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BSTETRICS

etaanalysis vs large clinical trials:hich should guide our management?

hristina M. Scifres, MD; Jay D. Iams, MD; Mark Klebanoff, MD, MPH; George A. Macones, MD, MSCE

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rofessional societies and govern-ment agencies are reluctant to pro-

ulgate or endorse guidelines for medi-al care until clinical trials produce aonsensus. When consensus cannot bechieved because only small trials arevailable or trial outcomes vary, meta-nalysis is often performed with the ex-ectation that larger numbers will allowconsensus to emerge. In some situa-

ions, both large randomized controlledrials (RCTs) and metaanalyses are avail-ble. In this case, which should guidelinical care: large clinical trials, or meta-nalysis? In this article, we compare thetrengths and weaknesses of each, using 2roposed therapies for the prevention ofreeclampsia as current examples of thisonundrum.

Preeclampsia is a common illness thatffects pregnant women. It manifests

rom the Department of Obstetrics andynecology (Drs Scifres and Macones),ashington University in St. Louis School ofedicine, St. Louis, MO; the Department ofbstetrics and Gynecology (Dr Iams), Thehio State University, Columbus, OH; and

he Division of Epidemiology, Statistics andrevention Research (Dr Klebanoff), Euniceennedy Shriver National Institute of Childealth and Human Development, National

nstitute of Child Health and Humanevelopment, National Institutes of Health,ethesda, MD.

eceived May 10, 2008; revised Aug. 10,008; accepted Sept. 26, 2008.

eprints not available from the authors.

his research was supported in part by thentramural Research Program of the Nationalnstitute of Child Health and Humanevelopment, National Institutes of Health.

uthorship and contribution to the manuscripts limited to the 4 authors indicated. There waso outside funding or technical assistance withhe production of this article.

002-9378/$36.002009 Mosby, Inc. All rights reserved.

eoi: 10.1016/j.ajog.2008.09.873

84.e1 American Journal of Obstetrics & Gynecolo

linically as new-onset elevated bloodressure and proteinuria in the secondalf of pregnancy. The precise cause ofreeclampsia is unknown, but it is char-cterized by disordered trophoblast in-asion1 and abnormal placental angio-enesis.2 In addition, an imbalanceetween prostacyclin (a vasodilator) andhromboxane (a vasoconstrictor) haseen implicated in the pathogenesis ofreeclampsia.3,4 Although the mecha-ism is unknown, epidemiologic datauggest that populations with a high di-tary intake of calcium have a decreasedisk of preeclampsia.5,6 Based on thisnowledge, a number of small and largelinical trials have been performed tovaluate the efficacy of antiplateletgents and calcium for the prevention ofreeclampsia. For each of the preventivetrategies, the studies vary in size, inclu-ion/exclusion criteria, and primaryutcomes.With regard to aspirin therapy, the

mallest of the studies included 20 pa-ients7; the largest included 9364 pa-ients.8 Among the calcium studies, themallest enrolled 30 patients,9 and theargest study enrolled � 8300 patients.10

or both aspirin and calcium, more ofhe smaller studies demonstrated a ben-

Large, randomized clinical trials have longclinical care. Metaanalysis is a type ofrandomized clinical trials are combined atreatment is ascertained. The clinician in prthe type of evidence that should be usedproblems, there are both randomized contcases of calcium and aspirin therapy foopportunity to explore the benefits and limpractice. We conclude that, when availablused to guide clinical practice.

Key words: metaanalysis, randomized clin

Cite this article as: Scifres CM, Iams JD, Klebantrials: which should guide our management? Am

fit, although many of the larger studies S

gy MAY 2009

id not. We make this point becausehese differences in the outcomes of pub-ished studies bring up the importantopic of publication bias, which we williscuss in depth later in the article.There were 2 large, RCTs performed in

he United States by the National Insti-ute of Child Health and Human Devel-pment–funded Maternal-Fetal Medi-ine Units Network to evaluate aspirinherapy for the prevention of preeclamp-ia. The first trial tested the hypothesishat daily low-dose aspirin therapy couldeduce the incidence of preeclampsia inealthy, nulliparous subjects.11 Morehan 3000 women were assigned ran-omly to aspirin therapy or placebo; thistudy revealed a relative risk (RR) of 0.7095% CI, 0.60-1.0) for the developmentf preeclampsia, no difference in neona-al morbidity, and a slight increase in thencidence of placental abruption. Theecond study assessed low-dose aspirinherapy in 2539 women who were at highisk for preeclampsia12 and demon-trated an overall RR of 0.90 (95% CI,.8-1.1) with no clear benefit in any sub-roup and no evidence of adverse out-omes, including placental abruption.he largest study to date was conductedy the Collaborative Low-dose Aspirin

en considered the gold standard to guidelysis in which results of a number of

a summary measure of effect for a givence often is faced with a dilemma regardingguide clinical practice; for many clinicaled trials and metaanalyses available. Thee prevention of preeclampsia afford an

ons of each type of study to guide clinicalarge randomized clinical trials should be

trial

M, Macones GA. Metaanalysis vs large clinicalObstet Gynecol 2009;200:484.e1-484.e5.

