Prediction and Prevention of Preeclampsia

Hypertension in Pregnancy, 28:138–155, 2009Copyright © Informa Healthcare USA, Inc.ISSN: 1064-1955 print / 1525-6065 onlineDOI: 10.1080/10641950802022384

LHIP1064-19551525-6065Hypertension in Pregnancy, Vol. 1, No. 1, December 2008: pp. 1–32Hypertension in PregnancyPrediction and Prevention of PreeclampsiaPrediction and Prediction of PreeclampsiaBriceno-Perez, Briceño-Sanabria, and Vigil-De Gracia

Carlos Briceño-Pérez,1 Liliana Briceño-Sanabria,2 and Paulino Vigil-De Gracia3

1Department of Obstetrics and Gynecology, University of Zulia, Maracaibo, Venezuela2Obstetrician and Gynecologist, Amado Clinic, Maracaibo, Venezuela3Department of Obstetrics and Gynecology, Hospital Complex “Arnulfo Arias Madrid”,Social Security, Panama City, Panama

Preeclampsia increases maternal and perinatal morbidity and mortality rates. Muchresearch has been done to identify unique screening tests that would predict the risk ofdeveloping preeclampsia before the classic symptoms appear. The possible use of ascreening test with high predictive accuracy in patients with high-risk or low-risk ofpreeclampsia remains to be investigated. At present, the search for additional testscontinues. There is growing interest in the use of combinations of tests. Effectiveprimary prevention is not possible because the causes are still unknown, but to identifyand to modify susceptible risk factors might decrease the frequency of preeclampsia. Acommunity guideline improves the screening and early detection of preeclampsia, anduniforms the referral thresholds and assessment procedures. Secondary preventionwith calcium supplementation and aspirin administration during pregnancy arebeneficial in low calcium intake women and in the patient at a very high risk of devel-oping severe early onset disease. Lifestyle choices, dietary nutritional measures(antioxidant as vitamin C, vitamin E, lycopene, selenium, zinc, magnesium and themitochondrial antioxidants nicotine, coenzyme Q10 and melatonin; and other dietarynutritional measures as low dietary salt, omega 3 fatty acids, folic acid, garlic, nutri-tional advice, protein and energy supplementation, isocaloric balanced protein andprotein and energy restriction for obese women) and others drugs; have not shownbenefits or there is insufficient evidence to recommend clinical use. Proper antenatalcare and timed delivery are of utmost importance in tertiary prevention.

Keywords Preeclampsia, Prediction, Screening, Prevention, Calcium, Antioxidant,Aspirin.

Address correspondence to Paulino Vigil-De Gracia, Department of Obstetrics andGynecology, Hospital Complex “Arnulfo Arias Madrid”, Social Security, Panama City,Panama. E-mail: [email protected]

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.

Prediction and Prediction of Preeclampsia 139

INTRODUCTION

Preeclampsia is unknown etiology, multifactorial, multiorganic and irrevers-ible disease. Definitive treatment is delivery. As injuries the mother and thefetus, causes a considerable proportion of maternal and perinatal complica-tions (as preterm birth and intrauterine growth restriction) and perinatal andmaternal deaths (15–20% maternal mortality in developed countries; 1–6).Expectant mothers with hypertension are predisposed to the development ofpotentially lethal complications, notably abruptio placentae, disseminatedintravascular coagulation, cerebral hemorrhage, hepatic failure and acuterenal failure.4 Worldwide, preeclampsia and eclampsia probably account formore than 50,000 maternal deaths a year(2). The reason for early screeningfor preeclampsia is to try to identify high-risk pregnancies allowing modifica-tion of antenatal care and preventive treatment regimens, to reduce complica-tions and deaths. Can preeclampsia be predicted? Can it be prevented? Wehypothetized that any interventions can predict and can prevent preeclampsiain any populations subgroups. What level can be prevented: primary, second-ary or tertiary? The aim of this clinical review is to assess critically, the recentevidence on prediction and prevention of preeclampsia.

MATERIALS AND METHODS

We searched MEDLINE/PubMed electronic database, the Cochrane Pregnancyand Childbirth Group trials register and the Cochrane Central Register of Con-trolled Trials; using medical subheading search words such as ‘preeclampsia’,matching with ‘prediction’, ‘screening’ and ‘prevention’. We also searchedmatching ‘preeclampsia’ with interventions, drugs, medication and others toobtain a comprehensive list of articles concerning this condition from January2000 to August 2007, trying to identify news trials that were not included inprevious systematic reviews. Additional articles were obtained from the cross-references of the relevant publications for bibliographical purpose. Of all thearticles found, we chose only published in English language journals and theEnglish abstracts of original articles in other languages from MEDLINE.Eligibility and trial quality were assessed. We included studies that evaluatedthe effectiveness of the mentioned interventions in women with predisposinghistorical risk factors of preeclampsia and reported clinically relevant mater-nal or perinatal outcomes. In the analysis we selected 5 randomized controlledtrials, 12 systematic reviews, 5 clinical reviews and 10 case-control studies.

PREDICTION

Early detection of hypertension during pregnancy permits clinical monitoringand prompt therapeutic intervention for severe preeclampsia or eclampsia,

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.

140 Briceño-Pérez, Briceño-Sanabria, and Vigil-De Gracia

and clinical experience suggests that is beneficial to the patient and fetus. Toscreen for a certain disease, the disease should have well-understood biology(7). Pregnancy-induced hypertension has always been assumed to represent apathological response (5). Much research has been done to identify uniquescreening tests that would predict the risk of developing preeclampsia beforethe classic symptoms appear and to distinguish preeclampsia from otherhypertensive disorders (7). Many unsuccessful studies have explored morethan 200 possible markers. Efforts have been focused on detecting early mani-festations of disease and in early pathogenesis changes and their biochemicalmarkers. Although, numerous tests have been proposed for the prediction orearly detection of preeclampsia, their results, either clinical, biophysical andbiochemical in nature, have been inconsistent and contradictory, with mostdeemed unreliable or unsuitable for routine use in clinical practice (4,6,8,9).

