groups the number needed to treat to obtain an effect was quite high. As the recent NICE Guidelines summarize: “The evidence for added calcium in the prevention of hypertensive disorders is conflicting and confusing, and more research is needed in this area.”
Two Cochrane reviews from 2006 included only few trials and concluded that evidence is insufficient to recommend bed rest or reduced activity in preventing preeclampsia. At the same time, it was concluded that there were no obvious beneficial effects of physical exercise. A systematic review from 2012 indicates a trend towards a protective effect of physical activity in the prevention of preeclampsia. However, the present documentation for recommending bed rest and/or exercise is weak, and the NICE Guidelines summarize that “advice on rest, exercise and work for women at risk of hypertensive disorders during pregnancy should be the same as for healthy pregnant women.” Likewise, the Task Force of the American College of Obstetricians and Gynecologists does not recommend bed rest or increased physical activity for primary prevention of preeclampsia or its complications.
Diuretics and Antihypertensive Drugs
As discussed previously, there was a presumed, although never proved, efficacy of low-salt diets given to treat edema, hypertension, or preeclampsia. Thus, it was not surprising that diuretic therapy became popular with the introduction of chlorothiazide in the 1960s. In a meta-analysis, Churchill et al. summarized nine randomized trials that evaluated more than 7000 pregnant women. Those given diuretics had a decreased incidence of edema and hypertension, but not of preeclampsia.
According to most studies, women with preexisting chronic hypertension are at significantly high risk of preeclampsia compared with normotensive women. There have been several randomized trials involving a total of 1055 participants – only a few were placebo-controlled – that evaluated the use of various antihypertensive drugs to reduce the incidence of superimposed preeclampsia in women with chronic hypertension. A critical analysis of these trials failed to demonstrate any risk reduction. We must caution that these trials did not have adequate power to show any potential benefits of therapy.
There are inferential data that an imbalance between oxidant and antioxidant activity may have an important role in the pathogenesis of preeclampsia. For example, lipid peroxides and free radicals contribute to endothelial cell injury. And there is evidence that elevated plasma concentrations of free radical oxidation products precede the development of preeclampsia. Two naturally occurring antioxidants – vitamins C and E – have been reported to decrease LDL oxidation and reduce both superoxide formation and cytokine production. Moreover, women who developed preeclampsia had reduced plasma vitamin levels prior to its development. Thus, supplementation with these two vitamins was proposed to improve the oxidative capability of women at risk of preeclampsia.
In a pilot study, Chappell et al. suggested a beneficial effect from pharmacological doses of vitamins C and E given to women identified as at risk of preeclampsia because of abnormal uterine artery Doppler flow velocimetry. Since then, a number of large randomized trials have been undertaken to evaluate vitamin C 1000 mg/d plus vitamin E 400 IU/d supplementation during pregnancy ( Table 12.5 ). In the largest of these, conducted at 25 clinical sites in the United Kingdom, Poston et al. enrolled 2410 women at risk of preeclampsia between 14 and 21 weeks. Heterogeneous risk factors included prior preeclampsia before 37 weeks, chronic hypertension, diabetes, antiphospholipid antibody syndrome, chronic renal disease, multifetal pregnancy, abnormal uterine artery Doppler findings, and nulliparas with body mass index (BMI)>30 kg/m 2 . As further shown in Table 12.5 , the incidence of preeclampsia was similar in treatment and placebo groups – 15% compared with 16%. Of note, there were significantly more low-birthweight infants, fetal deaths, and low Apgar scores among babies born to mothers in the supplemented group, although small-for-gestational age infants did not differ between groups. Among participants who became preeclamptic, those in the antioxidant group developed it earlier. The studies by Rumbold et al. and Spinnato et al. were multicenter randomized placebo-controlled trials in women assigned to daily treatment with both vitamin C and E, or a placebo. As shown in Table 12.5 , there were no differences in rates of preeclampsia between the study groups. In the study by Rumbold et al., hypertensive complications were significantly higher in the group given vitamins. In the study by Spinnato et al., however, there were no differences in mean gestational age at delivery or the incidence of perinatal mortality, abruptio placentae, preterm delivery, or growth-restricted or low-birth-weight infants. This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia.