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www.AJOG.org Obstetrics Clinical Opinion

omly assigned 9364 women who wereelieved to have a significant risk of pre-clampsia to either low-dose aspirinherapy or placebo for the prevention orreatment of preeclampsia and intra-terine growth restriction. Overall, 6.7%f women who were assigned randomlyo aspirin therapy experienced pre-clampsia, compared with 7.6% ofomen who received placebo, which is aonsignificant 12% reduction in risk.wo other large trials also failed to dem-nstrate a benefit for aspirin therapy inhe prevention of preeclampsia.13,14

The Perinatal Antiplatelet Review ofnternational Studies (PARIS) collabo-ative group performed a patient-leveletaanalysis to assess whether there is a

ole for anti–platelet agents (mainly low-ose aspirin) in the prevention of pre-clampsia.15 This metaanalysis includedndividual patient-level data from 32,217omen who were enrolled in 31 RCTs of

ntiplatelet agents for the prevention ofreeclampsia. This metaanalysis gener-ted RRs of 0.90 (95% CI, 0.84-0.97), forhe development of preeclampsia, 0.9095% CI, 0.83-0.98) for delivery at � 34eeks of gestation, and 0.90 (95% CI,.85-0.96) for a composite outcome ofreeclampsia, delivery at � 34 weeks ofestation, a small-for-gestational-ageaby, stillbirth or death of the baby be-ore discharge, or maternal death. Thenvestigators found no difference in ad-erse outcomes that included antepar-um hemorrhage, postpartum hemor-hage, and placental abruption.nterestingly, no particular subgroupould be identified in which aspirin ther-py appeared to provide greater benefit.ased on a 10% reduction in the risk ofreeclampsia, the authors of this meta-nalysis estimated the number of pa-ients that a physician would need toreat to prevent 1 case of preeclampsia.he number needed to treat takes intoccount how effective the treatment isin this case a 10% reduction in risk) andlso the baseline incidence of the disease.iven the 10% reduction in risk found in

he PARIS study, if one assumes a base-ine risk of preeclampsia of 18% (whichould represent a very high-risk popula-

ion), 56 women would need to receive

spirin therapy to prevent 1 case of pre- d

clampsia. If one assumes a baseline riskor preeclampsia of 6%, 167 womenould need to be treated to prevent 1

ase of preeclampsia. These results areimilar to a traditional metaanalysis ofntiplatelet agents for the prevention ofreeclampsia that was performed by theochrane Database that identified a RRf 0.83 (95% CI, 0.77-0.89) for the devel-pment of preeclampsia.16

Calcium supplementation for the pre-ention of preeclampsia has also beenvaluated in a number of large and smallrials, in women with both adequate anduboptimal calcium intake. The largestrial in women with adequate dietary in-ake of calcium was performed by thealcium for the Prevention of Pre-

clampsia group.17 This group assigned500 women with adequate dietary cal-ium intake to either calcium or placebond found an overall RR for preeclamp-ia in the treatment group of 0.94 (95%I, 0.76-1.16). The World Health Orga-ization subsequently assessed calciumupplementation in 8325 women withnadequate dietary intake and found aR for the development of preeclampsiaf 0.91 (95% CI, 0.69-1.19).10 Severalecondary analyses of this trial were per-ormed that revealed a RR of 0.76 (95%I, 0.66-0.89) for the development of a

omposite outcome of severe complica-ions of preeclampsia, RR of 0.8 (95% CI,.7-0.91) for maternal morbidity/mor-ality, and RR of 0.7 (95% CI, 0.56-0.88)or neonatal death. The Cochrane Col-aboration then combined 12 studieshat involved 15,000 women and found aR of 0.70 (95% CI, 0.57-0.86) for theevelopment of hypertension in preg-ancy and a RR of 0.48 (95% CI, 0.33-.69) for the development of preeclamp-ia. When they examined trials thatncluded patients with adequate dietaryntake, there was no overall benefit fromalcium supplementation (RR, 0.62;5% CI, 0.32-1.20), whereas when datarom 7 trials that involved 10,154 womenith inadequate dietary calcium intakeas combined, the risk of the develop-ent of preeclampsia was reduced with

alcium supplementation (RR, 0.36;5% CI, 0.18-0.70).18 We note that evi-

ence of benefit in patients with low di- c

MAY 2009 Americ

tary calcium intake was centered in tri-ls that enrolled � 300 patients.