Generally, the validity of the available tests is difficult to evaluate as aresult of the absence of a “gold standard” to confirm the diagnosis, and moststudies of potential screening tests for preeclampsia have relied on clinicalcriteria to confirm the diagnosis (7). In the World Health Organization (WHO)systematic review, Conde-Agudelo et al. (6) assessed the usefulness of clinical,biophysical, and biochemical tests in the prediction of preeclampsia andreviewed 48 screening test proposed for predicting preeclampsia, divided in4 groups (placental perfusion and vascular resistance dysfunction relatedtests, fetoplacental unit endocrinology dysfunction related tests, renaldysfunction related test and endothelial and oxidant stress dysfunctionrelated tests).

Moderate predictive accuracy of anticardiolipin antibodies, the presence ofbilateral diastolic notches during Doppler ultrasonography, and urinarykallikrein were found in women at low risk of developing preeclampsia.Nevertheless, because the pretest probability of preeclampsia with a positiveresult was but minimally increased, the clinical use of these tests is limited.Other ultrasonography characteristics and the measurement of fetal andplacental peptides showed low predictive accuracy. In populations that weredeemed at high risk for preeclampsia, the use of Doppler ultrasonography hadlow predictive accuracy. These authors concluded as of 2004 there was not clin-ically useful screening test to predict the development of preeclampsia. Theyfinished asseverating further prospective, longitudinal studies are needed (6).

Farag et al. (7) in a clinical review assessed screening test for preeclamp-sia divided in 7 groups (clinical assessment, angiotensin II sensitivity and rollover test, urine test, maternal and serum markers, fetal erythroblast inmaternal blood, genomic studies of preeclamptic risk and biophysical screen-ing). They asseverated that clinical assessment is not useful in the predictionof preeclampsia. Urine and serum biochemical assays have provided evidencethat there are differences in the metabolism of women who subsequentlydevelop preeclampsia, however, there are several problems.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


Placenta hormone markers do not predict future disease. They denouncethe early placental changes that are part of the evolving disease and onlypredict the imminent of preeclamptic syndrome. This explains why tests arebetter predictors when preeclampsia supervenes shortly, and why screeningin the first trimester is unlikely to work as well as in the second trimester.The identification of the vasodilator-stimulated phosphoprotein (VASP) in thehuman placenta from the first trimester could have a place in screening forpreeclampsia syndrome.

At present, several groups conducting linkage studies and completematernal genome wide scans to discover preeclampsia genes. However, so far,no such genes have been identified. The hunt for genes for preeclampsia willyield many that operate as risk factors. Whether this will lead to a clinicallyuseful predictor of risk remains to be seen. Overall, there is a lack of random-ized, controlled trials of the use of uterine artery Doppler studies in thescreening of pregnancy complications such as preeclampsia (7). AccordingChafetz et al. (10) in a case-control study, the screening of maternal PP13levels in the first trimester is a promising diagnostic tool for the prediction ofpreeclampsia with high sensitivity and specificity.

Recently, there is growing interest in the use of combinations of tests forpredicting preeclampsia. At the present time, there is a consensus that theetiology of preeclampsia is multifactorial. The use of multiple markers in thescreening should reflect different aspects of the disease process and couldincrease the specificity and sensitivity of the screening and work on differentetiologic factors (7). Two case-control studies (11,12) have documented that2 antiangiogenic peptides that are produced by the placenta, soluble fms-liketyrosine kinase 1 (sFlt-1) and soluble endoglin, are elevated in women withestablished preeclampsia, and may prove useful in differentiating preeclamp-sia from other hypertensive diseases of pregnancy. Levels are elevated partic-ularly in women with severe and early onset preeclampsia.

Several case-control studies (13–17) have shown that reduced first trimes-ter serum levels of placental growth factor, a potent angiogenic factor, andincreased levels of its soluble inhibitor, fms-like tyrosine kinase 1, predict thesubsequent development of preeclampsia. According a clinical review (7),combining the values of maternal biochemical markers serum inhibin A, freeβ-human chorionic gonadotropin (free β-hCG) and unconjugated estriol (uE3)to form a screening test, would detect an estimated 55% of affected pregnan-cies with a false-positive rate of 5%.

A prospective case-control study (18) demonstrated that 3 combinations ofmarkers of placental insufficiency and endothelial function (plasminogen acti-vator/inhibitor PAI-1/PAI-2 ratio, leptin, and placental growth factor) werehighly predictive of the development of preeclampsia when measured at20 and 24 weeks of gestation in women at high risk, and may prove useful inthe selective prediction of preeclampsia. Combining screening with maternal

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


serum biochemical markers and uterine artery Doppler improves the screeningefficacy for prediction of preeclampsia and has been explored in some studies(16,19).

In spite of countless efforts and numerous trials carried out during manyyears, the possible use of a screening test with high predictive accuracy inpatients with high-risk or low-risk of preeclampsia remains to be investigated(3,7,20). Despite the controversy about the validity of these methods inprevention of preeclampsia in a low-risk population, these methods could havea role in prevention of the disease in high-risk groups, making screeningimportant (7). At present, the search for additional tests continues (3,7,20).Several questions remain unanswered by studies with regard to the potentialvalue of serum angiogenic factors in the prediction of the future developmentof preeclampsia in low-risk or high-risk women and in identifying thosewomen whose condition will progress to severe disease or result in adversepregnancy outcome. Therefore, there is an urgent need for large prospectivestudies to evaluate the value of these markers in both normal and high-riskwomen (21).

PREVENTION

Prevention of preeclampsia would mean a big step forward in prenatalcares. The general term prevention of preeclampsia can have 3 differentconnotations: primary, secondary or tertiary. Primary prevention meansavoiding occurrence of a disease and in this context would mean avoidoccurrence of pregnancy in favorable conditions to the development ofpreeclampsia. Secondary prevention in the context of preeclampsia impliesbreaking off the disease process before emergence of clinically recogniz-able disease. Tertiary prevention means prevention of complicationscaused by the disease process, and is thus more or less synonymous withtreatment (5).