|Study||Risk Factors||Enrollment (wks)||Preeclampsia by Treatment Group|
|Vitamins No. (%)||Placebo No. (%)|
|Chappell et al.||Abnormal UAD||16–22||141 (8)||142 (17)|
|Beazley et al.||High-risk||14–21||52 (17.3)||48 (18.8)|
|Poston et al.||High-risk||14–22||1196 (15)||1199 (16)|
|Rumbold et al.||Nulliparas||14–22||935 (6)||942 (5)|
|Spinnato et al.||High-risk||12–20||355 (13.8)||352 (15.6)|
|Villar et al. a||High-risk||<20||681 (14)||674 (23)|
The World Health Organization conducted a randomized trial of vitamin C and E supplementation that included 1365 high-risk women who were randomly assigned before 20 weeks to either daily 1000 mg vitamin C plus 400 IU vitamin D or to placebo. The rates of preeclampsia were similar – 24% versus 23%. Subsequent meta-analyses and systematic reviews also concluded that there are no salutary protective effects of these antioxidant vitamins on the incidence of preeclampsia.
There are several theoretical reasons to consider the use of antithrombotic agents to prevent preeclampsia. As discussed thoughout this fourth edition of Chesley, the preeclampsia syndrome is characterized by vasospasm, endothelial cell activation and dysfunction, and activation of the coagulation cascade. As discussed in Chapter 17 , enhanced platelet activation and thromboxane production appear to play an important role in some of these pathophysiological abnormalities. It is likely that these abnormalities are caused at least partly by an imbalance in prostaglandin production of those that are vasoconstrictors – thromboxane A – and others that are vasodilators – prostacyclin. Indeed, evidence suggests that thromboxane A production is markedly increased while that of prostacyclin is reduced even in women prior to the onset of clinical preeclampsia. Putative sequelae are placental infarction and spiral artery thrombosis, notably in pregnancies with severe fetal-growth restriction, fetal death, or both.
The antithrombotic agents that have been most widely studied are low-dose aspirin regimens. In doses of 50–150 mg daily during pregnancy, aspirin effectively inhibits platelet thromboxane A biosynthesis with minimal effects on vascular prostacyclin reduction. The first randomized placebo-controlled double-blind study to assess preeclampsia prevention with low-dose aspirin was reported in 1986 by Wallenburg et al. This study included 46 nulliparas who had a positive angiotensin II sensitivity test at 28 weeks. In 21 women given low-dose aspirin, there was a significant reduction in the incidence of preeclampsia. These encouraging results led to numerous trials worldwide.
A National Institute of Child Health and Development (NICHD) randomized trial reported by Caritis et al. evaluated the effects of low-dose aspirin in high-risk women with previous preeclampsia, multifetal gestation, chronic hypertension, or insulin-dependent diabetes. As shown in Table 12.6 , in both groups the incidence of preeclampsia was particularly increased in those who had hypertension and proteinuria prior to 20 weeks. As also shown, however, low-dose aspirin failed to reduce the incidence of preeclampsia in any of these groups of extremely high-risk women.
|Risk Factors||Number||Preeclampsia (%)|
|Normotensive, no proteinuria||1613||14.5||17.7|
|Proteinuria plus hypertension||119||31.7||22.0|
The Paris Collaborative Group more recently performed a meta-analysis of the efficacy and safety of antiplatelet agents – predominantly aspirin – in preventing preeclampsia. They included 31 randomized trials involving 32,217 women. For women assigned to antiplatelet agents, the relative risk of developing preeclampsia was slightly decreased – RR 0.90 (95% CI 0.84–0.96). For 6107 women with a previous history of hypertension or preeclampsia who were assigned to antiplatelet agents, the relative risk of developing preeclampsia was also lowered slightly – RR 0.86 (95% CI 0.77–0.97). There were marginal benefits of aspirin in reducing delivery before 34 weeks (RR 0.90; 95% CI 0.83–0.98) and reducing serious adverse outcomes (RR 0.90; 95% CI 0.85–0.96). Once again, the number needed to treat to obtain these results was very large. These modest benefits accrued without major adverse effects of low-dose aspirin.