enefits and limitations of RCTsarge, well-done RCTs are the gold stan-ard for studies that change our clinicalractice. The goal of any RCT is to designstudy that is “big enough” so that a clin-

cally significant effect is statistically sig-ificant, but not “too big” so that clini-ally unimportant results becometatistically significant. In addition, ex-essively large trials may be prohibitivelyxpensive, and the sample size that iseeded may be large enough to prohibitompletion of the study in a reasonableime frame. The sample size for anytudy is calculated based on the amountf type I and II errors the investigator isilling to tolerate, the expected numberf outcomes in the placebo group, andhe reduction in the primary outcomehat the author wishes to be able toetect.One strength of the RCT is that ran-

om allocation largely avoids the issue ofonfounding. However, there are impor-ant drawbacks of single large RCTs.irst, some RCTs are so rigorous in theirreatment and follow-up requirementshat results may be “unique” to this set-ing. In addition, patients who are en-olled in clinical trials may have a base-ine risk for the outcome of interest

uch greater than the average patientopulation or may originate from veryifferent populations. For example,ome of the studies of calcium for therevention of preeclampsia (althoughell-powered and methodologically

ound) were performed in countriesith very different diets than the Unitedtates. A reasonable person may ques-ion whether these results can be appliedo practice in the United States, and thiseminds us that there are always con-erns about the generalizability of largelinical trials. Another limitation is sub-le variation across centers in subject en-ollment into multicenter trials. Oneenter may recruit lower risk womenho are enrolled from clinics where they

eceive routine care; others who use theame criteria may recruit higher riskomen who were referred for initial

are. In addition, some trials may recruit

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Clinical Opinion Obstetrics www.AJOG.org

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omen from different geographic areasr even from different countries. Theseariations can be accounted for by strictnclusion/exclusion criteria and by strat-fying randomization by center, but theeader of such articles should be aware ofhe potential impact of these consider-tions on trial outcome.

Often times clinical trials are poweredo detect a “composite outcome” ratherhan a single primary outcome. An ex-mple of this relates to the use of com-osite outcomes in prematurity re-earch, which often combine severeespiratory distress syndrome, necrotiz-ng enterocolitis, intraventricular hem-rrhage, and death into a single variable.omposite outcomes can be very helpful

n that they reduce the estimated sampleize in a clinical trial and make it easier tochieve statistically and clinically signif-cant results. However, the use of a com-osite outcome limits the ability of any 1tudy to detect differences in each ofhese important clinical outcomes indi-idually. In addition, single large clinicalrials may not be powered adequately tossess the frequency of rare, but poten-ially important, adverse events. One ex-mple is the previously discussedICHD-Maternal Fetal Medicine Unitsetwork trial that used aspirin therapy

or the prevention of preeclampsia inulliparous women.11 This trial indi-ated that there was an increase in theisk of placental abruption in patientsho receive low-dose aspirin therapy vslacebo. Other RCTs and large meta-nalyses found rates of abruption in thelacebo group that were similar to theate in the aspirin therapy group in theetwork trial, which suggests that the

nitial association between aspirin ther-py and placental abruption was likely ahance association.

Also, single large clinical trials oftenimes may not have sufficient numbersf subjects in important subgroups. This

s illustrated by the trials that evaluatespirin therapy for the prevention of pre-clampsia. Despite the large numbers ofomen who are enrolled in many of the

tudies, there is still limited informationvailable about important subgroupsuch as women with preexisting renal

isease. v

84.e3 American Journal of Obstetrics & Gynecolo

One final concern with RCTs is the is-ue of publication bias that we alluded toarlier in the article. Publication bias oc-urs when the results of studies that re-ort positive results are more likely to beublished than studies with negative re-ults. Studies that report significant re-ults may result in a greater number ofublications and may also be published

n higher impact journals.19 Althoughhis type of bias might occur more fre-uently in observational studies than inCTs,19 we posit that a small, positiveCT would be easier to publish than a

mall, negative RCT. Publication biasan have an important impact on theutcomes of metaanalyses.