Primary PreventionAlthough some key features in the pathogenesis of preeclampsia are

known, the mechanisms behind these features are unknown. However,several risk factors have been identified (5) and manipulation of some of thesemight allow primary prevention:

1. Partner related risk factors: nulliparity/primipaternity, limited spermmaternal exposure, teenage pregnancy, donor insemination, partner whofathered a preeclamptic pregnancy in another woman;

2. Maternal specific risk factors: history of previous preeclampsia, increasingmaternal age, interval between pregnancies;

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


3. Family history: patient requiring oocite donation, presence of specificunderlying disorders as chronic hypertension arterial, renal disease, obe-sity, insulin resistance, low maternal birth weight, gestational diabetes, type1 diabetes mellitus, activated protein C resistance or V factor of Leyden,protein S deficiency, antiphospholipid antibodies, hyperhomocysteinemia;

4. Exogenous factors: smoking, stress, work related psychosocial strain; and

5. Pregnancy associated risk factors: multiple pregnancy, urinary tractinfection, structural congenital anomalies, hydrops fetalis, chromosomalanomalies like trisomy 13 and triploidy and hydatidiform moles (5).

Examples of manipulation of risk factors that might allow primary pre-vention are limited sperm maternal exposure, interval between pregnancies,insulin resistance, smoking and urinary tract infection. Example of manipula-tion of risk factors that might not allow primary prevention are nulliparity,primipaternity, history of previous preeclampsia, low maternal birth weightand multiple pregnancy.

According Milne et al. (22) there is a failure to identify and act on knownrisk factors at booking and to recognize and respond to signs and symptomsfrom 20 weeks’ gestation. No guidelines exist for the screening and earlydetection of preeclampsia in the community, and there is no uniformity inreferral thresholds and assessment procedures. They developed the preec-lampsia community guideline (PRECOG) (22), that provides an evidencebased risk assessment, with criteria for early referral for specialist input, atwo-tiered schedule for monitoring women in the community after 20 weeks’gestation, and referral criteria for step-up care.

This guideline provides a framework by which pregnant women withpreeclampsia are offered specialist care at the appropriate time for the bestoutcome for them and their baby. The authors recommend that before devel-oping an antenatal care plan, women should be assessed for the followingfactors: first pregnancy, previous preeclampsia, ≥10 years since last baby, age≥40 years, body mass index ≥35, family history of preeclampsia (mother or sis-ter), booking diastolic blood pressure ≥80 mm Hg, proteinuria at booking (≥ +on more than one occasion or ≥300 mg/24 h), multiple pregnancy, underlyingmedical conditions (preexisting hypertension, preexisting renal disease, pre-existing diabetes, presence of antiphospholipid antibodies).

Women should be offered specialist input before 20 weeks if they have oneof the following criteria: previous preeclampsia, multiple pregnancy, underly-ing medical conditions as preexisting hypertension or booking diastolic bloodpressure ≥ 90 mm Hg, pre-existing renal disease or booking proteinuria (≥ +on more than one occasion or ≥ 300 mg/24 h), preexisting diabetes and pres-ence of antiphospholipid antibodies. After 20 weeks’ gestation, women shouldbe assessed for the following signs and symptoms of preeclampsia: new

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


hypertension, new proteinuria, symptoms of headache or visual disturbanceor both, epigastric pain or vomiting or both, reduced fetal movements, smallfor gestational age infant. Women should be referred to a hospital day assess-ment unit or similar that has facilities necessary for step-up assessment.

Secondary PreventionAt present time, strategies of secondary prevention have based on known

pathophysiological mechanisms: lifestyle choices, dietary-nutritional mea-sures and drugs (5).

1. Lifestyle choices:

RestBed rest or restriction of activity, with or without hospitalization, has beenadvocated for women with hypertension during pregnancy to improvepregnancy outcome. However, benefits needs to be demonstrated before suchintervention can be recommended since restricted activity may be disruptiveto women’s lives, expensive and increases the risk of tromboembolism (23).Few randomized trials have assessed rest for women with hypertensionduring pregnancy. At present there is insufficient evidence to provide clearguidance for clinical practice (23). Two systematic reviews did not demon-strate benefits of bed rest on preeclampsia.

Meher et al. (23) included four small randomized controlled trials(449 women). Three were of good quality. Two trials (145 women) comparedstrict bed rest with some rest, in hospital, for women with proteinuric hyper-tension. There was insufficient evidence to demonstrate any differencesbetween the groups for reported outcomes (RR 1.50; CI 95% 0.98–2.30). Twotrials (304 women) compared some bed rest in hospital with routine activity athome for non-proteinuric hypertension. Although one small trial suggests thatsome bed rest may be associated with reduced risk of severe hypertension,these findings need to be confirmed in larger trials. According them, bed restshould not be recommended routinely for hypertension in pregnancy, espe-cially since according these results, more women appear to prefer unrestrictedactivity, if the choice were given (1 trial; 86 women; RR 3.00; 95% CI 1.43–6.31). Duley et al. (20) considered that for women with hypertension is unclearwhether rest in hospital offers any advantage over normal activity (RR 0.98;95% CI 0.80–1.20).

ExerciseRegular exercise in people who are not pregnant is known to have generalhealth benefits, including increased blood flow and reduced risk of high bloodpressure. So, there is the potential for exercise to help prevent pregnantwomen developing preeclampsia (24). Two recent systematic reviews have

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


analyzed the effects of the exercise during pregnancy for preventing preec-lampsia. Both studies compared moderate intensity regular aerobic exercisewith maintenance of normal physical activity during pregnancy. Meher andDuley (24) included two small, good quality trials (45 women) and the confi-dence intervals were wide and crossed the line of no effect for all reportedoutcomes, including preeclampsia (RR 0.31; 95% CI 0.01–7.09). They consideredthere is insufficient evidence for reliable conclusions. In a systematic review,Duley et al. (20) considered as none evidence is strong, the balance betweenrest and the exercise should depend on each woman’s personal preference.