Roberge et al. performed an updated systematic review and meta-analysis and concluded that low-dose aspirin initiated at or before 16 weeks reduced the risk of severe preeclampsia, but not mild preeclampsia. But a small study by Villa et al. did not show a significant effect on preeclampsia. When these latter data were included in the Roberge meta-analysis, however, they supported the concept of low-dose aspirin reducing the risk of preeclampsia in women at high risk.
One problem with all the approaches described above, and apparently neglected or not discussed in the recommendations of the various national and international working groups summarized below, is the problem inherent in subgroup analysis, especially when such analysis was not included in the original study design. These flaws have been discussed in greater detail by Klebenoff.
Current recommendations restrict the use of low-dose aspirin prophylaxis for women at high risk of developing preeclampsia. Largely based on these marginal benefits with thus far no sustained deleterious effects, with these caveats, both NICE guidelines and the American College of Obstetricians and Gynecologists recommend the use of 60–80 mg aspirin beginning at the end of the first trimester for women at high risk. The latter includes those with hypertensive disease during a previous pregnancy, chronic kidney disease, autoimmune disease such as systemic lupus erythematosis or antiphospholipid syndrome, type 1 or type 2 diabetes, or chronic hypertension. Factors identifying moderate risk are: first pregnancy, age 40 years or older, pregnancy interval of more than 10 years, body mass index (BMI) of 35 kg/m 2 or more at first visit, a family history of preeclampsia, or multiple pregnancy.
Low-Dose Aspirin Plus Heparin
Because of the high prevalence of placental thrombotic lesions associated with severe preeclampsia, combining heparin with aspirin prophylaxis seemed a logical strategy to prevent recurrent disease. There have been several observational trials to evaluate such treatment. Kupferminc et al. studied 33 women with thrombophilia and a history of a previous pregnancy complicated by severe preeclampsia, placental abruption, fetal-growth restriction, or stillbirth. Those treated with low-molecular-weight heparin and low-dose aspirin had an 8% recurrence rate for preeclampsia and a 6% rate for recurrent fetal-growth restriction. In another observational study, Sergio et al. assessed prophylaxis with low-molecular-weight heparin plus low-dose aspirin on pregnancy outcome in women with a history of severe preterm preeclampsia and low-birthweight infants. They compared pregnancy outcomes in 23 women given low-dose aspirin alone with those in 31 women given low-molecular-weight heparin plus low-dose aspirin. The incidence of recurrent preeclampsia in women given low-dose aspirin was 30% compared with only 3% in those given the combination ( p <0.01). Furthermore, the group given low-dose aspirin plus heparin had a greater mean gestational age at delivery ( p <0.05), higher birthweight ( p <0.01), and a higher birth percentile ( p <0.01) compared with the group given low-dose aspirin alone.
Despite these findings providing further evidence of benefit, current guidelines advise against the use of low-molecular heparin to prevent hypertensive disorders in pregnancy.
At least one of these lipid-lowering agents – pravastatin – has been used in an attempt to decrease the placental production of antiangiogenic proteins in order to treat early-onset preeclampsia (StAmP trial: www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/womens/StAmP/index.aspx ). The rationale is that statins stimulate hemoxygenase-1 expression and inhibit sFlt-1 release in vivo and in vitro , which may ameliorate the progression of early-onset preeclampsia. If such studies are successful they will be the focus of future prevention trials. Importantly, statins as a class are traditionally considered to be contraindicated in pregnancy – class X FDA classification scheme – because of the theoretical risk of teratogenesis and of altered lipid accumulation during fetal brain development.