enefits and limitationsf metaanalysise have reviewed the findings of a pa-

ient-level metaanalysis and traditionaletaanalysis for therapies to prevent

reeclampsia. We will now provide somef the background methods for each typef study. Metaanalysis is a type of analy-is in which results of a number of RCTsre combined statistically, and a “sum-ary” measure of effect for a given treat-ent is ascertained. Many methods foretaanalysis are available, but the most

ommonly applied focus is on the com-ination of published summary statis-ics, usually in some form of weightedverage. This is the type of metaanalysishat is performed commonly by the Co-hrane Collaboration. One importantomponent of traditional metaanalysis ishe process by which each study is as-igned a “weight.” A summary statistic isenerated for each individual study toescribe the observed intervention ef-

ect, and a weight is then assigned whichepends on the precision of the effectize for that study.20 Instead of simplyssigning weight based on study size, theoal of this approach is to give moreeight to the more precise studies. This

s 1 way in which a small study with aigh incidence of the outcome in ques-ion may contribute significantly to theverall results of metaanalysis.In contrast, patient level metaanalysis

efers to a process by which individualsho conduct a metaanalysis obtain indi-

idual data on each patient who is en- i

gy MAY 2009

ered in all trials for central collection,rocessing, and analysis. This allowstandard analysis to be performed and anverall result, which is based on the to-ality of the available evidence, to be cal-ulated.21 Reanalysis of all of the individ-al patients’ data is considered widely toe the gold standard22 because it has sev-ral advantages: it avoids biases that aressociated with the use of summary sta-istics from separate studies; it allows thexamination of data in detail; and itliminates dependence on already per-ormed statistical analyses. Instead, it al-ows information from each of the stud-es to be analyzed together and time-to-vent analyses can be conducted. Inddition, adjustment for confoundersnd the search for differences in sub-roups of patients based on characteris-ics of individual women that go beyondhe summary results presented in theublished trials can be performed. Inome ways, patient-level metaanalysis al-ows the authors to reconstruct thequivalent of a “megatrial.” This mayrove particularly helpful in cases inhich the available RCTs are small andnderpowered for the outcome of inter-st. However, even a patient-level meta-nalysis cannot address the problemshat are associated with publication bias,ifferences in patient groups, and subtleifferences in trial protocols and execu-ion. One danger when multiple ade-uately powered RCTs are combined ishat the large sample sizes that are asso-iated with such a “megatrial” may resultn statistically significant results, which

ay not be clinically significant.One argument against metaanalysis is

hat it can combine patient populationshat are dissimilar in � 1 way. In the casef aspirin therapy for the prevention ofreeclampsia, studies differ in patientopulations, definitions of preeclamp-ia, the type and dose of antiplateletgent, and the timing of initiation ofherapy. Some trials that evaluate cal-ium for the prevention of preeclampsianrolled women with low calcium in-ake; others enrolled women with nor-

al dietary calcium intake. These vari-bles must be considered when decidinghether to combine studies or to pool

ndividual patient-level data, and it is

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asy to see how such differences canarkedly influence the results of aetaanalysis.A second, somewhat related issue

bout metaanalysis is management of di-ergent results of studies. For example,onsider 2 studies of equal size to evalu-te a drug for preeclampsia in whichtudy A found an improved outcomeRR, 0.5), and study B reported worseutcome with treatment (RR, 2.0). Aetaanalysis of these studies would

ikely result in the misleading conclusionhat treatment had no effect, either pos-tive or negative, on outcome (Fig-re). The epidemiologic term for this is

nterstudy heterogeneity. Heterogeneityay not always be this obvious, but it can

e detected with a variety of statisticalechniques. When heterogeneity is sig-ificant, we must consider why hetero-eneity is present and whether combin-ng the studies under consideration isppropriate. Of note, the Cochrane Re-iew assessment of calcium for the pre-ention of preeclampsia detected signif-cant heterogeneity among the studies.n this case heterogeneity seems to ariserom smaller studies that demonstratereater benefit. This may have resultedrom publication bias, or it may resultrom the fact that smaller studies tend tonroll the highest risk patients.