2. Dietary-nutritional measures:

CalciumStrategies to reduce the risk of hypertension disorders of pregnancy havereceived considerable attention and an inverse relationship between calciumintake and hypertensive disorders of pregnancy has been described since 1980(25). Low calcium intake may cause high blood pressure by stimulating eitherparathyroid hormone or renin release, thereby increasing, intracellularcalcium in vascular smooth muscle and leading to vasoconstriction. Possiblemodes of action for calcium supplementation are:

1. Calcium reduces parathyroid release and intracellular calcium, and soreduces smooth muscle contractility.

2. By a similar mechanism could also reduce uterine smooth muscle contractilityand prevent preterm labor and delivery.

3. Calcium might also have an indirect effect on smooth muscle by increasingmagnesium levels.25

Calcium supplementation is attractive as a potential intervention toreduce the risk of a woman developing preeclampsia. It is relatively cheap andreadily available. Also, it is likely to be safe for the woman and her child, andthe possibility of a protective effect on the risk of hypertension in the child-hood, makes this even more important (25). It has been certain reticence tocalcium supplementation, due in 1997 the largest trial (26) (4589 women) didnot find to be effective to prevent preeclampsia in healthy nulliparous women.

Subsequently, one randomized controlled trial (27) and two systematicreviews (25,28) demonstrated benefits of calcium supplementation at highrisk of preeclampsia or low calcium intake populations (Table 1): the risk ofhigh blood pressure was reduced with calcium supplementation (11 trials;14,946 women; RR 0.70; 95% CI 0.57–0.86), greatest for women at high risk(4 trials; 327 women; RR 0.47; 95% CI 0.22–0.97). Overall, there was also areduction in the risk of preeclampsia (12 trials; 15,206 women; RR 0.48; 95%CI 0.33–0.69) greatest for women at high risk (5 trials; 587 women; RR 0.22;

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


95% CI 0.12–0.42) and for those with low baseline calcium intake. Accordingthese three studies, reduction in preeclampsia, maternal death and seriousmorbidity, support the use of calcium supplementation during pregnancy,particularly for those women with low dietary intake (7 trials; 10,154 women;RR 0.36; 95% CI 0.18–0.70).

AntioxidantsAntioxidants are important in maintaining cellular integrity in normal preg-nancy by inhibiting peroxidation reactions and thus protecting enzymes,proteins and cells from destruction by peroxides (29). Numerous studies haveassessed effects of antioxidants on prevention of preeclampsia. Perhaps themost studied have been vitamins C and E. Vitamin C scavenges free radicalsin the aqueous phase, and the lipid soluble vitamin E acts in vivo to preventthe formation of lipid peroxides and thus, protect cell membranes (29). Since1994 had been encouraging results (20,30). This belief changed on March2006, behind three studies (29,31,32) concluded that concomitant supple-mentation with vitamin C and vitamin E does not reduce the risk of preec-lampsia, fetal or neonatal loss (2.6% versus 2.3%; RR 1.10; 95% CI 0.78–1.57),small for gestational age infant (20.6% versus 20%; RR 0.94; 95% CI

Table 1: Characteristics of calcium supplementation studies.

Study Methods PopulationMain outcomes in preeclampsia

Villar et al. (27) RCT, Multicentre, 1.5 g/d calcium (n: 4157) Placebo (n: 4168)

Low calcium intake <600 mg/d)

Preeclampsia: (RR 0.91; 95% CI 0.69–1.19), evident by 35 weeks of gestation (1.2% vs 2.8%; p = 0.04).

Eclampsia: (RR 0.68; 95% CI 0.48–0.97) and SGH (RR 0.71; 95% CI 0.61–0.82) were significantly lower in the calcium group. SPCI: (RR 0.76; 95% CI 0.66–0.89; p = 0.04)

Hofmeyr et al. (25,28)

Review (12 RCT, 15 528 women). At least 1 g/d calcium vs placebo

Low or normal calcium intake women

HBP: (RR 0.70; 95% CI 0.57–0.86) Preec-lampsia (RR 0.48; CI 95% 0.33–0.69). The effect was greatest for women at high risk (RR 0.12; 95% CI 0.12–0.42) and low cal-cium intake (RR 0.36; 95% CI 0.18–0.70)

RCT: Randomized controlled trial, SGH: Severe gestational hypertension, SPCI: severepreeclamptic complications index, HBP: High blood pressure.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


0.74–1.19) or preterm birth (19.5% versus 18%, RR 1.07; 95% CI 0.96–1.20)in women at risk; but does increase the rate of babies born with a low birthweight.

These results do not support routine supplementation to prevent preec-lampsia. However, Rumbold et al. (29) consider these results cannot be gener-alized to women with low dietary intakes of antioxidants. Maybe if startedearlier or given to women whose diets are less sufficient, antioxidants willexhibit efficacy. Several ongoing trials are also assessing whether antioxi-dants supplementation is beneficial for nulliparous women and for womenconsidered to be at increased risk for preeclampsia (USA, Canada, Mexico andBrazil), including women with diabetes (Ireland) (29).

Other antioxidants used for prevention of preeclampsia are lycopene, sele-nium, zinc, magnesium and mitochondrial antioxidants (nicotine, coenzymeQ10 and melatonin). Evidence shows that apparently do not prevent preec-lampsia, there is insufficient data or the methodological quality of the studiesis poor (zinc, magnesium, and mitochondrial antioxidants nicotine, coenzymeQ10 and melatonin) (20,34–36).

Fish oilThere is interest in the protective effects of n-3 fatty acids because of theassumed importance of the prostacyclin/tromboxane A2 balance in preeclamp-sia (5). Because potentially beneficial effects, recently several evidences haveassessed the preventive effects of fish oil (5), however, outcomes have not beensatisfactory. Olsen et al. (37) from Copenhagen, assessed the postulatedpreventive effects of dietary omega 3 fatty acids on pregnancy induced hyper-tension in a large multicenter, randomized, controlled trial (FOTIP study),conduced in 19 hospitals in Europe.

In six multicentre trials, women with high risk pregnancies wererandomly assigned to receive fish oil (Pikasol) or olive oil in identically-lookingcapsules from around 20 weeks (prophylactic trials) or 33 weeks (therapeutictrials) until delivery. The fish oil provided 2.7 g and 6.1 g n-3 fatty acids/dayin the prophylactic and therapeutic trials, respectively. Fish oil did not affectrecurrence risk for preeclampsia (6 trials; 1,619 women; RR 0.98; 95% CI0.63–1.53). They concluded that fish oil supplementation had no effect onpregnancy induced hypertension. Duley et al. (20) in a systematic review,included four randomized, controlled trials and there was no effect on therisk for preeclampsia (RR 0.86; 95% CI 0.59–1.27). Two clinical reviews(35,36) demonstrated fish oil showed no effect on pregnancy induced hyper-tension and there was a statistically significant modest reduction in the rateof preeclampsia (2 trials; 5,021 women; RR 0.70; CI 95% 0.55–0.90), but thisdecrease was influenced strongly by a large nonrandomized trial conductedin 1942, in which vitamins and minerals were given to women in addition tofish oil.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


Low dietary saltIn the past, women have been advised that lowering their salt intake mightreduce their risk of preeclampsia. Although this practice has largely ceased,it remains important to assess the evidence about possible effects of adviceto alter dietary salt intake during pregnancy (38). Two Cochrane systematicreviews (2 trials; 603 women; RR 1.11; 95% CI 0.46–2.66) (20,38) and twoclinical reviews (1 trials; 242 women; RR 0.97; 95% CI 0.49–1.94) (35,36)have assessed the preventive effects of low dietary salt in preeclampsia andshowed no effect of low dietary salt during pregnancy for prevention ofpreeclampsia.

Others dietary-nutritional measuresFolic acid, garlic, nutritional advice (1 trials; 136 women; RR 0.89; 95% CI0.42–1.88), protein and energy supplementation (3 trials; 516 women; RR1.20; 95% CI 0.77–1.89), isocaloric balanced protein (1 trial; 782 women; RR1.00; 95% CI 0.57–1.75), protein and energy restriction for obese women (2 trials;284 women; RR 1.13; 95% CI 0.59–2.18) and diets high in fibers andpotassium; do not reduce the risk of preeclampsia or do not have random-ized controlled trials. Thus, may not be recommended for clinical use(20,35,36,39,40).

3. Drugs:

Aspirin and others antiplatelets agentsAspirin have been used since 1986 to prevent preeclampsia. The rationale forrecommending low dose aspirin prophylaxis is that the vasospasm and coagu-lation abnormalities in preeclampsia are caused partly by an imbalance inthe thromboxane A2/prostacyclin ratio. Low dose aspirin treatment inpregnancy inhibits biosynthesis of platelet thromboxane A2 with little effecton vascular prostacyclin production, thus altering the balance of the prosta-cyclin and preventing development of preeclampsia (3). Aspirin also inhibitsendothelial cyclo-oxigenase (5). Six studies (20,35,41–44) demonstrated thatlow dose aspirin, have small-moderate benefits to reduce the risk both ofpreeclampsia and its complications, when used for prevention of preeclamp-sia (Table 2). Given the importance of these outcomes, the safety during preg-nancy and low cost of aspirin, reviewers recommended that despite thenumber to treat to avoid one case of preeclampsia still was considered high,low dose aspirin should be offered to high risk of developing preeclampsiawomen.

Heparin alone or in combination with an antiplatelet has been suggestedfor certain women at exceptionally high risk for preeclampsia, but trials hadbeen too small for reliable conclusions (20,42,45). Two randomized studies arecurrently ongoing and may provide additional information (45).

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.

149

Tab

le 2

:C

ha

rac

teris

tics

of a

spiri

n a

dm

inist

ratio

n s

tud

ies.

Stud

yM

eth

od

sPo

pul

atio

nM

ain

out

co

me

s in

pre

ec

lam

psi

a

Co

om

ara

sam

y e

t a

l.41R

evi

ew

: 14

RC

T, 2

416

wo

me

n. A

spiri

n v

s p

la-

ce

bo

or n

o t

rea

tme

nt

Hig

h ri

sk o

f p

ree

cla

mp

siaSi

gn

ific

an

t b

en

efit

of a

spiri

n th

era

py

in re

du

cin

g

pre

ec

lam

psia

(R

R 0

.86;

95%

CI 0

.76–

0.96

)

Du

ley

et

al.

(42)

Re

vie

w: 5

1 R

CT,

365

00

wo

me

n. A

ntip

late

let

vs

pla

ce

bo

or n

o t

rea

tme

nt

Hig

h ri

sk o

f p

ree

cla

mp

siaTh

ere

wa

s a

19%

red

uc

tion

in t

he

risk

of

PE

ass

oc

iate

d

with

th

e u

se o

f an

tipla

tele

ts a

ge

nts

(43

tria

ls; 3

3,43

9 w

om

en

; RR

0.8

1; 9

5% C

I 0.7

5–0.

88; N

NT

69: 5

1–10

9)V

illa

r et

al.

(35)

Re

vie

wH

igh

risk

of

pre

ec

lam

psia

Hig

h ri

sk w

om

en

, lo

w d

ose

asp

irin

red

uc

ed

th

e ri

sk o

f P

E (1

9 tr

ials;

4,2

22 w

om

en

; RR

: 0.7

3; 9

5% C

I 0.6

4–0.

83;

NN

T: 9

0). I

t a

lso s

ho

we

d a

gre

ate

r eff

ec

t a

mo

ng

w

om

en

tre

ate

d w

ith h

igh

er d

ose

s th

an

75

mg

/d

asp

irin

(19

tria

ls; 4

,222

wo

me

n; R

R: 0

.49;

95%

C

I 0.3

8–0.

63).

Th

e e

ffe

ct

am

on

g w

om

en

giv

en

a

low

er d

ose

wa

s o

f b

ord

erli

ne

sta

tistic

al s

ign

ific

an

ce

(2

1 tr

ials;

28,

352

wo

me

n; R

R: 0

.86;

95%

CI 0

.79–

0.93

).R

ua

no

et

al.

(43)

Re

vie

w: 2

2 R

CT,

33,

598

wo

me

n. A

spiri

n v

s p

lac

eb

o

Low

an

d h

igh

ris

k o

f p

ree

cla

mp

sia

The

inc

ide

nc

e o

f PE

wa

s 3.

75%

in t

he

low

risk

gro

up

(1

7,70

0 w

om

en

), 9

.01%

in t

he

hig

h ri

sk g

rou

p (

16,8

98

wo

me

n)

an

d 6

.40%

ove

rall

(34,

598

wo

me

n).