A third point regarding metaanalysiselates to the quality of data going in–theo called “garbage in, garbage out” the-ry. This is an important concern thatan have a significant impact on the re-

FIGUREHypothetical example

Relative Risk (95% CI)

tudy A

tudy B

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ypothetical example of interstudy heterogeneitynd the effect on summary statistics.cifres. Metaanalysis vs large clinical trials. Am J Obstetynecol 2009.

ults of metaanalyses. Schulz et al23 ana- t

yzed a database of 250 obstetric trialsrom 33 metaanalyses and provided evi-ence that RCTs with inadequate blind-

ng of patients and providers overesti-ated the intervention effect by 30-40%,hen compared with trials with ade-uate blinding. The authors of a meta-nalysis can address issues of study qual-ty by carefully selecting and reportingnclusion and exclusion criteria and theharacteristics of included and excludedtudies.24

For the examples of both aspirin andalcium for the prevention of pre-clampsia, we observed a trend that thearlier, smaller trials tended to provideore evidence of benefit than later larger

rials. This brings us to the point thatetaanalysis has a crucial role in gener-

ting hypotheses for future RCTs, espe-ially when only small trials exist. Impor-antly, 1 issue that relates to metaanalysisf small trials was addressed in a study byeLorier et al.25 These authors identified2 RCTs that enrolled � 1000 patients.hey were then able to identify 19 meta-nalyses that had been published on theame topic before publication of thearge RCT. Outcomes of the 12 largeCTs were not predicted accurately by

he previous metaanalyses 35% of theime. This highlights the fact that meta-nalysis cannot take the place of an ade-uately powered RCT and that large clin-

cal trials (such as those conducted foroth aspirin and calcium for the preven-ion of preeclampsia) are essential tolinical practice.

ow do we make choicesn clinical practice?here are benefits to both metaanalysisnd large RCTs, and each has its place inuiding clinical practice. In our opinion,hen available, a well-done, adequatelyowered RCT that enrolled a patientopulation comparable to the patient forhom a clinician is considering an inter-ention should be used to guide clinicalanagement for several reasons.First, we return to the example of cal-

ium for the prevention of preeclampsiao make the point that there are manyactors that can contribute to the overallesults of a metaanalysis (including the

ypes of trials that are included and how w

MAY 2009 Americ

uch weight is assigned to each trial).he overall summary result of the cal-ium for the prevention of preeclampsiaetaanalysis suggests that calcium sup-

lementation is associated with a 52%eduction in the risk of preeclampsia. Onloser examination, we observe that thisesult was centered on trials of womenith inadequate dietary calcium intake

nd that the metaanalysis results foromen with adequate dietary calcium

ntake agreed with the results of the Cal-ium for the Prevention of Preeclampsiarial, which failed to demonstrate a ben-fit. This highlights the importance ofnowing how summary results were ob-ained before adopting changes to clini-al practice on the basis of metaanalysisesults. When we compare the results ofhe World Health Organization trial,hich failed to demonstrate a reduction

n the risk of preeclampsia in womenith inadequate dietary calcium intake

o the metaanalysis which detected a7% reduction in the risk for preeclamp-ia in these women, we note that evi-ence of benefit was centered in thoserials that enrolled � 260 women. Al-hough smaller trials may be well-con-ucted and methodologically sound, weontinue to have concerns that signifi-ant publication bias in the case ofmaller trials may influence the overallesults of metaanalysis. We believe thatetaanalysis has an important role in

linical situations in which only small,nderpowered clinical trials exist andonducting a large, more definitive trials not feasible, in the examination of rareutcomes and hazards of therapy, and inhe identification of variation amongtudies. When possible, the hypothesesenerated by metaanalysis of small, un-erpowered clinical should lay theroundwork for future large clinicalrials.

In the case of aspirin therapy for therimary prevention of preeclampsia,here are a number of adequately pow-red clinical trials that encompass a largeumber of patients in a wide variety oflinical settings that failed to demon-trate a benefit. The number of patientshose data were analyzed by the PARIS

ollaboration is impressive. However,

e are concerned that such large num-

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ers may result in conclusions that, al-hough statistically significant, may rep-esent clinically unimportant results. Ofote, the analysis that was conducted by

he PARIS collaboration also failed todentify a subgroup that clearly demon-trated a benefit from preventive therapyith aspirin and only a very mild im-rovement in outcomes. Even assuming10% reduction in the incidence of pre-clampsia in a low-risk patient popula-ion, a very large number needed to treats present. If one considers a high-riskopulation, the number that is needed toreat appears much lower, based on theesults of the metaanalysis. However, ife contrast this with the results of the

arge RCTs that enrolled high-riskomen that failed to demonstrate a ben-

fit, we are inclined to use the results ofhe RCT to guide clinical management.lthough the results of any given RCTay not always be generalizable to all pa-

ient populations, the results of a meta-nalysis cannot be applied preferentiallyo a clinical scenario in which an ade-uately powered RCT exists. f

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