Lo

w

do

se a

spiri

n h

ad

no

sta

tistic

ally

sig

nifi

ca

ntly

eff

ec

t o

n t

he

inc

ide

nc

e o

f PE

in t

he

low

risk

gro

up

(R

R 0

.95;

95

% C

I 0.8

1–1.

11),

bu

t h

ad

a s

ma

ll b

en

efic

ial e

ffe

ct

in t

he

hig

h ri

sk g

rou

p (

RR

0.8

7; 9

5% C

I 0.7

9–0.

96)

Ask

ie e

t a

l. (4

4)R

evi

ew

: 31

RC

T, 3

2,21

7 w

om

en

. An

tipla

tele

t (m

ain

asp

irin

) vs

p

lac

eb

o o

r no

tre

atm

en

t

Hig

h ri

sk o

f p

ree

cla

mp

siaA

ntip

late

let

are

ass

oc

iate

d w

ith m

od

era

te (

10%

) b

ut

sign

ific

an

t re

du

ctio

ns

in t

he

risk

of P

E (2

4 tr

ials;

30,

822

wo

me

n; R

R 0

.90;

IC 9

5% 0

.84–

0.97

). T

he

re w

as

no

e

vid

en

ce

th

at

wo

me

n in

an

y o

ne

of

the

su

bg

rou

ps

be

ne

fite

d m

ore

or l

ess

th

an

th

ose

in a

ny

oth

er

sub

gro

up

. Th

ere

wa

s n

o e

vid

en

ce

th

at

usin

g m

ore

th

an

75

mg

of a

spiri

n h

ad

mo

re o

r le

ss e

ffe

ct

tha

n a

lo

we

r do

se, o

r th

at

co

mm

en

cin

g t

rea

tme

nt

be

fore

20

we

eks

’ g

est

atio

n w

as

mo

re o

r le

ss b

en

efic

ial

tha

n s

tart

ing

late

r in

pre

gn

an

cy.

RC

T: R

an

do

miz

ed

co

ntr

olle

d t

rial,

PE:

Pre

ec

lam

psia

.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


Data from literature report that angiotensine converting enzyme (ACE)insertion/deletion (I/D) polymorphism affects the recurrence of preeclampsiaand that low molecular weight heparin (dalteparin, enoxaparin, nadroparin,certoparin and calcic heparin) prevents adverse outcomes in thrombophilicwomen. Mello et al. (46) assessed the effect of low molecular weight heparin(LMWH) on the pregnancy outcome, on maternal blood pressure values, andon uteroplacental flow; in ACE DD nonthrombophilic women with history ofpreeclampsia. LMWH reduced the risk of clinical negative outcomes (74.1%reduction of preeclampsia and 77.5% reduction of fetal intrauterine growthrestriction and the severity (88.3% reduction of early onset of preeclampsiaand 86.4% reduction of early onset of fetal growth restriction). In treatedwomen, the relative risk for preeclampsia was 0.26 (p = 0.02), and the relativerisk for fetal growth restriction was 0.14 (p < 0.001). They concluded thatLMWH reduces the recurrence of preeclampsia, of negative outcomes, and theresistance of uteroplacental flow, and also prevents maternal blood pressureincrease in ACE DD homozygote women with a previous history of preeclampsia.

In two antiplatelet reviews (42,44), few studies (7/59) compared dipy-ridamole alone or in combination with aspirin versus placebo, thus there areinsufficient evidences to assess their benefits.

Other drugsDuley et al. (20) in a systematic review assessed the use of progesterone andnitric oxide for the prevention of preeclampsia and there was no reduction inthe risk of preeclampsia. At present, there is insufficient evidence to recom-mend clinical use.

Tertiary preventionProper antenatal care is the most important part of tertiary prevention andtreatment of preeclampsia (3,5). Reduction in maternal mortality and seriousmorbidity since the 1950s resulted not from the management of acute hyper-tension but mainly from the screening and intervention (such as a timed deliv-ery) that comes with organized antenatal care (5). Effective antenatal careincludes identification and referral of woman at high risk, prompt diagnosiswith prevention and treatment of complications and timely delivery (20).There should be an effort to develop antenatal care systems that allows closevigilance and easy reference for all pregnant women at risk. Greater attentionshould be made to identifying patients with high risk factors (5). Maternalantenatal monitoring includes identification of women at high risk, earlydetection by the recognition of clinical signs and symptoms, and progression ofthe condition to severe state. After diagnosis, subsequent treatment willdepend on the results of initial maternal and fetal assessment (3). Main objec-tive of management of preeclampsia must always be the maternal safety:prevention of complications (tertiary prevention) (5) and, is thus, more or less,synonymous with treatment.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


IMPLICATIONS FOR CLINICAL PRACTICE

The reduction in preeclampsia and in ‘maternal death or severe morbidity’supports the use of calcium supplementation during pregnancy for womenwith low dietary intake. For women with adequate dietary intake, theevidence of benefit from calcium supplementation is not conclusive (28).

Overall, administration of aspirin to women at risk leads to a 10–19%reduction in the risk of developing preeclampsia. On average, for every69 women treated, one case is prevented. There are also smaller reductions inthe risk of preterm birth (7%) and fetal or neonatal death (16%) with largernumbers of women needed to be treated to prevent such outcomes. Overalladverse effects appear to be low but under reporting makes it difficult to beconfident about this, especially where higher doses are used. As most of theevidence relates to low-dose aspirin, this is the antiplatelet agent that shouldbe used in clinical practice for prevention of preeclampsia.

Starting aspirin before 12 weeks and/or using higher doses cannot berecommended for clinical practice until more information is available aboutsafety. The evidence should be summarized and made available to women atrisk of preeclampsia. The decision about whether to take aspirin during preg-nancy should then be made in consultation between the woman and herdoctor. As reduction in risk are small-moderate, relatively large numbers ofwomen will need to be treated to prevent a single adverse outcome. However,from a public health perspective even these moderate benefits may be worth-while, and low-dose aspirin may be worth considering for more widespreaduse (44). If the 4% rate of preeclampsia in the United Status could be reducedby 10% (to 3.6%), we would have at least 16,000 fewer cases of preeclampsiaper year. In the developing world, where 99% of maternal deaths due to hyper-tensive disease occur, the benefits could be profound (47).

FUTURE RESEARCH

Research is needed in the following areas: to continue assessing other possiblescreening test to predict preeclampsia, to assess whether calcium supplemen-tation via dietary modification for women with low calcium intake has thesame benefits as the tablets administration, to provide reassurance thatcalcium supplementation during pregnancy does not have any adverse effectson the children exposed in uteru, to verify whether calcium reduces bloodpressure in childhood, to verify whether there are particular high risk groupsof women who might have greater benefit of low-dose aspirin, to verifywhether starting low dose aspirin before 12 weeks would have additionalbenefits without any increase in adverse effects, to verify whether a higheraspirin dose would be more effective and to continue assessing other agents orinterventions to prevent preeclampsia (28,41).

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


CONCLUSIONS

Strategies to reduce the risk of hypertensive disorders of pregnancy havereceived considerable attention. The possible use of a screening test with highpredictive accuracy in patients with high or low risk of preeclampsia remainsto be investigated (3–6,8,9).

Effective primary prevention is not possible because the causes are stillunknown. The diagnosis and manipulation of historical risk factors for preec-lampsia can be made inexpensively (without the need for any laboratorytests) at the primary care level. This is of critical importance in the developingworld (5).

Secondary prevention with calcium supplementation to patient at a veryhigh risk of developing of preeclampsia and low calcium intake women showsa halving in the relative risk of preeclampsia (28) Low-dose aspirin has asignificant effect in reducing the rates of a number of clinically relevantoutcomes, including preeclampsia and perinatal deaths, in women with histor-ical risk factors for preeclampsia (41,42). Reviewed studies did not show anyevidence of harm from aspirin therapy (41). Based on present findings and theestablished safety of aspirin, it seems reasonable to recommend aspirin ther-apy to women who are historically at high risk for preeclampsia, particularlythose with multiple risk factors. Lifestyle choices, other dietary nutritionalmeasures and others drugs, have not shown benefits or there is insufficientevidence to recommend clinical use.

Proper antenatal care and timed delivery are of utmost importance intertiary prevention (3,5).

REFERENCES

1. Vigil-De Gracia P, Montufar-Rueda C, Ruiz J. Expectant management of severepreeclampsia and preeclampsia superimposed on chronic hypertension between24 and 34 weeks’ gestation. Eur J Obstet Gynecol Reprod Biol 2003; 107:24–27.

2. Vigil-De Gracia P, Lasso M, Ruiz E, Vega-Malek J, Tem de Mena F, Lopez J.Severe hypertension in pregnancy: hydralazine or labetalol. A randomized clinicaltrial. Eur J Obstet Gynecol 2006; 128:157–162.

3. Sibai B, Dekker G, Kucferminc M. Preeclampsia. Lancet 2005; 365:785–799.

4. National high blood pressure education program working group on high bloodpressure in pregnancy. Report of the national high blood pressure educationprogram working group on high blood pressure in pregnancy. Am J ObstetGynecol 2000; 183:S1–S22.

5. Dekker G, Sibai B. Primary, secondary and tertiary prevention of preeclampsia.Lancet 2001; 357:209–215.

6. Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization systematicreview of screening test for preeclampsia. Obstet Gynecol 2004; 104:1367–1391.

7. Farag K, Hassan I, Ledger W. Prediction of preeclampsia: can it be achieved?Obstet Gynecol Surv 2004; 59:464–482.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


8. Helewa M, Burrow R, Smith J, Williams K, Brain P, Rabkin S. Report of theCanadian Hypertension Society Consensus Conference: 1. Definitions, evaluationand classification of hypertensive disorders in pregnancy. Can Med Assoc J 1997;157:715–725.

9. American College of Obstetricians and Gynecologist. Diagnosis and managementof preeclampsia and eclampsia. Practice Bulletin. Number 33. Obstet Gynecol2002; 99:159–167.

10. Chafetz I, Kuhnreich I, Sammar M, Tal Y, Gibor Y, Meiri H et al. First-trimesterplacental protein 13 screening for preeclampsia and intrauterine growth restric-tion. Am J Obstet Gynecol 2007; 197:35.e1–35.e7.

11. Levine R, Lam C, Qian C, Yu K, Maynard S, Sachs B et al. Soluble endoglin, anovel circulating anti-angiogenic factor in preeclampsia. N Engl J Med 2006;355:992–1005.

12. Salahuddin S, Lee Y, Vadnais M, Sachs B, Karumanchi A, Lim K. Diagnosticutility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensivediseases of pregnancy. Am J Obstet Gynecol 2007; 197:28.e1–28.e6.

13. Levine R, Maynard S, Qian C, Lim K, England L, Yu K, et al. Circulating angio-genic factors and the risk of preeclampsia. N Engl J Med 2004; 350:672–683.

14. Thadhani R, Mutter W, Wolf M, Levine R, Taylor R, Sukhatme V, et al. Firsttrimester placental growth factor and soluble fms-like tyrosine kinase 1 and riskfor preeclampsia. J Clin Endocrinol Metab 2004; 89:770–775.

15. Masuyama H, Suwaki N, Nakatsukasa H, Masumoto A, Tateishi Y, HiramatrsuY. Circulating angiogenic factors in preeclampsia, gestational proteinuria andpreeclampsia superimposed on chronic glomerulonephritis. Am J Obstet Gynecol2006; 194:551–556.

16. Crispi F, Domínguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placentalangiogenic growth factors and uterine artery Doppler findings for characteriza-tion of different subsets in preeclampsia and in isolated intrauterine growthrestriction. Am J Obstet Gynecol 2006; 195:201–207.

17. Vatten L, Eskild A, Nilsen T, Jeansson S, Jenum P, Staff A. Changes in circulatinglevel of angiogenic factors from the first to second trimester as predictors of preec-lampsia. Am J Obstet Gynecol 2007;196: 239.e1–239.e6.

18. Chappell L, Seed P, Briley A, Kelly F, Hunt B, Charnock-Jones D, et al. A longitu-dinal study of biochemical variables in women at risk of preeclampsia. AmJ Obstet Gynecol 2002; 187:127–136.

19. Aquilina J, Thompson O, Thilaganathan B, Harrington K. Improved early pre-diction of preeclampsia by combining second trimester maternal seruminhibin-A and uterine artery Doppler. Ultrasound Obstet Gynecol 2001;17:477–484.

20. Duley L, Meher S, Abalos E. Management of preeclampsia. BMJ 2006; 332:463–468.

21. Sibai B. Biomarkers for hypertension-preeclampsia: are we close yet? Am J ObstetGynecol 2007; 197:1–2.

22. Milne F, Redman C, Walker J, Baker P, Bradley J, Cooper C et al. The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset ofpre-eclampsia in the community. BMJ 2005; 330;576–580.

23. Meher S, Abalos E, Carroli G. Bed rest with or without hospitalization for hyper-tension during pregnancy (Cochrane Review). In: The Cochrane Library, Issue 1.2006. Oxford: Update Software.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


24. Meher S, Duley L. Exercise or other physical activity for preventing preeclampsiaand its complications (Cochrane Review). In: The Cochrane Library, Issue 2. 2006.Oxford: Update Software.

25. Hofmeyr G, Atallah A, Duley L. Calcium supplementation during pregnancy forpreventing hypertensive disorders and related problems (Cochrane Review). In:The Cochrane Library, Issue 3. 2006. Oxford: Update Software.

26. Levine R, Hauth J, Curet L. Trial of calcium to prevent preeclampsia. N EnglJ Med 1997; 337:69–76.

27. Villar J, Andel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta N, et al.World Health Organization randomized trial of calcium supplementationamong low calcium intake pregnant women. Am J Obstet Gynecol 2006;194:639–649.

28. Hofmeyr G, Duley L, Atallah A. Dietary calcium supplementation for preventionof preeclampsia and related problems: a systematic review and commentary.Br J Obstet Gynecol 2007; 114:933–943.

29. Rumbold A, Crowther C, Haslam R, Dekker G, Robinson J. Vitamins C and E andthe risks of preeclampsia and perinatal complications. ACTS Study Group. N EnglJ Med 2006; 354:1796–1806.

30. Rumbold A, Duley L, Crowther C, Haslam R. Antioxidants for preventing preec-lampsia (Cochrane Review). In: The Cochrane Library, Issue 1. 2006. Oxford:Update Software.

31. Poston L, Briley A, Seed P, Kelly F, Shennan A. Vitamins in Pre-eclampsia(VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk forpreeclampsia (VIP trial): randomized placebo controlled trial. Lancet 2006;367:1145–1154.

32. Polyzos N, Mauri D, Tsappi M, Tzioras S, Kamposioras K, Cotinovis I et al.Combined vitamin C and E supplementation during pregnancy forpreeclampsia prevention: a systematic review. Obstet Gynecol Surv 2007;62:202–206.

33. Rouse D. Vitamins C and E and the risks of preeclampsia and perinatal complica-tions. Obstet Gynecol Surv 2006; 61: 619–620.

34. Spinnato J, Livinston J. Prevention of preeclampsia with antioxidants: evidencefrom randomized trials. Clin Obstet Gynecol 2005; 48:416–429.

35. Villar J, Abalos E, Nardin J, Merialdi M, Carroli G. Strategies to prevent andtreat preeclampsia: evidence from randomized controlled trials. Semin Nephrol2004; 24:607–615.

36. Villar J, Merialdi M, Metin-Gülmezoglu A, Abalos E, Carroli G, Kulier R et al.Nutritional interventions during pregnancy for the prevention or treatment ofmaternal morbidity and preterm delivery: an overview of randomized controlledtrials. J Nutr 2003; 133:1606S–1625S.

37. Olsen S, Secher N, Tabor A, Weber T, Walter J, Gluud C. Randomized clinicaltrials of fish oil supplementation in high risk pregnancies. Fish Oil Trials InPregnancy (FOTIP) Team. Br J Obstet Gynecol 2000; 107:382–395.

38. Duley L, Henderson-Smart D. Reduced salt intake compared to normal dietarysalt or high intake in pregnancy (Cochrane Review). In: The Cochrane Library,Issue 1. 2006. Oxford: Update Software.

39. Kramer M, Kakuma R. Energy and protein intake in pregnancy (CochraneReview). In: The Cochrane Library, Issue 3. 2007. Oxford: Update Software.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.


40. Frederick I, Willimas M, Dashow E, Kestin M, Zhang C, Leisenring W. Dietaryfiber, potassium magnesium and calcium in relation to the risk of preeclampsia.J Reprod Med 2005; 50:332–344.

41. Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan K. Aspirin for preven-tion of preeclampsia in women with historical risk factors: a systematic review.Obstet Gynecol 2003; 101:1319–1332.

42. Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet agents for preventingpreeclampsia and its complications. (Cochrane Review). In: The Cochrane Library,Issue 1. 2006. Oxford: Update Software.

43. Ruano R, Fontes R, Zugaib M. Prevention of preeclampsia with low dose aspirin: asystematic review and meta-analysis of the main randomized controlled trials.Clinics 2005; 60:407–414.

44. Askie L, Duley L, Henderson-Smart D, Steward L, on behalf of the PARIS Collab-orative Group. Antiplatelet agents for prevention of preeclampsia: a meta-analysisof individual patient data. Lancet 2007; 369:1791–1798.

45. Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women with acquiredor inherited thrombophilias (Cochrane Review). In: The Cochrane Library, Issue1. 2006. Oxford: Update Software.

46. Mello G, Parretti E, Fatini C, Riviello C, Gensini F, Marchioni M et al. Low molec-ular weight heparin lowers the recurrence rate of preeclampsia and restores thephysiological vascular changes in angiotensine converting enzyme DD women.Hypertension 2005; 45:86–91.

47. Rouse D. Antiplatelet agents for prevention of preeclampsia: a meta-analysis ofindividual patient data. Obstet Gynecol Surv 2007; 62: 697–699.

Hyp

erte

ns P

regn

ancy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

The

Uni

vers

ity o

f M

anch

este

r on

12/

22/1

4Fo

r pe

rson

al u

se o

nly.

Documents

Prediction and Prevention of Preeclampsia